Details of a Researcher - HINOTSU Shiro

Papers - HINOTSU Shiro

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Primary management of prostate cancer by universal health coverage effective coverage index.

Leandro Blas, Masaki Shiota, Mizuki Onozawa, Jae Young Joung, Kyo Chul Koo, Levent Türkeri, Bahadır Şahin, Jasmine Lim, Teng Aik Ong, Peter Ka-Fung Chiu, Chi-Fai Ng, Tong-Lin Wu, Vu Le Chuyen, Bannakij Lojanapiwat, Jason L Letran, Lukman Hakim, Edmund Chiong, Ghazi M Al-Edwan, Satoru Taguchi, Yoshiyuki Yamamoto, Shinichi Sakamoto, Taketo Kawai, Masatoshi Eto, Tohru Nakagawa, Shiro Hinotsu, Haruki Kume

World journal of urology 43 ( 1 ) 146 - 146 2025.03 [International journal]

PURPOSE: Prostate cancer is under-researched in many Asian countries because the paucity of comprehensive cancer registries has prevented large studies from comparing primary prostate cancer therapies. We aimed to provide further insights into recent trends in primary prostate cancer management across multiple Asian countries and regions according to universal health coverage. METHODS: This is part of the Asian Prostate Cancer (A-CaP), a prospective and multicenter study conducted in 12 Asian countries. The study cohort comprised patients newly diagnosed between January 2016 and December 2018. Patients were allocated to three categories according to the universal health coverage effective coverage index (Category 1 ≥ 80; Category 2, 70-79; and Category 3, < 70). We assessed primary management of prostate cancer according to these categories and by clinic pathological characteristics such as clinical stage, and D'Amico risk group. RESULTS: In total, 34,994 patients were included in the final analysis. Category 1 had the highest proportion of patients diagnosed at early stages and Category 3 had the highest proportion of patients diagnosed at advanced stages. Most patients in Category 1 had undergone computed tomography scans, magnetic resonance imaging, and bone scans. In contrast, only 1.7% and 5.4% of men in Categories 2 and 3, respectively, had undergone all three of these investigations. The proportion of patients who had undergone radiation and androgen deprivation therapy as primary treatment was highest in Category 1, whereas the rate of conservative management was highest in Category 2. More patients in Category 3 than in the other two categories had undergone radical prostatectomy, but fewer had been treated with radiation therapy. CONCLUSIONS: Our findings highlighted differences in patterns of treatment of newly diagnosed prostate cancer across 12 Asian countries and regions and suggest that, despite guidelines, health access affects treatment received.

Trends in uptake of cancer screening among people with severe mental illness before and after the COVID-19 pandemic in Japan: A repeated cross-sectional study.

Yuto Yamada, Masaki Fujiwara, Naoki Nakaya, Koji Otsuki, Taichi Shimazu, Maiko Fujimori, Shiro Hinotsu, Kiwamu Nagoshi, Yosuke Uchitomi, Masatoshi Inagaki

PCN reports : psychiatry and clinical neurosciences 4 ( 1 ) e70062 2025.03 [International journal]

AIM: The aim of this study was to investigate trends in cancer screening participation among people with severe mental illness (PSMI) from periods before and after the COVID-19 pandemic. METHODS: In this repeated cross-sectional study, we used anonymized datasets on municipal cancer screening participation among PSMI in Okayama City. The data covered fiscal year (FY) 2018 to FY2022; we used the municipal cancer screening database and Medical Payment for Services and Supports for Persons with Disabilities. PSMI were defined as those with schizophrenia or related psychotic disorders (F20-29) or bipolar disorder (F30 or F31), identified using International Classification of Diseases, Tenth Revision, codes. The analysis included men and women aged 40-69 years for colorectal and lung cancer screening; men and women aged 50-69 years for gastric cancer screening; women aged 40-69 years for breast cancer screening; and women aged 20-69 years for cervical cancer screening. Municipal cancer screening rates among PSMI were calculated for each FY. RESULTS: For all cancer types, cancer screening rates for PSMI in FY2020 (colorectal: 9.0%; lung: 11.6%; gastric: 4.9%; breast: 6.2%; and cervical: 6.1%) were lower than the rates in FY2019 (11.5%, 14.0%, 6.5%, 9.3%, and 8.3%, respectively). In FY2022, the rates (9.9%, 12.9%; 5.3%; 8.0%, and 6.9%, respectively) recovered, but remained low. CONCLUSION: This study showed that cancer screening rates among PSMI were very low, both before and after the COVID-19 pandemic. Efforts to encourage participation in cancer screening in this population are urgently needed.

Changes in the trends of initial treatment for newly diagnosed prostate cancer in Japan: a nationwide multi-institutional study.

Taketo Kawai, Mizuki Onozawa, Satoru Taguchi, Masaki Shiota, Shinichi Sakamoto, Yoshiyuki Yamamoto, Yasuhide Kitagawa, Tohru Nakagawa, Shiro Hinotsu, Haruki Kume

Japanese journal of clinical oncology 54 ( 9 ) 1045 - 1051 2024.09 [International journal]

BACKGROUND: In previous large-scale studies conducted through 2010, androgen deprivation therapy (ADT) was the most common initial treatment for prostate cancer patients in Japan. However, recent advancements in treatment technologies have significantly affected the management of prostate cancer in Japan. This study analyzed the trends in initial treatments for prostate cancer based on two nationwide surveys. METHODS: Two Japan-wide multi-institutional surveys, J-CaP2010 and J-CaP2016, were conducted to enroll patients newly histologically diagnosed with prostate cancer in 2010 and 2016-18, respectively. Both surveys included age at diagnosis, initial PSA level, ISUP Grade Group, TNM classification, and initial treatment for prostate cancer. RESULTS: J-CaP2010 included data from 8192 patients across 140 institutions, whereas J-CaP2016 included data from 21 841 patients across 186 institutions. In J-CaP2016, the proportion of radical prostatectomy (RP) and radiation therapy (RT) in the initial treatment increased (from 32% to 36% and 21% to 26%, respectively), whereas the proportion of ADT decreased (from 40% to 29%) compared with those in J-CaP2010. The increase in RP or RT was noticeable in patients aged 75 years and older (from 20% to 38%) and those with high-risk localized cancer (from 58% to 74%) or locally advanced cancer (from 38% to 56%). The proportion of active surveillance or watchful waiting increased in patients with low-risk localized cancer (from 21% to 41%). The proportion of robot-assisted RP within all RPs and the proportion of intensity-modulated RT within all RTs increased remarkably (from 2.3% to 78% and 20% to 50%, respectively). CONCLUSIONS: In Japan, RP and RT have increased as initial treatments for prostate cancer, whereas ADT has decreased. Consequently, RP has emerged as the most commonly selected initial treatment, replacing ADT.

Summary of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma 2023 by the Japanese Urological Association.

Kazuyuki Mori, Shingo Hatakeyama, Hideki Enokida, Hideaki Miyake, Eiji Kikuchi, Hiroyuki Nishiyama, Tomohiko Ichikawa, Takao Kamai, Yasushi Kaji, Haruki Kume, Tsunenori Kondo, Hideyasu Matsuyama, Naoya Masumori, Akihiro Kawauchi, Atsushi Takenaka, Hirotsugu Uemura, Masatoshi Eto, Norio Nonomura, Yasuhisa Fujii, Shiro Hinotsu, Chikara Ohyama

International journal of urology : official journal of the Japanese Urological Association 31 ( 3 ) 194 - 207 2024.03 [International journal]

This article is an English translation of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma (2nd edition) published in June 2023. The Japanese Urological Association's (JUA) Guidelines Committee on Upper Tract Urothelial Carcinoma (UTUC) created a 2023 update guideline to support clinicians' current evidence-based management of UTUC and to incorporate its recommendations into clinical practice. The new guideline adhered as closely as possible to the Minds Manual for Guideline Development 2020 ver. 3.0. Findings related to epidemiological, pathological, diagnosis, treatment, and follow-up were reviewed. In addition, seven clinical questions (CQs) were set to determine the grade of recommendation and level of evidence. Preconceptions and biases were removed from the preparation process, the overall evidence was evaluated appropriately, and recommendations were made after fully considering the balance between benefits and harms. Although the evidence is still insufficient to be taken up as a CQ, the latest important information is described in seven columns, and clinical issues that should be resolved in the future related to the CQ are described as recommendations for tomorrow. We hope that these guidelines will help medical professionals, patients, and their families involved in the treatment of UTUC in their decision-making, and hope that a critical review of these guidelines will lead to further refinements in the next edition.

A feasibility study of provider-level implementation strategies to improve access to colorectal cancer screening for patients with schizophrenia: ACCESS2 (N-EQUITY 2104) trial.

Masaki Fujiwara, Yuto Yamada, Tsuyoshi Etoh, Taichi Shimazu, Masafumi Kodama, Norihito Yamada, Takahiro Asada, Shigeo Horii, Takafumi Kobayashi, Teruo Hayashi, Yoshitaka Ehara, Kenji Fukuda, Keita Harada, Maiko Fujimori, Miyuki Odawara, Hirokazu Takahashi, Shiro Hinotsu, Naoki Nakaya, Yosuke Uchitomi, Masatoshi Inagaki

Implementation science communications 5 ( 1 ) 2 - 2 2024.01 [Refereed] [International journal]

BACKGROUND: People with schizophrenia have a lower colorectal screening rate than the general population. A previous study reported an intervention using case management to encourage colorectal cancer screening for patients with schizophrenia in psychiatric outpatient settings. In this feasibility study, we developed provider-level implementation strategies and evaluated the feasibility of conducting a definitive trial in terms of the penetration of the intervention assessed at the patient level. Additionally, we examined the fidelity of strategies to implement the intervention at the provider level in a routine clinical psychiatric setting. METHODS: This was a multicenter, single-arm feasibility study with medical staff at psychiatric hospitals in Japan. The provider-level implementation strategies developed in this study included three key elements (organizing an implementation team appointed by the facility director, interactive assistance using a clear guide that outlines who in the hospital should do what, and developing accessible educational materials) to overcome major barriers to implementation of the intervention and four additional elements (progress monitoring, joint meetings and information sharing among participating sites, adaptation of encouragement methods to specific contexts, and education of on-site staff), with reference to the elements identified in the Expert Recommendations for Implementing Change (ERIC). The feasibility of the strategies was evaluated by the proportion of patients who were eligible for encouragement (patients with schizophrenia aged 40, 50, or 60) who received encouragement. We set the goal of providing encouragement to at least 40% of eligible patients at each site. RESULTS: Two public and four private psychiatric hospitals in Okayama and Shimane prefectures participated in this study. Regarding fidelity, all elements of the strategies were conducted as planned. Following the procedures in the guide, each team prepared and provided encouragement according to their own facility and region. Penetration, defined as the proportion of eligible patients who received encouragement, ranged from 33.3 to 100%; five of the six facilities achieved the target proportion. CONCLUSIONS: The provider-level implementation strategies to implement encouragement were feasible in terms of penetration of the intervention assessed at the patient level. The results support the feasibility of proceeding with a future definitive trial of these strategies. TRIAL REGISTRATION: jRCT, jRCT1060220026 . Registered on 06/04/2022.

Trends in Head and Neck Cancer Mortality from 1999 to 2019 in Japan: An Observational Analysis.

Tsukasa Higashionna, Keisaku Harada, Akinari Maruo, Takahiro Niimura, Elizabeth Tan, Quynh Thi Vu, Takayoshi Kawabata, Soichiro Ushio, Hirofumi Hamano, Makoto Kajizono, Yoshito Zamami, Keisuke Ishizawa, Ko Harada, Shiro Hinotsu, Mitsunobu R Kano, Hideharu Hagiya, Toshihiro Koyama

Cancers 15 ( 15 ) 2023.07 [International journal]

Globally, the numbers of head and neck cancer (HNC) cases and related deaths have recently increased. In Japan, few studies have examined crude or age-adjusted HNC mortality rates. Therefore, this study aimed to determine the trends in crude and age-adjusted mortality rates for HNC per million individuals in Japan from 1999 to 2019. Data on HNC-associated deaths were extracted from the national death certificate database using the International Classification of Diseases, Tenth Revision (n = 156,742). HNC mortality trends were analysed using joinpoint regression models to estimate annual percentage change (APC) and average APC (AAPC). Among men, no significant change was observed in the age-adjusted death rate trend from 1999 to 2014; however, a marked decrease was observed from 2014 to 2019. No changing point was observed in women. Age-adjusted mortality rates continuously decreased over the 21-year period, with an AAPC of -0.7% in men and -0.6% in women. In conclusion, the overall trend in age-adjusted rates of HNC-associated deaths decreased, particularly among men, in the past 5 years. These results will contribute to the formulation of medical policies to develop targeted screening and prevention programmes for HNC in Japan and determine the direction of treatment strategies.

Increasing disparities in cancer screening among people with severe mental illness during the COVID-19 pandemic.

Masaki Fujiwara, Yuto Yamada, Taichi Shimazu, Naoki Nakaya, Shiro Hinotsu, Maiko Fujimori, Yosuke Uchitomi, Masatoshi Inagaki

Schizophrenia research 258 18 - 20 2023.07 [International journal]

A multicenter, retrospective observational study investigating baseline characteristics and clinical outcomes in patients with hormone-sensitive prostate cancer treated with primary androgen deprivation therapy.

Satoru Taguchi, Mizuki Onozawa, Shiro Hinotsu, Taketo Kawai, Takeshi Mitomi, Satoshi Uno, Haruki Kume

Japanese journal of clinical oncology 53 ( 10 ) 957 - 965 2023.07 [International journal]

OBJECTIVE: This multicenter, retrospective, observational study investigated baseline characteristics and clinical outcomes in patients with hormone-sensitive prostate cancer who received primary androgen deprivation therapy, using Japan Study Group of Prostate Cancer registry data. METHODS: Among patients in the Japan Study Group of Prostate Cancer registry, those who initiated primary androgen deprivation therapy and were aged 20 years or older were enrolled in this study. The primary endpoint was time to disease progression, defined as time from primary androgen deprivation therapy initiation to either prostate-specific antigen or clinical progression. Secondary endpoints included prostate-specific antigen progression-free survival, prostate-specific antigen response (90% or greater reduction from baseline) and distribution of second-line treatment. RESULTS: Of the 2494 patients (goserelin, n = 564; leuprorelin, n = 1148; surgical castration, n = 161; degarelix, n = 621), those who received degarelix had higher prostate-specific antigen levels and Gleason scores and were at a more advanced clinical stage than those receiving goserelin or leuprorelin. The median time to disease progression (identical to the prostate-specific antigen progression-free survival result) was not reached for goserelin and leuprorelin, 52.7 months for surgical castration and 54.0 months for degarelix. Although baseline prostate-specific antigen values in the degarelix cohort were higher than those of the leuprorelin or goserelin cohorts, prostate-specific antigen responses were not different among the three cohorts. Regarding second-line treatment, the largest patient group received degarelix followed by leuprorelin (n = 195). CONCLUSIONS: This study clarified patient characteristics and long-term effectiveness of primary androgen deprivation therapy in real-world clinical practice. Japanese urologists appear to select appropriate primary androgen deprivation therapy based on patient background and tumour characteristics, with degarelix largely reserved for higher risk patients.

Global trends of seasonal influenza-associated mortality in 2001-2018: A longitudinal epidemiological study.

Hideharu Hagiya, Yuka Osaki, Michio Yamamoto, Takahiro Niimura, Ko Harada, Tsukasa Higashionna, Hirofumi Hamano, Yoshito Zamami, Shiro Hinotsu, Toshihiro Koyama

The Journal of infection 87 ( 3 ) e54-e57 2023.06 [International journal]

Perceptions toward issues in cancer care for people with mental illness among psychiatric care providers: A questionnaire study.

Yuto Yamada, Masaki Fujiwara, Tsuyoshi Etoh, Riho Wada, Shinichiro Inoue, Yoshiko Mimaki, Masafumi Kodama, Yusaku Yoshimura, Shigeo Horii, Takanori Matsushita, Maiko Fujimori, Taichi Shimazu, Naoki Nakaya, Shiro Hinotsu, Masahiro Tabata, Kenji Tamura, Yosuke Uchitomi, Norihito Yamada, Kiwamu Nagoshi, Masatoshi Inagaki

Psycho-oncology 32 ( 7 ) 1022 - 1029 2023.04 [International journal]

OBJECTIVES: To reduce cancer care disparities in people with mental illness, this study aimed to quantify psychiatric care providers' perceptions regarding issues that are insufficiently addressed or difficult to address. METHODS: Psychiatric care providers at 23 psychiatric hospitals in Japan were surveyed using mail questionnaires. Respondents were asked to rate 15 items with four categories related to insufficiencies/difficulties in cancer care for patients with mental illness on a five-point Likert scale. We analyzed the proportion of respondents who answered "insufficient/difficult" for each item. RESULTS: A total of 255 (76.3%) psychiatric care providers responded. For questions related to the skills and attitudes of psychiatric professionals, 48.3%-58.4% of respondents perceived that efforts for supporting cancer screening and treatment were insufficient. For the questions related to collaborations between cancer and psychiatric care providers, 75.3% of respondents perceived that inpatient visits between psychiatric and cancer hospitals were insufficient. For the questions related to in-psychiatric-hospital medical systems, 50.2%-87.2% of respondents perceived that support for screening, diagnosis/treatment, and palliative care for psychiatric inpatients were insufficient/difficult. 41.9%-57.4% of respondents perceived that social services in the community were insufficient. CONCLUSIONS: This study clarified the level of insufficiency/difficulty perceived by psychiatric care providers regarding issues related to cancer care for people with mental illness. Psychiatric care providers are required to have knowledge and skills in cancer screening and treatment. To improve access to cancer prevention, treatment, and palliative care, it may be helpful to establish systems to promote coordination between cancer hospitals and psychiatric hospitals.

ガイドライン・取扱い規約作成における関連学会との連携

石塚修, 井川掌, 樋之津史郎, 西山博之, 松本洋明, 三塚浩二

日本泌尿器科学会雑誌 ( (一社)日本泌尿器科学会 ) 113 ( Suppl. ) S62 - S64 2022.11

A novel ZC4H2 variant in a female with severe respiratory complications.

Tomohiro Wakabayashi, Miyako Mizukami, Kojiro Terada, Aki Ishikawa, Shiro Hinotsu, Masaki Kobayashi, Koji Kato, Tomoo Ogi, Takeshi Tsugawa, Akihiro Sakurai

Brain & development 44 ( 8 ) 571 - 577 2022.09 [International journal]

INTRODUCTION: An X-linked ZC4H2 variant is associated with a variety of phenotypes that have abnormalities related to external malformation and neurodevelopment. There have been no reports on severe respiratory dysfunction resulting in surgical treatments not being possible due to the deformity resulting from in this disease. Here we report a female with arthrogryposis multiplex congenita with a severe respiratory complication. CASE: A two-year-old girl had arthrogryposis multiplex congenita at delivery and subsequently had hypotonia and feeding difficulty. A novel ZC4H2 frameshift variant was identified by whole-exome sequencing in her genome. At eight months, she had recurrent aspiration pneumonia. A tracheostomy and gastrostomy were required; however, surgical intervention was not possible because of her short neck and complicated airway. CONCLUSION: We compared this case with previous reports. The truncation group had more described phenotypes than the non-truncation group. The patient had the most severe respiratory dysfunction in truncating variant.

Nephrectomy Is Not Associated with Increased Risk of Mortality or Acute Kidney Injury after High-Grade Renal Trauma: A Propensity Score Analysis of the Trauma Quality Improvement Program (TQIP). Letter.

Keiko Fujino, Tetsuya Shindo, Shiro Hinotsu, Naoya Masumori

The Journal of urology 101097JU0000000000002892 2022.08 [International journal]

Health-related quality of life with enzalutamide versus flutamide in castration-resistant prostate cancer from the AFTERCAB study.

Hiroji Uemura, Kazuki Kobayashi, Akira Yokomizo, Shiro Hinotsu, Shigeo Horie, Yoshiyuki Kakehi, Norio Nonomura, Osamu Ogawa, Mototsugu Oya, Kazuhiro Suzuki, Atsushi Saito, Keiko Asakawa, Satoshi Uno, Seiji Naito

International journal of clinical oncology 2022.08 [Domestic journal]

BACKGROUND: Patient-reported outcome (PRO) measures can provide valuable information in evaluating patients' health-related quality of life (HRQoL). Post hoc analysis of the AFTERCAB study was conducted to evaluate the HRQoL benefit of enzalutamide plus androgen deprivation therapy (ADT) compared to flutamide plus ADT for the treatment of patients with castration-resistant prostate cancer (CRPC) in Japan. METHODS: The open-label AFTERCAB study was conducted from November 2016 to March 2020 in Japanese men aged ≥ 20 years with asymptomatic or mildly symptomatic CRPC. Patients received enzalutamide plus ADT or flutamide plus ADT, respectively, as first-line alternative androgen therapy (AAT). HRQoL was analyzed through the Functional Assessment of Cancer Therapy-Prostate, EuroQoL 5-Dimension 5-Level instruments, Brief Pain Inventory-Short Form, and Brief Fatigue Inventory. The longitudinal changes in HRQoL, HRQoL deterioration based on minimally important difference (MID), and time to HRQoL deterioration were evaluated for first-line AAT. RESULTS: Overall, HRQoL between the enzalutamide and flutamide groups was similar during first-line treatment. No statistically significant HRQoL difference in change from baseline to week 61 (least square mean difference; p value) was observed. Furthermore, proportions of pain progression, symptom worsening, and HRQoL deterioration based on MID, were not significantly different between groups. CONCLUSIONS: The results were similar in all subscales of each PRO, demonstrating similar HRQoL deterioration based on MID criteria between the enzalutamide and flutamide groups.

Summary of the Clinical Practice Guidelines for Penile Cancer 2021 by the Japanese Urological Association.

Takahiro Yamaguchi, Yutaka Sugiyama, Toshiaki Tanaka, Tomokazu Kimura, Yasushi Yumura, Masahiro Nakano, Takayuki Sugiyama, Noriyoshi Miura, Masato Goya, Akira Yamamoto, Satoru Takahashi, Yuji Miura, Toyonori Tsuzuki, Naoya Masumori, Hiroyuki Nishiyama, Masahiro Yao, Takuya Koie, Hideaki Miyake, Takashi Saika, Seiichi Saito, Tetsuo Akimoto, Tsutomu Tamada, Yuichi Ando, Satoru Takahashi, Takaaki Suzuki, Shiro Hinotsu, Tomomi Kamba

International journal of urology : official journal of the Japanese Urological Association 29 ( 8 ) 780 - 792 2022.08 [International journal]

Penile cancer is a rare cancer for which no medical guidelines have been established before in Japan. These guidelines aim to standardize, as much as possible, the therapeutic modality for penile cancer, for which empirical evidence is limited on a global scale, thereby bolstering therapeutic outcomes for patients with penile cancer. The new guidelines conform to the Minds Guide for Developing Clinical Practice Guidelines (2017) as much as possible. However, virtually no randomized comparative studies and meta-analyses based on such randomized studies have been conducted. Therefore, only the findings available at present were listed after conducting an exhaustive literature review of items with extremely low evidence levels and for which bodies of evidence and grades of recommendation were not evaluated. Clinical questions were set for items with a relatively large number of studies, including retrospective studies. However, since it is virtually impracticable to summarize bodies of evidence by systematic reviews, recommendation grades and evidence levels were discussed and determined by the consensus panel of the Preparatory Committee. The following were outlined: epidemiological, pathological, diagnostic, therapeutic, follow-up, and quality of life-related findings. Additionally, seven clinical questions were established to determine recommendation grades and evidence levels. We hope that these guidelines will prove to be useful to medical professionals engaged in clinical practice related to penile cancer in Japan and anticipate that critical reviews of the guidelines will lead to further refinement of the next edition.

Issues of cancer care in people with mental disorders as perceived by cancer care providers: A quantitative questionnaire survey.

Yuto Yamada, Masaki Fujiwara, Tsuyoshi Etoh, Riho Wada, Shinichiro Inoue, Masafumi Kodama, Yusaku Yoshimura, Shigeo Horii, Takanori Matsushita, Maiko Fujimori, Taichi Shimazu, Naoki Nakaya, Shiro Hinotsu, Masahiro Tabata, Kenji Tamura, Yosuke Uchitomi, Norihito Yamada, Masatoshi Inagaki

Psycho-oncology 31 ( 9 ) 1572 - 1580 2022.06 [International journal]

OBJECTIVES: To reduce cancer care disparities, this study aimed to clarify the difficulties in cancer care for people with mental disorders as perceived by cancer care providers. METHODS: Cancer care providers at 17 designated cancer hospitals in Japan were surveyed using mail questionnaires. Respondents were asked to rate 29 items related to difficulties or insufficiencies in cancer care for patients with mental disorders on a five-point Likert scale. We analyzed the proportion of respondents who answered "difficult/insufficient" in each item. We also calculated the proportions of responders stratified according to the presence of psychiatric support systems within their hospitals. RESULTS: A total of 388 (58.4%) cancer care providers responded. Among the issues related to "difficulties in diagnosing and treating cancer," support for decision-making, assessment of treatment adherence, and assessment of physical symptoms were perceived as most difficult (73.5%-81.5% of respondents). Among the issues related to 'difficulties or insufficiencies in collaboration among multidisciplinary health care providers,' the issue of advance consultation and sharing information with the patient's primary psychiatric care provider was perceived as most difficult (52.2%). Among the issues related to "insufficiencies of in-hospital and community medical systems," education to provide reasonable accommodation was perceived as most insufficient (47.4%). The perceived difficulties of over half of the issues varied significantly between hospitals depending on the level of psychiatric support systems. CONCLUSIONS: This study clarified the difficulties of cancer care in patients with mental disorders as perceived by cancer care providers. Some issues may be resolved by psychiatric liaison teams.

Patients' acceptability and implementation outcomes of a case management approach to encourage participation in colorectal cancer screening for people with schizophrenia: a qualitative secondary analysis of a mixed-method randomised clinical trial.

Yuto Yamada, Masaki Fujiwara, Taichi Shimazu, Tsuyoshi Etoh, Masafumi Kodama, Ryuhei So, Takanori Matsushita, Yusaku Yoshimura, Shigeo Horii, Maiko Fujimori, Hirokazu Takahashi, Naoki Nakaya, Tempei Miyaji, Shiro Hinotsu, Keita Harada, Hiroyuki Okada, Yosuke Uchitomi, Norihito Yamada, Masatoshi Inagaki

BMJ open 12 ( 6 ) e060621 2022.06 [International journal]

OBJECTIVES: We examined the efficacy of case management (CM) interventions to encourage participation in colorectal cancer screening for patients with schizophrenia. This study aimed to clarify patients' acceptability of the intervention and the helpful components of the intervention. Simultaneously, the study aimed to determine the acceptability, appropriateness and feasibility of the intervention from the perspective of psychiatric care providers. STUDY DESIGN AND SETTING: This study was a secondary qualitative analysis of a mixed-method randomised controlled trial that evaluated the efficacy of the CM approach to encourage participation in cancer screening for people with schizophrenia. The intervention comprised education and patient navigation for colorectal cancer screening. Interviews were conducted with patients who received the intervention and staff from two psychiatric hospitals in Japan who delivered the intervention. PARTICIPANTS: Of the 172 patients with schizophrenia who participated in the trial, 153 were included. In addition, three out of six providers were included. DATA COLLECTION AND ANALYSIS: Using a structured interview, the case manager asked participants about patient acceptability and the helpful components of the intervention. Content analysis was conducted for the responses obtained, and the number of responses was tabulated by two researchers. For the interviews with the providers, opinions obtained from verbatim transcripts were extracted and summarised. RESULTS: Forty-three of the 56 patients perceived that the intervention was acceptable. For the intervention component, inperson counselling with an explanation of the screening process by psychiatric care providers was most frequently reported by the patients as helpful (48 of the 68 respondents). Psychiatric care providers evaluated the intervention as acceptable, appropriate and easy to understand and administer. However, providing the intervention to all patients simultaneously was considered difficult with the current human resources. CONCLUSIONS: This study showed that the CM intervention was perceived as acceptable by patients and acceptable and appropriate by psychiatric care providers. TRIAL REGISTRATION NUMBER: UMIN000036017.

Are there differences in the characteristics of patients who respond to gemcitabine plus cisplatin chemotherapy and those who respond to pembrolizumab therapy for metastatic urothelial carcinoma? Multicenter retrospective study.

Tetsuya Shindo, Takeshi Maehana, Toshiaki Tanaka, Kohei Hashimoto, Ko Kobayashi, Atsushi Takahashi, Hiroshi Hotta, Yasuharu Kunishima, Keisuke Taguchi, Hitoshi Tachiki, Naoki Ito, Masanori Matsukawa, Ryuichi Kato, Shintaro Miyamoto, Shiro Hinotsu, Naoya Masumori

International journal of urology : official journal of the Japanese Urological Association 2022.06 [International journal]

OBJECTIVES: To evaluate factors to predict overall survival of metastatic urothelial carcinoma patients treated with gemcitabine plus cisplatin chemotherapy or pembrolizumab therapy. METHODS: We retrospectively evaluated two metastatic urothelial carcinoma cohorts treated with (i) gemcitabine plus cisplatin or (ii) pembrolizumab. The gemcitabine plus cisplatin cohort was treated from December 2005 through December 2014 while the pembrolizumab cohort was treated from January 2018 through December 2020. Using multivariate analyses, we evaluated the risk factors for overall survival in each cohort and compared them. None of the gemcitabine plus cisplatin cohort patients were treated with pembrolizumab. All patients in the pembrolizumab cohort were treated with prior platinum-based chemotherapy. RESULTS: There were 184 patients in the gemcitabine plus cisplatin cohort and 91 in the pembrolizumab cohort. The mean follow-up periods were 714 and 284 days, respectively. In multivariate analysis, the risk factors for overall survival in the gemcitabine plus cisplatin cohort were liver metastasis, worse Eastern Cooperative Oncology Group performance status (1 or more), no primary site resection, and a high prognostic index (1 or more). In the pembrolizumab cohort, liver metastasis, bone metastasis, and worse Eastern Cooperative Oncology Group-performance status (1 or more), and high prognostic index (1 or more) were the risk factors for overall survival. In the pembrolizumab cohort, patients with a complete response or partial response during prior platinum-based chemotherapy had better overall survival with the following pembrolizumab treatment than those with stable or progressive disease (P = 0.004). CONCLUSIONS: Considering the similarity of these risk factors in two sequential treatments, it may be possible to predict the response to pembrolizumab according to the response to prior chemotherapy.

Prognostic usefulness of a modified risk model for solitary fibrous tumor that includes the Ki-67 labeling index.

Shintaro Sugita, Keiko Segawa, Noriaki Kikuchi, Tomoko Takenami, Tomomi Kido, Makoto Emori, Yukinori Akiyama, Kohichi Takada, Shiro Hinotsu, Tadashi Hasegawa

World journal of surgical oncology 20 ( 1 ) 29 - 29 2022.02 [International journal]

BACKGROUND: Predicting the prognosis of patients with solitary fibrous tumor (SFT) is often difficult. The prognostic risk models developed by Demicco et al. are now the standard for evaluating the risk of SFT metastasis in the current World Health Organization classification of soft tissue and bone tumors. METHODS: In this study, we examined the prognostic usefulness of a modified version of the Demicco risk models that replaces the mitotic count with the Ki-67 labeling index. We compared the three-variable and four-variable Demicco risk models with our modified risk models using Kaplan-Meier curves based on data for 43 patients with SFT. RESULTS: We found a significant difference in metastasis-free survival when patients were classified into low-risk and intermediate/high-risk groups using the three-variable (P = 0.022) and four-variable (P = 0.046) Demicco models. There was also a significant difference in metastasis-free survival between the low-risk and intermediate/high-risk groups when the modified three-variable (P = 0.006) and four-variable (P = 0.022) models were used. CONCLUSION: Modified risk models that include the Ki-67 labeling index are effective for prediction of the prognosis in patients with SFT.

Enzalutamide + androgen deprivation therapy (ADT) versus flutamide + ADT in Japanese men with castration-resistant prostate cancer: AFTERCAB study.

Hiroji Uemura, Kazuki Kobayashi, Akira Yokomizo, Shiro Hinotsu, Shigeo Horie, Yoshiyuki Kakehi, Seiji Naito, Norio Nonomura, Osamu Ogawa, Mototsugu Oya, Kazuhiro Suzuki, Atsushi Saito, Satoshi Uno, Hideyuki Akaza

BJUI compass 3 ( 1 ) 26 - 36 2022.01 [International journal]

Objectives: The objective of the study is to compare the efficacy and safety of alternative androgen therapy (AAT) with enzalutamide + androgen deprivation therapy (ADT) and flutamide + ADT in the treatment of Japanese men with metastatic or nonmetastatic castration-resistant prostate cancer (CRPC) who progressed despite combined androgen blockade (CAB) with bicalutamide + ADT. AAT treatment sequence was also investigated. Materials and methods: The open-label, Phase 4 AFTERCAB study (NCT02918968) was conducted from November 2016 to March 2020 in Japanese men aged ≥20 years with asymptomatic or mildly symptomatic CRPC. Patients were initially randomized to enzalutamide (160 mg/day) + ADT (enzalutamide first) or flutamide (375mg/day [125mg three times daily]) + ADT (flutamide first) as first-line therapy. Following prostate-specific antigen (PSA) progression, other disease progression, or discontinuation of first-line therapy due to an adverse event (AE), patients switched to the other treatment as second-line therapy. The primary endpoint was time to PSA progression with first-line therapy (TTPP1). Secondary endpoints included TTPP2 (TTPP1 + time to PSA progression with second-line therapy). AEs were monitored to assess safety. Results: Overall, 206 men were randomized (enzalutamide first, n = 102; flutamide first, n = 104) and stratified by study site and disease stage; 133 patients transitioned to second-line therapy (enzalutamide first, n = 48; flutamide first, n = 85). TTPP1 was significantly improved with enzalutamide first versus flutamide first (median 21.4 months vs. 5.8 months; hazard ratio [HR] 0.42; 95% confidence interval [CI] [0.29, 0.61]). TTPP2 was numerically improved with enzalutamide first versus flutamide first (median not reached vs. 21.2 months; HR 0.76; 95% CI [0.48, 1.19]). Both treatments were generally well tolerated, with AEs consistent with their known safety profiles. Conclusion: First-line AAT with enzalutamide + ADT provided a significant improvement in time to PSA progression versus flutamide + ADT. Enzalutamide + ADT may therefore be the preferred first-line AAT option in Japanese men with metastatic or nonmetastatic CRPC who progress despite CAB with bicalutamide + ADT.

Decrease in unscheduled pediatric outpatient visits due to SARS-CoV-2.

Tomohiro Wakabayashi, Yuta Sasaoka, Yoshiyuki Sakai, Shiro Hinotsu, Yukihiko Kawasaki

Pediatrics international : official journal of the Japan Pediatric Society 64 ( 1 ) e14748 2022.01 [International journal]

長期間無再発で経過した筋層非浸潤性膀胱癌術後患者における再発リスクの解析

平田由里絵, 大澤崇宏, 樋口まどか, 樋之津史郎, 原林透, 望月端吾, 榎並宣裕, 能中修, 信野祐一郎, 菊地央, 松本隆児, 安部崇重, 篠原信雄

日本泌尿器科学会総会 ( (一社)日本泌尿器科学会総会事務局 ) 109回 OP45 - 01 2021.12

Therapeutic options to reduce intravesical recurrence in newly diagnosed Ta high-grade bladder cancer according to risk stratification: A multicenter retrospective study.

Tetsuya Shindo, Kohei Hashimoto, Toshiaki Tanaka, Keisuke Taguchi, Atsushi Takahashi, Naoki Itoh, Manabu Okada, Hiroshi Hotta, Yasuharu Kunishima, Takaoki Hirose, Masanori Matsukawa, Hitoshi Tachiki, Ryuichi Kato, Shiro Hinotsu, Naoya Masumori

International journal of urology : official journal of the Japanese Urological Association 28 ( 11 ) 1136 - 1142 2021.11 [International journal]

OBJECTIVES: To evaluate the risk factors for intravesical recurrence in patients with newly diagnosed Ta high-grade non-muscle-invasive bladder cancer and the optimal management to reduce the risk of recurrence. METHODS: We retrospectively evaluated Ta high-grade bladder cancer in patients who were newly diagnosed by transurethral resection from January 2007 through October 2018. Using multivariate analyses, we evaluated the risk factors and therapeutic options affecting intravesical recurrence and stratified the patients according to the risk numbers. RESULTS: We included 390 patients and the median follow-up period was 31 months after the initial transurethral resection. According to multivariate analysis, having a previous history of upper urinary tract carcinoma, and multiple and sessile tumors were risk factors for intravesical recurrence (P = 0.001, P = 0.02 and P = 0.01, respectively). Risk groups were stratified according to these risk factors into favorable, intermediate and poor. In the entire cohort, induction and immediate intravesical instillation therapy were treatment options to reduce intravesical recurrence (P < 0.01 and P = 0.02, respectively). Analyses in each risk group showed that a second transurethral resection was the only therapeutic option to reduce intravesical recurrence in the favorable group (P = 0.048), whereas induction intravesical instillation therapy was effective in the intermediate and poor risk groups (P = 0.01 and P < 0.01, respectively), as was immediate intravesical instillation for the poor risk group (P < 0.001). CONCLUSIONS: Sessile, multiple tumors and a history of upper urinary tract carcinoma are risk factors for intravesical recurrence in Ta high-grade bladder cancer patients.

Encouraging participation in colorectal cancer screening for people with schizophrenia: A randomized controlled trial.

Masaki Fujiwara, Yuto Yamada, Taichi Shimazu, Masafumi Kodama, Ryuhei So, Takanori Matsushita, Yusaku Yoshimura, Shigeo Horii, Maiko Fujimori, Hirokazu Takahashi, Naoki Nakaya, Kyoko Kakeda, Tempei Miyaji, Shiro Hinotsu, Keita Harada, Hiroyuki Okada, Yosuke Uchitomi, Norihito Yamada, Masatoshi Inagaki

Acta psychiatrica Scandinavica 144 ( 4 ) 318 - 328 2021.10 [International journal]

OBJECTIVE: We examined the efficacy of a case management approach to improve participation in colorectal cancer screening among people with schizophrenia. METHODS: This was a randomized, parallel group trial. We recruited outpatients with schizophrenia aged 40 years or over from two psychiatric hospitals in Japan. Participants were randomly assigned (1:1) to treatment as usual or case management intervention plus treatment as usual using a web-based system. Attending clinicians and participants were unmasked to the allocation. Case management included education and patient navigation for colorectal cancer screening using a fecal occult blood test. Treatment as usual included direct mail government recommendations. The primary endpoint was participation in colorectal cancer screening assessed using municipal records. We also assessed the secondary endpoint of participation in other cancer screenings (lung, gastric, breast, and cervical). RESULTS: Between 3 June and 9 September 2019, 172 eligible participants were randomly assigned to the case management plus treatment as usual group (n = 86) or treatment as usual group (n = 86). One participant was ineligible and another withdrew consent; both were excluded from analysis. A significantly higher proportion of participants received colorectal cancer screening in the case management plus treatment as usual group than in the treatment as usual group (40 [47.1%] of 85 participants vs. 10 [11.8%] of 85 participants, p < 0.0001). The proportion of lung cancer screening also increased. No serious adverse events associated with the study intervention occurred. CONCLUSION: The case management intervention to encourage participation in colorectal cancer screening was effective for patients with schizophrenia.

Dynamics of conditional survival and risk factors in androgen deprivation therapy for prostate cancer using a multi-institutional Japan-wide database.

Sotaro Chikamatsu, Masaki Shiota, Mizuki Onozawa, Shiro Hinotsu, Yasuhide Kitagawa, Shinichi Sakamoto, Taketo Kawai, Masatoshi Eto, Haruki Kume, Hideyuki Akaza

International journal of urology : official journal of the Japanese Urological Association 28 ( 9 ) 927 - 935 2021.09 [International journal]

OBJECTIVES: The objectives of this study were to analyze the conditional survival and prognostic factors in androgen deprivation therapy for prostate cancer using the Japan Study Group of Prostate Cancer database. METHODS: Data on patients treated with primary androgen deprivation therapy between 2001 and 2003 from a nationwide database of the Japan Study Group of Prostate Cancer were used. The conditional 5-year progression-free rate, cancer-specific survival and overall survival, as well as the conditional mortality owing to prostate cancer and other causes were calculated as per subgroups. Prognostic factors for progression-free rate, cancer-specific survival and overall survival at each time after androgen deprivation therapy initiation were calculated using the Cox proportional hazards model. RESULTS: The conditional 5-year progression-free rate and cancer-specific survival, but not overall survival, gradually increased with time. The prognostic impact of stage IV characteristics (T4, N1 and M1) changed over time; however, the prognostic impact of the Gleason score remained unchanged. In the subgroup analysis, prostate-specific mortality risk reduced over time in patients with stage IV prostate cancer, whereas non-prostate cancer mortality increased over time in elderly patients. CONCLUSIONS: Information regarding conditional survival and mortality obtained in this study would provide a benchmark for physicians and cancer survivors.

Long-term outcomes of androgen deprivation therapy in prostate cancer among Japanese men over 80 years old.

Leandro Blas, Mizuki Onozawa, Masaki Shiota, Shiro Hinotsu, Shinichi Sakamoto, Yasuhide Kitagawa, Taketo Kawai, Masatoshi Eto, Haruki Kume, Hideyuki Akaza

Cancer science 112 ( 8 ) 3074 - 3082 2021.08 [International journal]

This study aimed to analyze the survival rate and to examine the risk of death from prostate cancer when accounting for competing risk of death, in men aged ≥80 y treated with primary androgen deprivation therapy (ADT). Data of patients with prostate cancer who had received ADT were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Prognostic variables, including progression-free survival, cancer-specific survival, overall survival, and death rates were compared between men stratified by prostate cancer risk. Overall, 4760 patients older than 80 y were included. The proportion of low-, intermediate-, high-, or very high-risk, regional, and metastatic prostate cancer among super-elderly men was 9.5%, 14.6%, 48.8%, 9.0%, 3.2%, and 24.9%, respectively. Survival rates decreased with increasing risk stratification. The cumulative 5-y death rate by prostate cancer for low-, intermediate-, high-, or very high-risk, regional, and metastatic prostate cancer, was 0.92% (95% confidence interval [CI]: 0.2%-3.6%), 1.6% (95% CI: 0.8%-3.4%), 5.75% (95% CI: 4.25%-7.75%), 15.6% (95% CI: 11.6%-23.3%), 20.7% (95% CI: 13.1%-31.7%), and 36.9% (95% CI: 32.8%-41.4%), respectively. Our findings support that there is no need for immediate ADT for low- and intermediate-risk groups. Conversely, in high- or very high-risk, regional, and metastatic prostate cancer, more efforts for curative therapy and intensive therapy are needed in selected patients.

Primary Androgen-Depletion Therapy Prevails Not Only for Metastatic but Also for Nonmetastatic Hormone-Naïve Prostate Cancer in Japan-Recent Trends and Efficacy.

Mizuki Onozawa, Shiro Hinotsu, Atsushi Saito, Satoshi Uno, Hideyuki Akaza

Gan to kagaku ryoho. Cancer & chemotherapy 48 ( 7 ) 911 - 919 2021.07 [Domestic journal]

OBJECTIVE: To investigate the real-world use of primary androgen-deprivation therapy(PADT; gonadotropin-releasing hormone agonists[leuprorelin/goserelin]and antagonists[degarelix]/surgical castration), its clinical effectiveness, and the characteristics of Japanese patients with hormone-sensitive prostate cancer treated with PADT. METHODS: In this retrospective, observational study, patients using PADT(≥1 record)in the 2016-2018 Japan Study Group of Prostate Cancer registry were followed up from their initial date of PADT until October 2018. The primary endpoints included prostate-specific antigen( PSA)response rate(PSA<4 ng/mL)and duration of initial treatment. RESULTS: Of 1,895 patients, 47.7%, 24.4%, and 22.0% received leuprorelin, goserelin, and degarelix, respectively; 5.9% underwent surgical castration. The degarelix group had the highest median PSA at diagnosis(116.7 ng/mL)and proportion of patients with clinical Stage Ⅳ prostate cancer (72.9%)and Gleason score 9-10(59.7%). A concomitant antiandrogen was used in >80% and 70% of patients in the leuprorelin/goserelin and degarelix groups, respectively; bicalutamide was used most commonly(99.0%). Median duration of initial treatment was 20.8 months in the degarelix group and not yet reached in the leuprorelin/goserelin groups; continuation rates at 24 months were 44.6% and 81.6%/87.3%, respectively. The PSA response rate was the highest in the leuprorelin group(93.7%); median percentage change in PSA was comparable across all treatment groups(-99.1% to -99.8%). CONCLUSIONS: Real-world use of PADT in patients with hormone-sensitive prostate cancer is likely based on its specific therapeutic attributes and patient characteristics.

Efficacy and safety of short-term (3 days) enoxaparin in preventing venous thromboembolism after gastric cancer surgery: A single-center, prospective cohort study.

Shinji Kuroda, Satoru Kikuchi, Yoshihiko Kakiuchi, Megumi Watanabe, Kazuya Kuwada, Tomoko Tsumura, Masahiko Nishizaki, Shunsuke Kagawa, Shiro Hinotsu, Toshiyoshi Fujiwara

International journal of surgery (London, England) 89 105946 - 105946 2021.05 [International journal]

BACKGROUND: Pharmacologic prophylaxis such as enoxaparin for venous thromboembolism (VTE) is rarely used in Japan, even following abdominal cancer surgery, for which it is recommended in relevant guidelines (at least 7 days of use) along with mechanical prophylaxis with intermittent pneumatic compression. Reasons for enoxaparin's unpopularity include concerns over postoperative bleeding and its inconvenience in clinical practice. Here, we conducted a prospective clinical study of short-term (3 days) use of enoxaparin, which is considered to minimally impact postoperative management without increasing bleeding risk. METHODS: Gastric cancer patients who underwent gastrectomy received enoxaparin for 3 days from postoperative day (POD) 1-4. The primary endpoint was the incidence of deep vein thrombosis (DVT), which was examined primarily via Doppler ultrasonography of the lower limbs between POD 8 and 14. The planned sample size was 70, which was calculated based on an estimated incidence rate of 9% and an upper limit of incidence rate of 20%, with alpha of 0.05 and beta of 0.2. RESULTS: A total of 70 gastric cancer patients were enrolled, and ultimately, 68 patients received the protocol intervention and DVT evaluation. Sixty-seven patients completed 6 enoxaparin injections, but 1 patient did not complete the course due to abdominal bleeding after initiation. The incidence of DVT was 4.4% (3/68), and the 95% upper confidence interval was 12.2%, lower than the 20% threshold we set as the upper limit of DVT incidence. DVT was detected only in the peripheral veins of the lower extremities in all 3 affected patients. The incidence of bleeding-related complications, which were not severe, was 1.5% (1/68). CONCLUSIONS: Short-term (3 days) use of enoxaparin was shown to be effective and safe for VTE prophylaxis, comparable to regular use (at least 7 days), in postoperative management of gastric cancer surgery.

Population-Based Observational Study of Adverse Drug Event-Related Mortality in the Super-Aged Society of Japan.

Tomoko Funahashi, Toshihiro Koyama, Hideharu Hagiya, Ko Harada, Syunya Iinuma, Soichiro Ushio, Yoshito Zamami, Takahiro Niimura, Kazuaki Shinomiya, Keisuke Ishizawa, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

Drug safety 44 ( 5 ) 531 - 539 2021.05 [International journal]

INTRODUCTION: Adverse drug events (ADEs) are a major cause of mortality. OBJECTIVE: We examined long-term trends for ADE-related deaths in Japan. METHODS: This observational study was conducted using the Japanese Vital Statistics from 1999 to 2016. Data for all ADE-related deaths were extracted using International Classification of Diseases, Tenth Revision codes. We analysed ADE-related deaths by age and sex and calculated crude and age-standardised mortality rates (ASMR) per 100,000 people. We used Joinpoint regression analysis to identify significant changing points in mortality trends and to estimate annual percentage change (APC). RESULTS: In total, 16,417 ADE-related deaths were identified. The crude mortality rate for individuals aged ≥ 65 years was higher than that of young individuals. The ASMR per 100,000 people increased from 0.44 in 1999 to 0.64 in 2016. The crude mortality rate increased from 0.44 in 1999 to 1.01 in 2016. The APC of ASMR increased at a rate of 2.8% (95% confidence interval [CI] 1.4-4.2) throughout the study period. In addition, crude mortality increased at a rate of 5.7% (95% CI 4.2-7.3) annually from 1999 to 2016. The ADE-related mortality rate was higher for men than for women during the study period. CONCLUSIONS: The number of and trend in ADE-related deaths increased in Japan from 1999 to 2016, particularly in the older population.

Regional and facility disparities in androgen deprivation therapy for prostate cancer from a multi-institutional Japan-wide database.

Masaki Shiota, Ryota Sumikawa, Mizuki Onozawa, Shiro Hinotsu, Yasuhide Kitagawa, Shinichi Sakamoto, Taketo Kawai, Masatoshi Eto, Haruki Kume, Hideyuki Akaza

International journal of urology : official journal of the Japanese Urological Association 28 ( 5 ) 584 - 591 2021.05 [International journal]

OBJECTIVES: To examine the differences in prognosis of prostate cancer patients receiving primary androgen deprivation therapy by region and facility type using a Japan-wide database. METHODS: Data on patients treated with primary androgen deprivation therapy between 2001 and 2003 from a nationwide community-based database established by the Japan Study Group of Prostate Cancer were obtained. Clinicopathological characteristics and prognostic variables, including progression, cancer-specific survival and overall survival, were compared according to region and facility type where the patients were treated. RESULTS: Among 19 162 patients, 7102 (37.1%) and 12 060 (62.9%) men were in urban and rural areas, respectively, and 3556 (18.6%), 13 623 (71.1%) and 1983 (10.3%) patients were enrolled from academic centers, non-academic hospitals and urological clinics, respectively. The risks of progression, cancer-specific mortality and all-cause mortality were comparable between urban and rural areas in propensity-score matched analysis. Risks of progression, cancer-specific mortality and all-cause mortality in urological clinics were higher than those in academic centers in propensity-score matched analysis. CONCLUSIONS: Our findings suggest that Japan facility type, but not geographical regions, might affect the prognosis of prostate cancer patients receiving primary androgen deprivation therapy.

A Multicenter Study of Docetaxel at a Dose of 100 mg/m2 in Japanese Patients with Advanced or Recurrent Breast Cancer.

Taizo Hirata, Shinji Ozaki, Masahiro Tabata, Takayuki Iwamoto, Shiro Hinotsu, Akinobu Hamada, Takayuki Motoki, Tomohiro Nogami, Tadahiko Shien, Naruto Taira, Junji Matsuoka, Hiroyoshi Doihara

Internal medicine (Tokyo, Japan) 60 ( 8 ) 1183 - 1190 2021.04 [Domestic journal]

Objective This study examined the pharmacokinetics, safety and anti-tumor activity of docetaxel at a dose of 100 mg/m2 in Japanese patients with advanced or recurrent breast cancer. Methods Japanese patients with advanced or recurrent breast cancer received docetaxel at a dose of 100 mg/m2 intravenously every three weeks. The pharmacokinetics were assessed during the first cycle. The patients were allowed to receive supportive care drugs based on the indications and dosages in Japan. Results Six eligible patients aged 39-65 years old and 27 treatment cycles were analyzed. All patients experienced one or more adverse events (AEs). The common AEs were neutropenia, thrombocytopenia, alopecia, rash, diarrhea, neuropathy (sensory), fatigue, nausea, fever, hypoalbuminemia, alanine transaminase (ALT) increased, constipation, and taste alteration. Grade 3 or 4 AEs included neutropenia, leukopenia, anemia, lymphopenia, decreased appetite, γ-glutamyl transpeptidase (GTP) increased, aspartate transaminase (AST) increased, ALT increased, hypertension and cellulitis which were all reversible. There were no cases of febrile neutropenia, serious AEs or deaths. The median number of cycles was six. Dose reductions were not observed and most cycles were administered at their intended doses. No complete response and three partial responses were observed in four assessable patients with evaluable lesions. The maximum concentration and area under the blood concentration-time curve were 3,417.5 ng/mL and 4.35 μg・hr/mL (mean), respectively. Conclusion Docetaxel at a dose of 100 mg/m2 was tolerable with acceptable safety profiles and effective for Japanese patients with advanced or recurrent breast cancer with appropriate supportive therapies, and pharmacokinetic (PK) profiles which corresponded approximately with the findings of previous clinical studies.

Trends in hepatitis C virus-associated mortality rates in Japan, 1998-2017.

Hideharu Hagiya, Toshihiro Koyama, Matsuo Deguchi, Yusuke Minato, Satomi Miura, Tomoko Funahashi, Yusuke Teratani, Yoshito Zamami, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu Kano

Journal of gastroenterology and hepatology 36 ( 9 ) 2486 - 2492 2021.04 [International journal]

BACKGROUND AND AIM: The current prevalence of hepatitis C virus infection and hepatitis C virus-associated mortality in Japan falls short of the World Health Organization goal of viral hepatitis elimination by 2030. We aimed to evaluate the trends in hepatitis C virus-associated mortality in Japan. METHODS: This nationwide observational study used the Japanese Vital Statistics from 1998 to 2017 and included all Japanese hepatitis C virus-associated deaths (84 936) of adults aged ≥ 40 years. We calculated the crude and age-standardized mortality rates per 100 000 persons by age and sex. Joinpoint regression analysis was used to identify significant changing points in trends and to estimate the annual percentage changes and the average annual percentage changes for the entire study period. RESULTS: The crude mortality rate per 100 000 persons (annual death number) increased from 5.5 (3548) in 1998 to 7.0 (4843) in 2005 and decreased to 4.0 (3095) in 2017. By 2017, the crude mortality rates per 100 000 persons among men and women had dropped to 3.6 and 4.3, respectively. The age-standardized mortality rate was higher in women than in men. The average annual percentage change was -3.8% (95% confidence interval: -5.0 to -2.5). The declining trend was more rapid in men (-4.5%, 95% confidence interval: -5.3 to -3.6) than in women (-2.7%, 95% confidence interval: -3.8 to -1.6). CONCLUSIONS: Trends in hepatitis C virus-associated mortality rates have declined in an accelerating manner in Japan, especially among men.

A randomized phase III trial of personalized peptide vaccination for castration‑resistant prostate cancer progressing after docetaxel.

Masanori Noguchi, Kiyohide Fujimoto, Gaku Arai, Hiroji Uemura, Katsuyoshi Hashine, Hiroaki Matsumoto, Satoshi Fukasawa, Yasuo Kohjimoto, Hideomi Nakatsu, Atsushi Takenaka, Masato Fujisawa, Hirotsugu Uemura, Seiji Naito, Shin Egawa, Hiroyuki Fujimoto, Shiro Hinotsu, Kyogo Itoh

Oncology reports 45 ( 1 ) 159 - 168 2021.01 [International journal]

First‑line chemotherapy for men with metastatic castration‑resistant prostate cancer (mCRPC) has been employed to improve overall survival (OS) and progression‑free survival (PFS). However, several new agents for CRPC after first‑line chemotherapy prolonged survival by only a few months. To develop a new treatment modality, we conducted a phase III randomized trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)‑A24‑positive patients with castration‑resistant prostate cancer (CRPC) for whom docetaxel chemotherapy failed. This randomized, double‑blind, placebo‑controlled, phase III trial was carried out at 68 medical centers in Japan. Patients were randomly assigned at a 2:1 ratio to receive PPV or placebo. Four of 12 warehouse peptides selected based on pre‑existing peptide‑specific immunoglobulin G levels or the corresponding placebo were subcutaneously injected in 6 doses weekly and then bi‑weekly following the maximum of 30 doses until disease progression. The primary end‑point was overall survival (OS). Efficacy analyses were performed by the full analysis set. Between August 2013 and April 2016, 310 patients were randomly assigned, and 306 patients were analyzed. Baseline characteristics were balanced between groups. The estimated median OS was 16.1 months [95% confidence interval (CI), 13‑18.2] with PPV and 16.9 months (95% CI, 13.1‑20.4) with placebo [hazard ratio (HR), 1.04, 95% CI, 0.80‑1.37; P=0.77]. Grade ≥3 adverse events were observed in 41% of both groups. The analysis of treatment arm effects among subgroups revealed lower HRs for OS in favor of the PPV arm in patients with <64% neutrophils (HR, 0.55, 95% CI, 0.33‑0.93; P=0.03) or ≥26% lymphocytes (HR, 0.70, 95% CI, 0.52‑0.92; P=0.02) at baseline. PPV did not prolong OS in HLA‑A24‑positive patients with CRPC progressing after docetaxel chemotherapy. Subgroup analysis suggested that the patients with a lower proportion of neutrophils or a higher proportion of lymphocytes at baseline can receive survival benefits from PPV treatment.

Modified J-CAPRA scoring system in predicting treatment outcomes of metastatic prostate cancer patients undergoing androgen deprivation therapy

Jasmine Lim, Shiro Hinotsu, Mizuki Onozawa, Rohan Malek, Murali Sundram, Guan C. Teh, Teng-Aik Ong, Shankaran Thevarajah, Rohana Zainal, Say C. Khoo, Shamsuddin Omar, Noor A. Nasuha, Hideyuki Akaza

Cancer Medicine ( Blackwell Publishing Ltd ) 9 ( 24 ) 9346 - 9352 2020.12

The J-CAPRA score is an assessment tool which stratifies risk and predicts outcome of primary androgen deprivation therapy (ADT) using prostate-specific antigen, Gleason score, and clinical TNM staging. Here, we aimed to assess the generalisability of this tool in multi-ethnic Asians. Performance of J-CAPRA was evaluated in 782 Malaysian and 16,946 Japanese patients undergoing ADT from the Malaysian Study Group of Prostate Cancer (M-CaP) and Japan Study Group of Prostate Cancer (J-CaP) databases, respectively. Using the original J-CAPRA, 69.6% metastatic (M1) cases without T and/or N staging were stratified as intermediate-risk disease in the M-CaP database. To address this, we first omitted clinical T and N stage variables, and calculated the score on a 0–8 scale in the modified J-CAPRA scoring system for M1 patients. Notably, treatment decisions of M1 cases were not directly affected by both T and N staging. The J-CAPRA score threshold was adjusted for intermediate (modified J-CAPRA score 3–5) and high-risk (modified J-CAPRA score ≥6) groups in M1 patients. Using J-CaP database, validation analysis showed that overall survival, prostate cancer-specific survival, and progression-free survival of modified intermediate and high-risk groups were comparable to those of original J-CAPRA (p > 0.05) with Cohen's coefficient of 0.65. Around 88% M1 cases from M-CaP database were reclassified into high-risk category. Modified J-CAPRA scoring system is instrumental in risk assessment and treatment outcome prediction for M1 patients without T and/or N staging.

Resveratrol improves motor function in patients with muscular dystrophies: an open-label, single-arm, phase IIa study

Kentaro Kawamura, Shinobu Fukumura, Koki Nikaido, Nobutada Tachi, Naoki Kozuka, Tsugumi Seino, Kingya Hatakeyama, Mitsuru Mori, Yoichi M. Ito, Akiyoshi Takami, Shiro Hinotsu, Atsushi Kuno, Yukihiko Kawasaki, Yoshiyuki Horio, Hiroyuki Tsutsumi

Scientific Reports ( Springer Science and Business Media LLC ) 10 ( 1 ) 2020.12

AbstractMuscular dystrophies (MDs) are inherited disorders characterized by progressive muscle weakness. Previously, we have shown that resveratrol (3,5,4′-trihydroxy-trans-stilbene), an antioxidant and an activator of the protein deacetylase SIRT1, decreases muscular and cardiac oxidative damage and improves pathophysiological conditions in animal MD models. To determine whether resveratrol provides therapeutic benefits to patients with MDs, an open-label, single-arm, phase IIa trial of resveratrol was conducted in 11 patients with Duchenne, Becker or Fukuyama MD. The daily dose of resveratrol was 500 mg/day, which was increased every 8 weeks to 1000 and then 1500 mg/day. Primary outcomes were motor function, evaluated by a motor function measure (MFM) scale, muscular strength, monitored with quantitative muscle testing (QMT), and serum creatine kinase (CK) levels. Adverse effects and tolerability were evaluated as secondary outcomes. Despite the advanced medical conditions of the patients, the mean MFM scores increased significantly from 34.6 to 38.4 after 24 weeks of medication. A twofold increase was found in the mean QMT scores of scapula elevation and shoulder abduction. Mean CK levels decreased considerably by 34%. Diarrhoea and abdominal pain was noted in six and three patients, respectively. Resveratrol may provide some benefit to MD patients.

新規アンドロゲン受容体阻害薬を用いた遠隔転移のない去勢抵抗性前立腺癌(MOCRPC)治療戦略のアップデート ARAMIS試験をはじめとした新規AR阻害薬第III相試験の最終解析結果を受けて

鈴木和浩, 上村博司, 鈴木啓悦, 樋之津史郎, 大家基嗣

泌尿器外科 ( 医学図書出版(株) ) 33 ( 11 ) 1451 - 1459 2020.11

近年、前立腺癌治療薬として新規アンドロゲン受容体(AR)阻害薬が登場し、遠隔転移のない去勢抵抗性前立腺癌(M0CRPC)の薬物療法においても、AR阻害薬であるダロルタミド、アパルタミド、エンザルタミドが中心的な役割を担いつつある。さらに2020年5月に開催されたAmerican Society of Clinical Oncology(ASCO)の年次学術集会において、これら3剤の第III相試験の最終解析結果が同時に発表され、すべての薬剤でプラセボ+アンドロゲン遮断療法(ADT)と比較して全生存期間の有意な延長が示されたことで、M0CRPCの治療戦略の変化がさらに加速することが想定される。本稿では、新規AR阻害薬の中でも最も新しいダロルタミドに焦点を当て、第III相試験の最終結果や実臨床に及ぼす影響などについて考察する。(著者抄録)

Effect of neoadjuvant chemotherapy on health-related quality of life in patients with muscle-invasive bladder cancer: results from JCOG0209, a randomized phase III study.

Hiroshi Kitamura, Shiro Hinotsu, Taiji Tsukamoto, Taro Shibata, Junki Mizusawa, Takashi Kobayashi, Makito Miyake, Naotaka Nishiyama, Takahiro Kojima, Hiroyuki Nishiyama

Japanese journal of clinical oncology 2020.07 [Refereed] [International journal]

BACKGROUND: Although neoadjuvant chemotherapy provides survival benefits in muscle-invasive bladder cancer, the impact of neoadjuvant chemotherapy on health-related quality of life has not been investigated by a randomized trial. The purpose of this study is to compare health-related quality of life in patients with muscle-invasive bladder cancer who received neoadjuvant chemotherapy followed by radical cystectomy or radical cystectomy alone based on patient-reported outcome data. METHODS: Patients were randomized to receive two cycles of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin followed by radical cystectomy or radical cystectomy alone. Health-related quality of life was measured using the Functional Assessment of Cancer Therapy-Bladder (version 4) questionnaire before the protocol treatments, after neoadjuvant chemotherapy, after radical cystectomy and 1 year after registration. RESULTS: A total of 99 patients were analysed. No statistically significant differences in postoperative health-related quality of life were found between the arms. In the neoadjuvant chemotherapy arm, the scores after neoadjuvant chemotherapy were significantly lower than the baseline scores in physical well-being, functional well-being, Functional Assessment of Cancer Therapy-General total, weight loss, diarrhoea, appetite, body appearance, embarrassment by ostomy appliance and total Functional Assessment of Cancer Therapy-Bladder. However, there was no difference in scores for these domains, except for embarrassment by ostomy appliance, between the two arms after radical cystectomy and 1 year after registration. CONCLUSIONS: Although health-related quality of life declined during neoadjuvant chemotherapy, no negative effect of neoadjuvant chemotherapy on health-related quality of life was apparent after radical cystectomy. These data support the view that neoadjuvant chemotherapy can be considered as a standard of care for patients with muscle-invasive bladder cancer regarding health-related quality of life.

Clinical Practice Guidelines for Bladder Cancer 2019 update by the Japanese Urological Association: Summary of the revision.

Hiroaki Matsumoto, Koji Shiraishi, Haruhito Azuma, Keiji Inoue, Hirotsugu Uemura, Masatoshi Eto, Chikara Ohyama, Osamu Ogawa, Eiji Kikuchi, Hiroshi Kitamura, Nobuo Shinohara, Satoru Takahashi, Toyonori Tsuzuki, Masayuki Nakagawa, Yoshifumi Narumi, Hiroyuki Nishiyama, Tomonori Habuchi, Shiro Hinotsu, Yasuhisa Fujii, Kiyohide Fujimoto, Hiroyuki Fujimoto, Takashi Mizowaki, Hideyasu Matsuyama

International journal of urology : official journal of the Japanese Urological Association 27 ( 9 ) 702 - 709 2020.06 [International journal]

OBJECTIVES: Despite just a 4-year interval from the last version (2015) of the Clinical Practice Guidelines for Bladder Cancer, several dramatic paradigm shifts have occurred in the latest clinical practice regarding both the diagnosis and treatment of bladder cancer. Herein, we updated the 2019 version of the Clinical Practice Guidelines for Bladder Cancer under the instruction of the Japanese Urological Association. METHODS: We previously reported in a revision working position paper for Clinical Practice Guidelines for Bladder Cancer 2019 edition and described the methods of revision detail. RESULTS: The major points of change in the 2019 version are presented and explanations are given as follows: (i) introduction of the new reference assessment system; (ii) modification of the risk classification for non-muscle-invasive bladder cancer; (iii) addition of clinical questions for the new tumor-visible techniques in non-muscle-invasive bladder cancer; (iv) inclusion of minimally invasive surgeries for muscle-invasive bladder cancer and immune checkpoint inhibitors for locally advanced/metastatic muscle-invasive bladder cancer; (v) overview chapter of the histological variant of urothelial cancer and rare cancers of the bladder; and (vi) recommendation of follow up in non-muscle-invasive bladder cancer and muscle-invasive bladder cancer. CONCLUSIONS: Guidelines should be updated based on the current evidence and updates carried out without delay. The hope is that this guidelines will be assessed by many urologists and will be the cornerstone for the next revision.

Risk for intravesical recurrence of bladder cancer stratified by the results on two consecutive UroVysion fluorescence in situ hybridization tests: a prospective follow-up study in Japan.

Atsushi Ikeda, Takahiro Kojima, Koji Kawai, Shiro Hinotsu, Naoto Keino, Kenichiro Shiga, Hideaki Miyake, Yasuyoshi Miyata, Yutaka Enomoto, Fumitaka Shimizu, Satoshi Anai, Hideyasu Matsuyama, Chieko Suzuki, Yusuke Kanimoto, Keisuke Shigeta, Seiji Naito, Hideyuki Akaza, Hiroyuki Nishiyama

International journal of clinical oncology 25 ( 6 ) 1163 - 1169 2020.06 [Domestic journal]

BACKGROUND: A previous comparative study in Japan has demonstrated that the two consecutive UroVysion tests are useful tools to detect the presence of bladder cancer during follow-up after transurethral resection, but they also presented their high rates of false-positive results. Here, we aimed to evaluate the relationship between the UroVysion tests and subsequent intravesical recurrence. METHODS: In the previous study, patients without bladder cancer during the first analysis showed the same examination set repeated 3 months later as the second analysis. In this follow-up study, 326 patients showed negative findings confirmed on cystoscopy during the second UroVysion test. Recurrence-free survival was assessed using a median follow-up of 27 months. RESULTS: In the two consecutive UroVysion tests, 214 patients (65.6%) showed negative UroVysion results in both tests, whereas 91 presented a positive result on either tests and 21 patients presented positive results in both tests. During the follow-up, 40 patients (12.3%) had an intravesical recurrence with non-muscle-invasive bladder cancer. The recurrence rates in patients with negative results in both tests, those with one positive result in either tests, and those with positive results in both tests were 8.4%, 16.5%, and 33.3%, respectively. The multivariate analysis indicated that the history of bladder cancer and the consecutive UroVysion test pattern were independent risk factors for recurrence. CONCLUSIONS: Our data confirmed the effectiveness of two consecutive UroVysion tests in predicting intravesical recurrence after TURBT. Further prospective studies would help determine an appropriate interval for cystoscopy follow-up.

Clinical Practice Guidelines for Bladder Cancer 2019 edition by the Japanese Urological Association: Revision working position paper.

Hiroaki Matsumoto, Koji Shiraishi, Haruhito Azuma, Keiji Inoue, Hirotsugu Uemura, Masatoshi Eto, Chikara Ohyama, Osamu Ogawa, Eiji Kikuchi, Hiroshi Kitamura, Nobuo Shinohara, Satoru Takahashi, Toyonori Tsuzuki, Masayuki Nakagawa, Yoshifumi Narumi, Hiroyuki Nishiyama, Tomonori Habuchi, Shiro Hinotsu, Yasuhisa Fujii, Kiyohide Fujimoto, Hiroyuki Fujimoto, Takashi Mizowaki, Hideyasu Matsuyama

International journal of urology : official journal of the Japanese Urological Association 27 ( 5 ) 362 - 368 2020.05 [International journal]

The Clinical Practice Guidelines for Bladder Cancer edited by the Japanese Urological Association were first published in 2009 and a revised edition was released in 2015. Four years has passed since the 2015 edition, and the clinical practice environment surrounding bladder cancer has drastically changed during that time. The main changes include: (i) insurance coverage of a new diagnostic method for non-muscle-invasive bladder cancer; (ii) insurance coverage of an immune checkpoint inhibitor in advanced and metastatic bladder cancer; and (iii) advances in robot-assisted radical cystectomy as a minimally invasive treatment for muscle-invasive bladder cancer. A paradigm shift in bladder cancer diagnosis and treatment is occurring day by day. Therefore, in this 2019 edition, while dealing with the above changes, we carefully selected clinical questions with clear evidence and included other clinically important points in the general statement. We also added a new chapter on rare cancers of the urinary tract. As a new method for the evaluation of study evidence level, we introduce "The Grading of Recommendations Assessment, Development and Evaluation" system modified to Japanese by the Medical Information Network Distribution Service.

Family history in primary hormone therapy for prostate cancer: Analysis from a community-based multi-institutional Japan-wide database.

Masaki Shiota, Mizuki Onozawa, Shiro Hinotsu, Masatoshi Eto, Seiji Naito, Hideyuki Akaza

International journal of urology : official journal of the Japanese Urological Association 27 ( 4 ) 313 - 318 2020.04 [International journal]

OBJECTIVES: To determine the association between hormone therapy and outcomes in a cohort of prostate cancer patients with a family history of prostate cancer. METHODS: Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 13 346 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival and overall survival, were compared between men with familial and men with sporadic prostate cancer. RESULTS: A positive family history was identified in 220 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a possible favorable prognostic factor for overall survival among patients with a prostate-specific antigen level at diagnosis <100 ng/mL and those with low or intermediate Japan Cancer of the Prostate Risk Assessment. CONCLUSIONS: Our findings show that familial prostate cancer has an early-onset feature or is diagnosed earlier than sporadic prostate cancer. However, the prognosis of individuals with familial prostate cancer undergoing hormone therapy is comparable to those with sporadic prostate cancer.

Antibiotic prescriptions for Japanese outpatients with acute respiratory tract infections (2013-2015): A retrospective Observational Study.

Toshihiro Koyama, Hideharu Hagiya, Yusuke Teratani, Yasuhisa Tatebe, Ayako Ohshima, Mayu Adachi, Tomoko Funahashi, Yoshito Zamami, Hiroyoshi Y Tanaka, Ken Tasaka, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 2020.03 [Refereed] [International journal]

OBJECTIVES: Appropriate antibiotic prescriptions for outpatients with acute respiratory tract infections (ARTIs) are urgently needed in Japan. However, the empirical proof of this need is under-documented. Therefore, we aimed to determine antibiotic prescription rates, and the proportions of antibiotic classes prescribed for Japanese patients with ARTIs. METHODS: We analysed health insurance claims data over 2013-2015 among Japanese patients aged <75 years and determined the following indicators: 1) visit rates for patients with ARTIs and antibiotic prescription rates per 1000 person-years, and 2) proportion of visits by antibiotic-prescribed patients with ARTIs. We defined broad-spectrum antibiotics using the WHO Anatomical Therapeutic Chemical classification 4 level codes. RESULTS: Among 8.65 million visits due to ARTIs at 6859 hospitals and 62,024 physicians' offices, the visit rate and antibiotic prescription rate per 1000 person-years were 990.6 (99% confidence interval [CI], 989.4-991.7) and 532.4 (99% CI, 531.6-533.3), respectively. The visit rates for patients aged 0-17, 18-59, and 60-74 years were 2410.0 (99% CI, 2407.2-2412.9), 683.6 (99% CI, 682.7-684.6), and 682.1 (99% CI, 678.2-686.0), and antibiotic prescription rates were 1093.3 (99% CI, 1091.4-1095.2), 434.1 (99% CI, 433.4-434.9), and 353.4 (99% CI, 350.7-356.1), respectively. The overall proportion of antibiotic prescriptions for ARTI visits was 52.7% and 91.3% of the antibiotics prescribed were broad-spectrum. CONCLUSIONS: Both the visit rates and antibiotic prescription rates for ARTIs were high in this Japanese cohort. The proportion of antibiotic prescriptions exceeded that recommended in the clinical guidelines. Thus, there might be a scope for reducing the current antibiotic prescription rate in Japan.

Efficacy and safety of scheduled early endoscopic ultrasonography-guided ethanol reinjection for patients with pancreatic neuroendocrine tumors: Prospective pilot study.

Kazuyuki Matsumoto, Hironari Kato, Seiji Kawano, Hiroyasu Fujiwara, Kenji Nishida, Ryo Harada, Masakuni Fujii, Ryuichi Yoshida, Yuzo Umeda, Shiro Hinotsu, Takahito Yagi, Hiroyuki Okada

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 32 ( 3 ) 425 - 430 2020.03 [International journal]

Endoscopic ultrasonography (EUS)-guided ethanol injection was recently proposed for treatment of patients with small pancreatic neuroendocrine tumors (p-NET); however, tips on how to carry out safe and effective procedures are unclear. We launched a pilot study for scheduled early EUS-guided ethanol reinjection for small p-NET. Major eligibility criteria were presence of pathologically diagnosed grade (G) 1 or G2, tumor size ≤2 cm and being a poor or rejected candidate for surgery. For the treatment, we used a 25-gauge needle and pure ethanol. Contrast-enhanced computed tomography (CE-CT) was carried out on postoperative day 3, and if enhanced areas of the tumor were still apparent, an additional session was scheduled during the same hospitalization period. Primary endpoint was complete ablation rate at 1 month after treatment, and secondary endpoint was procedure-related adverse events. A total of five patients were treated. Median size of the tumor was 10 (range: 7-14) mm. Of the five patients, three underwent an additional session. Median volume of ethanol injection per session was 0.8 (range: 0.3-1.0) mL, and the total was 1.0 (0.9-1.8) mL. Complete ablation was achieved in four of the five tumors (80%) with no adverse events. During 1 year of follow up, none of the patients reported any procedure-related adverse events, and no recurrence of tumor. Scheduled early EUS-guided ethanol reinjection appears to be safe and effective for treating small p-NET (UMIN number: 000018834).

日本における副作用に起因した死亡率の傾向に関する全国規模の観察研究

船橋智子, 小山敏広, 萩谷英大, 原田洸, 寺谷祐亮, 座間味義人, 建部泰尚, 三上奈緒子, 大島礼子, 四宮一昭, 北村佳久, 千堂年昭, 樋之津史郎, 狩野光伸

日本薬学会年会要旨集 ( (公社)日本薬学会 ) 140年会 28X - am11 2020.03

Trends in Place of Death in a Super-Aged Society: A Population-Based Study, 1998-2017.

Toshihiro Koyama, Hideharu Hagiya, Tomoko Funahashi, Yoshito Zamami, Miyu Yamagishi, Hiroshi Onoue, Yusuke Teratani, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

Journal of palliative medicine 23 ( 7 ) 950 - 956 2020.02 [Refereed] [International journal]

Background: Globally, the number of deaths is estimated to increase to 74 million per year by 2030. Place of death (PoD) is increasingly being recognized as an important aspect of end-of-life care. However, recent trends in PoD in Japan, one of the super-aged societies, are unknown. Objective: To analyze trends in PoD in Japan over two decades. Design: Population-based retrospective observational study. Setting: All deaths reported in Japan, 1998-2017. PoD was defined as hospital, nursing home, or own home. Results: All Japanese decedents (∼22.6 million) over the past 20 years were analyzed. The proportion of hospital deaths was consistently high (>80%), with a significant decreasing trend from the mid-2000s. Although the proportion of deaths at home decreased in the first half of the study period, they later increased. There was a low proportion of deaths in nursing homes compared to other places of death; however, the proportion increased continually throughout the study period, particularly among women. In 2015, more women died in nursing homes than at home. Although the proportion of hospital deaths declined in the second half of the study period, their overall number continued to increase, reflecting an increase in total deaths in Japan. Conclusions: This study highlighted rapid changes in trends in PoD in Japan, and the need to consider affordable end-of-life care in Japan as well as other countries with aging populations. The findings from this long-term epidemiological study provide important insights on this issue.

Place of death trends among patients with dementia in Japan: a population-based observational study.

Toshihiro Koyama, Misato Sasaki, Hideharu Hagiya, Yoshito Zamami, Tomoko Funahashi, Ayako Ohshima, Yasuhisa Tatebe, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

Scientific reports 9 ( 1 ) 20235 - 20235 2019.12 [Refereed] [International journal]

Dementia is a major public health concern in ageing societies. Although the population of Japan is among the most aged worldwide, long-term trends in the place of death (PoD) among patients with dementia is unknown. In this Japanese nationwide observational study, we analysed trends in PoD using the data of patients with dementia who were aged ≥65 years and died during 1999-2016. Trends in the crude death rates and PoD frequencies were analysed using the Joinpoint regression model. Changes in these trends were assessed using the Joinpoint regression analysis in which significant change points, the annual percentage change (APC) and average APCs (AAPC) in hospitals, homes, or nursing homes were estimated. During 1999-2016, the number of deaths among patients with dementia increased from 3,235 to 23,757 (total: 182,000). A trend analysis revealed increased mortality rates, with an AAPC of 8.2% among men and 9.3% among women. Most patients with dementia died in the hospital, although the prevalence of hospital deaths decreased (AAPC: -1.0%). Moreover, the prevalence of nursing home deaths increased (AAPC: 5.6%), whereas the prevalence of home deaths decreased (AAPC: -5.8%). These findings support a reconsideration of the end-of-life care provided to patients with dementia.

Fall-related mortality trends in older Japanese adults aged ≥65 years: a nationwide observational study.

Hideharu Hagiya, Toshihiro Koyama, Yoshito Zamami, Yasuhisa Tatebe, Tomoko Funahashi, Kazuaki Shinomiya, Yoshihisa Kitamura, Shiro Hinotsu, Toshiaki Sendo, Hiromi Rakugi, Mitsunobu R Kano

BMJ open 9 ( 12 ) e033462 2019.12 [Refereed] [International journal]

OBJECTIVES: Fall-related mortality among older adults is a major public health issue, especially for ageing societies. This study aimed to investigate current trends in fall-related mortality in Japan using nationwide population-based data covering 1997-2016. DESIGN: We analysed fall-related deaths among older persons aged ≥65 years using the data provided by the Japanese Ministry of Health, Labour and Welfare. RESULTS: The crude and age-standardised mortality rates were calculated per 100 000 persons by stratifying by age (65-74, 75-84 and ≥85 years) and sex. To identify trend changes, a joinpoint regression model was applied by estimating change points and annual percentage change (APC). The total number of fall-related deaths in Japan increased from 5872 in 1997 to 8030 in 2016, of which 78.8% involved persons aged ≥65 years. The younger population (65-74 years) showed continuous and faster-decreasing trends for both men and women. Average APC among men aged ≥75 years did not decrease. Among middle-aged and older women (75-84 and ≥85 years) decreasing trends were observed. Furthermore, the age-adjusted mortality rate of men was approximately twice that of women, and it showed a faster decrease for women. CONCLUSIONS: Although Japanese healthcare has shown improvement in preventing fall-related deaths over the last two decades, the crude mortality for those aged over 85 years remains high, indicating difficulty in reducing fall-related deaths in the super-aged population. Further investigations to uncover causal factors for falls in older populations are required.

Considering bone health in the treatment of prostate cancer bone metastasis based on the results of the ERA-223 trial.

Atsushi Mizokami, Go Kimura, Yasuhisa Fujii, Shiro Hinotsu, Kouji Izumi

International journal of clinical oncology 24 ( 12 ) 1629 - 1631 2019.12 [Refereed] [Domestic journal]

Oral anticoagulants usage in Japanese patients aged 18-74 years with non-valvular atrial fibrillation: a retrospective analysis based on insurance claims data.

Ayako Ohshima, Toshihiro Koyama, Aiko Ogawa, Yoshito Zamami, Hiroyoshi Y Tanaka, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Michael W Miller, Mitsunobu R Kano

Family practice 36 ( 6 ) 685 - 692 2019.11 [Refereed] [International journal]

BACKGROUND: Oral anticoagulants use has increased rapidly, internationally. Here we look at risks and benefits, based on Japanese data, of therapy with low risk non-valvular atrial fibrillation patients. OBJECTIVES: Using a health insurance claims data set we assessed: (i) oral anticoagulants usage in Japan, and (ii) efficacy and safety of dabigatran compared with warfarin, in Japanese patients with non-valvular atrial fibrillation, aged 18-74 years. METHODS: We identified 4380 non-valvular atrial fibrillation patients treated with anticoagulants between 1 January 2005, and 28 February 2014, and estimated the adjusted hazard ratio for stroke or systemic embolism, and any hemorrhagic event (Cox proportional hazards regression model with stabilized inverse probability treatment weighting). RESULTS: The data included 101 989 anticoagulant prescriptions for 4380 patients, of which direct oral anticoagulants increased to 40.0% of the total by the end of the study. After applying exclusion criteria, 1536 new non-valvular atrial fibrillation patients were identified, including 1071 treated with warfarin and 465 with dabigatran. Mean ages were 56.11 ± 9.70 years for warfarin, and 55.80 ± 9.65 years for dabigatran. The adjusted hazard ratio (95% confidence interval), comparing dabigatran with warfarin, was 0.48 (0.25-0.91) for stroke or systemic embolism, and 0.91 (0.60-1.39) for any hemorrhage including intracranial and gastrointestinal. CONCLUSIONS: Number of patients prescribed direct oral anticoagulants steadily increased, and incidence of all-cause bleeding related to dabigatran was similar to warfarin, in our study population of younger non-valvular atrial fibrillation patients. Dabigatran, compared with warfarin, generally reduced risk of all-cause stroke and systemic embolism.

A randomised controlled trial of a case management approach to encourage participation in colorectal cancer screening for people with schizophrenia in psychiatric outpatient clinics: study protocol for the J-SUPPORT 1901 (ACCESS) study.

Masaki Fujiwara, Masatoshi Inagaki, Taichi Shimazu, Masafumi Kodama, Ryuhei So, Takanori Matsushita, Yusaku Yoshimura, Shigeo Horii, Maiko Fujimori, Hirokazu Takahashi, Naoki Nakaya, Kyoko Kakeda, Tempei Miyaji, Shiro Hinotsu, Keita Harada, Hiroyuki Okada, Yosuke Uchitomi, Norihito Yamada

BMJ open 9 ( 11 ) e032955 2019.11 [Refereed] [International journal]

INTRODUCTION: One of the reasons for the high mortality rate from cancer in people with schizophrenia is delay in diagnosis. Many studies have shown lower cancer screening rates in people with schizophrenia; however, there are no interventions for people with schizophrenia to increase cancer screening. Therefore, we developed a case management (CM) intervention to encourage participation in cancer screening. The purpose of this study was to examine the efficacy of CM to encourage participation in cancer screening for people with schizophrenia, with particular focus on colorectal cancer screening by faecal occult blood testing, compared with usual intervention (UI), namely, municipal public education. METHODS AND ANALYSIS: This is an individually randomised, parallel group trial with blinded outcome assessments. The participants will be randomly allocated to either the CM plus UI group or UI alone group in a 1:1 ratio using a web-based program at a data management centre. The primary end point of the study is participation in colorectal cancer screening in the year of intervention, which will be assessed based on municipal records. ETHICS AND DISSEMINATION: This study is performed in accordance with Ethical Guidelines for Medical and Health Research Involving Human Subjects published by Japan's Ministry of Education, Science, and Technology and the Ministry of Health, Labour, and Welfare and the modified Act on the Protection of Personal Information as well as the Declaration of Helsinki. This study was approved by the institutional ethics committee at the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences and Okayama University Hospital on 23 April 2019 (approval number: RIN1904-003). The findings of this trial will be submitted to an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000036017.

A randomised controlled trial of a case management approach to encourage participation in colorectal cancer screening for people with schizophrenia in psychiatric outpatient clinics: Study protocol for the J-SUPPORT 1901 (ACCESS) study

Masaki Fujiwara, Masatoshi Inagaki, Taichi Shimazu, Masafumi Kodama, Ryuhei So, Takanori Matsushita, Yusaku Yoshimura, Shigeo Horii, Maiko Fujimori, Hirokazu Takahashi, Naoki Nakaya, Kyoko Kakeda, Tempei Miyaji, Shiro Hinotsu, Keita Harada, Hiroyuki Okada, Yosuke Uchitomi, Norihito Yamada

BMJ Open 9 ( 11 ) 2019.11 [Refereed]

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Introduction One of the reasons for the high mortality rate from cancer in people with schizophrenia is delay in diagnosis. Many studies have shown lower cancer screening rates in people with schizophrenia; however, there are no interventions for people with schizophrenia to increase cancer screening. Therefore, we developed a case management (CM) intervention to encourage participation in cancer screening. The purpose of this study was to examine the efficacy of CM to encourage participation in cancer screening for people with schizophrenia, with particular focus on colorectal cancer screening by faecal occult blood testing, compared with usual intervention (UI), namely, municipal public education. Methods and analysis This is an individually randomised, parallel group trial with blinded outcome assessments. The participants will be randomly allocated to either the CM plus UI group or UI alone group in a 1:1 ratio using a web-based program at a data management centre. The primary end point of the study is participation in colorectal cancer screening in the year of intervention, which will be assessed based on municipal records. Ethics and dissemination This study is performed in accordance with Ethical Guidelines for Medical and Health Research Involving Human Subjects published by Japan's Ministry of Education, Science, and Technology and the Ministry of Health, Labour, and Welfare and the modified Act on the Protection of Personal Information as well as the Declaration of Helsinki. This study was approved by the institutional ethics committee at the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences and Okayama University Hospital on 23 April 2019 (approval number: RIN1904-003). The findings of this trial will be submitted to an international peer-reviewed journal. Trial registration number UMIN000036017.

A randomised controlled trial of a case management approach to encourage participation in colorectal cancer screening for people with schizophrenia in psychiatric outpatient clinics: study protocol for the J-SUPPORT 1901 (ACCESS) study

Masaki Fujiwara, Masatoshi Inagaki, Taichi Shimazu, Masafumi Kodama, Ryuhei So, Takanori Matsushita, Yusaku Yoshimura, Shigeo Horii, Maiko Fujimori, Hirokazu Takahashi, Naoki Nakaya, Kyoko Kakeda, Tempei Miyaji, Shiro Hinotsu, Keita Harada, Hiroyuki Okada, Yosuke Uchitomi, Norihito Yamada

BMJ OPEN ( BMJ PUBLISHING GROUP ) 9 ( 11 ) 2019.11 [Refereed]

Introduction One of the reasons for the high mortality rate from cancer in people with schizophrenia is delay in diagnosis. Many studies have shown lower cancer screening rates in people with schizophrenia; however, there are no interventions for people with schizophrenia to increase cancer screening. Therefore, we developed a case management (CM) intervention to encourage participation in cancer screening. The purpose of this study was to examine the efficacy of CM to encourage participation in cancer screening for people with schizophrenia, with particular focus on colorectal cancer screening by faecal occult blood testing, compared with usual intervention (UI), namely, municipal public education.Methods and analysis This is an individually randomised, parallel group trial with blinded outcome assessments. The participants will be randomly allocated to either the CM plus UI group or UI alone group in a 1:1 ratio using a web-based program at a data management centre. The primary end point of the study is participation in colorectal cancer screening in the year of intervention, which will be assessed based on municipal records.

膵頭十二指腸切除術患者におけるenhanced recovery after surgeryプロトコールの有効性について前向きランダム化比較試験(Effect of an enhanced recovery after surgery protocol in patients undergoing pancreaticoduodenectomy: A randomized controlled trial)

高木弘誠, 吉田龍一, 八木孝仁, 楳田祐三, 信岡大輔, 杭瀬崇, 樋之津史郎, 松崎孝, 森松博史, 江口潤, 和田淳, 千田益生, 藤原俊義

学会誌JSPEN ( (一社)日本臨床栄養代謝学会 ) 1 ( Suppl. ) 15 - 15 2019.09

Pattern of antibiotic prescriptions for outpatients with acute respiratory tract infections in Japan, 2013-15: A retrospective observational study

Yusuke Teratani, Hideharu Hagiya, Toshihiro Koyama, Mayu Adachi, Ayako Ohshima, Yoshito Zamami, Hiroyoshi Y. Tanaka, Yasuhisa Tatebe, Ken Tasaka, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Mitsunobu R. Kano, Shiro Hinotsu, Toshiaki Sendo

Family Practice 36 ( 4 ) 402 - 409 2019.08 [Refereed]

© 2018 The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Background: In this age of antimicrobial resistance, unnecessary use of antibiotics to treat non-bacterial acute respiratory tract infections (ARTIs) and inappropriate use of antibiotics in treating bacterial ARTIs are public health concerns. Purpose: Our aim is to identify the pattern of oral antibiotic prescriptions for outpatients with ARTIs in Japan. Methods: We analysed health insurance claims data of patients (aged ≤74 years) from 2013 to 2015, to determine the pattern of antibiotic prescriptions for outpatient ARTIs and calculated the proportion of each antibiotic. Results: Data on 4.6 million antibiotic prescriptions among 1559394 outpatients with ARTIs were analysed. The most commonly prescribed classes of antibiotics included cephalosporins (41.9%), macrolides (32.8%) and fluoroquinolones (14.7%). The proportion of first-, second- and third-generation cephalosporins was 1.0%, 1.7% and 97.3%, respectively. Fluoroquinolones accounted for a quarter of the prescriptions for ARTIs in patients aged >20 years. In contrast, penicillins accounted for just 8.0% of the total number of antibiotic prescriptions for ARTIs. Conclusions: According to clinical guidelines, penicillins are first-line antibiotics against ARTIs. However, third-generation cephalosporins, macrolides and fluoroquinolones are more frequently prescribed in Japan. Although we could not assess the extent to which appropriate antibiotics are selected, our results support the necessity of improving antibiotic choices in the treatment of ARTIs.

Hypoglycemia associated with pivalate-conjugated antibiotics in young children: A retrospective study using a medical and pharmacy claims database in Japan.

Tatebe Y, Koyama T, Mikami N, Kitamura Y, Sendo T, Hinotsu S

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 26 ( 1 ) 86 - 91 2019.08 [Refereed] [International journal]

INTRODUCTION: Acute bacterial infectious diseases are major causes for outpatient visits for young children. Pivalate-conjugated antibiotics (PCAs) are frequently prescribed for these situations in Japan, while several literatures have shown a potential risk of hypoglycemia associated with PCAs. This study aimed to evaluate the incidence of PCA-induced hypoglycemia in children, compared with other oral beta-lactam antibiotics. METHODS: This retrospective cohort study using a Japanese medical and pharmacy claims database was performed on children aged 1 month to 5 years old with at least once prescription of PCAs or other oral beta-lactam antibiotics from January 2011 to December 2013. Hypoglycemia was defined based on diagnostic codes or the prescription of 10% or 20% glucose injection. We examined the prevalence of hypoglycemic events and performed multivariate analysis to investigate the risk of hypoglycemia with PCAs compared with the control oral beta-lactam antibiotics. RESULTS: We identified 179,594 eligible patients in this population. In the PCA and control groups, there were 454,153 and 417,287 prescriptions and 3356 (0.74%, 95% confidence intervals [CI] 0.71-0.76) and 2605 (0.62%, 95% CI 0.60-0.65) hypoglycemic events, respectively. Multivariate analysis revealed that PCAs were associated with hypoglycemia (adjusted odds ratios [OR] 1.18, 95% CI 1.12-1.24), and even a shorter duration of PCAs prescribing (≤7 days) was significantly associated with hypoglycemia (adjusted OR 1.17, 95% CI 1.11-1.24). CONCLUSION: These results suggest that in young children PCA use, even for a short period, is a risk factor of hypoglycemia.

Pattern of antibiotic prescriptions for outpatients with acute respiratory tract infections in Japan, 2013-15: a retrospective observational study.

Yusuke Teratani, Hideharu Hagiya, Toshihiro Koyama, Mayu Adachi, Ayako Ohshima, Yoshito Zamami, Hiroyoshi Y Tanaka, Yasuhisa Tatebe, Ken Tasaka, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Mitsunobu R Kano, Shiro Hinotsu, Toshiaki Sendo

Family practice 36 ( 4 ) 402 - 409 2019.07 [Refereed] [International journal]

BACKGROUND: In this age of antimicrobial resistance, unnecessary use of antibiotics to treat non-bacterial acute respiratory tract infections (ARTIs) and inappropriate use of antibiotics in treating bacterial ARTIs are public health concerns. PURPOSE: Our aim is to identify the pattern of oral antibiotic prescriptions for outpatients with ARTIs in Japan. METHODS: We analysed health insurance claims data of patients (aged ≤74 years) from 2013 to 2015, to determine the pattern of antibiotic prescriptions for outpatient ARTIs and calculated the proportion of each antibiotic. RESULTS: Data on 4.6 million antibiotic prescriptions among 1559394 outpatients with ARTIs were analysed. The most commonly prescribed classes of antibiotics included cephalosporins (41.9%), macrolides (32.8%) and fluoroquinolones (14.7%). The proportion of first-, second- and third-generation cephalosporins was 1.0%, 1.7% and 97.3%, respectively. Fluoroquinolones accounted for a quarter of the prescriptions for ARTIs in patients aged >20 years. In contrast, penicillins accounted for just 8.0% of the total number of antibiotic prescriptions for ARTIs. CONCLUSIONS: According to clinical guidelines, penicillins are first-line antibiotics against ARTIs. However, third-generation cephalosporins, macrolides and fluoroquinolones are more frequently prescribed in Japan. Although we could not assess the extent to which appropriate antibiotics are selected, our results support the necessity of improving antibiotic choices in the treatment of ARTIs.

Report of the third Asian Prostate Cancer study meeting.

Lojanapiwat B, Lee JY, Gang Z, Kim CS, Fai NC, Hakim L, Umbas R, Ong TA, Lim J, Letran JL, Chiong E, Lee SH, Türkeri L, Murphy DG, Moretti K, Cooperberg M, Carlile R, Hinotsu S, Hirao Y, Kitamura T, Horie S, Onozawa M, Kitagawa Y, Namiki M, Fukagai T, Miyazaki J, Akaza H

Prostate international 7 ( 2 ) 60 - 67 2019.06 [Refereed] [International journal]

The Asian Prostate Cancer (A-CaP) study is an Asia-wide initiative that was launched in December 2015 in Tokyo, Japan, with the objective of surveying information about patients who have received a histopathological diagnosis of prostate cancer (PCa) and are undergoing treatment and clarifying distribution of staging, the actual status of treatment choices, and treatment outcomes. The study aims to clarify the clinical situation for PCa in Asia and use the outcomes for the purposes of international comparison. Following the first meeting in Tokyo in December 2015, the second A-CaP meeting was held in Seoul, Korea, in September 2016. This, the third A-CaP meeting, was held on October 14, 2017, in Chiang Mai, Thailand, with the participation of members and collaborators from 12 countries and regions. In the meeting, participating countries and regions presented the current status of data collection, and the A-CaP office presented a preliminary analysis of the registered cases received from each country and region. Participants discussed ongoing challenges relating to data input and collection, institutional, and legislative issues that may present barriers to data sharing, and the outlook for further patient registrations through to the end of the registration period in December 2018. In addition to A-CaP-specific discussions, a series of special lectures were also delivered on the situation for health insurance in the United States, the correlation between insurance coverage and PCa outcomes, and the outlook for robotic surgery in the Asia-Pacific region. Members also confirmed the principles of authorship in collaborative studies, with a view to publishing original articles based on A-CaP data in the future.

Association between rapid antigen detection tests and antibiotics for acute pharyngitis in Japan: A retrospective observational study.

Yusuke Teratani, Hideharu Hagiya, Toshihiro Koyama, Ayako Ohshima, Yoshito Zamami, Yasuhisa Tatebe, Ken Tasaka, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 25 ( 4 ) 267 - 272 2019.04 [Refereed] [International journal]

The application and clinical impact of rapid antigen detection test (RADT) in the treatment of acute pharyngitis is unknown in Japan. We aimed to examine the proportions of RADT usage to identify Group A β-hemolytic Streptococcus (GAS) in outpatients with acute pharyngitis and evaluate the association between RADT and antibiotic treatment. We analyzed health insurance claims data from 2013 to 2015. Logistic regression models were used to analyze associated factors with RADT, overall antibiotic prescription, or penicillin use. We analyzed 1.27 million outpatient visits with acute pharyngitis, in which antibiotics were prescribed in 59.3% of visits. Of the total visits, 5.6% of patients received RADT, and 10.8% of the antibiotics were penicillin. Penicillin selection rates were higher in cases with RADT (25.4%) than those without RADT (9.7%). Compared to large-scale facilities, antibiotic prescription rates were higher in physicians' offices. For factor analysis, age (3-15 years), diagnosis code (streptococcal pharyngitis), size of the medical facility (large-scale hospitals), and physician's specialty (pediatrics) were associated with RADT use. Penicillin selection rate increased with RADT implementation (25.4% vs. 9.7%: adjusted odds ratio 1.55; 95% CI, 1.50-1.60). At 63% of the facilities, the RADT implementation rate was <5% of acute pharyngitis visits prescribed antibiotics. In conclusion, the proportion of RADT usage for outpatients with acute pharyngitis was low in Japan. With appropriate indication and evaluation, we expect that more utilization of RADT can help promote antimicrobial stewardship for outpatients with acute pharyngitis by prompting penicillin therapy. Further investigation with detailed clinical data are warranted.

Search for Therapeutic Agents for Cardiac Arrest Using a Drug Discovery Tool and Large-Scale Medical Information Database.

Yoshito Zamami, Takahiro Niimura, Toshihiro Koyama, Yuta Shigemi, Yuki Izawa-Ishizawa, Mizuki Morita, Ayako Ohshima, Keisaku Harada, Toru Imai, Hiromi Hagiwara, Naoto Okada, Mitsuhiro Goda, Kenshi Takechi, Masayuki Chuma, Yutaka Kondo, Koichiro Tsuchiya, Shiro Hinotsu, Mitsunobu R Kano, Keisuke Ishizawa

Frontiers in pharmacology 10 1257 - 1257 2019 [Refereed] [International journal]

The survival rate of cardiac arrest patients is less than 10%; therefore, development of a therapeutic strategy that improves their prognosis is necessary. Herein, we searched data collected from medical facilities throughout Japan for drugs that improve the survival rate of cardiac arrest patients. Candidate drugs, which could improve the prognosis of cardiac arrest patients, were extracted using "TargetMine," a drug discovery tool. We investigated whether the candidate drugs were among the drugs administered within 1 month after cardiac arrest in data of cardiac arrest cases obtained from the Japan Medical Data Center. Logistic regression analysis was performed, with the explanatory variables being the presence or absence of the administration of those candidate drugs that were administered to ≥10 patients and the objective variable being the "survival discharge." Adjusted odds ratios for survival discharge were calculated using propensity scores for drugs that significantly improved the proportion of survival discharge; the influence of covariates, such as patient background, medical history, and treatment factors, was excluded by the inverse probability-of-treatment weighted method. Using the search strategy, we extracted 165 drugs with vasodilator activity as candidate drugs. Drugs not approved in Japan, oral medicines, and external medicines were excluded. Then, we investigated whether the candidate drugs were administered to the 2,227 cardiac arrest patients included in this study. The results of the logistic regression analysis showed that three (isosorbide dinitrate, nitroglycerin, and nicardipine) of seven drugs that were administered to ≥10 patients showed significant association with improvement in the proportion of survival discharge. Further analyses using propensity scores revealed that the adjusted odds ratios for survival discharge for patients administered isosorbide dinitrate, nitroglycerin, and nicardipine were 3.35, 5.44, and 4.58, respectively. Thus, it can be suggested that isosorbide dinitrate, nitroglycerin, and nicardipine could be novel therapeutic agents for improving the prognosis of cardiac arrest patients.

Trends in Polypharmacy in Japan: A Nationwide Retrospective Study.

Hiroshi Onoue, Toshihiro Koyama, Yoshito Zamami, Hideharu Hagiya, Yasuhisa Tatebe, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Shiro Hinotsu, Toshiaki Sendo, Yasuyoshi Ouchi, Mitsunobu R Kano

Journal of the American Geriatrics Society 66 ( 12 ) 2267 - 2273 2018.12 [Refereed] [International journal]

OBJECTIVES: To describe and examine trends in polypharmacy according to age in Japan from 2010 to 2016. DESIGN: Retrospective observational study. SETTING: Outpatient settings. PARTICIPANTS: Japanese individuals aged 20 and older. MEASUREMENTS: We analyzed pharmacy claims data that the Japanese Ministry of Health, Labor, and Welfare provided in the Survey of Medical Care Activities in Public Health Insurance from 2010 to 2016. The use of 5 or more oral prescription medications per month was defined as polypharmacy and of 10 or more as excessive polypharmacy. Regression analysis was used to estimate trends in polypharmacy with annual percentage changes. Using number of medications (polypharmacy vs excessive polypharmacy), trends in polypharmacy and crude and age-adjusted rates of polypharmacy per 1,000 persons were calculated according to year and age group (20-34, 35-49, 50-64, 65-79, ≥ 80). RESULTS: We analyzed 240 million pharmacy claims data. The age-adjusted monthly prevalence rate of polypharmacy increased from 85.2 to 93.8 per 1,000 persons per month and of excessive polypharmacy from 13.6 to 14.0 per 1,000 persons per month from 2010 to 2016 in the entire study population. The highest rate of polypharmacy (per 1,000 persons) was observed in 2016 in those aged 80 and older (326.8), followed by those aged 65 to 79 (167.3). The polypharmacy rate increased by 6.3% (95% confidence interval (CI)=4.0-8.7) per year from 2010 to 2012, then decreased by 0.7% (95% CI=-1.3-0.0) per year from 2012 to 2016. The rate of excessive polypharmacy increased by 4.5% (95% CI=1.1-8.0) per year from 2010 to 2013 and then decreased by 3.7% (95% CI=-6.7 to -0.6) per year from 2013 to 2016. CONCLUSION: The overall trend of polypharmacy in Japan increased during the study period, although the increase ceased in 2013 and then declined from 2013 to 2016. Policy changes in Japan might be responsible for some of the changes. J Am Geriatr Soc 66:2267-2273, 2018.

Trends in incidence and mortality of tuberculosis in Japan: a population-based study, 1997-2016.

H Hagiya, T Koyama, Yoshito Zamami, Y Minato, Y Tatebe, N Mikami, Y Teratani, A Ohshima, K Shinomiya, Y Kitamura, T Sendo, S Hinotsu, K Tomono, R M Kano

Epidemiology and infection 147 e38 2018.11 [Refereed] [International journal]

Japan is still a medium-burden tuberculosis (TB) country. We aimed to examine trends in newly notified active TB incidence and TB-related mortality in the last two decades in Japan. This is a population-based study using Japanese Vital Statistics and Japan Tuberculosis Surveillance from 1997 to 2016. We determined active TB incidence and mortality rates (per 100 000 population) by sex, age and disease categories. Joinpoint regression was applied to calculate the annual percentage change (APC) in age-adjusted mortality rates and to identify the years showing significant trend changes. Crude and age-adjusted incidence rates reduced from 33.9 to 13.9 and 37.3 to 11.3 per 100 000 population, respectively. Also, crude and age-adjusted mortality rates reduced from 2.2 to 1.5 and 2.8 to 1.0 per 100 000 population, respectively. Average APC in the incidence and mortality rates showed significant decline both in men (-6.2% and -5.4%, respectively) and women (-5.7% and -4.6%, respectively). Age-specific analysis demonstrated decreases in incidence and mortality rates for every age category, except for the incidence trend in the younger population. Although trends in active TB incidence and mortality rates in Japan have favourably decreased, the rate of decline is far from achieving TB elimination by 2035.

Combined androgen blockade achieved better oncological outcome in androgen deprivation therapy for prostate cancer: Analysis of community-based multi-institutional database across Japan using propensity score matching.

Onozawa M, Akaza H, Hinotsu S, Oya M, Ogawa O, Kitamura T, Suzuki K, Naito S, Namiki M, Nishimura K, Hirao Y, Tsukamoto T

Cancer medicine 7 ( 10 ) 4893 - 4902 2018.10 [Refereed] [International journal]

BACKGROUND: This study investigated how differences in the method of the first-line androgen deprivation therapy (ADT) affected the time to castration-resistant prostate cancer. METHODS: The Japan Study Group of Prostate Cancer compiled a nationwide community-based database on prostate cancer patients who underwent ADT. That database included 13 774 patients who were started on ADT by surgical or medical castration alone (monotherapy group, 5395 cases) or ADT in combination with a nonsteroidal anti-androgen (combined androgen blockade (CAB) group, 8379 cases). We used logistic regression analysis with background factors as independent factors to calculate propensity scores in regard to selection of CAB. Next, for 8826 cases of propensity score-matched patients, we compared the survival rates in the two groups. RESULTS: The CAB group showed a significantly better progression-free survival (PFS) rate (65.6% vs 59.6% at 5 years; median time to progression, 11.6 vs 7.1 years; hazard ratio in the CAB group: 0.78, with a 95% confidence interval of 0.72 to 0.84; P < 0.001). In subgroup analysis based on the background factors, the PFS rate was generally better in the CAB group in all risk subgroups except for those having significant risk factors. CONCLUSION: Propensity score matching analysis revealed the prolongation of PFS by CAB in prostate cancer patients without significant risk factors. It would possible to decide the type of the first-line ADT according to the prostate cancer risk.

Trends in Polypharmacy in Japan: A Nationwide Retrospective Study.

Onoue H, Koyama T, Zamami Y, Hagiya H, Tatebe Y, Mikami N, Shinomiya K, Kitamura Y, Hinotsu S, Sendo T, Ouchi Y, Kano MR

Journal of the American Geriatrics Society 2018.10 [Refereed]

NCCN Asia Consensus Statement prostate cancer.

Hinotsu S, Namiki M, Ozono S, Akaza H

Japanese journal of clinical oncology 2018.09 [Refereed]

Clinical evaluation of two consecutive UroVysion fluorescence in situ hybridization tests to detect intravesical recurrence of bladder cancer: a prospective blinded comparative study in Japan.

Kojima T, Nishiyama H, Ozono S, Hinotsu S, Keino N, Yamaguchi A, Sakai H, Enomoto Y, Horie S, Fujimoto K, Matsuyama H, Okamura T, Kanimoto Y, Oya M, Nonomura N, Naito S, Akaza H

International journal of clinical oncology 23 ( 6 ) 1140 - 1147 2018.07 [Refereed] [Domestic journal]

BACKGROUND: We evaluated the use of UroVysion fluorescence in situ hybridization tests to detect the intravesical recurrence of bladder cancer during follow-up after a transurethral resection of bladder tumor (TURBT). METHODS: In this prospective, blinded, comparative study, 486 patients treated by TURBT within the prior 2 years were registered at 12 centers. Urine cytology and UroVysion tests were performed once or twice at a central testing laboratory. For the patients with no suspicious findings of bladder cancer in the first analysis, the same examination set was repeated 3 months later as the second analysis. Totals of 468 and 399 patients were eligible for the first and second analyses, respectively. We determined the sensitivity and specificity of two consecutive UroVysion tests. RESULTS: Bladder cancers were identified in 44 patients at the first analysis. The UroVysion test had 50.0% (95% CI 35.2-64.8%) sensitivity and 72.4% (68.3-76.8%). Urine cytology had 4.5% (0.0-10.7%) sensitivity and 99.8% (99.3-100.0%) specificity. The concordant rate of the first and second UroVysion test results was 72% (kappa coefficient 0.157). Interestingly, the patients with two consecutive positive UroVysion test results had the highest cancer detection rate (14.8%), which is greater than those of the patients with a positive result in either (7.2%) or neither (1.2%) of the two tests at the 3-month follow-up. CONCLUSIONS: The UroVysion test provided higher sensitivity than urine cytology to detect bladder cancer during post-TURBT follow-up. Two consecutive UroVysion tests might be a better indicator to predict intravesical recurrence.

Decrease in Histidine-Rich Glycoprotein as a Novel Biomarker to Predict Sepsis Among Systemic Inflammatory Response Syndrome.

Kuroda K, Wake H, Mori S, Hinotsu S, Nishibori M, Morimatsu H

Critical care medicine 46 ( 4 ) 570 - 576 2018.04 [Refereed] [International journal]

OBJECTIVES: Many biomarkers for sepsis are used in clinical practice; however, few have become the standard. We measured plasma histidine-rich glycoprotein levels in patients with systemic inflammatory response syndrome. We compared histidine-rich glycoprotein, procalcitonin, and presepsin levels to assess their significance as biomarkers. DESIGN: Single-center, prospective, observational cohort study. SETTING: ICU at an university-affiliated hospital. PATIENTS: Seventy-nine ICU patients (70 with systemic inflammatory response syndrome and 9 without systemic inflammatory response syndrome) and 16 healthy volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We collected blood samples from patients within 24 hours of ICU admission. Histidine-rich glycoprotein levels were determined using enzyme-linked immunosorbent assay. The median histidine-rich glycoprotein level in healthy volunteers (n = 16) was 63.00 µg/mL (interquartile range, 51.53-66.21 µg/mL). Histidine-rich glycoprotein levels in systemic inflammatory response syndrome patients (n = 70; 28.72 µg/mL [15.74-41.46 µg/mL]) were lower than those in nonsystemic inflammatory response syndrome patients (n = 9; 38.64 µg/mL [30.26-51.81 µg/mL]; p = 0.049). Of 70 patients with systemic inflammatory response syndrome, 20 had sepsis. Histidine-rich glycoprotein levels were lower in septic patients than in noninfective systemic inflammatory response syndrome patients (8.71 µg/mL [6.72-15.74 µg/mL] vs 33.27 µg/mL [26.57-44.99 µg/mL]; p < 0.001) and were lower in nonsurvivors (n = 8) than in survivors (n = 62) of systemic inflammatory response syndrome (9.06 µg/mL [4.49-15.70 µg/mL] vs 31.78 µg/mL [18.57-42.11 µg/mL]; p < 0.001). Histidine-rich glycoprotein showed a high sensitivity and specificity for diagnosing sepsis. Receiver operating characteristic curve analysis for detecting sepsis within systemic inflammatory response syndrome patients showed that the area under the curve for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.97, 0.82, and 0.77, respectively. In addition, survival analysis in systemic inflammatory response syndrome patients revealed that the Harrell C-index for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.85, 0.65, and 0.87, respectively. CONCLUSIONS: Histidine-rich glycoprotein levels were low in patients with sepsis and were significantly related to mortality in systemic inflammatory response syndrome population. Furthermore, as a biomarker, histidine-rich glycoprotein may be superior to procalcitonin and presepsin.

Background factors and short-term health-related quality of life in patients who initially underwent radical prostatectomy or androgen deprivation therapy for localized prostate cancer in a Japanese prospective observational study (J-CaP Innovative Study-1)

Satoru Ueno, Yasuhide Kitagawa, Mizuki Onozawa, Shiro Hinotsu, Hideyuki Akaza, Atsushi Mizokami, Mikio Namiki

Prostate International ( Elsevier B.V. ) 6 ( 1 ) 7 - 11 2018.03 [Refereed]

Background: This prospective observational study elucidated the usefulness of hormonal therapy for localized prostate cancer. Background factors and the health-related quality of life in patients who initially underwent radical prostatectomy (RP) or primary androgen deprivation therapy (PADT) for localized prostate cancer are summarized. Materials and methods: Patients aged 67–76 years with clinical stage T1c or T2 localized prostate cancer treated with PADT or RP, a prostate-specific antigen concentration of < 20 ng/mL, and Gleason score of ≤7 were included. Health-related quality of life results estimated by the Medical Outcomes Study 8-Item Short-Form Health Survey (SF-8) and the Expanded Prostate Cancer Index Composite (EPIC) were investigated. Results: In total, 850 patients who underwent RP and 370 patients who underwent PADT were enrolled. The proportion of patients with comorbidities of hypertension, cardiovascular disease, and/or cerebrovascular disease was greater in the PADT group than in the RP group. The proportion of patients deciding on treatment was significantly higher in the PADT group than in the RP group. In the RP group, the scores of many SF-8 and EPIC domains decreased at 3 months following surgery and returned to baseline levels at 1 year. In the PADT group, several domains gradually decreased during the year after treatment initiation. The proportion of patients with decreased satisfaction scores at 1 year compared with baseline was lower in the PADT group than that in the RP group. Conclusion: Treatment risk influenced decisions on primary treatment for localized prostate cancer. Although there was a selection bias, short-term overall satisfaction in the PADT group was superior to that in the RP group in this clinical study.

非弁膜症性心房細動患者における医療費に関する研究

大島礼子, 野村和喜, 小山敏弘, 座間味義人, 樋之津史郎, 狩野光伸

日本薬学会年会要旨集 ( (公社)日本薬学会 ) 138年会 ( 4 ) 185 - 185 2018.03 [Refereed]

A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non–Small Cell Lung Cancer

Katsuyuki Hotta, Keisuke Aoe, Toshiyuki Kozuki, Kadoaki Ohashi, Kiichiro Ninomiya, Eiki Ichihara, Toshio Kubo, Takashi Ninomiya, Kenichi Chikamori, Daijiro Harada, Naoyuki Nogami, Taizo Hirata, Shiro Hinotsu, Shinichi Toyooka, Katsuyuki Kiura

Journal of Thoracic Oncology ( Elsevier Inc ) 13 ( 2 ) 273 - 279 2018.02 [Refereed]

Trastuzumab emtansine (T-DM1), an anti–erb-b2 receptor tyrosine kinase 2 (HER2) antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry [IHC] score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years male sex, 47% performance status of 0 to 1, 80% HER2 status IHC 3+, 33% HER status IHC 2+/fluorescence in situ hybridization–positive, 20% and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1–11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2–32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging thus, additional molecular approaches are warranted.

Effect of an enhanced recovery after surgery protocol in patients undergoing pancreaticoduodenectomy: A randomized controlled trial.

Takagi K, Yoshida R, Yagi T, Umeda Y, Nobuoka D, Kuise T, Hinotsu S, Matsusaki T, Morimatsu H, Eguchi J, Wada J, Senda M, Fujiwara T

Clinical nutrition (Edinburgh, Scotland) 38 ( 1 ) 174 - 181 2018.01 [Refereed] [International journal]

BACKGROUND & AIMS: Evidence of the advantages of enhanced recovery after surgery (ERAS) protocols following pancreaticoduodenectomy (PD) is limited. The aim of this study was to examine the efficiency of ERAS protocols in patients following PD. METHODS: Between June 2014 and October 2016, patients undergoing PD were randomly assigned to receive ERAS protocols or standard care. The primary endpoint was the postoperative length of stay. Secondary endpoints included postoperative complications, postoperative quality-of-life (QoR-40J), readmission, and medical cost. RESULTS: Of 80 eligible patients, 74 were analyzed in intention-to-treat principles: 37 in the control group and 37 in the ERAS group. The mean length of stay in the ERAS group was significantly shorter than that in the control group (20.1 ± 5.4 vs 26.9 ± 13.5 days, P < 0.001). The ERAS group had a significantly lower percentage of postoperative complications (32.4% vs 56.8%, P = 0.034) and readmissions (0% vs 8.1%, P = 0.038). Quality-of-life was also significantly better in the ERAS group (184 ± 12.4 vs 177 ± 14.5, P = 0.022). The total medical cost was lower in the ERAS group, but not significantly ($25,445 ± 5065 vs $28,384 ± 9999, P = 0.085). CONCLUSIONS: The optimization of ERAS protocols in patients undergoing PD is safe and accelerates perioperative recovery and quality-of-life, thereby reducing the length of stay. Morbidity was significantly decreased in the ERAS group without compromising surgical outcome. REGISTRATION NUMBER: UMIN000014068.

Hydrocortisone administration was associated with improved survival in Japanese patients with cardiac arrest.

Takahiro Niimura, Yoshito Zamami, Toshihiro Koyama, Yuki Izawa-Ishizawa, Masashi Miyake, Tadashi Koga, Keisaku Harada, Ayako Ohshima, Toru Imai, Yutaka Kondo, Masaki Imanishi, Kenshi Takechi, Keijo Fukushima, Yuya Horinouchi, Yasumasa Ikeda, Hiromichi Fujino, Koichiro Tsuchiya, Toshiaki Tamaki, Shiro Hinotsu, Mitsunobu R Kano, Keisuke Ishizawa

Scientific reports 7 ( 1 ) 17919 - 17919 2017.12 [Refereed] [International journal]

There are few reports on hydrocortisone administration after cardiac arrest, and those that have been published included few subjects. This study aimed to evaluate the effect of hydrocortisone administration on the outcomes of patients who experienced cardiac arrest. We investigated the survival discharge rates and the length of hospital stay from cardiac arrest to discharge, stratified by use of hydrocortisone, using a Japanese health-insurance claims dataset that covers approximately 2% of the Japanese population. The study included the data of 2233 subjects who experienced either in-hospital or out-of-hospital cardiac arrest between January 2005 and May 2014. These patients were divided into two groups, based on the administration of hydrocortisone. We adjusted the baseline characteristics, medical treatment, and drug administration data of the two groups using propensity scores obtained via the inverse probability of treatment weighted method. The hydrocortisone group had a significantly higher survival discharge rate (13/61 [21.1%] vs. 240/2172 [11.0%], adjusted odds ratio: 4.2, 95% CI: 1.60-10.98, p = 0.004). In addition, the administration of hydrocortisone was independent predictor of survival to discharge (hazard ratio: 4.6, p < 0.001). The results demonstrate a correlation between hydrocortisone administration and the high rates of survival to discharge.

Report of the Second Asian Prostate Cancer (A-CaP) Study Meeting

Choung-Soo Kim, Ji Youl Lee, Byung Ha Chung, Wun-Jae Kim, Ng Chi Fai, Lukman Hakim, Rainy Umbas, Teng Aik Ong, Jasmine Lim, Jason L. Letran, Edmund Chiong, Tong-lin Wu, Bannakij Lojanapiwat, Levent Türkeri, Declan G. Murphy, Robert A. Gardiner, Kim Moretti, Matthew Cooperberg, Peter Carroll, Seong Ki Mun, Shiro Hinotsu, Yoshihiko Hirao, Seiichiro Ozono, Shigeo Horie, Mizuki Onozawa, Yasuhide Kitagawa, Tadaichi Kitamura, Mikio Namiki, Hideyuki Akaza

Prostate International ( Elsevier B.V. ) 5 ( 3 ) 95 - 103 2017.09 [Refereed]

The Asian Prostate Cancer (A-CaP) Study is an Asia-wide initiative that has been developed over the course of 2 years. The study was launched in December 2015 in Tokyo, Japan, and the participating countries and regions engaged in preparations for the study during the course of 2016, including patient registration and creation of databases for the purpose of the study. The Second A-CaP Meeting was held on September 8, 2016 in Seoul, Korea, with the participation of members and collaborators from 12 countries and regions. Under the study, each participating country or region will begin registration of newly diagnosed prostate cancer patients and conduct prognostic investigations. From the data gathered, common research themes will be identified, such as comparisons among Asian countries of background factors in newly diagnosed prostate cancer patients. This is the first Asia-wide study of prostate cancer and has developed from single country research efforts in this field, including in Japan and Korea. At the Second Meeting, participating countries and regions discussed the status of preparations and discussed various issues that are being faced. These issues include technical challenges in creating databases, promoting participation in each country or region, clarifying issues relating to data input, addressing institutional issues such as institutional review board requirements, and the need for dedicated data managers. The meeting was positioned as an opportunity to share information and address outstanding issues prior to the initiation of the study. In addition to A-CaP-specific discussions, a series of special lectures was also delivered as a means of providing international perspectives on the latest developments in prostate cancer and the use of databases and registration studies around the world.

Impact of lymph node dissection on clinical outcomes during nephroureterectomy in patients with clinically node-negative upper urinary tract urothelial cancer: subanalysis of a multi-institutional nationwide case series of the Japanese Urological Association

Junichi Inokuchi, Masatoshi Eto, Tomohiko Hara, Hiroyuki Fujimoto, Hiroyuki Nishiyama, Jun Miyazaki, Eiji Kikuchi, Shiro Hinotsu, Takuya Koie, Chikara Ohyama

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 47 ( 7 ) 652 - 659 2017.07 [Refereed]

To evaluate the impact of lymph node dissection (LND) on the clinical outcomes during radical nephroureterectomy (RNU) in patients with clinically node-negative upper urinary tract urothelial cancer (UTUC). Within the nationwide case series of the Japanese Urological Association, which comprises 1509 patients with UTUC diagnosed in 2005, we identified 823 patients with clinically node-negative UTUC who underwent RNU. The extent of limited LND was defined as the renal hilar region only for renal pelvic cancer and as either the pelvic region or para-aortic/paracaval region only for ureteral cancer, while the extent of wider LND was defined as at least one perilesional LND region in addition to limited LND. Multivariate analysis with a Cox regression hazard model was used to evaluate the survival benefit. Among the 823 patients, LND was performed in 197 (23.9%) patients, and 26 (13.2%) of them had pathologically node-positive disease. Of 197 patients who underwent LND, limited and wider LND was performed in 119 (60.4%) and 78 (39.6%) patients, respectively. Patients with node-positive disease showed significantly shorter overall survival than those with node-negative disease. No LND-associated survival improvement was observed in a direct comparison between patients with and without LND. In addition, limited or wider LND was not associated with overall survival or cancer-specific survival. The therapeutic benefit obtained by LND remains unclear regardless of the extent of LND, although LND has diagnostic value with respect to the prediction of a poor prognosis especially in patients with clinically muscle-invasive disease.

Efficacy and safety of sequential use of everolimus in Japanese patients with advanced renal cell carcinoma after failure of first-line treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitor: a multicenter phase II clinical trial

Masafumi Oyama, Takayuki Sugiyama, Masahiro Nozawa, Kiyohide Fujimoto, Takeshi Kishida, Go Kimura, Noriaki Tokuda, Shiro Hinotsu, Kojiro Shimozuma, Hideyuki Akaza, Seiichiro Ozono

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 47 ( 6 ) 551 - 559 2017.06 [Refereed]

Objective: Many studies have shown the efficacy of everolimus after pretreatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors. We investigated the efficacy and safety of everolimus as a second-line treatment after the failure of vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy in Japanese patients with advanced renal cell carcinoma. Methods: This was an open-label, multicenter, phase II trial conducted in Japan through the central registration system. A total of 57 patients were enrolled. Patients were administered 10 mg of everolimus q.d. orally. The primary efficacy endpoint was progression-free survival achieved by administration of everolimus. Results: The median progression-free survival of patients administered everolimus was 5.03 months (95% confidence interval: 3.70-6.20). The median overall survival was not reached. The objective response rate was 9.4% (95% confidence interval: 3.1-20.7). The progression-free survival in the group of <100% relative dose intensity was 6.70 months (95% confidence interval: 4.13-11.60), and that in the group of 100% relative dose intensity was 3.77 months (hazard ratio: 2.79, 95% confidence interval: 2.77-5.63). The commonly observed adverse events and laboratory abnormalities were stomatitis (49.1%), hypertriglyceridemia (26.4%), interstitial lung disease (26.4%), anemia (22.6%) and hypercholesterolemia (22.6%). Conclusion: The median progression-free survival was almost similar to that recorded in the RECORD-1 study, whereas prolongation of overall survival was observed in the present study compared with the RECORD-1 study. The treatment outcomes of first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy and second-line everolimus treatment in Japanese patients were successfully established in the present study.

Prostate cancer trends in Asia

Hideyuki Akaza, Mizuki Onozawa, Shiro Hinotsu

WORLD JOURNAL OF UROLOGY ( SPRINGER ) 35 ( 6 ) 859 - 865 2017.06 [Refereed]

Differences in the incidence and mortality rates for prostate cancer between East and West are clearly defined, with higher rates in the West and lower rates in the East. Treatment methods are generally selected in accordance with general practice guidelines, but the current reality in Asia is that there is not sufficient clinical data to set Asia-specific guidelines for treatment. This leads to a situation whereby for the large part guidelines based on scientific evidence accumulated in Western countries are followed, but from time to time cases are encountered when such guidelines may not be considered to be the most appropriate for the case at hand. Although there is a relatively large volume of clinical evidence relating to endocrine therapy in Asia, the treatment choices and effects differ to those in the West. These regional differences are thought to be due to various factors, including not only differences in genetic background, but also distinct differences in the living and healthcare environments. If the differences between East and West in terms of trends in prostate cancer could be examined, with positive aspects being adopted and negative aspects being improved, this could also be expected to be of use in developing a better treatment strategy for prostate cancer. The exchanging of information on a broader, global level will enable improvements in prevention, diagnosis and treatment of prostate cancer. It is in pursuit of this objective that it is important to promote high-quality clinical trials and joint epidemiological studies in Asia and work to accumulate data that are comparable to data available in Western countries.

Healthcare resource utilization and clinical outcomes associated with acute care and inpatient rehabilitation of stroke patients in Japan

Kyoko Murata, Shiro Hinotsu, Nobutake Sadamasa, Kazumichi Yoshida, Sen Yamagata, Shoji Asari, Susumu Miyamoto, Koji Kawakami

INTERNATIONAL JOURNAL FOR QUALITY IN HEALTH CARE ( OXFORD UNIV PRESS ) 29 ( 1 ) 26 - 31 2017.02 [Refereed]

Objective: To investigate healthcare resource utilization and changes in functional status in stroke patients during hospitalization in an acute hospital and a rehabilitation hospital. Design: Retrospective cohort study. Setting: One acute and one rehabilitation hospital in Japan. Participants: Patients who were admitted to the acute hospital due to stroke onset and then transferred to the rehabilitation hospital (n = 263, 56% male, age 70 +/- 12 years). Main outcome measures: Hospitalization costs and functional independence measure (FIM) were evaluated according to stroke subtype and severity of disability at discharge from the acute hospital. Results: Median (IQR) costs at the acute hospital were dependent on the length of stay (LOS) and implementation of neurosurgery, which resulted in higher costs in subarachnoid hemorrhage [$52 413 ($49 166-$72 606) vs $14 129 ($11 169-$19 459) in cerebral infarction; and vs $15 035 ($10 920-$21 864) in intracerebral hemorrhage]. The costs at the rehabilitation hospital were dependent on LOS, and higher in patients with moderate disability than in those with mild disability [$30 026 ($18 419-$39 911) vs $18 052 ($10 631-$24 384)], while those with severe disability spent $25 476 ($13 340-$43 032). Patients with moderate disability gained the most benefits during hospitalization in the rehabilitation hospital, with a median (IQR) total FIM gain of 16 (5-24) points, compared with a modest improvement in patients with mild (6, 2-14) or severe disability (0, 0-5). Conclusions: The costs for in-hospital stroke care were substantial and the improvement in functional status varied by severity of disability. Our findings would be valuable to organize efficient post-acute stroke care.

Trastuzumab Emtansine in HER2+Recurrent Metastatic Non-Small-Cell Lung Cancer: Study Protocol

Kadoaki Ohashi, Katsuyuki Hotta, Taizo Hirata, Keisuke Aoe, Toshiyuki Kozuki, Kiichiro Ninomiya, Hiroe Kayatani, Hiroyuki Yanai, Shinichi Toyooka, Shiro Hinotsu, Minoru Takata, Katsuyuki Kiura

CLINICAL LUNG CANCER ( CIG MEDIA GROUP, LP ) 18 ( 1 ) 92 - 95 2017.01 [Refereed]

The treatment outcome has been unsatisfactory for patients with non small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patientg with HER2+ lung cancers. The major eligibility criteria are as follows: age >= 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer. (C) 2016 Elsevier Inc. All rights reserved.

Impact of Surgeon and Hospital Volume on the Safety of Robot-Assisted Radical Prostatectomy: A Multi-Institutional Study Based on a National Database

Yosuke Hirasawa, Kunihiko Yoshioka, Yasutomo Nasu, Masumi Yamamoto, Shiro Hinotsu, Atsushi Takenaka, Masato Fujisawa, Ryoichi Shiroki, Keiichi Tozawa, Satoshi Fukasawa, Akira Kashiwagi, Katsunori Tatsugami, Masaaki Tachibana, Toshiro Terachi, Momokazu Gotoh

UROLOGIA INTERNATIONALIS ( KARGER ) 98 ( 3 ) 334 - 342 2017 [Refereed]

Introduction: We aimed to perform a multi-institutional study using a national database led by the Japanese Society of Endourology to investigate the effect of surgeon or hospital volume on the safety of robot-assisted radical prostatectomy (RARP). Materials and Methods: Clinical data of 3,214 patients who underwent RARP for the treatment of clinically localized prostate cancer between April 2012 and March 2013 in Japan were evaluated. Surgical outcomes and all intra- and perioperative complications were collected. Results: The intraoperative complication rate was 0.56%. In a total number of 241 patients, 261 perioperative complications were observed. The following percentages of patients presented the Clavien-graded complications: 7.2%, grades 1-2; 0.84%, grade 3; and 0.093%, grade 4a. No cases of multiple organ dysfunction or death (grades 4b and 5) were found. Multivariable logistic regression analysis showed that the hospital volume (OR 3.6; p = 0.010) for intraoperative complications and surgeon volume (OR 0.19; p < 0.0001) and extended lymph node discectomy (OR 3.9; p < 0.0001) for perioperative complications were significant independent risk factors. Conclusions: Hospital volume for intraoperative complications and surgeon volume and extended lymph node dissection for perioperative complications were significantly associated with increased risk of each complication in RARP. (C) 2017 S. Karger AG, Basel

A Phase II Clinical Trial of the Efficacy and Safety of Short-term (3 days) Enoxaparin for the Prevention of Venous Thromboembolism after Gastric Cancer Surgery

Shinji Kuroda, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Shiro Hinotsu, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA ( OKAYAMA UNIV MED SCHOOL ) 70 ( 5 ) 401 - 404 2016.10 [Refereed]

Although intermittent pneumatic compression (IPC) has become common as perioperative prophylaxis for venous thromboembolism (VTE) consisting of pulmonary thromboembolism (PE) and deep vein thrombosis (DVT), the prophylactic effect against VTE, especially lethal PE, is not yet satisfactory. Therefore, pharmacologic prophylaxis, such as with enoxaparin, is desirable. While the efficacy and safety of enoxaparin have been proven in several clinical trials, concern about bleeding with long-term (at least 7 days) use have potentially decreased its widespread adoption. We have launched a phase II study to evaluate the efficacy and safety of short-term (3 days) enoxaparin, in which a total of 70 gastric cancer patients undergoing gastrectomy will be recruited, and the primary endpoint is the incidence of DVT. This study could contribute to making pharmacologic prophylaxis for VTE more common.

A Phase I Trial of 100mg/m(2) Docetaxel in Patients with Advanced or Recurrent Breast Cancer

Tomoki Tamura, Taizo Hirata, Masahiro Tabata, Shiro Hinotsu, Akinobu Hamada, Takayuki Motoki, Takayuki Iwamoto, Taeko Mizoo, Tomohiro Nogami, Tadahiko Shien, Naruto Taira, Junji Matsuoka, Hiroyoshi Doihara

ACTA MEDICA OKAYAMA ( OKAYAMA UNIV MED SCHOOL ) 70 ( 5 ) 425 - 427 2016.10 [Refereed]

Docetaxel is a standard treatment for patients with advanced or recurrent breast cancer. The recommended dose is 60 to 100 mg/m(2). Previous study have shown that the tumor response rates of patients who received docetaxel monotherapy at doses of 60, 75, and 100 mg/m(2) were 22.1%, 23.3%, and 36.0%, respectively, and there was a significant relationship between the dose and response. In Europe and the United States, docetaxel is approved at a dose of 100 mg/m(2), and Japanese guidelines also recommend a dose of 100 mg/m(2). However, the approved dose in Japan is up to 75 mg/m(2). We have launched a phase I trial evaluating 100 mg/m(2) docetaxel in patients with advanced or relapsed breast cancer. The major eligibility criteria are as follows: age >= 20 years, pathologically diagnosed breast cancer, recurrent or advanced breast cancer, a good performance status, and HER2 [human epidermal growth factor receptor 2] negative. The primary endpoint is demonstrated safety of 100 mg/m(2) docetaxel. This study will clarify whether 100mg/m(2) docetaxel can be administrated safely in Japanese patients with advanced or recurrent breast cancer.

Asia prostate cancer study (A-CaP Study) launch symposium

Hideyuki Akaza, Yoshihiko Hirao, Choung-Soo Kim, Mototsugu Oya, Seiichiro Ozono, Dingwei Ye, Matthew Cooperberg, Shiro Hinotsu, Ji Youl Lee, Gang Zhu, Mikio Namiki, Shigeo Horie, Byung Ha Chung, Chung-Hsin Chen, Ng Chi Fai, Lukman Hakim, Edmund Chiong, Jason Letran, Rainy Umbas, Kazuhiro Suzuki, Kazuo Nishimura, Teng Aik Ong, Bannakij Lojanapiwat, Tong-lin Wu, Wun-Jae Kim, Declan Murphy, Osamu Ogawa, Peter Carroll, Seiji Naito, Taiji Tsukamoto

Prostate International ( Elsevier B.V. ) 4 ( 3 ) 88 - 96 2016.09 [Refereed]

The Asian Prostate Cancer (A-CaP) Study is an Asia-wide initiative that has been developed over the course of 2 years. The A-CaP Study is scheduled to begin in 2016, when each participating country or region will begin registration of newly diagnosed prostate cancer patients and conduct prognosis investigations. From the data gathered, common research themes will be identified, such as comparisons among Asian countries of background factors in newly diagnosed prostate cancer patients. This is the first Asia-wide study of prostate cancer and has developed from single country research efforts in this field, including in Japan and Korea. The inaugural Board Meeting of A-CaP was held on December 11, 2015 at the Research Center for Advanced Science and Technology, The University of Tokyo, attended by representatives of all participating countries and regions, who signed a memorandum of understanding concerning registration for A-CaP. Following the Board Meeting an A-CaP Launch Symposium was held. The symposium was attended by representatives of countries and regions participating in A-CaP, who gave presentations. Presentations and a keynote address were also delivered by representatives of the University of California San Francisco, USA, and the Peter MacCallum Cancer Centre, Australia, who provided insight and experience on similar databases compiled in their respective countries.

Study about the Efficacy of Metformin to Immune Function in Cancer Patients

Mototsugu Watanabe, Hiromasa Yamamoto, Shingo Eikawa, Kazuhiko Shien, Tadahiko Shien, Junichi Soh, Katsuyuki Hotta, Jun Wada, Shiro Hinotsu, Toshiyoshi Fujiwara, Katsuyuki Kiura, Hiroyoshi Doihara, Shinichiro Miyoshi, Heiichiro Udono, Shinichi Toyooka

ACTA MEDICA OKAYAMA ( OKAYAMA UNIV MED SCHOOL ) 70 ( 4 ) 327 - 330 2016.08 [Refereed]

A study to evaluate the effect of metformin on the immune system was commenced in July 2014. Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and previous studies have reported that metformin has an anti-tumor effect. The aim of this study is to evaluate the efficacy of metformin on the immune system in human cancer patients in vivo. The primary outcome parameter will be the rate change in the population of CD8(+) T cells, which produce multiple cytokines.

Essential content of evidence-based clinical practice guidelines for bladder cancer: The Japanese Urological Association 2015 update

Yoshinobu Kubota, Noboru Nakaigawa, Hiroyuki Nishiyama, Shiro Hinotsu, Osamu Ogawa, Keiji Inoue, Seiichiro Ozono, Eiji Kikuchi, Tsuneharu Miki, Hideyasu Matsuyama, Tomoaki Fujioka, Chikara Ohyama, Hiroyuki Fujimoto, Haruhito Azuma, Tomonori Habuchi, Masayuki Nakagawa, Takashi Mizowaki, Yoshiyuki Matsui, Takashi Kobayashi, Kimito Osaka, Hiroshi Furuse, Yoshio Naya, Wataru Obara, Takuya Koike, Takahiro Yoneyama, Yasuhiro Hashimoto, Shingo Hatakeyama, Atsushi Imai, Hiroyuki Nakanishi, Tomohiko Hara, Norihiko Tsuchiya, Takamitsu Inoue, Junichi Ohta, Kotaro Suzuki, Atsushi Fujikawa, Susumu Umemoto, Koji Izumi, Sumio Noguchi

International Journal of Urology 23 ( 8 ) 640 - 645 2016.08

The Japanese Urological Association revised the clinical practice guidelines for bladder cancer in April 2015. This was the first update carried out in the 6 years since the development of the initial clinical practice guidelines for bladder cancer in 2009. The descriptive content was revised, and additions were made with a focus on new-found evidence and advances in the latest medical practices, and on the basis of the increasingly aging population observed in the underlying social context in Japan. An algorithm for the treatment of bladder cancer has been presented as a new trial. In the present article, we will introduce the essential contents and clinical questions that address the present revisions.

Diversity in treatment modalities of Stage II/III urothelial cancer in Japan: sub-analysis of the multi-institutional national database of the Japanese Urological Association.

Takuya Koie, Chikara Ohyama, Hiroyuki Fujimoto, Hiroyuki Nishiyama, Jun Miyazaki, Shiro Hinotsu, Eiji Kikuchi, Mizuaki Sakura, Junichi Inokuchi, Tomohiko Hara, Chikara Ohyama, Hiroyuki Nishiyama, Masato Fujisawa, Hirotsugu Uemura, Hiroyuki Fujimoto, Kazuhiro Suzuki, Masatoshi Eto, Isao Hara, Akio Matsubara, Norio Nonomura, Hiroyuki Nakanishi, Takuya Koie, Hiroomi Kanayama, Tsuneharu Miki, Tomoharu Fukumori, Seiji Naito

Japanese journal of clinical oncology 46 ( 5 ) 468 - 74 2016.05 [Refereed] [International journal]

OBJECTIVE: We aimed to survey treatment modalities for the patients with Stage II/III urothelial cancer in Japan. METHODS: We used the multi-institutional national database of the Japanese Urological Association from 348 Japanese institutions, in which a total of 3707 patients with muscle-invasive bladder cancer and 1538 with upper urinary tract urothelial carcinoma were registered in 2008 and 2011, respectively. Primary treatment was classified as surgery alone, surgery with chemotherapy, surgery with radiation, radiation alone, chemotherapy alone, combination of radiation and chemotherapy and observation. Overall and cancer-specific survivals were examined using the Kaplan-Meier method, and survival in the subgroups was analyzed using the log-rank test. RESULTS: In Stage II/III bladder cancer patients, 49.7% of those were treated with radical operation and 22.3% received observation only. A total 97.2% of Stage II/III upper urinary tract urothelial carcinoma patients treated with radical surgery. A total 30.4% of Stage II/III bladder cancer patients received chemotherapy. Majority of the patients received cisplatin-based regimen, however, regimens of chemotherapy was rich in variety up to 13 regimens. Chemotherapy regimens for the patients with upper urinary tract urothelial carcinoma were also various up to eight regimens. Overall and cancer-specific survivals were statistically significantly stratified according to the clinical stage. The upper urinary tract urothelial carcinoma patients diagnosed with clinical stage T3 had significantly poor prognosis compared with those diagnosed with clinical stage T2. CONCLUSIONS: This study demonstrated the variety of treatments used for Japanese patients with Stage II/III urothelial cancer. Treatment standardization for these entities may be necessary.

Laparoscopic Versus Open Nephroureterectomy in Muscle-Invasive Upper Tract Urothelial Carcinoma: Subanalysis of the Multi-Institutional National Database of the Japanese Urological Association

Jun Miyazaki, Hiroyuki Nishiyama, Hiroyuki Fujimoto, Chikara Ohyama, Takuya Koie, Shiro Hinotsu, Eiji Kikuchi, Mizuaki Sakura, Junichi Inokuchi, Tomohiko Hara

JOURNAL OF ENDOUROLOGY ( MARY ANN LIEBERT, INC ) 30 ( 5 ) 520 - 525 2016.05 [Refereed]

Objectives: Open nephroureterectomy (ONU) is the current standard for muscle-invasive upper tract urothelial carcinoma (UTUC) in the European Association of Urology/Japanese Urological Association (JUA) guidelines. In this study, we compared the postsurgical survival of muscle-invasive UTUC patients treated with ONU or with laparoscopic nephroureterectomy (LNU), using the multi-institutional national database of the JUA. Methods: The 1509 patients with UTUC who were diagnosed at 348 Japanese institutions in 2005 were registered. We collected the clinical data of the patients in 2011. The muscle-invasive UTUC patients who underwent ONU or LNU were identified, and survival curves were estimated using the Kaplan-Meier method. Results: Overall, 749 pT2cNxM0 patients underwent a nephroureterectomy (ONU, n=527 and LNU, n=222). The overall survival and cause-specific survival rates were not significantly different between the ONU and LNU groups (p=0.1263 and p=0.0893, respectively). In addition, 459 of the 749 (61.3%) patients experienced disease recurrence (bladder recurrence, local recurrence, or distant metastasis), with no significant difference between the ONU and LNU groups. Even when patients were stratified by pT3/pT4 and/or pN+, overall survival was not significantly different between the ONU and LNU groups (p=0.2876). The results of a univariate analysis showed that lymphovascular invasion was an independent prognostic factor for overall survival, but the surgical approaches were not found to be associated with overall survival. Conclusions: Our data suggest that there is no evidence that the oncologic outcome of LNU is inferior to that of ONU in muscle-invasive UTUC, when the appropriate patients are selected.

[Epidemiology of prostate cancer: International variation].

Hinotsu S

Nihon rinsho. Japanese journal of clinical medicine 74 Suppl 3 34 - 38 2016.05 [Refereed]

Clinical outcomes and nadir prostate-specific antigen (PSA) according to initial PSA levels in primary androgen deprivation therapy for metastatic prostate cancer

Yasuhide Kitagawa, Satoru Ueno, Kouji Izumi, Yoshifumi Kadono, Atsushi Mizokami, Shiro Hinotsu, Hideyuki Akaza, Mikio Namiki

WORLD JOURNAL OF UROLOGY ( SPRINGER ) 34 ( 3 ) 319 - 327 2016.03 [Refereed]

Purpose To investigate the clinical outcomes of metastatic prostate cancer patients and the relationship between nadir prostate-specific antigen (PSA) levels and different types of primary androgen deprivation therapy (PADT). This study utilized data from the Japan Study Group of Prostate Cancer registry, which is a large, multicenter, population-based database. Methods A total of 2982 patients treated with PADT were enrolled. Kaplan-Meier analysis was used to compare progression-free survival (PFS) and overall survival (OS) in patients treated using combined androgen blockade (CAB) and non-CAB therapies. The relationships between nadir PSA levels and PADT type according to initial serum PSA levels were also investigated. Results Among the 2982 enrolled patients, 2101 (70.5 %) were treated with CAB. Although CAB-treated patients had worse clinical characteristics, their probability of PFS and OS was higher compared with those treated with a non-CAB therapy. These results were due to a survival benefit with CAB in patients with an initial PSA level of 5001000 ng/mL. Nadir PSA levels were significantly lower in CAB patients than in non-CAB patients with comparable initial serum PSA levels. Conclusions A small survival benefit for CAB in metastatic prostate cancer was demonstrated in a Japanese large-scale prospective cohort study. The clinical significance of nadir PSA levels following PADT was evident, but the predictive impact of PSA nadir on OS was different between CAB and non-CAB therapy.

Impact of multimodal treatment on prognosis for patients with metastatic upper urinary tract urothelial cancer: Subanalysis of the multi-institutional nationwide case series study of the Japanese Urological Association

Junichi Inokuchi, Seiji Naito, Hiroyuki Fujimoto, Tomohiko Hara, Mizuaki Sakura, Hiroyuki Nishiyama, Jun Miyazaki, Eiji Kikuchi, Shiro Hinotsu, Takuya Koie, Chikara Ohyama

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL ) 23 ( 3 ) 224 - 230 2016.03 [Refereed]

ObjectivesTo describe the nature of metastatic upper urinary tract urothelial cancer and determine the prognostic predictors or treatment modality associated with all-cause mortality. MethodsWithin the nationwide case series study of the Japanese Urological Association, consisting of 1509 patients with urinary tract urothelial cancer diagnosed in 2005, we identified 102 patients with metastatic urinary tract urothelial cancer. Univariate and multivariate survival analyses identified prognostic outcome variables. ResultsPredominant sites of distant metastasis at diagnosis were the lungs (54.9%), distant lymph nodes (37.3%), bone (32.4%) and liver (19.6%). Of 102 patients, 70 patients (68.6%) died during the median follow-up period of 6 months, and the 2-year overall survival rate was estimated at 22%. The median survival time to all-cause mortality was 8.5 months (95% confidence interval 6.4-10.7 months). On multivariate analysis, independent predictive factors for all-cause mortality were age (hazard ratio 2.36, P = 0.015) and liver metastasis (hazard ratio 2.35, P = 0.037). Patients who received multimodal treatment including chemotherapy and surgery showed significantly better prognosis (median survival time 25.8 months) compared with patients treated with chemotherapy alone (median survival time 7.3 months) or best supportive care (median survival time 4.3 months). ConclusionsAge at diagnosis and the presence of liver metastasis seem to have an impact on survival of metastatic urinary tract urothelial cancer patients. Multimodal treatment including systemic chemotherapy and surgery might result in better prognosis in some of these patients.

Validation of TNM classification for metastatic prostatic cancer treated using primary androgen deprivation therapy

Yoshifumi Kadono, Takahiro Nohara, Satoru Ueno, Kouji Izumi, Yasuhide Kitagawa, Hiroyuki Konaka, Atsushi Mizokami, Mizuki Onozawa, Shiro Hinotsu, Hideyuki Akaza, Mikio Namiki

WORLD JOURNAL OF UROLOGY ( SPRINGER ) 34 ( 2 ) 261 - 267 2016.02 [Refereed]

The current tumor-node-metastasis (TNM) classification system has been used for many years. The prognosis of patients with metastatic prostate cancer (mPC) treated using primary androgen deprivation therapy (PADT) was analyzed according to the TNM classification. A total of 5618 cases with lymph node metastases only (N1M0), non-regional lymph node metastasis (M1a), bone metastasis (M1b), and distant metastasis (M1c) were selected from the Japanese Study Group of Prostate Cancer database. Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) rates were calculated using Kaplan-Meier analysis. The influence of clinical variables on patient prognosis was evaluated using the Cox proportional hazard regression model. The 5-year OS, CSS, and PFS were 76.0, 83.2, and 38.8 % in N1M0, 57.5, 69.0, and 23.0 % in M1a, 54.0, 63.1, and 23.0 % in M1b, and 40.0, 51.5, and 16.6 % in M1c, respectively. OS, CSS, and PFS worsened as the stages progressed. OS, CSS, and PFS were all significantly worse in N1M1b compared with N0M1b. Multivariate analysis revealed that OS and CSS were worse in patients with a Gleason score a parts per thousand yen8 and that combined androgen blockade (CAB) treatment provided better OS than non-CAB treatments at any tumor stage. However, OS and CSS were worse in individuals with a prostate-specific antigen > 100 ng/ml only in M1b. Patient prognosis worsened with stage progression; therefore, current TNM classification system of mPC for PADT was shown to be trustworthy. Each PC cell that develops bone or lymphoid metastasis may exhibit different characteristics.

Sitagliptin monotherapy has better effect on insulinogenic index than glimepiride monotherapy in Japanese patients with type 2 diabetes mellitus: a 52-week, multicenter, parallel-group randomized controlled trial

Yaeko Kondo, Norio Harada, Akihiro Hamasaki, Shizuka Kaneko, Koichiro Yasuda, Eiichi Ogawa, Shin-ichi Harashima, Hiroko Yoneda, Yoshihito Fujita, Norikazu Kitano, Yoshio Nakamura, Fujio Matsuo, Megumi Shinji, Shiro Hinotsu, Takeo Nakayama, Nobuya Inagaki

DIABETOLOGY & METABOLIC SYNDROME ( BIOMED CENTRAL LTD ) 8 15 2016.02 [Refereed]

Background: The 52-week monotherapy with the dipeptidyl peptidase-4 inhibitor sitagliptin and the sulphonylurea glimepiride on early-phase insulin secretion in Japanese patients with type 2 diabetes mellitus (T2DM) is not known. Methods: A randomized, parallel-group, open-label trial was conducted at 18 centers between February, 2011 and March, 2013. 171 outpatients with T2DM were recruited and randomly assigned to glimepiride or sitagliptin by minimization. Doses of glimepiride (0.25-1.0 mg/day) and sitagliptin (25-100 mg/day) were adjusted for hemoglobin A1c (HbA1c) > 6.9 %. Analyses were performed on full analysis set (FAS) of randomized subjects taking medications as allocated, and underwent 75 g oral glucose tolerance test (OGTTs) before and after treatment. The primary outcome was insulinogenic index to quantify early-phase insulin secretion after treatment, which was evaluated by analysis of covariance (ANCOVA). Results: Of 171 enrolled subjects, 68 in the sitagliptin group and 65 in the glimepiride group were included in the FAS (mean age, 64 years; baseline (HbA1c), 7.4 %). The primary outcome revealed a significantly higher insulinogenic index in the sitagliptin group than that in the glimepiride group (p = 0.036). Sitagliptin also reduced plasma glucose levels at 60 and 120 min during OGTT compared with glimepiride, while achieving a similar improvement in HbA1c during treatment. Body weight did not change in either of the two groups, and one case of hypoglycemia was observed in the glimepiride group. Conclusions: Sitagliptin shows better effects on insulinogenic index after 52-week treatment compared with glimepiride in Japanese patients with T2DM.

Trans-Pacific variation in outcomes for men treated with primary androgen-deprivation therapy (ADT) for prostate cancer

Matthew R. Cooperberg, Shiro Hinotsu, Mikio Namiki, Peter R. Carroll, Hideyuki Akaza

BJU INTERNATIONAL ( WILEY-BLACKWELL ) 117 ( 1 ) 102 - 109 2016.01 [Refereed]

Objectives To compare directly survival outcomes of primary androgen-deprivation therapy (PADT) in Japan, where this treatment is endorsed by guidelines, with outcomes in the USA, where it is not. Patients and Methods Data were compared between men receiving PADT in the USA Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry and the Japanese Cancer of the Prostate (J-CaP) registry database. Competing risks regression was used to assess prostate cancer-specific mortality (CSM), adjusting for age, Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score, diagnosis year, and treatment type [combined androgen blockade (CAB) vs castration monotherapy], comorbidity, and practice type. Results Men on PADT in J-CaP (13 880 men) were older than those in CaPSURE (1633 men), and had higher-risk disease (mean J-CAPRA score 3.8 vs 2.1, P < 0.001). They more often received CAB: 66.9% vs 46.4% (P < 0.001). Despite different risk profiles between the cohorts, CSM was similar on univariate analysis (log-rank P = 0.88). On multivariable regression, the subhazard ratio for CSM was 0.52 for J-CaP vs CaPSURE (95% confidence interval 0.40-0.68). Conclusions Men on PADT in Japan have less than half the adjusted CSM than those in the USA. These findings support both existing guidelines endorsing PADT in Asia and discouraging its use in the West. Elucidating the reasons behind these substantial differences, which probably include both genetic and dietary/environmental factors, may help explain the varying epidemiology of prostate cancer on either side of the Pacific.

Prognostic factors of recurrent disease in upper urinary tract urothelial cancer after radical nephroureterectomy: Subanalysis of the multi-institutional national database of the Japanese Urological Association

Tomohiko Hara, Hiroyuki Fujimoto, Mizuaki Sakura, Junichi Inokuchi, Hiroyuki Nishiyama, Jun Miyazaki, Chikara Ohyama, Takuya Koie, Eiji Kikuchi, Shiro Hinotsu

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL ) 22 ( 11 ) 1013 - 1020 2015.11 [Refereed]

ObjectivesTo explore predictive factors of disease recurrence after radical nephroureterectomy in patients with upper urinary tract urothelial cancer. MethodsA multi-institutional national database promoted by the Japanese Urological Association including 293 institutions and 1172 patients was used for the present study. Patient with non-metastatic upper urinary tract urothelial cancer who underwent primary radical nephroureterectomy with curative intent were analyzed. Univariate analysis using the Kaplan-Meier method and multivariate Cox regression models with stepwise selection was used to evaluate time to recurrence after surgery. ResultsThe median duration of follow up was 55.8months, and disease recurred in 325 (27.7%) patients at a median of 11.4months after radical nephroureterectomy. According to a Cox proportional hazards model, the Union International Contre le Cancer 2002 pathological stage of the primary tumor, lymph node status, presence of lymphatic and/or vascular invasion, infiltrative growth pattern, and age were independent predictors (P<0.05) of recurrence-free survival. ConclusionsDespite several limitations, our analysis suggests that pathological tumor stage, lymph node status, lymphovascular invasion, infiltrative growth pattern and age represent important prognostic variables after radical nephroureterectomy in Japanese patients with upper urinary tract urothelial cancer. This information could be potentially used to select patients for adjuvant systemic therapy.

Impact of smoking on the age at diagnosis of upper tract urothelial carcinoma: Subanalysis of the Japanese Urological Association multi-institutional national database

Jun Miyazaki, Hiroyuki Nishiyama, Hiroyuki Fujimoto, Chikara Ohyama, Takuya Koie, Shiro Hinotsu, Eiji Kikuchi, Mizuaki Sakura, Junichi Inokuchi, Tomohiko Hara

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL ) 22 ( 11 ) 1023 - 1027 2015.11 [Refereed]

ObjectivesTo examine the influence of smoking history on the diagnosis and other tumor characteristics of upper tract urothelial carcinoma in Japan. MethodsA total of 1509 patients with upper tract urothelial carcinoma who were diagnosed in 2005 from 348 Japanese institutions were registered using the multi-institutional national database of the Japanese Urological Association and included in this analysis. Clinical data of the patients were collected in 2011. The associations between the patients' self-reported smoking history and their age at the diagnosis of upper tract urothelial carcinoma, sex, pathological Tstage and tumor grade were analyzed. ResultsThe mean age at the diagnosis of upper tract urothelial carcinoma was approximately 5years earlier for the 238 current smokers than for the 618 current non-smokers (P<0.0001). Similar associations between smoking and the early diagnosis of upper tract urothelial carcinoma were shown in the sex subgroups and in subgroups stratified by pathological Tstages. Among the current smokers, the age at diagnosis for the smoking 20 cigarettes per day group was 6.5years lower than that of the <20 cigarettes per day group, which was significantly different (P<0.0001). ConclusionCurrent smoking is a significant risk factor for the earlier diagnosis of upper tract urothelial carcinoma. The finding is important from the perspective of both healthcare and medical economies.

Phase II clinical trial of sorafenib plus interferon-alpha treatment for patients with metastatic renal cell carcinoma in Japan

Masatoshi Eto, Yoshiaki Kawano, Yoshihiko Hirao, Koji Mita, Yoichi Arai, Taiji Tsukamoto, Katsuyoshi Hashine, Akio Matsubara, Tomoaki Fujioka, Go Kimura, Nobuo Shinohara, Katsunori Tatsugami, Shiro Hinotsu, Seiji Naito

BMC CANCER ( BIOMED CENTRAL LTD ) 15 667 2015.10 [Refereed]

Background: To improve antitumor effects against metastatic renal cell carcinoma (mRCC), use of molecular target-based drugs in sequential or combination therapy has been advocated. In combination therapy, interferon (IFN)-alpha amplified the effect of sorafenib in our murine model (J Urol 184: 2549, 2010), and cytokine-treated mRCC patients in Japan had good prognoses (Eur Urol 57: 317, 2010). We thus conducted a phase II clinical trial of sorafenib plus IFN-alpha for untreated mRCC patients in Japan. Methods: In this multicenter, prospective study, provisionally registered patients with histologically confirmed metastatic clear cell RCC received natural IFN-alpha (3 dosages of 3 million U per week) for 2 weeks. Only IFN-alpha-tolerant patients were registered to this trial, and treated additionally with oral sorafenib (400 mg, bid). The primary end point of the study was rate of response (CR + PR) to sorafenib plus IFN-alpha treatment assessed using RECIST v1.0. The secondary end points were disease control rate (CR + PR + SD), progression free survival (PFS), overall survival (OS), and safety of the combined treatment. PFS and OS curves were plotted using the Kaplan-Meier method. Results: From July 2009 to July 2012, a total of 53 untreated patients were provisionally registered, and 51 patients were finally registered. Rate of Response to the combined therapy of sorafenib plus IFN-alpha was 26.2 % (11/42) (CR 1, PR 10). The median PFS was 10.1 months (95 % CI, 6.4 to 18.5 months), and the median OS has not been reached yet. The combined therapy increased neither the incidence of adverse effects (AE) nor the incidence of unexpected AE. A limitation was that a relatively high number of patients (9 patients) were excluded for eligibility criteria violations. Conclusion: Our data have demonstrated that sorafenib plus IFN-alpha treatment is safe and effective for untreated mRCC patients.

Long-term outcomes of combined androgen blockade therapy in stage IV prostate cancer

Taeko Matsuoka, Koji Kawai, Tomokazu Kimura, Takahiro Kojima, Mizuki Onozawa, Jun Miyazaki, Hiroyuki Nishiyama, Shiro Hinotsu, Hideyuki Akaza

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY ( SPRINGER ) 141 ( 4 ) 759 - 765 2015.04 [Refereed]

To clarify which subset of stage IV prostate cancer patients benefit from combined androgen blockade (CAB) using Japanese nationwide database. A total of 3,752 patients with stage IV disease from the prospective nationwide cohort database of the Japan Study Group of Prostate Cancer (J-CaP) were enrolled. All patients started primary androgen deprivation therapy (PADT) between 2001 and 2003, and the present study was performed using the data set from December 2011. Patients were divided into two groups according to initial treatments: CAB with luteinizing hormone-releasing hormone agonist (LHRH) plus anti-androgen (AA) and non-CAB treatments such as LHRH monotherapy. The overall survival (OS) and cancer-specific survival (CSS) for each group were estimated by the Kaplan-Meier method. A total of 2,967 patients (79.1 %) received CAB. Overall, no significant difference was observed in OS and CSS between the CAB group and the non-CAB group. However, CAB resulted in significantly better OS and CSS compared to non-CAB in patients with very high Japan Cancer of the Prostate Risk Assessment (J-CAPRA) scores of ten or greater (P = 0.007 and 0.013, respectively). Multivariate analysis revealed that CAB was an independent predictive factor for better OS (P = 0.013, hazard ratio = 0.83). Based on large-scale nationwide database, as PADT for prostate cancer patients with very high-risk disease, CAB resulted in better OS than other endocrine treatments.

A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan, and the penetrance rates in children with WT1 germline mutation

Kaneko Y, Okita H, Haruta M, Arai Y, Oue T, Tanaka Y, Horie H, Hinotsu S, Koshinaga T, Yoneda A, Ohtsuka Y, Taguchi T, Fukuzawa M

British Journal of Cancer 112 1121 - 1133 2015.03

<p>Background: Bilateral Wilms tumours (BWTs) occur by germline mutation of various predisposing genes; one of which is WT1 whose abnormality was reported in 17-38% of BWTs in Caucasians, whereas no such studies have been conducted in East-Asians. Carriers with WT1 mutations are increasing because of improved survival. Methods: Statuses of WT1 and IGF2 were examined in 45 BWTs from 31 patients with WT1 sequencing and SNP array-based genomic analyses. The penetrance rates were estimated in WT1-mutant familial Wilms tumours collected from the present and previous studies. Results: We detected WT1 abnormalities in 25 (81%) of 31 patients and two families, which were included in the penetrance rate analysis of familial Wilms tumour. Of 35 BWTs from the 25 patients, 31 had small homozygous WT1 mutations and uniparental disomy of IGF2, while 4 had large 11p13 deletions with the retention of 11p heterozygosity. The penetrance rate was 100% if children inherited small WT1 mutations from their fathers, and 67% if inherited the mutations from their mothers, or inherited or had de novo 11p13 deletions irrespective of parental origin (P=0.057). Conclusions: The high incidence of WT1 abnormalit

Domperidone With ORT in the Treatment of Pediatric Acute Gastroenteritis in Japan: A Multicenter, Randomized Controlled Trial

Fumiyo Kita, Shiro Hinotsu, Tohru Yorifuji, Hisashi Urushihara, Tetsuro Shimakawa, Kenji Kishida, Yoshihiro Wakazono, Eiko Yamauchi, Hiroshi Sasaki, Tatsutoshi Nakahata, Koji Kawakami

ASIA-PACIFIC JOURNAL OF PUBLIC HEALTH ( SAGE PUBLICATIONS INC ) 27 ( 2 ) NP174 - NP183 2015.03 [Refereed]

Domperidone is an antiemetic that is often prescribed for children with acute gastroenteritis in Japan. In this study, the authors assessed the efficacy of domperidone prescription in combination with oral rehydration treatment (ORT) in the treatment of vomiting during acute gastroenteritis in children during the early period. They performed a prospective multicenter randomized trial in Japan. Patients received either ORT or ORT and domperidone prescription. The primary outcome was the proportion of patients who had vomiting during the first 2 hours after randomization. A total of 56 children were eligible; 24 received ORT alone, and 32 received ORT and prescribed domperidone suppository. Results showed that 27.3% of children in the ORT group vomited as compared with 20.7% of children in the ORT and domperidone group (P = .41). In this study, it appears that domperidone in combination with ORT in the treatment of acute gastroenteritis does not reduce vomiting in the early period.

The changing patterns of dispensing branded and generic drugs for the treatment of gastroesophageal reflux disease between 2006 and 2011 in Japan: a retrospective cohort study

Kyoko Murata, Shiro Hinotsu, Shota Hamada, Yasumasa Ezoe, Manabu Muto, Koji Kawakami

BMC HEALTH SERVICES RESEARCH ( BIOMED CENTRAL LTD ) 15 76 2015.02 [Refereed]

Background: Despite rising healthcare costs, generic drugs are less frequently dispensed in Japan compared with other developed countries. This study aimed to describe changes in dispensing of branded and generic drugs and to explore possible factors that promote the use of generic drugs. Methods: We conducted a retrospective cohort study using a Japanese medical and pharmacy claims database. All proton pump inhibitors (PPIs) and histamine H-2-receptor antagonists (H2RAs) with indications for gastroesophageal reflux disease (GERD) described on Japanese labels were included. Patterns of dispensing branded and generic drugs for the treatment of GERD between 2006 and 2011 were analyzed. Multivariate logistic regression was applied to investigate factors associated with receiving generic drugs. Results: The study cohort included 14,590 patients (male: 50.2%, mean age: 43.1 years). Branded drugs for GERD were still frequently dispensed despite an increase in the share of generic drugs. Only 4.3% of patients who initially received branded drugs switched to generic drugs. The percentage of patients who received only generic drugs increased over time (6.5% to 22.1%). The frequency of generic drug dispensing was the highest in the setting where both prescription and dispensing were implemented in clinics (43.3%), while the lowest in the setting where both prescription and dispensing were implemented in hospitals (11.5%). Factors associated with receiving generic drugs included year of dispensing (adjusted OR 2.22, 95% CI 1.94 to 2.55 for 2009-11 v 2006-8), prescription and dispensing setting (OR 1.81, 95% CI 1.44 to 2.26 for prescription in hospitals and dispensing in community pharmacies; OR 2.21, 95% CI 1.80 to 2.72 for prescription in clinics and dispensing in community pharmacies; and OR 4.55, 95% CI 3.68 to 5.62 for prescription and dispensing in clinics v prescription and dispensing in hospitals) and H2RAs (OR 1.64, 95% CI 1.49 to 1.81 compared to PPIs). Conclusions: The share of generic drugs for the treatment of GERD increased over time although branded drugs for GERD were still dispensed frequently. The use of generic drugs for GERD was influenced not only by government policies but also by changes in treatment approach and the setting of prescription and dispensing.

Experience with Androgen Deprivation Therapy for Prostate Cancer in Japan and Future Perspectives

Yasuhide Kitagawa, Satoru Ueno, Hiroyuki Konaka, Atsushi Mizokami, Shiro Hinotsu, Hideyuki Akaza, Mikio Namiki

CURRENT CANCER DRUG TARGETS ( BENTHAM SCIENCE PUBL LTD ) 15 ( 4 ) 314 - 326 2015 [Refereed]

Novel anti-androgens and androgen biosynthesis inhibitors have been developed to treat castration-resistant prostate cancer. However, knowledge of androgen deprivation therapy (ADT) has not been developed in the criticism, including information regarding the adverse effects of hormonal therapy. We hypothesize that there are ethnic differences in the efficacy and adverse effects of ADT; therefore, this review summarizes the experience of ADT, mainly in Japan. A risk stratification instrument, the Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score, was developed based on the Japan Study Group of Prostate Cancer registry, which is a large, multicenter, population-based database. It revealed that clinical outcomes were substantially better for males treated with ADT in Japan compared with those in the United States. Moreover, there were small survival differences in patients with localized and locally advanced cancer who received local therapy and primary ADT in another Japanese cohort study. In terms of adverse effects, including bone loss and cardiovascular risk, ADT appears to be better tolerated in Japanese populations than in Western cohorts. An ongoing randomized controlled trial of a trimodality treatment comprising brachytherapy, external beam radiation therapy, and neoadjuvant with or without adjuvant ADT in patients with localized high-risk prostate cancer will provide novel insights regarding adjuvant ADT. As a future perspective, the optimal selection of the type of primary ADT, including combining androgen blockade and novel hormonal compounds, adjusted according to each patient's clinicopathological background, may provide better clinical outcomes in patients with advanced prostate cancer.

Patterns and trends in diagnostic tests used for detection of colorectal cancer after screening with the immunochemical fecal occult blood test in Japan

Yamamichi J, Seto K, Hinotsu S, Nagata K, Kobayashi Y, Urushihara H, Kawakami K

Open Journal of Clinical Diagnostics 5 107 - 116 2015 [Refereed]

Approaches to the evaluation of safety warnings using claim database

KOYAMA Toshihiro, HINOTSU Shiro, OSHIMA Ayako, ZAMAMI Yoshito, SHIRAISHI Naoko, TATEBE Yasuhisa, SHINOMIYA Kazuaki, KANO Mitsunobu

Annual Meeting of the Japanese Society of Toxicology ( The Japanese Society of Toxicology ) 42 ( 0 ) S2 - 5 2015 [Refereed]

現在、医療に関わる大規模情報の利活用は、医薬品を安全に使用するために今後ますます重要性が高まるとされている。厚生労働省やPMDAはより効果的な安全性対策のため、さまざまな医療情報データベース構築事業を実施し、試行期間の終了とともに、順次、公益性の高い研究課題への利活用の推進に移行しつつある。これらの大規模医療情報は疫学的手法と情報技術によって抽出・解析され、医薬品等の安全対策とその効果検証や、医療の質向上にも広く役立てられつつある。また、我が国の課題解決のため、厚生労働科学研究の戦略研究においては、これまでの大規模介入研究とは異なる「健康医療分野における大規模データの分析及び基盤整備に関する研究」課題が採択され、国民や行政の大規模医療データの利活用に対する期待を映している。
現在、我々は健保組合の提供する診療報明細書情報を用いて、医療安全対策の効果について解析を行っており、その1例を紹介する。
炭酸リチウムは躁病や躁状態の治療に用いられるが、リチウムの血中濃度上昇によってリチウム中毒を引き起こすことが知られている。そのため、定期的なリチウム血中濃度の測定が求められている。しかし、PMDAが2005～2010年のレセプトデータをもとに調査した結果、炭酸リチウムの処方を受けた患者のうち、1度もリチウムの血中濃度測定を実施していない患者の割合が52 %である可能性が示された。この結果を受け、PMDAは2012年9月に炭酸リチウムの血中濃度測定遵守について通知を発出した。しかし、臨床で炭酸リチウムの適正使用が客観的に改善したのかは検証されていない。
そこで、本研究では、安全性対策が実施された効果について、炭酸リチウムの血中濃度測定実施割合を１つの指標として、安全対策前後での変化を明らかにすることにより、今後のさらに効果的な安全性対策に資するエビデンスを発信することを目的としている。

A systematic review and meta-analysis on the safety and efficacy of different strains of Mycobacterium bovis bacillus Calmette-Guérin for non-muscle invasive bladder cancer in Japan and US

Shiro Hinotsu, Naoyuki Kamatani, Timothy L Ratliff, Hideyuki Akaza

European Journal of Oncology Pharmacy ( Pharma Publishing and Media Europe ) 8 ( 4 ) 8 - 18 2015

Objective: To compare efficacy and safety of different strains of Mycobacterium bovis bacillus Calmette-Guérin (BCG) used in Japan and the US as intravesical therapeutics for non-muscle invasive bladder cancer. Materials and methods: Papers for review were selected from PubMed and Igakuchuozasshi databases, and meta-analysis was performed using the data obtained. Results: 352 papers from Japanese hospitals and 333 papers from US hospitals were reviewed. Strains used in Japan were Immunobladder®> (Tokyo 172) and ImmuCyst® (Connaught (JP)), while those used in the US were TICE® (TICE) and TheraCys® (Connaught (US)). CR (complete remission) rates for patients with CIS (carcinoma in situ) were 0.824 (n = 380, 95% CI 0.782–0.861), 0.868 (n = 38, 95% CI 0.719–0.956), 0.714 (n = 35, 95% CI 0.537–0.854) and 0.574 (n = 385, 95% CI 0.523–0.624) for Tokyo 172, Connaught (JP), TICE and Connaught (US), respectively. Non- recurrence survival (NRS) rates for non-CIS patients were 0.754 (n = 429, 95% CI 0.714–0.794), 0.790 (n = 83, 95% CI 0.702–0.878), 0.673 (n = 250, 95% CI 0.615–0.731) and 0.598 (n = 255, 95% CI 0.538–0.658) for Tokyo 172, Connaught (JP), TICE and Connaught (US), respectively. Conclusion: No significant differences were observed neither in efficacy nor in safety between two strains of BCG used Japan and the US. However, the rates of CR and NRS may be higher in Japan than the US, and the rates of severe adverse events may be higher in Japan than the US, although the data were not from controlled studies.

Long-term Survival of Extremely Advanced Prostate Cancer Patients Diagnosed with Prostate-specific Antigen over 500 ng/ml

Toru Sugihara, Changhong Yu, Michael W. Kattan, Hideo Yasunaga, Hiroyuki Ihara, Mizuki Onozawa, Shiro Hinotsu, Hideyuki Akaza

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 44 ( 12 ) 1227 - 1232 2014.12 [Refereed]

To investigate survival of hormone-na < ve prostate cancer patients diagnosed with prostate-specific antigen a parts per thousand yen500 ng/ml, stratified according to the prostate-specific antigen level and type of therapy. Data of prostate cancer patients with prostate-specific antigen a parts per thousand yen500 ng/ml diagnosed between 2001 and 2003 and receiving primary androgen deprivation therapy were extracted from the Japan Study Group of Prostate Cancer database. Cancer-specific survival and overall survival were assessed according to the prostate-specific antigen level (500-999, 1000-4999 and a parts per thousand yen5000 ng/ml) and type of therapy using Kaplan-Meier analyses and multivariate Cox proportional hazards models including age, Gleason score, oncological stage and comorbidity. The median follow-up was 27 months (interquartile range, 13-51) and a total of 1961 patients were included. Five-year cancer-specific and overall mortalities were 39.0 and 33.0%, respectively. There was a significant inverse relationship between overall survival and prostate-specific antigen magnitude among combination therapy patients, but not monotherapy patients (log-rank test, P = 0.034 and 0.558, respectively). The median overall survival in combination therapy patients with low-, intermediate- and high prostate-specific antigen and monotherapy patients with any prostate-specific antigen were 79, 59, 45 and 43 months, respectively. Multivariate analysis showed that combination therapy in patients with low- and intermediate prostate-specific antigen was significantly associated with a favorable overall survival compared with monotherapy (hazard ratios 0.66 and 0.75, respectively, both P < 0.001). Similar results were obtained for cancer-specific survival. There are major survival differences in extremely high prostate-specific antigen cases according to the prostate-specific antigen level and hormone therapy type and those patients would benefit notably from combination androgen blockade.

Recent Trends in the Initial Therapy for Newly Diagnosed Prostate Cancer in Japan

Mizuki Onozawa, Shiro Hinotsu, Taiji Tsukamoto, Mototsugu Oya, Osamu Ogawa, Tadaichi Kitamura, Kazuhiro Suzuki, Seiji Naito, Mikio Namiki, Kazuo Nishimura, Yoshihiko Hirao, Hideyuki Akaza

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 44 ( 10 ) 969 - 981 2014.10 [Refereed]

Objective: The objective of the present study was to investigate the trends over time in the initial treatment of prostate cancer in Japan. Methods: A total of 8291 patients with newly diagnosed prostate cancer whose treatment started in 2010 were registered in a multi-institutional observational study undertaken nationwide across Japan by the Japan Prostate Cancer Study Group. Each patient's background characteristics and initial treatment were recorded. Results: The median age at diagnosis was 71 years. The proportion of T1c disease was 40.5% and that of M1 disease was 10.4%. The prostate-specific antigen level was <10 ng/ml in 52.0% of the patients. High-, intermediate-and low-risk patients as determined by D'Amico's classification system made up 19.3, 29.8 and 25.9% of the cases, respectively. The initial treatment was androgen depletion therapy in 40.2%, radical prostatectomy in 32.0% (17.3% of these involved laparoscopic prostatectomy), radiation in 21.0% (46.4% of these involved brachytherapy). In cases of organ-confined disease, radical prostatectomy was selected in 39.5%, androgen depletion therapy in 28.0% and radiation in 23.9%. In D'Amico's low-risk group, the proportion treated with radiation was nearly equal to that treated with radical prostatectomy (30.2 and 32.7%, respectively); 73.2% of the radiation treatments involved brachytherapy. Conclusion: Compared with previous Japanese studies, radiation use was increased by similar to 10%. This increased proportion of radiation use was a typical trend in initial therapy for newly diagnosed prostate cancer cases in Japan. Although androgen depletion therapy use was decreased, it was selected in a high proportion of the patients irrespective of the disease stage.

Antiemetic efficacy and safety of a combination of palonosetron, aprepitant, and dexamethasone in patients with testicular germ cell tumor receiving 5-day cisplatin-based combination chemotherapy

Shota Hamada, Shiro Hinotsu, Koji Kawai, Shigeyuki Yamada, Shintaro Narita, Tomomi Kamba, Hiroyuki Nishiyama, Yoichi Arai, Tomonori Habuchi, Osamu Ogawa, Koji Kawakami

SUPPORTIVE CARE IN CANCER ( SPRINGER ) 22 ( 8 ) 2161 - 2166 2014.08 [Refereed]

This study aimed to determine the antiemetic efficacy and safety of a combination of palonosetron, aprepitant, and dexamethasone in patients with testicular germ cell tumor (TGCT) receiving 5-day cisplatin-based combination chemotherapy. An open-label, single-arm, multicenter study was performed in patients with TGCT who were scheduled to receive 5-day cisplatin-based combination chemotherapy. The antiemetic therapy consisted of palonosetron 0.75 mg on day 1, aprepitant 125 mg on day 1 and 80 mg on days 2 to 5, and dexamethasone 9.9 mg on day 1 and 6.6 mg on days 2 to 8. The primary endpoint was complete response (CR) rate, which was defined as no vomiting and no rescue medication, in the overall period (0 to 216 h) in the first chemotherapy course. Incidence and severity of nausea were assessed based on the Common Terminology Criteria for Adverse Events (CTCAE) and a subjective rating scale completed by patients. Thirty patients were included in the analysis. CR was achieved in 90.0 % of the patients in the first chemotherapy course, and high CR rates were also observed in the second and third courses (82.1 and 78.3 %, respectively). The incidence of nausea peaked on days 4 to 6 in about 50 % of the patients. The reported adverse drug reactions were hiccups (13.3 %), anorexia (3.3 %), and stomach pain (3.3 %). None of these were unexpected and none were grade 3 or 4. The combination antiemetic therapy examined in this study was highly effective and well-tolerated in patients with TGCT receiving 5-day cisplatin-based combination chemotherapy.

Age at diagnosis on prostate cancer survival undergoing androgen deprivation therapy as primary treatment in daily practice: results from Japanese observational cohort

Teruo Inamoto, Haruhito Azuma, Shiro Hinotsu, Taiji Tsukamoto, Mototsugu Oya, Osamu Ogawa, Tadaichi Kitamura, Suzuki Kazuhiro, Seiji Naito, Mikio Namiki, Kazuo Nishimura, Yoshihiko Hirao, Michiyuki Usami, Masaru Murai, Hideyuki Akaza

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY ( SPRINGER ) 140 ( 7 ) 1197 - 1204 2014.07 [Refereed]

Primary androgen deprivation therapy (PADT) had been used extensively in Japan than in the USA and European countries regardless of the disease risk or patient's age. To illustrate the consequence of PADT from daily clinical practice, we evaluated the relationship among age, disease risk, and survival of patients with prostate cancer treated by PADT in largest Asian cohort. The 19,246 men subjected to PADT enrolled in the Japan Study Group of Prostate Cancer were enrolled for the present analysis. Patients were divided into four groups based on age at diagnosis: age < 66, 66-70, 71-75, and > 75. Risk was stratified according to the Japan Cancer of the Prostate Risk Assessment (J-CAPRA). Multivariate competing risks regression analysis was performed for OS and PFS. There was downward stage migration over age. Among men aged > 75 years, 34.1 % had nodal or distant metastatic disease. In contrast, 56.0 % of patients aged < 66 years presented with advanced disease. The modality of hormonal therapy varied with age across risk groups; the younger age group showed a higher proportion of maximal androgen blockade, while the proportion of monotherapy use was higher in older men. The likelihood of low-risk disease by J-CAPRA classification increased significantly with increasing age (p < 0.0001 by Pearson's chi-square test). The same as OS, the PFS rate increased with age until after the age of 75. Men aged 71-75 had better survival rates even after adjustments for treatment modality alone, or for treatment modality plus disease risk. Age cohorts do affect orientation toward favorable disease course after PADT with men aged 71-75 being benefiting more from PADT than other age groups.

Bilateral Wilms Tumors Treated According to the Japan Wilms Tumor Study Group Protocol

Takaharu Oue, Tsugumichi Koshinaga, Hajime Okita, Yasuhiko Kaneko, Shiro Hinotsu, Masahiro Fukuzawa

PEDIATRIC BLOOD & CANCER ( WILEY-BLACKWELL ) 61 ( 7 ) 1184 - 1189 2014.07 [Refereed]

Background Children with diffuse intrinsic pontine glioma (DIPG) continue to have poor outcomes, and radiotherapy (RT) is the only temporarily effective treatment. In this retrospective analysis, we studied the effect of time from diagnosis to start of RT on event-free survival (EFS) and overall survival (OS) in children with DIPG. Methods Records of children (n = 95) with DIPG treated with RT at a single institution between April 1999 and September 2009 were analyzed. RT was delivered at doses of 54.0-55.8 Gy at 1.8 Gy per fraction, and children were followed prospectively. The effect of gender, race, interruption during treatment course, age at diagnosis, duration of symptoms prior to diagnosis, use of protocol-based chemotherapy, and time from diagnosis to initiation of RT on EFS and OS was assessed by the Cox proportional hazards model. Results Time as a continuous variable from diagnosis to start of RT did not affect outcome. Time dichotomized to <= 14 days significantly affected OS (hazard ratio [HR] = 1.70, P = 0.014) and race other than white or black affected EFS (HR = 2.32, P = 0.017). The 95 patients had a 6-month EFS and OS of 60 +/- 5% and 94.7 +/- 2.3%, respectively, and a 12-month EFS and OS of 11.6 +/- 3.1% and 49.5 +/- 5%, respectively. Conclusions Time as a continuous variable did not affect OS or EFS in our cohort; however, children treated within 2 weeks of diagnosis had poor outcomes. Although rapid initiation of RT is desirable, our findings do not support intensive efforts aimed at shortening delays from diagnosis to start of RT. Pediatr Blood Cancer 2014;61:1180-1183. (c) 2014 Wiley Periodicals, Inc.

Prognostic impact of young age on stage IV prostate cancer treated with primary androgen deprivation therapy

Tomokazu Kimura, Mizuki Onozawa, Jun Miyazaki, Taeko Matsuoka, Akira Joraku, Koji Kawai, Hiroyuki Nishiyama, Shiro Hinotsu, Hideyuki Akaza

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL ) 21 ( 6 ) 578 - 583 2014.06 [Refereed]

Objectives To elucidate whether the disease characteristics and prognosis of stageIV prostate cancer treated with primary androgen deprivation therapy differ between young and elderly patients. Methods A total of 3006 patients identified from the database of the Japan Study Group of Prostate Cancer were included in the analysis according to the following entry criteria: age of 75 years or less and stageIV disease. These patients were stratified into three groups: young (aged 55 years); middle-aged (aged 56 and 65 years); and elderly (aged 66 and 75 years). Their prognoses were analyzed both within age groups and according to whether or not there was metastasis. Results The proportion of lymph node metastasis was significantly higher in the young group than in the elderly group (P=0.007), and there were no significant differences in other factors among age groups. The overall survival rate at 5 years in the young group was significantly worse than that in the middle-aged and elderly groups (26.6%, 59.7% and 55.3%, respectively) in patients with stageIV disease with metastasis, although there was no difference among age groups in patients with stageIV disease without metastasis. Multivariate analysis showed that younger age was an independent strong prognostic factor in stageIV disease with metastasis. Conclusions Young men with metastatic prostate cancer have a poor prognosis. Young age is an independent prognostic factor in stageIV metastatic prostate cancer patients treated with primary androgen deprivation therapy.

Nadir prostate-specific antigen (PSA) level and time to PSA nadir following primary androgen deprivation therapy as independent prognostic factors in a Japanese large-scale prospective cohort study (J-CaP)

Yasuhide Kitagawa, Satoru Ueno, Kouji Izumi, Atsushi Mizokami, Shiro Hinotsu, Hideyuki Akaza, Mikio Namiki

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY ( SPRINGER ) 140 ( 4 ) 673 - 679 2014.04 [Refereed]

Purpose The aim of this study was to investigate whether nadir prostate-specific antigen (PSA) level and time to PSA nadir (TTN) are independent prognostic factors equivalent to the pretreatment factors in the data of the Japan Study Group of Prostate Cancer registry, which is a large, multicenter, population-based database of patients undergoing primary androgen deprivation therapy (PADT). Methods A total of 10,958 patients treated with PADT were enrolled into the present study. Univariate and multivariate Cox proportional hazards regression analysis and Kaplan-Meier analysis were used to evaluate the associations of PSA nadir level and TTN with progression-free survival (PFS) and overall survival (OS), adjusting for the pretreatment factors adopted in the Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score. Results Of the 10,958 patients, 3,451 (31.5 %) had lymph node and/or distant metastases. The median PSA level was 27.0 ng/ml before treatment, and the nadir PSA level in 6,983 patients (63.7 %) reached below 0.2 ng/ml. Disease progression occurred in 4,736 cases, and 2,163 patients died during a mean follow-up period of 3.86 years. Nadir PSA level and TTN were independent prognostic factors, similar to the pretreatment factors adopted in the J-CAPRA score. The probabilities of PFS and OS showed significant differences among the groups categorized by the combination of nadir PSA level and TTN in all J-CAPRA risk stratifications. Conclusions The present study demonstrated that nadir PSA level and TTN are strong predictors in patients undergoing PADT in a large-scale prospective cohort study.

Application of a Self-Controlled Case Series Study to a Database Study in Children

Hanae Ueyama, Shiro Hinotsu, Shiro Tanaka, Hisashi Urushihara, Masaki Nakamura, Yuji Nakamura, Koji Kawakami

DRUG SAFETY ( ADIS INT LTD ) 37 ( 4 ) 259 - 268 2014.04 [Refereed]

Post-marketing surveillance activities are particularly important for safety issues in children, the elderly, and patients with severe comorbidities since these populations are usually excluded from clinical trials. In addition, using electronic databases for monitoring of safety of marketed products has been of considerable interest. This study aimed to clarify the advantages and difficulties of the self-controlled case series method relative to cohort studies in pharmacoepidemiological studies in children, using an administrative database, and to explore the impact on results of handling the period eligible for analysis and recurrent events in different ways. Datasets of only individuals who had the outcome of interest were derived from an anonymized hospital administrative database in Japan from April 2003 through August 2011. We calculated incidence rate ratios (IRRs) and their 95 % confidence intervals (CIs) for the risks of diarrhea, bronchitis, and eczema related to palivizumab treatment in young children. The analysis included 'first diagnosed' events or 'multiple' events during an eligible period. An eligible period was defined in two ways: first-time inpatient periods of more than 3 continuous days (EPA); and a continuous period in cases where the interval between visits was below the 75th percentile of the interval between visits for patients with the same diagnosis (EPB). We extracted data for 70,771 patients and identified 641 who were exposed to palivizumab. The age-adjusted IRRs for diarrhea, bronchitis, and eczema were 3.0 (95 % CI 1.7-5.4), 10.3 (95 % CI 8.0-13.2), and 16.9 (95 % CI 12-23), respectively, in multiple events and the EPB eligible period. The IRRs varied greatly between the two eligible periods. This method could be a useful tool in pharmacoepidemiological studies in children. Careful consideration in the handling of inpatient and outpatient periods, including sensitivity analyses, is necessary because this method is a within-individual comparison.

Multicenter phase II clinical trial of everolimus in Japanese patients with unresectable or metastatic renal cell carcinoma (mRCC) after failure of treatment with first-line tyrosine kinase inhibitor (TKI) therapy

Seiichiro Ozono, Masafumi Oyama, Masahiro Nozawa, Kiyohide Fujimoto, Ken Kishida, Noriaki Tokuda, Go Kimura, Kazuo Nishimura, Akio Matsubara, Hideyasu Matsuyama, Takayuki Sugiyama, Tomomi Kamba, Haruki Kume, Naoya Masumori, Mototsugu Oya, Hiro-Omi Kanayama, Seiji Naito, Shiro Hinotsu, Kojiro Shimozuma, Hideyuki Akaza

JOURNAL OF CLINICAL ONCOLOGY ( AMER SOC CLINICAL ONCOLOGY ) 32 ( 4 ) 2014.02 [Refereed]

Seventh Joint Meeting of K-J-CaP and CaPSURE: extending the global initiative to improve prostate cancer management.

Akaza H, Kim CS, Carroll P, Choi IY, Chung BH, Cooperberg MR, Hirao Y, Hinotsu S, Horie S, Lee JY, Namiki M, Ng CF, Onozawa M, Ozono S, Ueno S, Umbas R, Ye D, Zhu G

Prostate international 2 ( 2 ) 50 - 69 2014 [Refereed]

Selection of appropriate design in the development of interventional and observational research

Shiro Hinotsu

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. ) 41 ( 4 ) 405 - 409 2014 [Refereed]

Selecting the appropriate study design is crucial when developing clinical research. A fundamental decision is whether to collect data to address the research question using an observational study or to apply an intervention and measure outcomes in a clinical trial. There are two well-known types of observational studies: cohort studies and cross-sectional studies. In the former, a cohort of subjects is observed over time. In prospective cohort studies, observations begin in the present and follow subjects for a given time period. In retrospective cohort studies, information is collected at time intervals in the past. The third potential study design is the case-control study. In such studies, the researcher compares a group of subjects who have a disease or some other outcome with a group without that characteristic. Among clinical trial options, the randomized clinical trial is thought to be higher evidence level than other clinical trials. Developing clinical research begins with the research question, which specifies the primary endpoint, explanatory variables, and the target population. Then, the clinical question and study outline are expanded to the study protocol and case report form. In developing the study protocol, the investigators consider study design, study size, data quality, and feasibility.

NCCN Asian Consensus Statement - Can Asian patients with cancer accept treatment modalities from NCCN guidelines?

Seiichiro Ozono, Shiro Hinotsu, Mikio Namiki, Hideyuki Akaza

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. ) 41 ( 6 ) 683 - 686 2014 [Refereed]

To spread the National Comprehensive Cancer Network (NCCN) guidelines widely in Asia, committee members from Asian countries have been preparing an Asia Consensus Statement (ACS) along the NCCN guidelines. The ACS for Kidney Cancer guidelines and Prostate Cancer guidelines were issued in 2009 and in 2011, respectively. In addition, second versions of both these guidelines were issued in 2011 and 2013, respectively. In this review, the process and contents of NCCN ACS have been described.

Does late morning waking-up affect sleep during the following night in patients with primary insomnia?

Atsushi Ogawa, Shiro Hinotsu, Koji Kawakami

BIOLOGICAL RHYTHM RESEARCH ( TAYLOR & FRANCIS LTD ) 44 ( 6 ) 938 - 948 2013.12 [Refereed]

Night-to-night variability in sleep duration and schedule is common in patients with insomnia. Among the various sleep variables, waking-up time is focused upon as the important factor for cognitive behavioural therapy for insomnia. This study examined the effect of a single late waking-up episode on sleep in the immediate following night in patients with chronic insomnia, using data from a placebo group (380 patients) of a double-blind placebo-controlled study. Patients tended to wake up later and have a longer total sleep time on weekends than weekdays. It was suggested that patients who woke up late one morning (>= 60 min later than the individual's regular waking-up time) extended their sleep onset latency by 4.3min in the immediate following night. The effects of late waking-up on total sleep time and bedtime were not clear. The importance of keeping regular waking-up time is highlighted for better sleep in patients with insomnia.

Prescription patterns following first-line new generation antidepressants for depression in Japan: A naturalistic cohort study based on a large claims database

Toshi A. Furukawa, Yoshie Onishi, Shiro Hinotsu, Aran Tajika, Nozomi Takeshima, Kiyomi Shinohara, Yusuke Ogawa, Yu Hayasaka, Koji Kawakami

Journal of Affective Disorders ( Elsevier B.V. ) 150 ( 3 ) 916 - 922 2013.09 [Refereed]

Background: Several studies have described real-world prescription patterns of first-line antidepressants for depression but little is known about their fate in terms of duration, intensity and changes. Methods: An inception cohort of new onset non-psychotic depression initiating antidepressant treatment with a new generation antidpressive agent was identified in a large health insurance claims database in Japan between 2009 and 2010. The duration and intensity of first-line antidepressants, the timing and kind of second-line antidepressants and the total duration of antidepressant treatment were examined. Results: We identified 1592 patients. The starting dose and the maximum dose attained with the firstline agent appeared to be largely in line with the guideline recommendations although the latter tended toward the minimum of the recommended range. The continuity of the first-line antidepressant was far below the guideline recommendations, with 28%never returning after the initial prescription and 55%dropping out within 3 months. Of all the first-line antidepressants, 14%were subsequently augmented by another psychotropic agent while 17%were switched to another antidepressant after a median of 3 or 2 months, respectively. The choice of the second-line agents varied extremely widely. The total duration of antidepressant therapy was as short as a median of 4 months, with 68%stopping treatment by 6 months. Limitations: The diagnosis of non-psychotic unipolar depression in the claims database analyses remains approximate. Conclusions: The current guidelines are grossly out of touch with the clinical realities. On the one hand, guidelines need to reflect the real-world practices on the other hand clinicians should limit their treatment options and allow evidence-based comparative effectiveness research among them so that patients shall no longer be given less effective and more effective treatments without being able to distinguish among them. © 2013 Elsevier B.V. All rights reserved.

Validation of the prognostic grouping of the seventh edition of the tumor-nodes-metastasis classification using a large-scale prospective cohort study database of prostate cancer treated with primary androgen deprivation therapy

Tomokazu Kimura, Mizuki Onozawa, Jun Miyazaki, Koji Kawai, Hiroyuki Nishiyama, Shiro Hinotsu, Hideyuki Akaza

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL ) 20 ( 9 ) 880 - 888 2013.09 [Refereed]

Objective: In the TNM seventh edition, a prognostic grouping for prostate cancer incorporating prostate-specific antigen and Gleason score was advocated. The present study was carried out to evaluate and validate prognostic grouping in prostate cancer patients. Methods: The 15259 study patients treated with primary androgen deprivation therapy were enrolled in the Japan Study Group of Prostate Cancer. Overall survival was stratified by tumor-nodes-metastasis, Gleason score and prostate-specific antigen, and extensively analyzed. The accuracy of grouping systems was evaluated by the concordance index. Results: The 5-year overall survival in prognostic grouping-I, IIA, IIB, III and IV was 90.0%, 88.3%, 84.8%, 80.6% and 57.1%, respectively. When considering subgroup stratification, the 5-year overall survival of subgroups prognostic grouping-IIA, IIB, III and IV was 80.9 approximate to 90.5%, 75.4 approximate to 91.8%, 75.7 approximate to 89.0% and 46.9 approximate to 86.2%, respectively. When prognostic grouping-IIB was subclassified into IIB1 (except IIB2) and IIB2 (T1-2b, prostate-specific antigen >20, Gleason score 8, and T2c, Gleason score 8), the 5-year overall survival of IIB2 was significantly lower than that of IIB1 (79.4% and 87.3%, P<0.0001). Also, when prognostic grouping-IV was subclassified into IV1 (except IV2) and IV2 (M1, prostate-specific antigen >100 or Gleason score 8), the 5-year overall survival of prognostic grouping-IV1 was superior to that of IV2 (72.9% and 49.5%, P<0.0001). Prognostic groupings were reclassified into modified prognostic groupings, divided into modified prognostic grouping-A (prognostic grouping-I, IIA, and IIB1), modified prognostic grouping-B (prognostic grouping-IIB2 and III), modified prognostic grouping-C (prognostic grouping-IV1) and modified prognostic grouping-D (prognostic grouping-IV2). The concordance index of prognostic grouping and modified prognostic grouping for overall survival was 0.670 and 0.685, respectively. Conclusion: Prognostic grouping could stratify the prognosis of prostate cancer patients. However, there is considerable variation among the prognostic grouping subgroups. Thus, the use of a modified prognostic grouping for patients treated with primary androgen deprivation therapy is advisable.

Does late morning waking-up affect sleep during the following night in patients with primary insomnia?

Atsushi Ogawa, Shiro Hinotsu, Koji Kawakami

JOURNAL OF BIOLOGICAL EDUCATION ( ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD ) 47 ( 3 ) 938 - 948 2013.09 [Refereed]

Night-to-night variability in sleep duration and schedule is common in patients with insomnia. Among the various sleep variables, waking-up time is focused upon as the important factor for cognitive behavioural therapy for insomnia. This study examined the effect of a single late waking-up episode on sleep in the immediate following night in patients with chronic insomnia, using data from a placebo group (380 patients) of a double-blind placebo-controlled study. Patients tended to wake up later and have a longer total sleep time on weekends than weekdays. It was suggested that patients who woke up late one morning ( <inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="nbrr_a_781329_o_ilm0001.gif"></inline-graphic> later than the individual's regular waking-up time) extended their sleep onset latency by 4.3min in the immediate following night. The effects of late waking-up on total sleep time and bedtime were not clear. The importance of keeping regular waking-up time is highlighted for better sleep in patients with insomnia.

Adverse reactions related to treatment compliance during BCG maintenance therapy for non-muscle-invasive bladder cancer

Jun Miyazaki, Shiro Hinotsu, Naoki Ishizuka, Seiji Naito, Seiichiro Ozono, Hideyuki Akaza, Hiroyuki Nishiyama

Japanese Journal of Clinical Oncology 43 ( 8 ) 827 - 834 2013.08 [Refereed]

Objective: The aim of the study was to investigate the factor of adverse reactions related to compliance with Mycobacterium bovis bacillus Calmette-Gué rin maintenance therapy in patients with high-risk non-muscle-invasive bladder cancer. Methods: This study was a post hoc analysis using the database of a randomized controlled trial that examined the efficacy of bacillus Calmette-Gué rin (Connaught strain) maintenance therapy. Among the 42 patients assigned to the bacillus Calmette-Gué rin maintenance therapy group, six patients dropped out or withdrew consent before the bacillus Calmette- Gué rin maintenance therapy. The adverse reactions and clinical backgrounds of the remaining 36 patients who underwent bacillus Calmette-Gué rin maintenance therapy were compared between the two groups: the patients who completed the bacillus Calmette-Gué rin maintenance therapy (the Completed group), and those who discontinued the bacillus Calmette- Gué rin maintenance therapy (the Discontinued group). Results: Of the 36 patients who underwent bacillus Calmette-Gué rin maintenance therapy, 15 (41.7%) were in the Completed group and 21 (58.3%) were in the Discontinued group. Local adverse reactions (≥G2) were observed during maintenance therapy in 86.7% of the Completed group and 95.2% of the Discontinued group. As for adverse reactions during the induction therapy (bacillus Calmette-Gué rin induction therapy), the frequencies of gross hematuria and systemic adverse reactions (any grade) tended to be higher in the Discontinued group than in the Completed group, although not significantly so. In the Cochran-Armitage trend test, the linear T trend (i.e. the trend in the risk of an increased rate of discontinuation according to gross hematuria and systemic adverse reactions with bacillus Calmette-Gué rin induction therapy) was statistically significant (P = 0.0179). Conclusions: Most patients who completed bacillus Calmette-Gué rin maintenance therapy experienced local adverse reactions (≥G2) during the maintenance therapy. Gross hematuria and systemic adverse reactions during bacillus Calmette-Gué rin induction therapy might be related to the discontinuation of bacillus Calmette-Gué rin maintenance therapy because of severe adverse reactions. © The Author 2013. Published by Oxford University Press. All rights reserved.

Japan Cancer of the Prostate Risk Assessment for combined androgen blockade including bicalutamide: Clinical application and validation

Yasuhide Kitagawa, Shiro Hinotsu, Kazuyoshi Shigehara, Kazufumi Nakashima, Shohei Kawaguchi, Hiroshi Yaegashi, Atsushi Mizokami, Hideyuki Akaza, Mikio Namiki

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL ) 20 ( 7 ) 708 - 714 2013.07 [Refereed]

Objectives: The Japan Cancer of the Prostate Risk Assessment was developed as a risk stratification instrument for patients undergoing primary androgen deprivation therapy. However, there have been no studies to validate the accuracy of the Japan Cancer of the Prostate Risk Assessment in predicting clinical outcomes. We examined whether the clinical outcomes of patients treated with combined androgen blockade could be stratified using the Japan Cancer of the Prostate Risk Assessment. Methods: A total of 319 patients with prostate cancer treated with luteinizing hormone-releasing hormone agonist plus bicalutamide were included in this analysis. Progression-free survival, cause-specific survival and overall survival were compared among patients divided according to the prostate-specific antigen level at diagnosis, Gleason score on biopsy specimens, tumor-nodes-metastasis classification and Japan Cancer of the Prostate Risk Assessment score. Results: The median age of the patients was 75years, and the median prostate-specific antigen at diagnosis was 25.4ng/mL. A total of 102 patients (32.0%) had lymph node and/or distant metastases. On univariate analysis, the factors adopted in the Japan Cancer of the Prostate Risk Assessment points were significant predictors of progression-free survival. On multivariate analysis, clinical T stage and M stage were significant predictors of progression-free survival. The probabilities of progression-free survival and cause-specific survival were significantly different among the groups categorized according to the Japan Cancer of the Prostate Risk Assessment risk strata. The probability of overall survival in the low-risk group was higher than in the other groups. Conclusions: The progression-free survival, cause-specific survival and overall survival of prostate cancer patients treated by combined androgen blockade with bicalutamide were stratified by the Japan Cancer of the Prostate Risk Assessment. The Japan Cancer of the Prostate Risk Assessment score is clinically useful as a predictor of the prognosis of prostate cancer treated with combined androgen blockade.

Sixth Joint Meeting of J-CaP and CaPSUREuA Multinational Perspective on Prostate Cancer Management and Patient Outcomes

Hideyuki Akaza, Shiro Hinotsu, Matthew R. Cooperberg, Byung-Ha Chung, Ji Youl Lee, Rainy Umbas, Taiji Tsukamoto, Mikio Namiki, Peter Carroll

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 43 ( 7 ) 756 - 766 2013.07 [Refereed]

This report summarizes the presentations and discussions that took place at the Sixth Joint Meeting of J-CaP and CaPSURE held in San Francisco, USA, in August 2012. The J-CaP and CaPSURE Joint Initiative was established in 2007 with the objective of analyzing, reviewing, comparing and contrasting data for prostate cancer patients from Japan and the USA within the two important large-scale, longitudinal, observational databasesuJ-CaP and CaPSURE. Since this initial collaboration between teams in the USA and Japan, the initiative has now expanded to include representatives of other Asian countries, several of whom have either established or are planning their own national prostate cancer databases. Several key topics were considered at this Sixth Joint Meeting including the current status of the J-CaP and CaPSURE databases and opportunities for collaboration with the more recently developed Asian prostate cancer databases. The latest comparative data from J-CaP and CaPSURE regarding outcomes following androgen deprivation therapy and combined androgen blockade were also reviewed. The possibility of a global chemoprevention trial to investigate the influence of soy isoflavones on prostate cancer incidence was considered. In addition, the ongoing debate regarding the role of screening and the use of active surveillance as a treatment option in the USA was discussed. The collaborators agreed that sharing of data and treatment practices on a global scale would undoubtedly benefit the clinical management of prostate cancer patients worldwide.

Economic evaluation of pravastatin for primary prevention of coronary artery disease based on risk prediction from JALS-ECC in Japan

Yoshie Onishi, Shiro Hinotsu, Yoko M. Nakao, Hisashi Urushihara, Koji Kawakami

Value in Health Regional Issues 2 ( 1 ) 5 - 12 2013.05 [Refereed]

Objectives: The clinical efficacy of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin) therapy in cardiovascular disease has been established in clinical trials. Nonetheless, it is unclear to whom and when statin treatment should be initiated for patients without cardiovascular disease with regard to overall absolute risk reduction of cardiovascular disease and the cost-effectiveness of long-term statin therapy. The objective of this study was to examine the cost-effectiveness of pravastatin 10 mg/d compared with no-drug therapy for primary prevention of coronary artery disease (CAD), using cardiac risk factors from risk predictions for CAD from Japanese cohort studies. Methods: A Markov transition model was used to evaluate the cost-effectiveness of pravastatin compared with no-drug therapy. The incidence of acute myocardial infarction was estimated by using risk predictions for CAD in Japan. A hypothetical population from 45 to 75 years old was examined by using the cardiac risk factors. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio over a lifetime horizon were estimated from a perspective of payers. Results: Incremental cost-effectiveness ratios of pravastatin therapy compared with no-drug therapy were 9,677,000 yen per QALY in 55-year-old men and 8,648,000 yen per QALY in 65-year-old men with diabetes mellitus, hypertension (grade II), and smoking as cardiac risk factors. Pravastatin therapy was not cost-effective compared with no-drug therapy in all subgroups evaluated. Conclusions: Using risk prediction for CAD based on a Japanese cohort with no history of cardiovascular events, the cost-effectiveness of pravastatin for primary prevention of CAD may not be cost-effective in populations at both low and high cardiac risk. © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR).

Socioeconomic advantages of longer screening intervals for men with low prostate-specific antigen levels in prostate cancer mass screening

Takashi Kobayashi, Rei Goto, Shiro Hinotsu, Osamu Ogawa

Acta Urologica Japonica 59 ( 3 ) 159 - 166 2013.03 [Refereed]

In prostate specific antigen (PSA)-based prostate cancer mass screening, the optimal re-screening interval is still in question, although guidelines suggest that a prolonged interval would be safe and cost-saving. We examined the socioeconomic feasibility of prolonged re-screening interval based on individual baseline PSA values. Markov decision-analytic models of prostate cancer screening were established for cost-effectiveness comparison of prolonged re-screening in men with low (≤ 1 ng/ml) PSA level (metainterval strategy) and annual re-screening in every participant (control strategy). Effectiveness and socioeconomic feasibility were evaluated according to quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER Δ cost per Δ QALY), respectively. As a result, outcomes including cancer detection rates and stage shift suggested that these models well recapitulated actual prostate cancer mass screening. The meta-interval strategy was more cost-effective than the control strategy. The ICER for the control strategy with respect to the meta-interval strategy exceeded US$62,000/QALY through the sensitivity analyses for every assumption. The meta-interval strategy was more effective and less expensive if the trade-off of impaired clinical outcomes caused by delayed detection was small. In conclusion, our models suggest that the meta-interval strategy is more cost-effective than annual screening. It can be even more effective if the interval is determined appropriately such that cancer can be detected within the therapeutic window.

Randomized controlled study of natural interferon α as adjuvant treatment for stage II or III renal cell carcinoma

Shiro Hinotsu, Koji Kawai, Seiichiro Ozono, Tomoyasu Tsushima, Noriaki Tokuda, Koichiro Nomata, Seiji Naito, Hideyuki Akaza

International Journal of Clinical Oncology 18 ( 1 ) 68 - 74 2013.02 [Refereed]

Background: The prophylactic effect of postoperative interferon on recurrence and distant metastasis in stage II or III renal cell carcinoma is unclear. In most studies, interferon has been administered for 6 months or less. Therefore, we performed a clinical study of the efficacy of 1-year postoperative administration of natural interferon α, which is generally used in Japan. Methods: The subjects were patients diagnosed with stage II or III renal cell carcinoma who underwent radical nephrectomy. The subjects were randomly allocated to receive an intramuscular injection of natural interferon α (3 million to 6 million units) 3 times a week for 1 year or to receive follow-up observation until recurrence or metastasis occurred. Chest and abdominal CT were performed once yearly for all patients. The primary endpoint was progression-free survival. Results: From September 2001 to August 2006, a total of 107 patients were registered, but 7 subsequently withdrew from the study. Therefore, 100 patients were included in the analysis. The primary endpoint of progression-free survival did not differ significantly between the groups that received natural interferon α or follow-up observation (p = 0.456, log-rank test). However, peak hazards of progression in the interferon group were delayed for about 6-10 months compared with the observation group. Conclusion: Progression-free survival showed no improvement after administration of natural interferon α to patients with stage II or III renal cell carcinoma for 1 year after radical nephrectomy. The peak hazards of progression might be delayed by about 6 months by interferon administration. © 2011 Japan Society of Clinical Oncology.

Predictive value of clinical chorioamnionitis in extremely premature infants

Hironobu Tokumasu, Shiro Hinotsu, Fumiyo Kita, Koji Kawakami

PEDIATRICS INTERNATIONAL ( WILEY-BLACKWELL ) 55 ( 1 ) 35 - 38 2013.02 [Refereed]

Background Clinical chorioamnionitis and histological chorioamnionitis are important risk factors for neonatal complications and neurodevelopmental impairment in premature infants. It is unclear, however, whether a diagnosis of clinical chorioamnionitis is sufficient to establish a diagnosis of histological chorioamnionitis. The aim of this study was to evaluate the predictive value of clinical chorioamnionitis in the diagnosis of histological chorioamnionitis in extremely premature infants. Methods This study was a secondary analysis of data from the Neonatal Research Network in Japan, a population-based cohort study aimed at identifying the clinical characteristics and morbidity of very low-birthweight infants. Data for extremely premature infants <28weeks' gestational age from 2003 to 2007, were used. Subset analysis investigated positive predictive value by gestational age. Results Of the 2470 infants analyzed, 786 were diagnosed with clinical chorioamnionitis and 1129 with histological chorioamnionitis. The positive predictive value of clinical chorioamnionitis for histological chorioamnionitis was 86.6% (681/786; 95% confidence interval [CI]: 84.488.6%), sensitivity was 60.3% (681/1129; 95%CI: 58.861.7%), and specificity was 92.2% (1236/1341; 95%CI: 90.993.3%). In subset analysis, the positive predictive value was particularly high at 23weeks of gestation (89.1%; 115/129), with sensitivity of 65.3% (115/176) and specificity of 89.6% (120/134). Conclusions The finding that clinical chorioamnionitis is a useful predictor of histological chorioamnionitis provides important insights into the relationship between these two diagnoses, and has important implications in determining the appropriate timing of delivery of extremely premature infants.

A survey of physicians' understanding of the regulatory systems for clinical trials in japan.

Yamauchi Y, Kawashima Y, Urushihara H, Uosaki F, Kobayashi Y, Hinotsu S, Nakagawa M, Kawakami K

General Medicine 14(2) 92-103 2013.02 [Refereed]

Cross-National Comparison of Medical Costs Shared by Payers and Patients: A Study of Postmenopausal Women with Early-Stage Breast Cancer Based on Assumption Case Scenarios and Reimbursement Fees

Shota Hamada, Shiro Hinotsu, Hiroshi Ishiguro, Masakazu Toi, Koji Kawakami

BREAST CARE ( KARGER ) 8 ( 4 ) 282 - 288 2013 [Refereed]

Background: The objectives of this study were to estimate and cross-nationally compare the medical costs shared by payers and patients and the distributions of medical costs by cost category. Material and Methods: We estimated the medical costs covered from definitive diagnosis to completion of treatments of early-stage breast cancer and follow-up, assuming almost identical medical care provided in Japan, the UK, and Germany. The analysis was performed from the payer's perspective. Medical costs were calculated by multiplying the unit costs by the number of units consumed, based on assumption case scenarios. The medical costs incurred by payers or patients were estimated according to the cost-sharing and the cost-bearing systems in each country. Results: The total medical costs in Japan were much lower than those in the UK and Germany, and these differences were mainly caused by the low costs of surgery and radiotherapy in Japan. For the base-case scenario, the co-payment in Japan ((sic) 3,486) was found to be 6.4-fold higher than that in Germany ((sic) 548). The payers in the European countries paid 2.9-fold more than those in Japan ((sic) similar to 25,000 vs. (sic) 8,627). Conclusion: Our results will be useful for policy makers in considering how to share medical costs and how to allocate limited resources.

Psychotropic Prescription Patterns Among Patients Diagnosed With Depressive Disorder Based on Claims Database in Japan

Yoshie Onishi, Shiro Hinotsu, Toshiaki A. Furukawa, Koji Kawakami

CLINICAL DRUG INVESTIGATION ( ADIS INT LTD ) 33 ( 8 ) 597 - 605 2013 [Refereed]

Clinical guidelines recommend monotherapy with antidepressants for the treatment of major depression. This study examined prescription patterns with regard to both duration and type of treatment used among patients with newly diagnosed non-psychotic major depression based on a claims database from health insurance societies between 2008 and 2011 in Japan. A retrospective cohort (N = 600,000) followed up for 4 years was used to identify patients (age a parts per thousand yen18 years) with newly diagnosed non-psychotic major depression. The prescription patterns and polypharmacy were examined. Four different types of pharmaceutical drugs were defined as possible psychotropic agents for major depression: (1) first- and/or second-generation antidepressants; (2) benzodiazepines; (3) sulpiride; and (4) antipsychotics. The data were analyzed by an intent-to-treat approach at months 0, 1, 3, 6, and 12 from the date of diagnosis. A total of 7,338 patients (3,684 males and 3,654 females, mean age 36.8 +/- A 10.9 years) with newly diagnosed non-psychotic major depression were identified. The median duration of treatment was 122 days. The proportion of patients in the cohort prescribed at least one type of defined psychotropic agents was 75.6 % (month 0), 47.3 % (month 1), 36.0 % (month 3), 26.8 % (month 6), and 17.4 % (month 12). The proportion of patients in the cohort prescribed at least one first- and/or second-generation antidepressant was 50.2 % (month 0), 34.9 % (month 1), 27.5 % (month 3), 20.3 % (month 6), and 12.5 % (month 12). The proportion of patients receiving at least one benzodiazepine was 58.0 % (month 0), 36.7 % (month 1), 27.1 % (month 3), 20.0 % (month 6), and 12.0 % (month 12). The proportion of patients receiving an antidepressant as monotherapy was only 12.0 % (month 0), 7.8 % (month 1), 6.5 % (month 3), 4.8 % (month 6), and 2.9 % (month 12), whereas the proportion of patients treated with a benzodiazepine alone was 13.5 % (month 0), 6.9 % (month 1), 4.6 % (month 3), 3.5 % (month 6), and 2.7 % (month 12). Various combinations of polypharmacy were observed. The most common was a combination of at least one antidepressant and benzodiazepine, which was prescribed to 36.7 % (month 0), 25.8 % (month 1), 19.9 % (month 3), 14.9 % (month 6), and 9.2 % (month 12) of the cohort. Based on analysis of prescription patterns and type of treatment used for treating non-psychotic major depression, a majority of patients were not treated according to the recommended guidelines in Japan. Various patterns of prescription and use of polypharmacy were observed over time. The median duration of treatment was shorter than the recommendation (6 months) in the guidelines.

Evaluation of primary androgen deprivation therapy in prostate cancer patients using the J-CAPRA risk score.

Akaza H, Hinotsu S, Usami M, Ogawa O, Kitamura T, Suzuki K, Tsukamoto T, Naito S, Namiki M, Hirao Y, Murai M

Prostate international 1 ( 2 ) 81 - 88 2013 [Refereed] [International journal]

PURPOSE: To determine the influence of maximal androgen blockade (MAB) and non-MAB hormonal therapy with an luteinizing hormone releasing hormone (LHRH) analog on overall survival of prostate cancer patients in the Japan Study Group of Prostate Cancer (J-CaP) registry according to risk, as assessed using the novel J-CAPRA risk instrument. To undertake a multivariate analysis combining J-CAPRA risk score, type of hormonal therapy and comorbidities, in order to assess their impact on overall survival. METHODS: The J-CaP database includes men in Japan diagnosed with any stage of prostate cancer between 2001 and 2003 and treated with primary androgen deprivation therapy (PADT), as monotherapy or in combination. A total of 26,272 men were enrolled and of these 19,265 were treated with PADT. This analysis was undertaken using the latest data set (30 April, 2010) including a total of 15,727 patients who received PADT and had follow-up data for periods ranging from 0 to 9.2 years. RESULTS: MAB for prostate cancer patients with intermediate- or high-risk disease has a significant benefit in terms of overall survival compared with LHRH analog monotherapy or surgical castration alone. Better results may be achieved in older (≥75 years) patients. Patient comorbidities are an important factor in determining overall survival, notably in older patients, and should be considered when selecting therapy. CONCLUSIONS: Based on large-scale registry data, this report is the first to analyze the outcomes of MAB therapy in patients with prostate cancer at a wide range of disease stages. MAB therapy may provide significant survival benefits in intermediate- and high-risk patients.

A survey of non-small cell lung cancer patients with meningeal carcinomatosis in Japan: Incidence and medical resource consumption.

S.Ohno, S.Hinotsu, K.Murata, S.Tanaka, K.Kawakami

Adv Pharmacoepidem Drug Safety 2 133 2013 [Refereed]

Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor

Junjiro Ohshima, Masayuki Haruta, Yuiko Fujiwara, Naoki Watanabe, Yasuhito Arai, Tadashi Ariga, Hajime Okita, Tsugumichi Koshinaga, Takaharu Oue, Shiro Hinotsu, Hisaya Nakadate, Hiroshi Horie, Masahiro Fukuzawa, Yasuhiko Kaneko

PEDIATRIC BLOOD & CANCER ( WILEY ) 59 ( 3 ) 499 - 505 2012.09 [Refereed]

Background Wilms tumor (WT) has a survival rate of 90% following multimodality therapy. Nevertheless, there are some groups of patients with event-free survival rates less than 75%. In addition to clinical prognostic factors, loss of heterozygosity at 1p and/or 16q has been used to determine treatment intensity. However, the incidence of this abnormality is low, and new biomarkers are still needed. Procedure We analyzed methylation status of three tumor suppressor genes; Ras-association domain family 1 protein, isoform A (RASSF1A), DCR2, and CASP8, in 84 WTs using conventional methylation-specific PCR (cMSP), and the results were correlated with outcome. Furthermore, we analyzed the methylation status of RASSF1A by quantitative MSP (qMSP) in 171 WTs, and evaluated clinical and genetic differences between the methylated and unmethylated tumors. Results RASSF1A was the most frequently methylated gene identified by cMSP, and associated with a poor outcome. Patients with a RASSF1A-methylated tumor had shorter overall and event-free survival periods (P?=?0.043 and 0.018, respectively), when a cut-off value of 7% by qMSP was used. The methylation was more frequent in tumors of older children than younger children (P?<?0.001), and in advanced-stage tumors than early stage tumors (P?=?0.001). However, multivariate analysis could not confirm the prognostic significance of RASSF1A methylation, possibly because of a small number of advanced stage tumors examined. RASSF1A methylation was correlated with LOH at 1p and/or 16q (P?=?0.017), but not with WT1 abnormality, suggesting the methylation and LOH to involve the same tumorigenic pathway. Conclusions The methylation status of RASSF1A might be a novel biomarker to predict outcome of WT patients. Pediatr Blood Cancer 2012;59:499505. (c) 2012 Wiley Periodicals, Inc.

Analysis of Intravesical Recurrence After Bladder-preserving Therapy for Muscle-invasive Bladder Cancer

Mizuki Onozawa, Naoto Miyanaga, Shiro Hinotsu, Jun Miyazaki, Takehiro Oikawa, Tomokazu Kimura, Ei-ichiro Takaoka, Koji Kawai, Toru Shimazui, Hideyuki Sakurai, Hiroyuki Nishiyama, Hideyuki Akaza

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 42 ( 9 ) 825 - 830 2012.09 [Refereed]

The aim of the present study was to analyze the pattern of recurrences after bladder-preserving therapy for muscle-invasive bladder cancer. The subjects were 77 patients with T2-3N0M0 bladder cancer whose bladder was preserved by intra-arterial chemotherapy and radiation. The patterns of the first recurrences were retrospectively analyzed. With a median follow-up of 38.5 months, 17 patients (22.1) experienced intravesical recurrence without metastasis, 14 (82.4) of which were cases of non-muscle-invasive bladder cancer recurrence and 3 (17.6) of which were muscle-invasive bladder cancer recurrences. Muscle-invasive bladder cancer recurred at the same site as the initial tumor site in all three cases, whereas non-muscle-invasive bladder cancer recurred at different sites in 64 of the patients in that group. The peak hazard of the non-muscle-invasive bladder cancer recurrence was observed at around a year after treatment. Recurrent non-muscle-invasive bladder cancer was of a significantly lower histological grade with lower Ki-67-labeling indices than the initial muscle-invasive bladder cancer. Twelve (85.7) of 14 patients with non-muscle-invasive bladder cancer recurrence achieved disease-free status. The multivariate analysis revealed that multiplicity, grade and tumor size were significantly correlated with the recurrence (P 0.0001, 0.0442 and 0.0412, respectively). Most of the recurrences after bladder-preserving therapy were cases of non-muscle-invasive bladder cancer. The recurrence pattern and characteristics of the tumors did not differ from those of primary non-muscle-invasive bladder cancer. Patients with high-risk factors would be candidates for prophylactic intravesical therapy for non-muscle-invasive bladder cancer recurrence.

The cost of antiemetic therapy for chemotherapy-induced nausea and vomiting in patients receiving platinum-containing regimens in daily practice in Japan: a retrospective study

Shota Hamada, Shiro Hinotsu, Katsuhito Hori, Hiroshi Furuse, Takehiro Oikawa, Junichi Kawakami, Seiichiro Ozono, Hideyuki Akaza, Koji Kawakami

SUPPORTIVE CARE IN CANCER ( SPRINGER ) 20 ( 4 ) 813 - 820 2012.04 [Refereed]

The objective of this study was to estimate the cost of antiemetic therapy for chemotherapy-induced nausea and vomiting (CINV) in daily practice in Japan. This was a retrospective observational study using medical records. Eligible patients were those with bladder or testicular cancer receiving platinum-containing highly emetogenic chemotherapy. The incidence of CINV on days 1-5 in single-day chemotherapy and on days 1-9 in multiple-day chemotherapy, and the costs of antiemetic therapy directly associated with the administration of antiemetics were estimated. The analysis of costs was performed from a hospital perspective. A total of 54 patients or 169 chemotherapy courses were included. In all chemotherapy courses 5-HT3 receptor antagonists were used on the day(s) that platinum-containing agents were administered and frequently used on subsequent days. In contrast, the use of corticosteroids was infrequent. Acute CINV in single-day chemotherapy was well controlled, but the incidences of delayed CINV in single-day chemotherapy and CINV in multiple-day chemotherapy were relatively high. The costs for antiemetic therapy were $484.65 in courses with CINV and $318.56 in courses without CINV, and the difference was approximately $170 per chemotherapy course, which was considered to be mainly imputable to the prevalence of CINV. The cost of antiemetic therapy for CINV is substantial in Japan as well as in other countries, and it is suggested that the onset of CINV is a possible cost driver. The improvements in antiemetic therapy may contribute not only to improved patient well-being but also to a reduction of economic burden.

Effects of renin-angiotensin system blockades on cardiovascular outcomes in patients with diabetes mellitus: A systematic review and meta-analysis

Yoko M. Nakao, Satoshi Teramukai, Sachiko Tanaka, Shinji Yasuno, Akira Fujimoto, Masato Kasahara, Kenji Ueshima, Kazuhiro Nakao, Shiro Hinotsu, Kazuwa Nakao, Koji Kawakami

DIABETES RESEARCH AND CLINICAL PRACTICE ( ELSEVIER IRELAND LTD ) 96 ( 1 ) 68 - 75 2012.04 [Refereed]

Aim: To determine whether renin-angiotensin system (RAS) blockade is beneficial for cardiovascular outcomes in patients with diabetes mellitus (DM) using meta-analysis. Methods: The MEDLINE and Cochrane library databases were searched for randomized controlled trials published up to June 2010. We also reviewed reference lists from identified trials and review articles to identify any other relevant studies, and the ClinicalTrials.gov website to identify randomized controlled trials that were registered as completed but not yet published. A random-effects model was used to combine the estimates for risk ratios (RR). Results: Eligible studies were randomized controlled trials (including post hoc analyses) assessing the effects of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on cardiovascular events compared to controls in patients with DM. Nineteen clinical trials with 41,042 patients and 6039 cardiovascular events were identified. RAS blockade significantly reduced the risk of major cardiovascular events (RR 0.92, 95% confidence interval [CI] 0.84-1.00, I-2 statistic 53%) and myocardial infarction (RR 0.82, 95% CI 0.72-0.94, I-2 = 55%). There were trends towards fewer strokes and lower all-cause mortality but these were not statistically significant. Conclusions: The available evidence shows that treatment with RAS blockade can routinely be considered for diabetic patients to reduce major cardiovascular events. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Fifth joint meeting of J-CaP and CaPSURE: Advancing the global understanding of prostate cancer and its management

Hideyuki Akaza, Peter Carroll, Matthew R. Cooperberg, Shiro Hinotsu

Japanese Journal of Clinical Oncology 42 ( 3 ) 226 - 236 2012.03 [Refereed]

This report summarizes the presentations and discussions that took place at the Fifth Joint Meeting of J-CaP and CaPSURE held in Tokyo, Japan, in July 2011. The J-CaP and CaPSURE Joint Initiative was established in 2007 with the objective of analyzing, reviewing, comparing and contrasting data on prostate cancer patients from Japan and the USA within the two important large-scale, longitudinal, observational databases-J-CaP and CaPSURE. Since its inception, the initiative has reviewed a wide range of topics and generated valuable data on the patterns of prostate cancer treatment and patient outcomes in the two geographical regions. The objectives of this 5th Joint Meeting were to provide an update on the current status of the J-CaP and CaPSURE databases, and also to discuss perspectives from a range of other Asian countries-Japan, China, Indonesia and Korea-on the use of androgen deprivation therapy for prostate cancer. The collaborators recognize that large databases, such as J-CaP and CaPSURE, provide valuable 'real-world' information, to complement data from clinical trials, which can help to advance the clinical management of prostate cancer patients worldwide. It is anticipated that in the near future, the Joint Initiative will expand globally to include patient registries from other countries so that best practice can be shared and regional differences in patients, treatments and outcomes can be explored. © The Author 2012. Published by Oxford University Press. All rights reserved.

Editorial Comment to Population screening for prostate cancer: An overview of available studies and meta-analysis

Shiro Hinotsu

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL ) 19 ( 2 ) 108 - 109 2012.02 [Refereed]

[Health service research (19) "Guideline for medical care and health service research"].

Hinotsu S

[Nihon koshu eisei zasshi] Japanese journal of public health 59 ( 2 ) 120 - 125 2012.02 [Refereed]

Prostate Cancer Chemoprevention Study: An investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen

Naoto Miyanaga, Hideyuki Akaza, Shiro Hinotsu, Tomoaki Fujioka, Seiji Naito, Mikio Namiki, Satoru Takahashi, Yoshihiko Hirao, Shigeo Horie, Taiji Tsukamoto, Mitsuru Mori, Hirokazu Tsuji

Cancer Science 103 ( 1 ) 125 - 130 2012.01 [Refereed]

Our previous case-control study suggested that equol, a metabolite of isoflavone, has a preventive effect on prostate cancer. To examine the prostate cancer risk based on isoflavone intake and equol production, we carried out a phase II, randomized, double-blind, placebo-controlled trial of oral isoflavone (60mg/day) for 12months. The inclusion criteria were Japanese men between 50 and 75years of age, a serum prostate-specific antigen level of 2.5-10.0ng/mL, and a single, negative prostate biopsy within 12months prior to enrollment. The study included 158 men in eight Japanese centers. Their median age was 66.0years, and the numbers of equol producers and non-producers were 76 (48%) and 82 (52%), respectively. The majority of adverse events were mild or moderate in severity, and the scheduled intake of tablets was completed by 153 patients (96.8%). The prostate-specific antigen value showed no significant difference before and after treatment. Of the 89 patients evaluated by central pathological review, the incidence of biopsy-detectable prostate cancer in the isoflavone and placebo groups showed no significant difference (21.4%vs 34.0%, P=0.140). However, for the 53 patients aged 65years or more, the incidence of cancer in the isoflavone group was significantly lower than that in the placebo group (28.0%vs 57.1%, P=0.031). These results support the value of isoflavone for prostate cancer risk reduction. A large-scale phase III randomized study of isoflavone tablets in men with different hereditary factors and living environments is warranted. Registered with the UMIN Clinical Trials Registry (UMIN-CTR) for clinical trials in Japan (C000000446). © 2011 Japanese Cancer Association.

Chromosomal variability of human mesenchymal stem cells cultured under hypoxic conditions

Hanae Ueyama, Tomohisa Horibe, Shiro Hinotsu, Tomoaki Tanaka, Takeomi Inoue, Hisashi Urushihara, Akira Kitagawa, Koji Kawakami

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE ( WILEY-BLACKWELL ) 16 ( 1 ) 72 - 82 2012.01 [Refereed]

Bone marrow derived human mesenchymal stem cells (hMSCs) have attracted great interest from both bench and clinical researchers because of their pluripotency and ease of expansion ex vivo. However, these cells do finally reach a senescent stage and lose their multipotent potential. Proliferation of these cells is limited up to the time of their senescence, which limits their supply, and they may accumulate chromosomal changes through ex vivo culturing. The safe, rapid expansion of hMSCs is critical for their clinical application. Chromosomal aberration is known as one of the hallmarks of human cancer, and therefore it is important to understand the chromosomal stability and variability of ex vivo expanded hMSCs before they are used widely in clinical applications. In this study, we examined the effects of culturing under ambient (20%) or physiologic (5%) O2 concentrations on the rate of cell proliferation and on the spontaneous transformation of hMSCs in primary culture and after expansion, because it has been reported that culturing under hypoxic conditions accelerates the propagation of hMSCs. Bone marrow samples were collected from 40 patients involved in clinical research. We found that hypoxic conditions promote cell proliferation more favourably than normoxic conditions. Chromosomal aberrations, including structural instability or aneuploidy, were detected in significantly earlier passages under hypoxic conditions than under normoxic culture conditions, suggesting that amplification of hMSCs in a low-oxygen environment facilitated chromosomal instability. Furthermore, smoothed hazard-function modelling of chromosomal aberrations showed increased hazard after the fourth passage under both sets of culture conditions, and showed a tendency to increase the detection rate of primary karyotypic abnormalities among donors aged 60 years and over. In conclusion, we propose that the continuous monitoring of hMSCs will be required before they are used in therapeutic applications in the clinic, especially when cells are cultured under hypoxic conditions.

Prostate Cancer Chemoprevention Study: An investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen

Naoto Miyanaga, Hideyuki Akaza, Shiro Hinotsu, Tomoaki Fujioka, Seiji Naito, Mikio Namiki, Satoru Takahashi, Yoshihiko Hirao, Shigeo Horie, Taiji Tsukamoto, Mitsuru Mori, Hirokazu Tsuji

CANCER SCIENCE ( WILEY-BLACKWELL ) 103 ( 1 ) 125 - 130 2012.01 [Refereed]

Our previous case-control study suggested that equol, a metabolite of isoflavone, has a preventive effect on prostate cancer. To examine the prostate cancer risk based on isoflavone intake and equol production, we carried out a phase II, randomized, double-blind, placebo-controlled trial of oral isoflavone (60 mg/day) for 12 months. The inclusion criteria were Japanese men between 50 and 75 years of age, a serum prostate-specific antigen level of 2.5-10.0 ng/mL, and a single, negative prostate biopsy within 12 months prior to enrollment. The study included 158 men in eight Japanese centers. Their median age was 66.0 years, and the numbers of equol producers and non-producers were 76 (48%) and 82 (52%), respectively. The majority of adverse events were mild or moderate in severity, and the scheduled intake of tablets was completed by 153 patients (96.8%). The prostate-specific antigen value showed no significant difference before and after treatment. Of the 89 patients evaluated by central pathological review, the incidence of biopsy-detectable prostate cancer in the isoflavone and placebo groups showed no significant difference (21.4%vs 34.0%, P = 0.140). However, for the 53 patients aged 65 years or more, the incidence of cancer in the isoflavone group was significantly lower than that in the placebo group (28.0%vs 57.1%, P = 0.031). These results support the value of isoflavone for prostate cancer risk reduction. A large-scale phase III randomized study of isoflavone tablets in men with different hereditary factors and living environments is warranted. Registered with the UMIN Clinical Trials Registry (UMIN-CTR) for clinical trials in Japan (C000000446). (Cancer Sci 2012; 103: 125-130)

Effect of HMG-CoA reductase inhibitors on blood pressure in hypertensive patients treated with blood pressure-lowering agents: Retrospective study using an anti-hypertensive drug database

S. Hashimoto, H. Urushihara, S. Hinotsu, S. Kosugi, K. Kawakami

European Review for Medical and Pharmacological Sciences 16 ( 2 ) 235 - 241 2012 [Refereed]

Background and Objectives: We used a Japanese antihypertensive drug database to investigate the blood pressure-lowering effect of statins in hypertensive patients receiving antihypertensive medication. We also examined the class effect of antihypertensive drugs on blood pressure lowering by statins. Material and Methods: The Risk/Benefit Assessment of Drugs-Analysis and Response (RAD-AR) Council has developed an antihypertensive drug database which contains the results of post-marketing surveillance for various antihypertensive agents from 143,509 antihypertensive users in clinical settings. Antihypertensive patients in the database with concurrent hyperlipidemia were grouped into statin users and non-users, and changes in systolic and diastolic blood pressure over a three-month period were compared. Further, the class effects of antihypertensive drugs on the lipid lowering effects of statins were also investigated. Results: A total of 1,070 statin users and 1,974 non-users were analyzed. Changes in systolic blood pressure were significantly greater in the statin user than in the non-user group (mean difference: 1.63 mmHg, p=0.03). In contrast, no significant effect of statin use was observed on the change in diastolic blood pressure (DBP) (0.87 mmHg, p = 0.08). When stratified by antihypertensive class, reductions in blood pressure were greater in statin user groups for all antihypertensive classes without statistical significance, except for a significant change in DBP in those receiving beta-blockers (mean difference: 2.98 mmHg, p = 0.03). Discussion: The present study documented that statin's effect on blood pressure in hypertensive patients with hyperlipidemia in clinical setting is statistically significant but has a minimal significance. With regard to class differences among antihypertensive agents, the decrease was greatest in the DBP of patients treated with beta-blockers. In contrast, no significant changes were seen in the ACE inhibitor or Ca antagonist subgroups. One possible explanation for the differential effects of antihypertensive class in our study might be the lack of a vasodilatation effect.

Clinical usefulness of pit patterns for detecting colonic lesions requiring surgical treatment

Yasutoshi Kobayashi, Shin-ei Kudo, Hideyuki Miyachi, Toshihisa Hosoya, Nobunao Ikehara, Kazuo Ohtsuka, Hiroshi Kashida, Shigeharu Hamatani, Shiro Hinotsu, Koji Kawakami

INTERNATIONAL JOURNAL OF COLORECTAL DISEASE ( SPRINGER ) 26 ( 12 ) 1531 - 1540 2011.12 [Refereed]

Background The number of patients suffering from colorectal cancer is increasing. According to Japanese guidelines, lesions with a submucosal invasive depth > 1,000 mu m should be treated with radical proctocolectomy. We propose and evaluate a new clinical classification for pit patterns that uses endoscopy to assess lesion depth for determination of the appropriate therapeutic approach for early colorectal cancers and adenomas. Methods Endoscopic images of colorectal adenomas and early cancer cases with type V(I) pit pattern, resected surgically or endoscopically from April 2002 to April 2007 at Showa University Yokohama Northern Hospital, were utilized for analysis. Each image was retrospectively analyzed for (A) pit narrowness, (B) irregular pit margins, and (C) indistinct stromal staining. Sensitivity, specificity, and predictive value were evaluated as major outcomes, using pathological results as the standard. Result In total, 186 cases were assessed. With all features considered (A, B, and C), the sensitivity, specificity, and positive and negative predictive values were 47.8%, 86.3%, 66.0%, and 74.2%, respectively. When limited to two features (A and B), these values were 75.3%, 81.2%, 70.2%, and 84.8%, respectively. Conclusion Our results suggest that the established criteria can, to a certain degree, distinguish between high and low irregularity in colorectal lesions with V(I) pit pattern indicating submucosal cancer infiltration of more or less than 1,000 mu m with the clinical consequence of surgery versus endoscopic mucosal resection/endoscopic mucosal dissection.

Maintenance therapy with bacillus Calmette-Guérin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer.

Shiro Hinotsu, Hideyuki Akaza, Seiji Naito, Seiichiro Ozono, Yoshiteru Sumiyoshi, Sumio Noguchi, Akito Yamaguchi, Satoshi Nagamori, Akito Terai, Yasutomo Nasu, Haruki Kume, Yoshihiko Tomita, Yoshinori Tanaka, Shoji Samma, Hirotsugu Uemura, Hirofumi Koga, Tomoyasu Tsushima

BJU international 108 ( 2 ) 187 - 95 2011.07 [Refereed] [International journal]

OBJECTIVE: • To confirm the recurrence-preventing efficacy and safety of 18-month bacillus Calmette-Guérin (BCG) maintenance therapy for non-muscle-invasive bladder cancer. PATIENTS AND METHODS: • The enrolled patients had been diagnosed with recurrent or multiple non-muscle-invasive bladder cancer (stage Ta or T1) after complete transurethral resection of bladder tumours (TURBT). • The patients were randomized into three treatment groups: a maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks as induction therapy, followed by three once-weekly instillations at 3, 6, 12 and 18 months after initiation of the induction therapy), a non-maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks) and an epirubicin group (epirubicin, 40 mg, intravesically instilled nine times). The primary endpoint was recurrence-free survival (RFS). RESULTS: • Efficacy analysis was performed for 115 of the full-analysis-set population of 116 eligible patients, including 41 maintenance group patients, 42 non-maintenance group patients and 32 epirubicin group patients. • At the 2-year median point of the overall actual follow-up period, the final cumulative RFS rates in the maintenance, non-maintenance and epirubicin groups were 84.6%, 65.4% and 27.7%, respectively. • The RFS following TURBT was significantly prolonged in the maintenance group compared with the non-maintenance group (generalized Wilcoxon test, P= 0.0190). CONCLUSION: • BCG maintenance therapy significantly prolonged the post-TURBT RFS compared with BCG induction therapy alone or epirubicin intravesical therapy.

The current status of umbilical cord blood collection in Japanese medical centers: Survey of obstetricians

Noriko Tada, Shiro Hinotsu, Hisashi Urushihara, Fumiyo Kita, Shunro Kai, Tsuneo A. Takahashi, Shunichi Kato, Minoko Takanashi, Kiminari Ito, Hideaki Sawai, Taira Maekawa, Shinji Kosugi, Koji Kawakami

TRANSFUSION AND APHERESIS SCIENCE ( PERGAMON-ELSEVIER SCIENCE LTD ) 44 ( 3 ) 263 - 268 2011.06 [Refereed]

As the first step of UCB banking, UCB collection has an important role in banking procedures. The aim of this study was to reveal the current status of UCB collection and discuss the management of the UCB bank. We conducted a questionnaire survey at medical centers collecting UCB, followed by semi-structured interviews with some respondents. Out of 38 institutes, 11 respondents (28.9%) thought that collection of UCB in addition to their routine medical services puts a burden on physicians. The obstetricians involved in the UCB collection are generally willing to participate in the procedure under current circumstances at medical institutes. (C) 2011 Elsevier Ltd. All rights reserved.

Night-to-night variability of sleep latency significantly predicts the magnitude of subsequent change in sleep latency during placebo administration

Atsushi Ogawa, Shiro Hinotsu, Hisashi Urushihara, Koji Kawakami

SLEEP MEDICINE ( ELSEVIER SCIENCE BV ) 12 ( 6 ) 565 - 571 2011.06 [Refereed]

Objective: To investigate the association between subjective sleep latency (sSL) fluctuation during the lead-in period and the placebo response in the subsequent double-blind period. Methods: The current study is a secondary analysis of data from the placebo arm (380 patients) of a double-blind study in outpatients with primary insomnia. Results: Higher fluctuation of lead-in sSL was associated with a greater decrease in sSL in the subsequent weeks. Multivariate analysis suggested that a wider standard deviation for daily sSL and a higher weekly mean sSL during the lead-in period were independent predictors of greater improvement in mean sSL during the subsequent weeks of placebo treatment. Likewise, a wider standard deviation and lower mean of subjective total sleep time (sTST) during the lead-in period were independent predictors of greater improvement in mean sTST in the subsequent weeks, but predictability of change in sTST with these parameters appears lower than those for sSL (R-2 = 0.13 and 0.44, respectively, in Week 2). Conclusions: The importance of night-to-night variability of sSL in sleep assessment is highlighted. Excluding patients with high variability of lead-in sSL should be considered in clinical studies evaluating an effect on sleep onset, especially in the early stages of clinical development. (C) 2011 Elsevier B.V. All rights reserved.

[An international comparison of epidemiologic factors of prostate cancer].

Hinotsu S

Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 5 187 - 192 2011.06 [Refereed]

[Urologic cancer and NCCN guideline].

Hinotsu S

Gan to kagaku ryoho. Cancer & chemotherapy 38 ( 1 ) 59 - 63 2011.01 [Refereed]

治療費の国際比較-乳癌患者におけるシミュレーション-

川上浩司, 樋之津史郎, 浜田将太

内閣府経済社会総合研究所ディスカッションペーパー 2011 [Refereed]

わが国における高脂血症治療薬の適正使用にかかる経済的評価(2)

川上浩司, 樋之津史郎, 漆原尚巳, 大西佳恵

内閣府経済社会総合研究所ディスカッションペーパー 2011 [Refereed]

Cancer death from non-muscle invasive bladder cancer: Report of the Japanese Urological Association of data from the 1999-2001 registry in Japan

Eijiro Okajima, Hiroyuki Fujimoto, Yoichi Mizutani, Eiji Kikuchi, Hirofumi Koga, Shiro Hinotsu, Nobuo Shinohara, Tsuneharu Miki

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL ) 17 ( 11 ) 905 - 912 2010.11 [Refereed]

Objectives: Our aim was to clarify the risk factors of cancer death in order to reduce mortality from T1 bladder cancer. Methods: The Japan registration database (1999-2001) was used for the analysis. Data were collected at least 3 years after the initial diagnosis. Cause-specific survival using a Kaplan-Meier survival estimation with the log-rank method was evaluated. Univariate and multivariate analysis using the Cox proportional hazard model was also carried out. The 1997 TNM classification was used for pathological staging, and the 1973 WHO classification was used for pathological grading. Results: There were 76 cancer deaths among a total of 1919 clinical T1 cases. Regardless of the subsequent treatment strategies, non-papillary tumor appearance, non-peduncular tumor stalk, multiple tumors, a tumor size greater than 3 cm, positive urinary cytology and pathological grade 3 were found to be statistically significant in cancer death by univariate analysis. By multivariate analysis, non-papillary tumor appearance, positive urinary cytology and a tumor size greater than 3 cm were confirmed as significant risk factors. Cancer death cases were found in 47.4% of worst-grade 2 tumors, and in 67.1% of predominantly grade 1 or 2 tumors. Conclusion: Non-papillary tumor appearance, positive urinary cytology and a tumor size greater than 3 cm should be included to enable the assessment of risk criteria in cancer death from T1 bladder cancer.

Updated Japanese Urological Association Guidelines on prostate-specific antigen-based screening for prostate cancer in 2010

Seiji Naito, Yoshiyuki Kakehi, Akihiko Okuyama, Tomoaki Imamura, Hideo Yasunaga, Hideyuki Akaza, Shiro Hinotsu, Yoichi Arai, Takushi Dokiya, Shin Egawa, Kazuhiro Suzuki, Hirofumi Koga, Naoya Masumori, Koichiro Akakura, Kiyotaka Kawashima, Koji Okihara, Kazuto Ito

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL ) 17 ( 10 ) 830 - 838 2010.10 [Refereed]

The exposure rate of screening for prostate cancer using prostate-specific antigen (PSA) in Japan is still very low compared with that in the USA or western Europe. The mortality rate of prostate cancer will increase in the future and in 2020 it will be 2.8-fold higher than in 2000. Therefore, there is an urgent need to determine the best available countermeasures to decrease the rate of prostate cancer death. PSA screening, which can reduce the risk of death as a result of prostate cancer, should be offered to all men at risk of developing prostate cancer with fact sheets showing updated benefits and drawbacks of screening for prostate cancer.

Prostate Cancer Working Group Report

Mikio Namiki, Hideyuki Akaza, Sang Eun Lee, Jae-Mann Song, Rainy Umbas, Liqun Zhou, Boon Cheok Lee, Christopher Cheng, Moon Kee Chung, Takashi Fukagai, Shiro Hinotsu, Shigeo Horie

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 40 i70 - i75 2010.09 [Refereed]

The incidence of prostate cancer, while still lower than in Western nations, is increasing rapidly in Asian countries due to a more westernized lifestyle. Prostate cancer mortality is declining in the USA, where most prostate cancers are diagnosed in the early stage. In contrast, the mortality rates of prostate cancer in Asian countries are expected to continue to increase, because the percentage of advanced-stage prostate cancers remains high. Therefore, early detection by prostate-specific antigen screening and a comprehensive strategy for cancer prevention are essential for Asian people. The exposure rate of prostate-specific antigen screening is very low in Asian countries. Increased prostate-specific antigen screening may reduce the mortality rate. The stances regarding population screening differ among countries. Urological associations should promote population screening. Reliable data from Asian countries are needed. The prostate cancer incidence is low in Asian countries, perhaps due to high soy consumption. Isoflavones may prevent prostate cancer in Asian countries, but that is not yet clear. A large, multinational study in Asia is needed to clarify whether or not isoflavone consumption shows efficacy in preventing prostate cancer. Clinical data suggest that hormonal therapy is more effective in Asians than in Westerners. Clinical guidelines should consider including hormonal therapy as one of the options for the treatment of localized prostate cancer. At the same time, effort should be made to decrease the adverse effects of each treatment. Collaborative studies on the treatment of prostate cancer should be carried out among Asian countries.

Clinical Trials and Approval of Anti-cancer Agents

Masaru Iwasaki, Shiro Hinotsu, Jun Katsura

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 40 i65 - i69 2010.09 [Refereed]

Nowadays, drug development requires large-scale studies to show the real clinical benefit for the patients, which means recruiting a sufficient number of patients, even internationally. As global studies enable simultaneous delivery of new drugs and sharing of safety information around the world, multinational studies now account for around 20% of Japanese clinical studies. Until recently, drug development has been centered in Western countries, but interest in Asian regions has increased. In this environment, one important factor in drug development is ethnicity. Various cancers show regional patterns in their incidence, and some (such as liver cancer and gastric cancer) show high incidences in Asian countries. Ethnic factors including genetic differences, such as the CYP drug-metabolizing enzymes in the liver and gene mutations, may result in different drug responses in terms of efficacy and safety. Examples of ethnic differences in drug responses were seen with gefitinib, which showed a different efficacy data, and with sunitinib, showing a clearly different toxicity profile between the West and Asia. Therefore, ethnic differences need to be taken into account in the early phase of drug development, and Asian countries need to be involved early in clinical development. Asian collaboration among physicians and networks of specialists is also important, and there is good potential for successful establishment of the infrastructure needed for collaborative clinical trials. Establishment of a so-called third development center in Asian countries that will complement the USA and European centers is highly desired.

Antedrug Budesonide by Intrapulmonary Treatment Attenuates Bleomycin-Induced Lung Injury in Rats with Minimal Systemic Adverse Effects

Masayuki Kohno, Mari Haramoto, Oumi Nakajima, Liying Yang, Shiro Hinotsu, Masanao Yokohira, Katsumi Imaida, Koji Kawakami

BIOLOGICAL & PHARMACEUTICAL BULLETIN ( PHARMACEUTICAL SOC JAPAN ) 33 ( 7 ) 1206 - 1211 2010.07 [Refereed]

Corticosteroids are routinely used in patients with pulmonary fibrosis, yet they have several adverse effects. To improve this situation, we used an animal model of pulmonary injury and early fibrosis and investigated whether the combination of an intrapulmonary inhalation device with antedrug budesonide (BUD) administered to the lung had greater efficacy and fewer systemic adverse effects compared to long-acting dexamethasone (DEX). BUD or DEX was administrated either intrapulmonary or intravenously to bleomycin-treated rats. Antiinflammatory and antifibrotic effects were evaluated according to inflammatory cell count, total protein concentration and soluble collagen concentration in bronchoalveolar lavage fluid. The systemic immunosuppressive effects were also assessed by measuring body, spleen and thymus weight. BUD and DEX were compared with respect to their pharmacokinetic profiles in plasma and lung. Intrapulmonary treatment of BUD attenuates various inflammatory and early fibrotic indices with minimal systemic adverse effects compared with DEX. The area under the curve (AUC) of BUD by intrapulmonary spray was 6.6-fold higher than the AUC of DEX in the lung. This study suggests that antedrug BUD by intrapulmonary treatment has local anti-inflammatory and antifibrotic effects with minimal systemic adverse effects.

Pattern of intravesical recurrence after surgical treatment for urothelial cancer of the upper urinary tract: A single institutional retrospective long-term follow-up study

Ei-ichiro Takaoka, Shiro Hinotsu, Akira Joraku, Takehiro Oikawa, Noritoshi Sekido, Naoto Miyanaga, Koji Kawai, Toru Shimazui, Hideyuki Akaza

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL ) 17 ( 7 ) 623 - 628 2010.07 [Refereed]

Objectives: To estimate the risk of intravesical recurrence in patients with primary urothelial cancer of the upper urinary tract. Methods: Ninety patients who underwent radical nephroureterectomy for clinically localized urothelial cancer of the upper urinary tract were initially considered. Those with a previous and/or concomitant history of bladder cancer, and those who had previously received systemic chemotherapy were excluded. Overall, data from 60 patients with no evidence of bladder cancer and distant or lymph node metastasis were retrospectively reviewed. The clinical course and the risk pattern of intravesical recurrence were estimated by using a smoothing technique on estimated hazard function plots. Multivariate analysis was carried out using a Cox proportional hazards regression model. Results: Mean patient age was 64.7 years. Median follow up was 51.3 months. Thirty patients (50%) had intravesical recurrence during the follow-up period. The peak of intravesical recurrence was detected in the early period (less than 2.5 years) after surgery. The intravesical recurrence hazard became lower afterwards. Nevertheless, it persisted over a long period of time. On univariate and multivariate analyses, none of the clinical or pathological parameters had a statistically significant impact on intravesical recurrence. Conclusions: Even if an intravesical recurrence in patients with upper urinary tract urothelial cancer is more likely in the early period, it persists over a long period of time. This might reflect different mechanisms of recurrence, having a significant impact on the definition of the optimal treatment and follow-up schedules.

Prostate cancer

Shiro Hinotsu

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. ) 37 ( 4 ) 620 - 623 2010.04 [Refereed]

The first edition of Clinical Practice Guidelines for Prostate Cancer was created mainly by the Japanese Urological Association as a part of the 2003-2004 Ministry of Health, Labour and Welfare (MHLW) Scientific Research Fund-supported Thorough Researches for the Evaluation of Medical Technologies. The guidelines were aimed to be used by general urologists committed to the treatment of all stages of prostate cancer patients. The guidelines supervised by the Japanese Urological Association were published in May 2006. The present edition of the guidelines are accepted as a good summary of prostate cancer treatment. However, since the present edition is over 3 years old, a revision of the guidelines is planned to update the contents and findings. In this article, I will summarize the chanaes and updates in each field.

FOXO1 and TCF7L2 Genes Involved in Metastasis and Poor Prognosis in Clear Cell Renal Cell Carcinoma

Takahiro Kojima, Toru Shimazui, Ryo Horie, Shiro Hinotsu, Takehiro Oikawa, Koji Kawai, Hideaki Suzuki, Kohji Meno, Hideyuki Akaza, Kazuhiko Uchida

GENES CHROMOSOMES & CANCER ( WILEY-LISS ) 49 ( 4 ) 379 - 389 2010.04 [Refereed]

The goal of this study was to identify genes related to the metastasis of clear cell renal cell carcinoma (CRCC). We analyzed copy number alterations in renal tissue specimens of patients with CRCC patients with or without metastasis by using high-resolution single-nucleotide polymorphism (SNP) arrays and then integrated these data with gene expression profiling data obtained using oligonucleotide microarrays. The expression levels of target genes were determined by quantitative real-time RT-PCR (qRT-PCR) with an independent tumor set. An analysis of specimens from 23 CRCC cases with SNP arrays revealed that hemizygous deletions at 10q and 13q were found only in cases of metastatic disease. We found the homozygous deletion of TCF7L2 at 10q25.2 in an aggressive case that had hemizygous deletions at 10q. In addition, a qRT-PCR analysis of TCF7L2 mRNA levels in tumor samples revealed significantly lower levels in patients with metastasis when compared with those without metastasis. FOX01 was identified as a down-regulated gene in the minimal overlapping region of the 13q hemizygous deletion in CRCC. Decreased FOXO1 expression was significantly correlated with metastasis and poor survival outcome. Knockdown of FOX01 inhibited apoptosis after doxorubicin treatment in CRCC cells and reduced the expression of downstream genes involved in cell proliferation (CDKN1B) and survival (BCL2L11). Lower levels of FOXO1 expression were associated with decreased expression of CDKN1B and BCL2L11 in CRCC specimens. We conclude that FOXO1 and TCF7L2 are involved in metastasis and that molecules in these signaling pathways may be targets for diagnostic procedures and therapies for CRCC. (C) 2010 Wiley-Liss, Inc.

Hormonal therapy for prostate cancer: Current topics and future perspectives

Hiroyoshi Suzuki, Shiro Hinotsu, Hideyuki Akaza, Yasuhisa Fujii, Satoru Kawakami, Kazunori Kihara, Koichiro Akakura, Motofumi Suzuki, Tadaichi Kitamura, Yukio Homma, Atsushi Mizokami

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL ) 17 ( 4 ) 302 - 313 2010.04 [Refereed]

Relationship Between Low Back Pain and Competitive Sports Activities During Youth

Mika Hangai, Koji Kaneoka, Yu Okubo, Shumpei Miyakawa, Shiro Hinotsu, Naoki Mukai, Masataka Sakane, Naoyuki Ochiai

AMERICAN JOURNAL OF SPORTS MEDICINE ( SAGE PUBLICATIONS INC ) 38 ( 4 ) 791 - 796 2010.04 [Refereed]

Background: Low back pain is a significant problem not only for the adult, but also during youth. However, the relationship between low back pain during youth and the duration or types of competitive sports has not been clarified. Hypothesis: Low back pain during youth is associated with the duration and types of competitive sports. Study Design: Cross-sectional study; Level of evidence, 4. Methods: Study participants were 4667 new university students who, from 2004 to 2006, answered a questionnaire concerning low back pain and their participation in competitive sports. The participants were divided into a "no'' group (NO), a middle group (MID), and a high group (HI) based on the duration of participation in competitive sports. The answers to the questionnaire were analyzed using the Cochran-Mantel-Haenszel test. Furthermore, we selected students who had participated in the same sport for 5 or more years and categorized the students according to the type of sport. Differences in low back pain among the groups were analyzed using logistic regression with the NO group as the reference group. Results: There were statistically significant linear associations in the NO, MID, and HI groups, with 50.0%, 61.8%, and 71.7%, respectively, of the students experiencing low back pain. Among the NO, MID, and HI groups, 4.4%, 5.7%, 9.6%, respectively, had experienced school absence due to low back pain; and 4.0%, 8.5%, and 14.6%, respectively had low back pain with associated lower extremity pain and numbness. All 8 sports groups that were analyzed had experienced low back pain significantly higher than the NO group, and the odds ratios differed by sport with the highest (3.8) for the volleyball group. Conclusion: Excessive exposure to competitive sports activities during youth was associated with low back pain and symptoms in the lower extremities, with the severity varying with the sport. To reduce low back pain in youth, factors that may be causing low back pain, such as sport-specific postures and motions, need to be investigated.

Non muscle invasive bladder cancer cases initially failing to respond to bacillus Calmette-Guérin intravesical instillation therapy

Takehiko Okamura, Hidetoshi Akita, Yoshihiro Hashimoto, Keiichi Tozawa, Shiro Hinotsu, Hideyuki Akaza, Kenjiro Kohri

Current Urology 4 ( 1 ) 18 - 24 2010.01 [Refereed]

Objective: Bacillus Calmette-Guérin (BCG) is used as the gold standard for prevention of recurrence after transurethral resection of bladder tumor of non muscle invasive bladder cancer. However, in some cases the outcome is not optimal. In order to assess the possible impact of different variables on outcome, the present clinical evaluation of initially failed cases was performed. Patients and Methods: A total of 68 patients treated with BCG were evaluated. All suffered recurrence. Their original urothelial carcinomas were: G1/G2/G3 = 13/41/14, and Ta/T1 = 30/38. Thirteen high-risk T1G3 cases were included. Intravesical chemotherapy pretreatment was given to 10 cases. Results: The overall progression-free survival rates at 3, 5 and 10 years were 83.3, 80.9, and 72.0% respectively, with cancer-specific survival rates of 98.3, 89.0 and 89.0%. High-risk T1G3 patients were confirmed to have higher progression rates (p = 0.03, log-rank test). Total cystectomy was performed in 5 of 13 T1G3 patients, one died during the follow-up. Additional BCG treatments were performed for 8 patients, and all of them remain alive at the present time. Conclusions: These findings indicate that the response to BCG is definitely influenced by high-risk category, so that early selection of total cystectomy may improve the prognosis with T1G3 patients. However, it was also suggested that more than 1 course of BCG is a feasible option in some cases with a tendency for a worse outcome when pretreated with anti-cancer drugs. Copyright © 2010 S. Karger AG.

Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: A randomized phase III trial

Takuji Okusaka, Hiroshi Kasugai, Yasukazu Shioyama, Katsuaki Tanaka, Masatoshi Kudo, Hiromitsu Saisho, Yukio Osaki, Michio Sata, Shigetoshi Fujiyama, Takashi Kumada, Keiko Sato, Seiichiro Yamamoto, Shiro Hinotsu, Tosiya Sato

JOURNAL OF HEPATOLOGY ( ELSEVIER SCIENCE BV ) 51 ( 6 ) 1030 - 1036 2009.12 [Refereed]

Background/Aims: Transcatheter arterial chemoembolization (TACE) is a combination of transarterial infusion chemotherapy (TAI) and embolization, and has been widely used to treat patients with hepatocellular carcinoma (HCC). However, since the impact of adding embolization on the survival of patients treated with TAI had never been evaluated in a phase III study, we conducted a multi-center, open-label trial comparing TACE and TAI to assess the effect of adding embolization on survival. Methods: Patients with newly diagnosed unresectable HCC were randomly assigned to either a TACE group or a TAI group. Zinostatin stimalamer was injected into the hepatic artery, together with gelatin sponge in the TACE group and without gelatin sponge in the TAI group. Treatment was repeated when follow-up computed tomography showed the appearance of new lesions in the liver or re-growth of previously treated tumors. Results: Seventy-nine patients were assigned to the TACE group, and 82 were assigned to the TAI group. The two groups were comparable with respect to their baseline characteristics. At the time of the analysis, 51 patients in the TACE group and 58 in the TAI group had died. The median overall survival time was 646 days in the TACE group and 679 days in the TAI group (p = 0.383). Conclusions: The results of this study suggest that treatment intensification by adding embolization did not increase survival over TAI with zinostatin stimalamer alone in patients with HCC. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Outcome of pediatric renal tumor treated using the Japan Wilms Tumor Study-1 (JWiTS-1) protocol: a report from the JWiTS Group

Takaharu Oue, Masahiro Fukuzawa, Hajime Okita, Hideo Mugishima, Hiroshi Horie, Jun-ichi Hata, Masahiro Saito, Miwako Nozaki, Motoaki Chin, Hisaya Nakadate, Shiro Hinotsu, Tsugumichi Koshinaga, Yasuhiko Kaneko, Yoshihiro Kitano, Yukichi Tanaka

PEDIATRIC SURGERY INTERNATIONAL ( SPRINGER ) 25 ( 11 ) 923 - 929 2009.11 [Refereed]

In 1996, the Japan Wilms Tumor Study (JWiTS) group was founded to elucidate the efficacy and safety of the regimen established by the National Wilms Tumor Study (NWTS) group in the USA, and a multicenter cooperative study (JWiTS-1) was started in Japan. This report reviews the results of JWiTS-1. A total of 307 patients with malignant renal tumor were enrolled in the JWiTS-1 study between 1996 and 2005. Central pathological diagnosis and follow-up data were available in 210 cases. The protocol regimens were similar to the NWTS-5 regimens. Clinical stage was classified according to the Japanese Staging System. Five-year overall survival (OS) rate was 91.1% for nephroblastoma, 72.9% for clear cell sarcoma of the kidney (CCSK), and 22.2% for rhabdoid tumor of the kidney (RTK). In the nephroblastoma patients, 5-year OS was 90.5% for stage I disease, 92.2% for stage II, 90.9% for stage III, 86.7% for stage IV, and 78.7% for stage V. The OS of patients in the JWiTS-1 study were comparable with the results of other multicenter studies in the USA and Europe. The outcome for patients with nephroblastoma and CCSK was fair. In contrast, the cure rate for those with RTK was not satisfactory. New treatment strategies are needed for patients with RTK.

Good Laboratory Practice (GLP) status of Asian countries and its implementation in non-clinical safety studies in pharmaceutical drug development

Madoka Sasaki, Shiro Hinotsu, Koji Kawakami

JOURNAL OF TOXICOLOGICAL SCIENCES ( JAPANESE SOC TOXICOLOGICAL SCIENCES ) 34 ( 5 ) 493 - 500 2009.10 [Refereed]

Non-clinical animal studies to assess the safety of compounds under development have to comply with Good Laboratory Practice (GLP). The Organization for Economic Co-operation and Development (OECD) has established the Mutual Acceptance of Data (MAD) system in OECD member countries for the mutual acceptance of non-clinical safety study data. Since 1997 non-OECD-member countries have also been able to participate in the MAD system, if the country meets the level of standardized compliance with OECD GLP. Thus, several Asian non-OECD countries are trying to develop their GLP standards in order to become official members of the MAD system. Pharmaceutical companies face significant expense in the drug-development process, including the cost of non-clinical safety studies; in response, companies in Asian countries are seeking to establish GLP facilities to provide cost-effective services for drug development. To assess the quality and cost of GLP performance in Asian countries, in this study we approached GLP facilities in a number of Asian countries to obtain price and quality information on a 'virtual compound' to be assessed in non-clinical safety studies. Also, the development status of GLP in Asian Countries in terms of policy and infrastructure was analyzed. We found that, among Asian countries, India and Singapore may be candidates for participation in the MAD system in terms of their compliance with GLP, language, and costs. These findings will be beneficial to pharmaceutical companies planning GLP studies in Asian Countries.

Risk Assessment Among Prostate Cancer Patients Receiving Primary Androgen Deprivation Therapy

Matthew R. Cooperberg, Shiro Hinotsu, Mikio Namiki, Kazuto Ito, Jeanette Broering, Peter R. Carroll, Hideyuki Akaza

JOURNAL OF CLINICAL ONCOLOGY ( AMER SOC CLINICAL ONCOLOGY ) 27 ( 26 ) 4306 - 4313 2009.09 [Refereed]

Purpose Prostate cancer epidemiology has been marked overall by a downward risk migration over time. However, in some populations, both in the United States and abroad, many men are still diagnosed with high-risk and/or advanced disease. Primary androgen deprivation therapy (PADT) is frequently offered to these patients, and disease risk prediction is not well-established in this context. We compared risk features between large disease registries from the United States and Japan, and aimed to build and validate a risk prediction model applicable to PADT patients. Methods Data were analyzed from 13,740 men in the United States community-based Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry and 19,265 men in the Japan Study Group of Prostate Cancer (J-CaP) database, a national Japanese registry of men receiving androgen deprivation therapy. Risk distribution was compared between the two datasets using three well-described multivariable instruments. A novel instrument (Japan Cancer of the Prostate Risk Assessment [ J-CAPRA]) was designed and validated to be specifically applicable to PADT patients, and more relevant to high-risk patients than existing instruments. Results J-CaP patients are more likely than CaPSURE patients to be diagnosed with high-risk features; 43% of J-CaP versus 5% of CaPSURE patients had locally advanced or metastatic disease that could not be stratified with the standard risk assessment tools. J-CAPRA-scored 0 to 12 based on Gleason score, prostate-specific antigen level, and clinical stage-predicts progression-free survival among PADT patients in J-CaP with a c-index of 0.71, and cancer-specific survival among PADT patients in CaPSURE with a c-index of 0.84. Conclusion The novel J-CAPRA is the first risk instrument developed and validated for patients undergoing PADT. It is applicable to those with both localized and advanced disease, and performs well in diverse populations.

Fourth Joint Meeting of the American Urological Association and the Japanese Urological Association Specialty Society Program at the 104th Annual Meeting of the American Urological Association at Chicago 2009

Matthew R. Cooperberg, Shiro Hinotsu, Michael B. Chancellor, Yukio Homma, Peter S. Nelson, Hideyasu Matsuyama, Mani Menon, Omer Kucuk, Isao Hara, Shin Egawa, Robert G. Uzzo, Hiro-omi Kanayama, Akihiko Okuyama, Hideyuki Akaza

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL PUBLISHING, INC ) 16 ( 8 ) 703 - 703 2009.08 [Refereed]

Preface: We are heartily grateful for the warm support of all of the people concerned, including the moderators and panelists of both societies for giving us the opportunity to hold the 4th American Urological Association/Japanese Urological Association (AUA/JUA) Joint Meeting, held once again at the 104th Annual Meeting of the American Urological Association (25-30 April 2009, Chicago, Illinois, USA). 2009 is a memorable year, being the start of new collaborations between AUA and JUA. The JUA in collaboration with AUA is promoting an academic exchange program whereby outstanding and promising Japanese and American junior faculty members will be given the opportunity to work in the USA and Japan for one month. The program not only allows the sharing of knowledge and experience, but is designed to foster a closer alliance between the AUA and JUA, and assists in identifying future leaders within both organizations. The JUA will have an exhibit booth at the AUA annual meeting, promoting our new joint activities. The Journal of Urology and International Journal of Urology will share reviewers. The JUA will participate in developing AUA guidelines. With all of these activities, the JUA hopes it will provide greater opportunities to young Japanese urologists to participate in educational projects in the US. We would like to thank Professor Robert C. Flanigan, the Secretary General of AUA, Professor Glenn M. Preminger, the Chairman of the AUA Office of Education and the staff of AUA and JUA for supporting our program. We hope to keep holding the joint meeting and have plenty of ideas on themes and forums. We believe that this international program helps to establish a closer relationship between JUA and AUA in the scientific field. Akihiko Okuyama md, President of JUA Hideyuki Akaza md, Chairman of the International Committee of JUA.

Combined Androgen Blockade With Bicalutamide for Advanced Prostate Cancer Long-Term Follow-Up of a Phase 3, Double-Blind, Randomized Study for Survival

Hideyuki Akaza, Shiro Hinotsu, Michiyuki Usami, Yoichi Arai, Hiroshi Kanetake, Seiji Naito, Yoshihiko Hirao

CANCER ( JOHN WILEY & SONS INC ) 115 ( 15 ) 3437 - 3445 2009.08 [Refereed]

BACKGROUND: A previously reported, double-blind, randomized, multicenter phase 3 trial in 205 patients with stage C/D prostate cancer compared combined androgen blockade (CAB) with luteinizing hormone-releasing hormone agonist (LHRH-A) plus bicalutamide 80 mg versus LHRH-A plus bicalutamide-matching placebo (LHRH-A monotherapy). The analysis at a median follow-up of 2.4 years indicated that CAB significantly (P < .001) prolonged the time to progression and the time to treatment failure. In the current report, survival data from a long-term follow-up (median, 5.2 years) were analyzed. METHODS: All deaths irrespective of cause and all prostate cancer-specific deaths were recorded. The data were analyzed using Cox regression analysis and the log-rank test. RESULTS: At a median follow-up of 5.2 years, a significant overall survival advantage was observed in favor of CAB over LHRH-A monotherapy (Cox regression analysis: hazard ratio, 0.78; 95% confidence interval, 0.60-0.99; P = .0498; log-rank test: P = .0425). The difference in cause-specific survival between the 2 groups was not significant. The achievement of a prostate-specific antigen (PSA) nadir concentration <= 1 ng/mL was a prognostic factor for improved survival. More patients attained PSA nadir concentrations <= 1 ng/mL with CAB compared with patients who received LHRH-A monotherapy (81.4% vs 33.7%; P < .001). CONCLUSIONS: CAB with bicalutamide 80 mg offered a significant overall survival benefit compared with LHRH-A monotherapy without reducing tolerability in patients with locally advanced or metastatic prostate cancer. Cancer 2009;115:3437-45. (C) 2009 American Cancer Society.

Clinical outcome of tumor recurrence for Ta, T1 non-muscle invasive bladder cancer from the data on registered bladder cancer patients in Japan: 1999-2001 report from the Japanese Urological Association

Eiji Kikuchi, Hiroyuki Fujimoto, Yoichi Mizutani, Eijiro Okajima, Hiroshi Koga, Shiro Hinotsu, Nobuo Shinohara, Mototsugu Oya, Tsuneharu Miki

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL PUBLISHING, INC ) 16 ( 3 ) 279 - 286 2009.03 [Refereed]

To characterize the clinical outcome in a large contemporary series of Japanese patients with newly diagnosed Ta, T1 non-muscle invasive bladder cancer who underwent transurethral bladder tumor resection with or without intravesical chemotherapy or Bacillus Calmette-GuErin (BCG) therapy. We developed a database incorporating newly diagnosed non-muscle invasive bladder cancer data and outcomes from a Japanese bladder cancer registry between 1999 and 2001 and identified a study population of 3237 consecutive patients who had complete data based on pathological features. Median patient age was 69.9 years. The 1-year, 3-year, and 5-year overall recurrence-free survival rates were 77.0%, 61.3%, and 52.8%, respectively. In multivariate analyses, the multiplicity of bladder tumors, tumor size greater than 3 cm, pathological stage T1, tumor grade G3, and the absence of adjuvant intravesical instillation were independent risk factors for tumor recurrence. Overall, 1710 patients (52.8%) received intravesical instillation; chemotherapy in 1314 (76.8%) and BCG treatment in 396 (23.2%). In patients treated with intravesical chemotherapy in which an anthracycline chemo-agent was used in 90.5% of the cases, multivariate analyses demonstrated that male gender, multiple bladder tumors, a tumor size greater than 3 cm, and pathological stage T1 were associated with tumor recurrence. The accumulation and analysis of data from the Japanese National Bladder Cancer Registry made it possible to determine the clinical characteristics, management trends, and survival rates for the period studied. Further study with a dataset created from longer follow-up data would be warranted to analyze tumor progression and disease survival.

Lumbar Intervertebral Disk Degeneration in Athletes

Mika Hangai, Koji Kaneoka, Shiro Hinotsu, Ken Shimizu, Yu Okubo, Shumpei Miyakawa, Naoki Mukai, Masataka Sakane, Naoyuki Ochiai

AMERICAN JOURNAL OF SPORTS MEDICINE ( SAGE PUBLICATIONS INC ) 37 ( 1 ) 149 - 155 2009.01 [Refereed]

Background: Several studies have reported that physical loading related to competitive sports activities is associated with lumbar intervertebral disk degeneration. However, the association between types of sports activities and disk degeneration has not been clarified. Hypothesis: The frequencies of disk degeneration may vary with the competitive sport because of the different postures and actions specific to each sport. Study Design: Cross-sectional study (prevalence); Level of evidence, 3. Methods: Study participants were 308 well-trained university athletes (baseball players, basketball players, kendo competitors, runners, soccer players, swimmers) and 71 nonathlete university students (reference group). Disk degeneration was evaluated using T2-weighted magnetic resonance imaging. A self-reported questionnaire concerning low back pain was also conducted. Results: The proportions of the participants who had disk degeneration among the baseball players (odds ratio, 3.23) and the swimmers (odds ratio, 2.95) were significantly higher than among the nonathletes using logistic regression analysis. When all patients were grouped together, the association between lifetime experience of low back pain and participants with disk degeneration was significant, and a linear association between the degree of severest low back pain experienced and participants with disk degeneration, analyzed by a Cochran-Mantel-Haenszel test, was also significant. Conclusion: Continuous competitive baseball and swimming activities during youth may be associated with disk degeneration. Furthermore, the study indicates that the experience of severe low back pain might be a predictor of disk degeneration in youth. The authors hope that preventive measures and management to protect against disk degeneration and low back pain in athletes will be established by further studies based on these results.

Bladder cancer develops 6 years earlier in current smokers: Analysis of bladder cancer registry data collected by the cancer registration committee of the Japanese Urological Association

Shiro Hinotsu, Hideyuki Akaza, Tsuneharu Miki, Hiroyuki Fujimoto, Nobuo Shinohara, Eiji Kikuchi, Yoichi Mizutani, Hirofumi Koga, Eijiro Okajima, Akihiko Okuyama

INTERNATIONAL JOURNAL OF UROLOGY ( WILEY-BLACKWELL PUBLISHING, INC ) 16 ( 1 ) 64 - 69 2009.01 [Refereed]

It is generally recognized that cigarette smoking is the most important risk factor for bladder cancer. The present study was undertaken to examine the relationships between smoking history of bladder cancer patients and the age of onset of bladder cancer and tumor characteristics. The present study examined the data for 5959 cases (4728 males and 1231 females) collected in the bladder cancer database of the Japanese Urological Association from 1999 to 2001. Patients were divided by smoking history into three categories as current non-smokers, current smokers and unknown smoking history. Relationship between smoking history and the age at diagnosis of bladder cancer, gender, T stage, grade, tumor size, tumor number and initial symptoms was analyzed In both males and females the onset of bladder cancer is about 6 years (6.1 years in males and 5.9 years in females) earlier for current smokers than for current non-smokers. At the time of diagnosis, tumor stage was significantly higher in the current smokers group. The current smokers group tended to have larger tumor size. The finding of 6-year-earlier onset of bladder cancer among current smokers is of great importance to both health care and medical economics. It is essential to make people better informed concerning the need to quit smoking.

IS O-07 Outcome of Pediatric Renal Tumor Treated With the JWiTS-1 Protocol : A Report from the Japanese Wilms Tumor Study Group(International Session 2 Tumor,Science and Art for Sick Children)

Oue Takaharu, Koshinaga Tsugumichi, Fukuzawa Masahiro, Okita Hajime, kaneko Yasuhiko, Nozaki Miwako, Hinotsu Shiro, Horie Hiroshi, Chin Motoaki, Mugishima Hideo

Journal of the Japanese Society of Pediatric Surgeons ( The Japanese Society of Pediatric Surgeons ) 45 ( 3 ) 459 - 459 2009

Factors associated with lumbar intervertebral disc degeneration in the elderly

Mika Hangai, Koji Kaneoka, Shinya Kuno, Shiro Hinotsu, Masataka Sakane, Naotaka Mamizuka, Shinsuke Sakai, Naoyuki Ochiai

SPINE JOURNAL ( ELSEVIER SCIENCE INC ) 8 ( 5 ) 732 - 740 2008.09 [Refereed]

BACKGROUND CONTEXT: Lumbar intervertebral disc degeneration (DD) precedes degenerative diseases of the lumbar spine. Various factors in addition to normal aging are reported to be associated with DD, and recently atherosclerosis and risk factors for cardiovascular diseases (cardiovascular risk factors) have received much attention; however, the links between these risk factors and DD are unclear. PURPOSE: By correlating magnetic resonance images (MRI) with suspected degenerative disc risk factors such as obesity, cardiovascular risk factors, and atherosclerosis, we hope to clarify the factors associated with DD. STUDY DESIGN/SETTING: An observational study. PATIENT SAMPLE: Two hundred seventy adults (51-86 years old) who participated in a health promotion program. OUTCOME MEASURES: DD evaluated based on the signal intensity of MR T2-weighted midsagittal images of the lumbar spine. METHODS: Age, gender, body mass index (BMI), low-density lipoprotein cholesterol (LDLc), triglyceride (TG), glycosylated hemoglobin (HbA(1c)), brachial-ankle pulse wave velocity (baPWV) as an index of atherosclerosis, osteo-sono-assessment index (OSI) calculated from quantitative ultrasound assessment of the calcaneus as an index of bone mineral density (BMD), history of low back pain (LBP), smoking and drinking habits, and physical loading related to occupations and sports were assessed. The univariate relationships between DD and the variables were evaluated, and finally, odds ratios (OR) and 95% confidence intervals (0) for the associations of each factor with DD were calculated using logistic regression at each disc level. RESULTS: Aging correlated significantly with DD of L1/2 (OR, 2.14), L2/3 (OR, 3.56), L3/4 (OR, 2.84), and L4/5 (OR, 3.05); high BMI, with 1-2/3 (OR, 2.98), L3/4 (OR, 3.58), L4/5 (OR, 2.32), and L5/S1 (OR, 3.34); high LDLc, with L4/5 (OR, 2.65); occupational lifting, with L1/2 (OR, 4.25); and sports activities, with L5/S1 (OR, 3.36). CONCLUSIONS: Aging, high BMI, high LDLc, occupational lifting, and sports activities are associated with DD. The results of this study raise our index of suspicion that cardiovascular risk factors and particular physical loading may contribute to DD; however additional studies are required to further investigate associations between DD and these factors. (C) 2008 Elsevier Inc. All rights reserved.

Negative impact of metabolic syndrome on the responsiveness to sildenafil in Japanese men

Takahiro Suetomi, Koji Kawai, Shiro Hinotsu, Akira Joraku, Takehiro Oikawa, Noritoshi Sekido, Naoto Miyanaga, Toru Shimazui, Hideyuki Akaza

JOURNAL OF SEXUAL MEDICINE ( BLACKWELL PUBLISHING ) 5 ( 6 ) 1443 - 1450 2008.06 [Refereed]

Introduction. Several recent studies suggested that the prevalence of erectile dysfunction (ED) was higher in men with metabolic syndrome (MS). Aim. We analyzed the impact of MS on the responsiveness to sildenafil. Methods. A total of 133 ED patients were evaluated for the prevalence of MS and graded on severity of ED. MS was diagnosed according to the International Diabetes Federation (IDF) definition. The severity of ED was evaluated by the International Index of Erectile Function (IIEF) questionnaire. Hormonal parameters were measured for all patients, and the IIEF questionnaire was conducted after administration of eight tablets of 50-mg doses of sildenafil. If the scores to questions 3 and 4 of the IIEF were 4 or higher after administration, the patients were defined as responders to sildenafil. Main Outcome Measures. To clarify the negative impact of MS on the responsiveness to sildenafil. Results. The mean age of the patients was 56.9 years, and 25 patients were diagnosed with MS. The IIEF-erectile function score and the response rate for sildenafil decreased as the number of MS components increased. Logistic regression analysis showed that the presence of MS along with severity of ED and history of pelvic surgery were significant independent risk factors of nonresponse for sildenafil. The hazard ratio for the presence of MS was 3.30 (95% confidence interval [CI]: 1.17-9.73). No meaningful association was observed between total testosterone or free testosterone levels and MS in this population. Conclusion. We demonstrated the negative impact of MS on the responsiveness to sildenafil. Erectile function and response rate for sildenafil decreased as the number of MS components increased.

[Future directions of anticancer drug development in Japan].

Akaza H, Kawai K, Tsuruo T, Tsukagoshi S, Aiba K, Shimada Y, Kakeji Y, Ishikawa H, Ikeda T, Nakamura S, Tamura T, Yamamoto N, Isonishi S, Hinotsu S, Hirose M, Katsura J

Gan to kagaku ryoho. Cancer & chemotherapy 35 ( 2 ) 351 - 360 2008.02 [Refereed]

Evidence-based clinical practice guidelines for prostate cancer (Summary JUA 2006 edition)

Sadao Kamidono, Shinichi Ohshima, Yoshihiko Hirao, Kazuhiro Suzuki, Yoichi Arai, Hiroyuki Fujimoto, Shin Egawa, Hideyuki Akaza, Isao Hara, Shiro Hinotsu, Yoshiyuki Kakehi, Tomonori Hasegawa

INTERNATIONAL JOURNAL OF UROLOGY ( BLACKWELL PUBLISHING ) 15 ( 1 ) 1 - 18 2008.01 [Refereed]

Background variables for the patients with invasive bladder cancer suitable for bladder-preserving therapy

Naoto Miyanaga, Hideyuki Akaza, Shiro Hinotsu, Akira Joraku, Takehiro Oikawa, Noritoshi Sekido, Koji Kawai, Toru Shimazui

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 37 ( 11 ) 852 - 857 2007.11 [Refereed]

Objective: The present study was undertaken to identify the patients suitable for bladder preservation by analysis of our data. Methods: The subjects of this study were all 72 patients with T2-3NOMO bladder cancer who underwent bladder-preserving therapy in our institute. The therapy involved intra-arterial chemotherapy with MTX and CDDP and concomitant radiotherapy. Results: Of the evaluable 70 cases, complete response (CR) was confirmed in 57 cases (81.4%). Among 56 bladder preserved cases, 47 (83.9%) preserved their functioning bladder, and 9 underwent salvage radical cystectomy at the following period. The median follow-up was 45.3 months. The 5-year cause-specific survival rate was 81% and the 5-year overall survival rate was 66%. On the basis of the results of univariate analysis, variables contributing to CR were selected. In T2, tumor size of <= 3 cm was scored 0 and >3 cm was scored 1, whereas single tumor was scored 0 and multiple were scored 1. In T3, tumor size of <= 3 cm was scored 0 and >3 cm was scored 1, whereas G2 was scored 0 and G3 scored 1. The CR rates were 93.8, 92.6, and 62.9% for total scores of 0, 1, and 2, respectively (P = 0.003; score 0 or 1 versus 2). The overall survival rate was significantly higher in the former group (P = 0.003). Conclusion: Bladder-preserving therapy can be acceptable for cases of single T2NOMO tumor with a size of <= 3 cm and for T3NOMO cases with a tumor size of <= 3 cm.

Current status of endocrine therapy for prostate cancer in Japan - Analysis of primary androgen deprivation therapy on the basis of data collected by J-CaP

Shiro Hinotsu, Hideyuki Akaza, Michiyuki Usami, Osamu Ogawa, Susumu Kagawa, Tadaichi Kitamura, Taiji Tsukamoto, Seiji Naito, Mikio Namiki, Yoshihiko Hirao, Masaru Murai, Hidetoshi Yamanaka

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 37 ( 10 ) 775 - 781 2007.10 [Refereed]

Background:Based on the data of current status of endocrine therapy for prostate cancer registered in the Japan Study Group of Prostate Cancer (J-CaP), we conducted an analysis of primary androgen deprivation therapy (PADT) and an interim analysis of the prognosis. Methods: Of the 26 272 cases registered in the server of J-CaP, the 19 409 cases initially receiving PADT were included in this study. The initial therapy was divided into eight categories according to its features. Results: Of the 19 409 patients, 1513 (7.8%) were given anti-androgen monotherapy, 955 patients (4.9%) surgical castration only, 1001 patients (5.2%) surgical castration + anti-androgen, 3015 patients (15.5%) LHRH monotherapy, 1658 patients (8.5%) LH-RH + short-term anti-androgen, 10 434 patients (53.8%) LH-RH + anti-androgen, 37 patients (0.2%) watchful waiting and 796 patients (4.1%) other therapy. In progression-free survival, the prognosis was slightly better following maximum androgen blockade (MAB) in each stage. Conclusions: The pattern of PADT is more typical in Japan compared with that in the United States. Patients who received MAB accounted for 59.0% of all the patients. MAB tends to be more often selected for patients who are rated as being at high risk on the basis of high Gleason score or PSA level upon diagnosis in each clinical stage of the disease. Investigations of the outcome are on-going and they will make clear the significance of this trend in Japan.

Three-weekly docetaxel with prednisone is feasible for Japanese patients with hormone-refractory prostate cancer: A retrospective comparative study with weekly docetaxel alone

Toru Shimazui, Koji Kawai, Naoto Miyanaga, Takahiro Kojima, Noritoshi Sekido, Shiro Hinotsu, Takehiro Oikawa, Akira Joraku, Hideyuki Akaza

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 37 ( 8 ) 603 - 608 2007.08 [Refereed]

Background: We previously reported that weekly treatment with docetaxel alone is useful for and well tolerated by patients with hormone-refractory prostate cancer (HRPC). Here, we compare it with the regimen of docetaxel once every 3 weeks (q3w) plus daily prednisone (PSL) based on a TAX 327 trial in order to clarify the efficacy and toxicity of docetaxel regimens in Japan. Methods: Thirty-two patients with HRPC were treated with docetaxel weekly (regimen 1) or docetaxel q3w plus PSL daily (regimen 2) at Tsukuba University Hospital and the changes in serum prostate-specific antigen (PSA), tumor size and survival were evaluated. The dose of docetaxel in regimen 1 was based on our previous report and that of regimen 2 was modified from a TAX 327 trial. Results: A >50% decrease in PSA was observed in 53% of the patients with a median time to progression of 3.5 months and 69% with 8.5 months with regimens 1 and 2, respectively. Patients who received regimen 2 had a significantly better survival rate than those who received regimen 1. Myelosuppression and neuropathy were statistically more frequent in regimen 2 than in regimen 1. Conclusion: A regimen of docetaxel q3w with PSL daily was associated with a high rate of PSA reduction and prolongation of patient survival. Although docetaxel has not been approved in Japan yet, this treatment is considered feasible for Japanese patients with HRPC.

Prediction of in vitro response to interferon-alpha in renal cell carcinoma cell lines

Toru Shimazui, Yoshihiro Ami, Kazuhiro Yoshikawa, Kazuhiko Uchida, Takahiro Kojima, Takehiro Oikawa, Kogenta Nakamura, Nobuaki Honda, Shiro Hinotsu, Jun Miyazaki, Noriko Kunita, Hideyuki Akaza

CANCER SCIENCE ( BLACKWELL PUBLISHING ) 98 ( 4 ) 529 - 534 2007.04 [Refereed]

We analyzed the correlation between interferon-alpha (IFN alpha) response and gene expression profiles to predict IFN alpha sensitivity and identified key molecules regulating the IFN alpha response in renal cell carcinoma (RCC) cell lines. To classify eight RCC cell lines of the SKRC series into three subgroups according to IFN alpha sensitivity, that is, sensitive, resistant and intermediate group, responses to IFN alpha (300-3000 IU/mL) were quantified by WST-1 assay. Microarray, followed by supervised hierarchical clustering analysis, was applied to selected genes according to IFN alpha sensitivity. In order to find alteration of expression profiles induced by IFN alpha, sequential microarray analyses were performed at 3, 6, and 12 h after IFN alpha treatment of RCC cell lines and mRNA expression level was confirmed using quantitative real time polymerase chain reaction. According to the sequential microarray analysis between IFN alpha-sensitive and -resistant line, seven genes were selected as candidates for IFN alpha-sensitivity-related genes in RCC cell lines. Among these seven genes, we further developed a model to predict tumor inhibition with four genes, that is, adipose differentiation-related protein, microphthalmia associated transcription factor, mitochondrial tumor suppressor 1, and troponin T1 using multiple linear regression analysis (coefficient = 0.948, P = 0.0291) and validated the model using other RCC cell lines including six primary cultured RCC cells. The expression levels of the combined selected genes may provide predictive information on the IFN alpha response in RCC. Furthermore, the IFN alpha response to RCC might be modulated by regulation of the expression level of these molecules.

Does tumor size or microvascular invasion affect prognosis in patients with renal cell carcinoma?

Tomoaki Miyagawa, Toru Shimazui, Shiro Hinotsu, Takehiro Oikawa, Noritoshi Sekido, Naoto Miyanaga, Koji Kawai, Hideyuki Akaza

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 37 ( 3 ) 197 - 200 2007.03 [Refereed]

Background: We retrospectively evaluated the effects of tumor size and microvascular tumor invasion on the clinical outcomes of patients who had undergone radical nephrectomy for renal cell carcinoma (RCC). Methods: One-hundred and sixty-two patients who received radical nephrectomy for localized or locally invasive RCC from1989 to 2002 were included. We evaluated a new cut-off value for tumor size by dividing patients into groups by tumor diameter from 3.0 to 7.0 cm in 1.0 cm increments and compared the prognosis with that predicted by the 2002 TNM classification. We also re-classified localized microvascular tumor invasion as invasive disease. Results: Univariate analyses showed a 5.0 cm cut-off provided the greatest difference in recurrence (p = 0.004) and survival (p = 0.001). Microvascular invasion made no significant difference in tumor recurrence and tumor-specific survival. However, in the new categories used in this study, survival in the locally invasive group was poor compared with the localized group. Conclusion: Our study showed that a tumor diameter of 5.0 cm might be the critical size to determine the prognosis of patients with localized RCC. Microvascular invasion seemed to have the necessity of re-evaluation in the TNM classification for patients with RCC.

The 5th Conference on Asian Trends in Prostate Cancer Hormone Therapy.

Akaza H, Moore MA, Chang SJ, Cheng C, Choi HY, Esuvaranathan K, Hinotsu S, Hong SJ, Kim CS, Kim WJ, Murai M, Naito S, Soebadi D, Song JM, Umbas R, Usami M, Xia S, Yang CR

Asian Pacific journal of cancer prevention : APJCP 8 ( 1 ) 3 - 12 2007.01 [Refereed]

The case for androgen deprivation as primary therapy for early stage disease: Results from J-CaP and CaPSURE (TM)

Hideyuki Akaza, Shiro Hinotsu, Michiyuki Usami, Osamu Ogawa, Susumu Kagawa, Tadaichi Kitamura, Taiji Tsukamoto, Seiji Naito, Yoshihiko Hirao, Masaru Murai, Hidetoshi Yamanaka, Mikio Namiki

JOURNAL OF UROLOGY ( ELSEVIER SCIENCE INC ) 176 ( 6 ) S47 - S49 2006.12 [Refereed]

Purpose: We analyzed the outcome of primary androgen depletion therapy, which has gained more attention as a potential therapeutic option in patients with localized or locally advanced prostate cancer as it has been increasingly implemented despite limited data on its therapeutic impact in Japan and the United States. Materials and Methods: We analyzed data from CaPSURE (TM) and the Japanese Prostate Cancer study. Results: In Japan primary androgen depletion therapy has long been the treatment of choice for localized and locally advanced prostate cancer. Based on CaPSURE (TM) data the frequency of primary androgen depletion therapy being chosen to treat localized and locally advanced disease is also increasing in clinical practice in the United States. A study of the outcomes of endocrine therapy is currently being performed in Japan by the Japanese Prostate Cancer Study Group. Conclusions: It is important to obtain such information about the role of primary androgen depletion therapy for localized and locally advanced prostate cancer from studies of natural history and clinical trials. It is also important to update practical treatment guidelines.

Tissue elasticity imaging for diagnosis of prostate cancer: A preliminary report

Naoto Miyanaga, Hideyuki Akaza, Makoto Yamakawa, Takehiro Oikawa, Noritoshi Sekido, Shiro Hinotsu, Koji Kawai, Toru Shimazui, Tsuyoshi Shiina

INTERNATIONAL JOURNAL OF UROLOGY ( BLACKWELL PUBLISHING ) 13 ( 12 ) 1514 - 1518 2006.12 [Refereed]

Background: Elastography is a diagnostic imaging technique that evaluates the hardness of a lesion. It is expected to become a new diagnostic modality for prostate cancer. The aim of this study was to examine the usefulness of elastography in the diagnosis of prostate cancer. Methods: A total of 29 patients with untreated, histologically proven prostate cancer were examined using an elastographic imaging technique. The patient was scanned in the dorsosacral position and the prostate was manually compressed with a transrectal ultrasonic probe. The echo signals from inside the tissue were measured before and after the tissue compression and an elastogram was generated by spatially differentiation of the displacement distribution. Results: Elastography depicted the cancer lesion as a harder tissue than the surrounding normal prostatic tissue. Elastography successfully detected 93% (27 patients) of the untreated prostate cancer lesions. Detection of cancer lesions using elastography was significantly higher than by digital rectal examination (59%; 17 patients) and transrectal ultrasonography (55%; 16 patients). Conclusion: Elastography has great potential as a useful modality for diagnosis of prostate cancer. Differentiation between cancerous and normal tissues can be expected to become more accurate as a result of technical advances in the quantification of tissue hardness.

Treatment outcome of metastatic testicular cancer at a single institution in Japan, a country with low incidence of germ cell tumor

Koji Kawai, Shiro Hinotsu, Takehiro Oikawa, Noritoshi Sekido, Kazunori Hattori, Naoto Miyanaga, Yuichi Hasegawa, Hiroshi Kojima, Toru Shimazui, Hideyuki Akaza

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 36 ( 11 ) 723 - 730 2006.11 [Refereed]

Background: Incidence of testicular cancer is low in Japan. Recent investigations showed that the outcome of metastatic testicular cancer is associated with the experience of the treatment institution. Objectives of the present investigation are to evaluate outcome of a single institution in Japan, and to identify prognostic factors for testicular cancer. Methods: We retrospectively analysed the outcome of 74 patients with metastatic testicular cancer who were treated at Tsukuba University Hospital (TUH) between January 1981 and January 2003. Forty-five patients (61%) were referred to the TUH for the treatment of metastatic disease. The progression-free survival (PFS) rates according to the International Germ Cell Cancer (IGCC) classification and the Indiana University classification were used to evaluate the treatment outcome. Results: The median follow-up period of all patients was 87 months (range, 13-260 months). Forty patients (54%) were classified as having good prognosis, 20 (27%) intermediate, and 14 (19%) poor. The overall 5- and 10-year PFS was 79 and 74%, respectively. The 5-year PFS with good, intermediate and poor prognosis was 90, 70 and 64%, respectively. There was a significant difference between the three groups (P = 0.02), but the survival of the intermediate-prognosis group was not statistically different from that of the poor-prognosis group. The Indiana University classification failed to discriminate the prognoses of moderate and advanced disease, but proved to be an independent prognostic factor for progression-free survival in intermediate- and poor-prognosis patients (P = 0.025, hazard ratio = 5.39). Conclusions: Our treatment outcome is not different from that of the institutions participating in the International Germ Cell Cancer Consensus Group (IGCCCG).

How many uncomplicated male and female overactive bladder patients reveal detrusor overactivity during urodynamic study?

Noritoshi Sekido, Shiro Hinotsu, Koji Kawai, Toru Shimazui, Hideyuki Akaza

INTERNATIONAL JOURNAL OF UROLOGY ( BLACKWELL PUBLISHING ) 13 ( 10 ) 1276 - 1279 2006.10 [Refereed]

Objective: We retrospectively evaluated the incidence of detrusor overactivity (DO) in uncomplicated overactive bladder syndrome (OAB) patients. Methods: From December 1993 to October 2003, 139 adult patients were referred to an urodynamic clinic for urodynamic evaluation of frequency and/or urinary incontinence. Of these, 50 patients (12 males and 38 females) with urgency, without any overt pathological conditions, were retrospectively evaluated in regard to patient age, storage symptoms, urodynamic parameters, and the presence or absence of DO (DO patients or no DO patients, respectively). Results: The overall incidence of DO was 75% (nine of 12 patients) and 36.8% (14 of 38 patients) in male and female patients, respectively. Two of nine male DO patients and five of 14 female DO patients revealed DO after provocative maneuvers. In male patients, all DO patients were OAB wet. In female patients, 13 of 14 DO patients were OAB wet (92.9%), whereas 17 of 24 no DO patients were also OAB wet (70.8%). Compared with no DO patients, female DO patients revealed statistically significant lower maximum cystometric capacity (P = 0.0139) and lower vesical compliance (P = 0.0002). Although aged 60 years or more was associated with DO in univariate analysis in female patients, any symptoms, even incontinence, were not associated with DO in both sexes. Conclusion: It is supposed that, in contrast to male OAB, DO might not be a major underlying cause of uncomplicated female OAB.

Completion and toxicity of induction chemotherapy for metastatic testicular cancer: An updated evaluation of Japanese patients

Koji Kawai, Satoshi Ando, Shiro Hinotsu, Takehiro Oikawa, Noritoshi Sekido, Naoto Miyanaga, Toru Shimazui, Hideyuki Akaza

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 36 ( 7 ) 425 - 431 2006.07 [Refereed]

Background: Combination of bleomycin, etoposide and cisplatin (BEP) remains the standard chemotherapy for testicular cancer. Since the development of BEP in the 1980s, there has been a considerable advance in supportive therapies, such as granulocyte colony-stimulating-factor and 5-HT3 antagonists. Therefore, we re-evaluated the completion and toxicity of BEP combined with modern supportive care. Methods: The medical records of all 42 testicular cancer patients who received induction chemotherapy at Tsukuba University Hospital were reviewed. Toxicities during the induction chemotherapy were graded according to the Japanese CTCAE v3.0. Results: Dose reduction was needed in only three patients. The subsequent chemotherapy was started at the planned 3 week interval or within 3 days of postponement in 89% of the treatment cycles. The average relative dose intensity (RDI) of bleomycin was 0.95, while that for etoposide and cisplatin was 0.97. There was no death due to toxicity. The most frequent toxicity was leukopenia (grade 3 in 44% and grade 4 in 55%). Post-chemotherapy diffusion capacity was significantly decreased in 30% of patients. Two patients developed bleomycin-induced pneumonitis, but recovered successfully. Sixteen patients received second line or salvage chemotherapy after BEP, subsequently. The overall 5 year cause-specific survival rate was 85%. Conclusion: BEP with high RDIs is acceptable if combined with modern supportive care, with acceptable toxicity profile in most patients.

[Recent progress of clinical trials in urologic oncology].

Hinotsu S

Gan to kagaku ryoho. Cancer & chemotherapy 33 ( 2 ) 188 - 192 2006.02 [Refereed]

Renal cell carcinoma with bilateral adrenaland the small intestinal metastases: A case report

Satoshi Ando, Yoshiharu Fukuhara, Jun Miyazaki, Kazunori Hattori, Sadamu Tsukamoto, Shiro Hinotsu, Toru Shimazui, Hideyuki Akaza

Japanese Journal of Urology ( Japanese Urological Association ) 97 ( 1 ) 64 - 67 2006 [Refereed]

A 69-year-old man who had a complaint of melena and hematemesis was 5referred to our hospital for further evaluation and treatment of renal masses, bilateral adrenal swelling and a tumor in the small intestine. The abdominal CT scan demonstrated two tumors sized 45 mm and 15 mm in diameter, located in the center and lower pole of the left kidney. Bilateral adrenal swelling and a small intestinal tumor with invagination were also observed. We diagnosed left renal cell carcinomas with bilateral adrenal metastases or hyperplasia, and a primary or metastatic small intestinal tumor. He received left radical nephrectomy. right adrenalectomy. and small intestinal resection. Pathological diagnosis was renal cell carcinoma, granular cell carcinoma, G2> G3> G1, INFα, v (+), pT1a, pM1, Stage IV. Bilateral adrenal swelling and small intestinal tumor were metastases from the renal cell carcinoma. After operation, we administered interferon-alpha and steroid replacement. He died after 27-month follow-up period because of renal cell carcinoma. Renal cell carcinoma with simultaneous metastases to bilateral adrenal glands and the small intestine is extremely rare.

Serum creatinine and cholesterol levels of testicular cancer patients in long-term follow up

E Hisamatsu, K Kawai, S Hinotsu, N Miyanaga, T Shimazui, H Akaza

INTERNATIONAL JOURNAL OF UROLOGY ( BLACKWELL PUBLISHING ) 12 ( 8 ) 751 - 756 2005.08 [Refereed]

Purpose: Most patients with advanced testicular cancer can be cured with cisplatin-based chemotherapy. Therefore, the long-term effects of the treatment are clinically important. In the present study, we evaluated the serum creatinine and cholesterol levels of long-term survivors of testicular cancer. Methods: Serum creatinine and cholesterol levels were determined in 23 testicular cancer patients who had received cisplatin-based chemotherapy more than 5 years earlier. They were compared with a control group of 16 patients who did not receive chemotherapy. In addition, follow-up data of beyond 10 years after the initial treatment was obtained from 17 patients. We also analysed the trends of both serum creatinine and cholesterol determinations over 10 or more years using a generalized linear model. Results: There was no significant difference in the serum creatinine and cholesterol levels 5 years after the treatment between the chemotherapy and control groups. Analysis using a generalized linear model showed a significant trend toward an increase in serum creatinine in patients who had developed renal dysfunction during chemotherapy (P = 0.0024). The elevation of the serum creatinine level was mainly observed during the first 5 years. In addition, a significant trend toward an increase in serum cholesterol was revealed in both the chemotherapy and control groups. Conclusion: Patients who have developed renal dysfunction during chemotherapy may be at risk of gradually increasing serum creatinine levels even after it has become normal. Although further analysis is needed, we recommend long-term follow up in the survivors of metastatic testicular cancer patients treated with cisplatin-based chemotherapy.

Lectin-reactive alpha-fetoprotein as a marker for testicular tumor activity

K Kawai, T Kojima, N Miyanaga, K Hattori, S Hinotsu, T Shimazui, H Akaza

INTERNATIONAL JOURNAL OF UROLOGY ( BLACKWELL PUBLISHING ASIA ) 12 ( 3 ) 284 - 289 2005.03 [Refereed]

Background:Lens culinaris agglutin (LCA)-affinity electrophoresis resolves serum alpha-fetoprotein (AFP) into three isoforms, AFP-L1, -L2 and -L3. The ratio of AFP-L3 to total AFP (AFP-L3%) is frequently high in hepatocellular carcinoma (HCC) patients, and thus, it is widely used for early diagnosis of HCC. In the present study, we used the subfraction profile of LCA-binding AFP to diagnose and monitor testicular tumor activity. Methods: Serum samples were collected from 21 testicular tumor patients, and the LCA-reactive fractions were determined by LCA-affinity electrophoresis coupled with antibody-affinity blotting. The histological diagnosis was non-seminomatous germ cell tumor (NSGCT) in 15 patients and pure seminoma in six patients. Results: Serum AFP levels were abnormally elevated (> 20 ng/mL) in 10 of 15 NSGCT patients. One NSGCT patient and two seminoma patients showed borderline AFP levels between 10 and 20 ng/mL. LCA-reactive AFP was detected in all 11 NSGCT patients with serum AFP levels above 10 ng/mL, but not in the two seminoma patients with serum AFP levels above 10 ng/mL. In testicular tumor patients, the broad band of AFP-L2 could not be completely separated from AFP-L3. The mean ratio of AFP-L3 plus AFP-L2 (AFP-L2 + 3%) was as high as 94% (range 80-99%) in these patients. Serial determinations of LCA-reactive fractions were performed in eight of the 11 LCA-reactive AFP-positive patients. They included five patients who received chemotherapy, and three patients who underwent orchiectomy for stage I NSGCT. In three of eight patients, LCA-reactive AFP was detected even after normalization of total AFP levels. All three patients relapsed, with elevation of serum AFP within several months. Conclusion: Determination of LCA-reactive AFP might be a useful marker for testicular tumor activity in patients with lower AFP levels.

The 3rd Conference on Asian Trends in Prostate Cancer Hormone Therapy.

Akaza H, Naito S, Chang SJ, Chen KK, Cheng C, Choi HY, Fujioka T, Hinotsu S, Hirao Y, Hong SJ, Kim CS, Kim WJ, Lee SE, Murai M, Ogawa O, Rim JS, Soebadi DM, Song JM, Tsukamoto T, Umbas R, Usami M, Xia S, Yang CR, Yoon JH, Zhou L

Gan to kagaku ryoho. Cancer & chemotherapy 31 ( 8 ) 1285 - 1295 2004.08 [Refereed]

Clinical parameters that predict histology of postchemotherapy retroperitoneal lymph node mass in testicular cancer

M Onozawa, K Kawai, T Yamamoto, S Hinotsu, S Tsukamoto, K Hattori, N Miyanaga, T Shimazui, H Akaza

INTERNATIONAL JOURNAL OF UROLOGY ( BLACKWELL PUBLISHING ASIA ) 11 ( 7 ) 535 - 541 2004.07 [Refereed]

Background: Since the advent of cisplatin-based chemotherapy, the majority of metastatic testicular cancers can be cured by chemotherapy followed by retroperitoneal lymph node dissection (RPLND). However, postchemotherapy RPLND confers no therapeutic benefit if the residual mass contains no viable cells. Therefore, to determine which parameters predict a patient's likelihood of having only necrosis in the residual mass, we retrospectively analyzed clinical parameters of patients who underwent postchemotherapy RPLND. Methods: Data from 27 patients with metastatic testicular cancer were analyzed. The histology of the primary tumor was seminoma in 11 cases and non-seminoma in 16 cases. All of the patients with non-seminoma showed a normalization of tumor markers after chemotherapy. Analysis of clinical parameters included data for the initial histology, pretreatment tumor marker levels, postchemotherapy retroperitoneal mass size, and the histology of the dissected RPLNs. Results: Histological examination of dissected RPLNs showed residual tumor in 27% of seminoma patients and 38% of non-seminoma patients. In seminoma patients, no viable cells were found in all six patients with pretreatment lactate dehydrogenase (LDH) levels below 7.5 times the upper limit of normal, or in all five of the patients with postchemotherapy RPLNs less than 2.5 cm. In non-seminoma patients, no viable cells were found in nine of 10 patients with pretreatment alpha-fetoprotein (AFP) levels less than 2700 ng/mL, or in eight of nine patients with residual mass less than 2.5 cm. Conclusions: Both postchemotherapy RPLN mass size and pretreatment tumor marker levels are possible predictors for necrosis of the residual mass in testicular cancer patients.

Characteristics of patients with prostate cancer who have initially been treated by hormone therapy in Japan: J-CaP surveillance

H Akaza, M Usami, S Hinotsu, O Ogawa, S Kagawa, T Kitamura, T Tsukamoto, S Naito, Y Hirao, M Murai, H Yamanaka

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 34 ( 6 ) 329 - 336 2004.06 [Refereed]

Objective: Hormone therapy for prostate cancer has empirically prevailed in Japan. We planned to evaluate the trends and outcome of hormone therapy for establishing an adequate guideline. Methods: Patients with prostate cancer who were initially treated by hormone therapy were registered through the J-CaP registration system. This report summarizes the background factors. Results: From January 2001 to October 2003, 17 872 patients were registered from 395 institutes throughout Japan. The background factors of 17 312 patients were analyzed. The 17 872 patients were estimated as composing more than half of newly diagnosed prostate cancer patients in Japan. Of these, 22.9, 35.1, 32.9 and 8.6% belonged to T1, T2, T3 and T4, respectively. For the purposes of hormone therapy, 77.5% was primary hormone therapy. Neoadjuvant setting and adjuvant setting were 18.1 and 4.3%, respectively. About 60% of the hormone therapy was combined hormone therapy with LH-RHa plus anti-androgens. Conclusion: Irrespective of patients' age, TNM, stage of illness, or histological background, the majority of prostate cancer patients in Japan are receiving hormone therapy. It is necessary to evaluate whether this trend is merely a continuation of past experience of Japanese urologists or if there is a difference in the profile of effect and side-effect in the case of Japanese patients compared to therapy given in Westerners.

Bladder neck contraction after radical prostatectomy: Morbidity and risk factors

Masakazu Tsutsumi, Satoru Ishikawa, Shiro Hinotsu

Acta Urologica Japonica 50 ( 6 ) 397 - 400 2004.06 [Refereed]

We retrospectively analyzed the morbidity and risk factors of bladder neck contraction (BNC) after retropubic prostatectomy. Of 99 consecutive patients who underwent radical retropubic prostatectomy between 1995 and 2001, 10 (10%) developed anastomotic stricture after surgery. BNC was diagnosed 7 months on average after the surgery. Nine patients were successfully treated by cold-knife incision, but 5 required additional incision against the recurrence of BNC. None of them revealed newly diagnosed stricture or incontinence. Thirteen potential risk factors including age, stage, PSA, neoadjuvant treatment, pathology, intraoperative blood loss, operation time, operator, nerve sparing, extravasation of urine, marginal status, the year of operation, and the method of ureterovesical anastomosis were evaluated using univariate and multivariate analysis. The BNC rate was increased in patients with longer (more than 4 hrs) operations and excessive bleeding (more than 1,000 ml) (p=0.0027, respectively). The year of operation (before 1998, p=0.0015), the method of ureterovesical anastomosis (p=0.0017), operator experience (less than 5 cases, p=0.0056), and neoadjuvant treatment (p=0.09) were also risk factors. In multivariate analysis, the year of operation (p=0.03) and operator experience (p=0.04) were strong predictors of BNC. The skill levels of surgeons and institutes are expected to decrease BNC.

Effect of prophylactic treatment with intravesical epirubicin on recurrence of superficial bladder cancer - The 6th trial of the Japanese Urological Cancer Research Group (JUCRG): A randomized trial of intravesical epirubicin at dose of 20 mg/40 ml, 30 mg/40 ml, 40 mg/40 ml

M Kuroda, T Niijima, T Kotake, H Akaza, S Hinotsu

EUROPEAN UROLOGY ( ELSEVIER SCIENCE BV ) 45 ( 5 ) 600 - 605 2004.05 [Refereed]

Objectives: We compared the prophylactic efficacy and safety of epirubicin (EPI) in primary superficial bladder cancer. Methods: The major inclusion criteria were primary superficial bladder tumour (Ta, T1, G1, G2) and new cases of primary multiple tumours, or recurrent cases. The major exclusion criteria were Tis or G3 tumours. Group A received 17 doses of EPI 20 mg/40 ml over a period of 12 months for a total dose of 340 mg. In contrast, Group B received 12 doses of EPI 30 mg/40 ml over a period of 7 months, while Group C received 9 doses of EPI 40 mg/40 ml over a period of 4 months, both for a total dose of 360 mg. This study enrolled a total of 622 patients diagnosed as having primary superficial bladder cancer during the period from June 1994 through November 1996 at the 118 institutions. Follow-up of the patients was conducted through October 1999. Results: The relationship between the EPI concentration and the recurrence-free rate was evaluated by Tarone's test, and it was found that the recurrence-free rate became significantly higher as the drug concentration increased (p = 0.0375). In the safety evaluation, with regard to adverse drug reactions, pollakiuria and pain on urination occurred at significantly higher incidences as the concentration of the EPI solution increased. Conclusions: The greatest effect of intravesical instillation of EPI after TUR-BT was shown by the regimen using the highest concentration of the drug solution which was administered during a short period of time. (C) 2004 Elsevier B.V. All rights reserved.

Weekly administration of docetaxel in patients with hormone-refractory prostate cancer: a pilot study on Japanese patients

T Kojima, T Shimazui, M Onozawa, S Tsukamoto, S Hinotsu, N Miyanaga, K Hattori, K Kawai, H Akaza

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 34 ( 3 ) 137 - 141 2004.03 [Refereed]

Objective: Although treatment of hormone-refractory prostate cancer (HRPC) is difficult, a single-agent weekly dose of docetaxel has been reported as a promising regimen for patients with HRPC. The purpose of this study was the investigation of the efficacy of docetaxel for Japanese patients with HRPC. Methods: Ten patients with HRPC were treated with weekly docetaxel at Tsukuba University Hospital and were evaluated for the responses with respect to serum prostate-specific antigen (PSA), tumor size and survival. Considering the ethnic balance, the dose of docetaxel was reduced to 30 mg/m(2) weekly compared with 36 mg/m(2) in the study reported previously. Results: A biochemical response (>50% decrease in PSA) was observed in five patients (56%; 5/9) with an average time to progression of 4.5 months. In two partial responders as determined by PSA, respective metastatic lesions in bone and soft tissue were also improved. The estimated median survival duration was 6 months. Most of these responses were accompanied by a significant reduction in the requirement for analgesic agents. No severe toxicity of this regimen was observed, except for gastric ulcer in one patient who was excluded from the evaluation. Conclusions: Weekly administration of docetaxel as a single agent was associated with a high rate of PSA reduction. This treatment is feasible for patients with HRPC, even those who have a poor performance status and extensive prior treatments.

[Molecule based diagnosis].

Akaza H, Ichikawa T, Tsuruo T, Shimada Y, Moriwaki H, Mori M, Noguchi S, Nakamura S, Saijo N, Sone S, Isonishi S, Ohashi Y, Hinotsu S, von Euler M, Blackedge G

Gan to kagaku ryoho. Cancer & chemotherapy 31 ( 1 ) 125 - 133 2004.01 [Refereed] [Domestic journal]

Based on reviews of the concept of diagnostics and in general and in specific tumour areas it was clear that development of diagnostic procedures involving genomics will allow for much better targeted and tailored treatments in the future. This will result in better efficacy and better tolerability of cancer treatments, but will also allow for progress in prediction, diagnosis and dose selection. Large collaborative projects studying the efficacy and safety of drugs on the genome level is promising to bring important benefits to both patients and the national economy by reducing useless drug therapy. In colorectal cancer there are several genetic defects identified that can act as the target for directed therapy in the future. Expressions of tumour specific antigens open the way for immunological targeted therapies. Developments in the understanding of the genomic basis for resistance to anti-tumour therapy is promising to help targeting patients likely to respond and not develop resistance. A Japanese model is being developed to determine the relative risk of breast cancer of Japanese women. Based on this prevention therapies can be instigated. The last four years have seen the introduction of four novel targeted therapies. If this model should become a standard in the future, much stronger collaboration between academic research and pharmaceutical industry need to develop.

A comparison of error detection rates between the reading aloud method and the double data entry method

M Kawado, S Hinotsu, Y Matsuyama, T Yamaguchi, S Hashimoto, Y Ohashi

CONTROLLED CLINICAL TRIALS ( ELSEVIER SCIENCE INC ) 24 ( 5 ) 560 - 569 2003.10 [Refereed]

Data entry and its verification are important steps in the process of data management in clinical studies. In Japan, a kind of visual comparison called the reading aloud (RA) method is often used as an alternative to or in addition to the double data entry (DDE) method. In a typical RA method, one operator reads previously keyed data aloud while looking at a printed sheet or computer screen, and another operator compares the voice with the corresponding data recorded on case report forms (CRFs) to confirm whether the data are the same. We compared the efficiency of the RA method with that of the DDE method in the data management system of the Japanese Registry of Renal Transplantation. Efficiency was evaluated in terms of error detection rate and expended time. Five hundred sixty CRFs were randomly allocated to two operators for single data entry. Two types of DDE and RA methods were performed. Single data entry errors were detected in 358 of 104,720 fields (per-field error rate = 0.34%). Error detection fates were 88.3% for the DDE method performed by a different operator, 69.0% for the DDE method performed by the same operator, 59.5% for the RA method performed by a different operator, and 39.9% for the RA method performed by the same operator. The differences in these rates were significant (p < 0.001) between the two verification methods as well as between the types of operator (same or different). The total expended times were 74.8 hours for the DDE method and 57.9 hours for the RA method. These results suggest that in detecting errors of single data entry, the RA method is inferior to the DDE method, while its time cost is lower. (C) 2003 Elsevier Inc. All rights reserved.

The 2nd conference on Asian trends in prostate cancer hormone therapy.

Akaza H, Chang SJ, Chen KK, Esuvaranathan K, Fujioka T, Hirao Y, Hong SJ, Hinotsu S, Kim WJ, Lau W, Lee SE, Murai M, Naito S, Ogawa O, Rim JS, Soebadi DM, Song JM, Tsukamoto T, Umbas R, Usami M, Yang CR, Yoon JH, Zhou L

Gan to kagaku ryoho. Cancer & chemotherapy 30 ( 10 ) 1533 - 1542 2003.10 [Refereed]

The limited efficacy of methotrexate, actinomycin D and cisplatin (MAP) for patients with advanced testicular cancer

J Miyazaki, K Kawai, H Hayashi, M Onozawa, S Tsukamoto, N Miyanaga, S Hinotsu, T Shimazui, H Akaza

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 33 ( 8 ) 391 - 395 2003.08 [Refereed]

Background: Combination chemotherapy of methotrexate, actinomycin D and cisplatin (MAP) is reported to be effective against gestational choriocarcinoma. Methods: Eight patients with metastatic testicular cancer who had elevated beta-hCG were treated with MAP. They included three refractory cases and two relapsed cases. An additional three patients received MAP as part of the induction therapy. The MAP therapy consisted of methotrexate (10 mg/m(2)) on days 1-5, actinomycin D (0.01 mg/kg) on days 1-5 and cisplatin (70 mg/m(2)) on day 1. Results: In all three refractory patients, MAP failed to achieve tumor marker normalization. However, the elevated tumor markers normalized after MAP in the two cases of relapse. Of these two, one patient relapsed again 7 months after MAP and was subsequently salvaged with high-dose chemotherapy. The other patient relapsed and died of the disease 30 months after receiving MAP. Of the three patients who received MAP as part of the induction chemotherapy, one with pure choriocarcinoma achieved tumor marker normalization after MAP and is still alive without disease progression. In the other two patients, MAP failed to achieve marker normalization and the patients received high-dose chemotherapy. The toxicities were mainly bone marrow suppression and mucositis, which were almost acceptable. Conclusions: The results demonstrated the limited efficacy of MAP as salvage therapy. In addition, the efficacy of MAP as part of induction chemotherapy was negligible. However, there might be some role for MAP as a salvage therapy for patients with pure choriocarcinoma.

Paclitaxel, ifosfamide and cisplatin regimen is feasible for Japanese patients with advanced germ cell cancer

K Kawai, J Miyazaki, S Tsukamoto, S Hinotsu, K Hattori, T Shimazui, H Akaza

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 33 ( 3 ) 127 - 131 2003.03 [Refereed]

Background: Paclitaxel, ifosfamide and cisplatin (TIP) has been tested with successful results on metastatic testicular cancer in Western countries. Because paclitaxel, the key drug of this regimen, has not been approved for testicular cancer in Japan, there are no established data concerning TIP. The purpose of this study was to assess the feasibility of a TIP regimen for Japanese patients with advanced germ cell cancer. Methods: Eight patients with advanced germ cell cancer were treated with TIP that was originally reported by Motzer et al (1). The treatment was used for three refractory cases and two late relapse cases as salvage therapy and for three poor-risk cases with extra-pulmonary visceral metastases as a part of induction chemotherapy. TIP consisted of paclitaxel 175 mg/m(2) by 24 h infusion on day 1, followed by ifosfamide 1.2 g/m(2) infusions over 2 h and cisplatin 20 mg/m2 given over 2 h on days 2-6. Results: Five patients (62%) achieved a disease-free status after chemotherapy and surgical resection of residual tumor. Three of five patients have remained continuously free from disease progression at a median follow-up duration of 24 months and one additional patient is currently free of evidence of disease. Most patients developed grade 3 or 4 leukocytopenia and thrombocytopenia; however, they could be managed with routine supportive care. Sensory neuropathy was frequently seen, but no patient experienced over grade 3 neurotoxicity. Conclusions: TIP regimen as salvage chemotherapy is feasible for Japanese patients with advanced germ cell cancer. TIP as a part of induction chemotherapy for poor-risk patients is also feasible; however, larger and longer-term follow-up studies are needed to define the role of TIP in this setting.

[Meta-analysis and evidence based medicine].

Hinotsu S, Akaza H

Gan to kagaku ryoho. Cancer & chemotherapy 29 ( 10 ) 1705 - 1710 2002.10 [Refereed]

[Urology].

Hinotsu S, Akaza H

Gan to kagaku ryoho. Cancer & chemotherapy 29 ( 9 ) 1549 - 1569 2002.09 [Refereed]

[Intravesical instillation of doxorubicin or epirubicin for chemoprophylaxis of superficial bladder cancer--the fifth study of the Japanese Urological Cancer Research Group for Adriamycin/Farumorubicin].

Hinotsu S, Akaza H, Isaka S, Kagawa S, Koiso K, Kotake T, Machida T, Matsumura Y, Niijima T, Obata K, Ohashi Y, Ohe H, Shimazaki J, Tashiro K, Japanese Urological Cancer Research Group for Adriamycin, Farumorubicin

Gan to kagaku ryoho. Cancer & chemotherapy 29 ( 1 ) 73 - 80 2002.01 [Refereed]

Comparison of losartan with ACE inhibitors and dihydropyridine calcium channel antagonists - A pilot study of prescription-event monitoring in Japan

K Samizo, E Kawabe, S Hinotsu, T Sato, S Kageyama, C Hamada, Y Ohashi, K Kubota

DRUG SAFETY ( ADIS INTERNATIONAL LTD ) 25 ( 11 ) 811 - 821 2002 [Refereed]

Introduction: Two pilot studies for prescription-event monitoring in Japan (J-PEM) were launched in 1997 and 1998. Here we present data regarding adverse events that were reported in the second pilot J-PEM study where losartan was compared with ACE inhibitors and dihydropyridine calcium channel antagonists. Study design: We conducted a cohort study with a concurrent control. Methods/patient group: Study subjects prescribed losartan, an ACE inhibitor or a calcium channel antagonist were identified from prescriptions in hospital or community pharmacies. Events and other information were collected from doctors and pharmacists by mailed questionnaires. Events were coded and analysed using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Crude event rates were calculated and compared between patients treated with losartan and those receiving control drugs. When the difference was statistically significant, the event was further examined in several ways, including follow-up studies and by comparison with the data of the UK PEM study on losartan. Results: Pharmacists were sent 4344 questionnaires and returned 3591 (83%), while doctors were sent 3517 questionnaires and returned 1380 (39%). In the doctors' data, the adverse event rate for losartan treatment was greater than that for ACE inhibitors and/or calcium channel antagonists for the following seven events: headache, palpitations, anaemia, insomnia, feeling abnormal, increased blood pressure and asthma. Most of these are known adverse drug reactions (ADRs) of losartan except for two events: increased blood pressure and asthma. In pharmacists' data, the event rate for losartan was significantly greater than that for control drugs for the following ten events: hot flushes, abnormal hepatic function, oedema, peripheral swelling, decreased blood pressure, increased blood pressure, rhinitis, contact dermatitis, dry skin and heat rash. The first five events were known ADRs of losartan but the other five were not. When the two sets of data were combined, the rate of an additional event, increased blood creatinine phosphokinase, which is a known ADR of losartan, was significantly greater than that for the control drugs. The six events that were not documented as ADRs for losartan were not judged to be ADRs based on the results of follow-up studies and comparison with the UK PEM study on losartan. The crude rate of cough with losartan treatment was similar to that with calcium channel antagonists, but was significantly less than that with ACE inhibitors. Conclusion: No novel safety problems were found in this observational cohort study on losartan. The rates of some known ADRs differed significantly between patients treated with losartan and those in the control groups.

Pilot study of prescription-event monitoring in Japan comparing troglitazone with alternative oral hypoglycemics

K Kubota, E Kawabe, S Hinotsu, C Hamada, Y Ohashi, K Kurokawa

EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY ( SPRINGER-VERLAG ) 56 ( 11 ) 831 - 838 2001.01 [Refereed]

Objective: To examine adverse events reported in a pilot study of the prescription-event monitoring in Japan (J-PEM) scheme, comparing troglitazone with other oral hypoglycemics. Methods: We used a cohort study with a concurrent control in which information was gathered from both doctors and pharmacists. Crude event rates were calculated and compared between troglitazone (T) and alternative oral hypoglycemics (control drugs, C) using the likelihood ratio test. When the difference was statistically significant, possible confounding mechanisms were examined using Poisson regression analysis. Results: Of 3115 patient codes registered, pharmacists were sent 2078 questionnaires and returned 1814 (87%), while doctors were sent 1858 questionnaires and returned 671 (36%). The difference in crude rates was statistically significant in 11 events (seven where T > C and four where C > T) reported by pharmacists and ten events (three where T > C and seven where C > T) reported by doctors. Among those, in two events, "weight increased" (T > C) and "abnormal hepatic function" (T > C), significant differences were observed in data from both doctors and pharmacists. Regression analysis revealed that the difference in crude rates for "nausea" (T > C) was possibly due to an uneven distribution of genders and that for "weight increased" (T > C) was possibly due to an uneven distribution of compliance. Patients with hepatic function abnormalities associated with troglitazone could be divided into two subtypes: one with a slight increase in serum lactate dehydrogenase concentration only and the other with elevated serum alanine aminotransferase. Conclusions: Comparison of the event rates between troglitazone and control drugs, followed by regression analysis, revealed several features of adverse events associated with drugs, including possible confounding mechanisms. Troglitazone-induced hepatic function abnormalities may be divided into two subtypes.

Development of molecular targeting drugs for the treatment of cancer-therapeutic potential and issues to be addressed in global development

H. Akaza, K. Aiba, S. Isonishi, O. Ogawa, M. Shibuya, S. Sone, T. Tsuruo, S. Noguchi, S. Hinotsu, S. Kono, O. Mikami, G. Blackledge, B. Vose, D. Stribling

Gan to kagaku ryoho. Cancer & chemotherapy 27 ( 11 ) 1681 - 1693 2000

A survey of cancer treatment in a sample of hospitals > 100 beds conducted in 1998 compared with experience in the US showed that good progress has been achieved in Japan in the screening and early treatment of gastric cancer, and that the prognosis for breast cancer is better than in the West. Although in the past, the cytotoxic therapies available to physicians in Japan vs the West have been different, recent acceleration of regulatory review will result in a convergence of treatment paradigms and some improvement in acute response in many tumour types. However, world wide there is a need for new improved therapies in all cancers evaluated. Particular needs are in the management of NSCLC, advanced disease and cancers which form micrometastases. The eventual hope is that cancer can be turned from a lethal disease into a chronic disease where patients maintain a good QOL. Apart from anti hormonal therapies, the usual approach has been to kill the cancerous cells. However, the new approaches to intervening in the growth and migration of cancerous cells or the host tissue response by molecular targeting offer the promise of achieving a step change in therapy. Although EGF tyrosine Kinase inhibitors such as ZD 1839 have been shown to cause a conventional tumour response in NSCLC, many of these new approaches are unlikely to show a short term response even if they have the capacity to affect tumour development and increase disease free survival. Some compounds will require combination therapy with a conventional cytotoxic or radiotherapy to show their full benefit. For conventional cytotoxics, the usual approach to development has been to select the maximum tolerated dose and then evaluate the efficacy in advanced disease. However, for the new approaches which will not have such severe dose limiting toxicities, it will be necessary to select a surrogate marker of the intended biological effect to select the optimal biological dose (OBD) and dose regimen in phase I/II studies for further evaluation in phase II or III studies which are designed to show the expected patient benefit. The tumour target, the stage of the disease and the possible need for concomitant therapy will also have to be considered according to the mechanism of action of the product.

Argyrophilic nucleolar organizer region in proliferating cell has a predictive value for local recurrence in superficial bladder tumor

M Tomobe, T Shimazui, K Uchida, S Hinotsu, H Akaza

JOURNAL OF UROLOGY ( LIPPINCOTT WILLIAMS & WILKINS ) 162 ( 1 ) 63 - 68 1999.07 [Refereed]

Purpose: It has been shown in many carcinomas that the proliferation rate and number of argyrophilic nucleolar organizer regions (AgNOR) are associated with tumor aggressiveness. However, in bladder tumor the significance of the correlation between the number of AgNOR and tumor behavior remains controversial. Therefore, it would be helpful if a new technique could be developed that would allow for more accurate AgNOR counting in association with tumor behavior. We established the simultaneous staining technique of AgNOR with Ki-67 labeling to reveal the significance of AgNOR count in superficial bladder tumor. Materials and Methods: A total of 50 paraffin sections of superficial bladder tumor were stained with AgNOR and Ki-67 (MIB-1). The numbers of AgNORs in proliferating (MIB-1 positive) or resting (MIB-1 negative) cells were counted from a total of 100 nuclei. Correlations between MIB-1 associated AgNOR count and clinicopathological parameters were statistically analyzed. Results: The AgNOR count in proliferating cells was significantly higher than that in resting cells (p <0.01), and the count significantly increased with tumor grade (p <0.01). Based on recurrence-free survival analyses the local recurrence rate was significantly higher in patients with high proliferating cell NOR but not for those with resting or whole cells. However, no AgNOR score helped to select patients at high risk for disease progression. Conclusions: Proliferating cell NOR had a predictive value for local recurrence in patients with superficial bladder tumor.

Intravesical chemotherapy and immunotherapy for superficial tumors: Basic mechanism of action and future direction

H. Akaza, K. H. Kurth, R. Williams, S. Hinotsu, M. A.S. Jewett, K. Naito, K. Okada, P. F. Schellhammer, R. F. Van Velthoven, J. A. Witjes

Urologic Oncology ( Elsevier Inc. ) 4 ( 4-5 ) 121 - 129 1999 [Refereed]

Early detection and prevention of cancers in various therapeutic areas. Discussion

H. Akaza, T. Tsuruo, T. Tsukamoto, S. Noguchi, H. Moriwaki, S. Isonishi, N. Masuda, S. Hinotsu, A. F. Nash, M. von Euler, J. Wildin, D. Stribling

Gan to kagaku ryoho. Cancer & chemotherapy 26 ( 11 ) 1585 - 1597 1999

As illustrated by prostate cancer screening provides an opportunity for early intervention and treatment. However the screening test needs to detect patients with cancer with a low rate of false positives and at a stage which can be treated. Recently the concept of treating patients at high risk of developing breast cancer or suffering a recurrence has been highlighted by the western studies with Nolvadex (tamoxifen). Thus roundtable discussion (held in Tokyo) discussed the different strategies in Japan compared to US & Europe for screening & early intervention/prevention of cancer for breast, prostate, bladder, liver, lung, gynaecological & GI cancers. The range of strategies for cancer screening, how it is funded, whether it is appropriately targeted and whether there is any evidence for a beneficial effect on morbidity or mortality & future prospects for improved sensitivity through new methodology or markers were discussed. Although the relative rates of cancer vary between Japan & the West, the same factors seem to influence cancer development & the data on intervention were seen to be valid. The changing patterns of cancer in Japan suggest a clear opportunity for reducing, the incidence of cancer through lifestyle modification. For some cancers, e.g. cervical & bladder where there is a clear link between abnormal cytology & development cancer true prevention is already practiced. In other cases, preventive treatment is limited by the efficacy of available therapies. As far as drug treatment is concerned, funding of healthcare in Japan does not recognise the concept of prevention although there is, in practice, no barrier to the use of interventions where there is a clear link between biochemical/histological markers & development of cancer.

医学統計学の実際 : がん治療研究・薬理実験を対象として

大橋靖雄, 樋之津史郎

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 88 ( 2 ) 74 - 74 1997

Comparison of clinical effects between granisetron alone and combination of granisetron and methylprednisolone against the nausea and vomiting induced by CDDP chemotherapy comparative study by the cross-over trial

K. Uchida, H. Akaza, T. Shimazui, K. Kikuchi, F. Manabe, A. Iwasaki, S. Ishikawa, R. Noguchi, M. Otani, K. Hattori, F. Kondo, Y. Nishijima, K. Sato, K. Koiso, S. Hinotsu

Japanese Journal of Cancer and Chemotherapy 23 ( 1 ) 81 - 86 1996 [Refereed]

A cross over clinical trial was carried out to compare the antiemetic effort and safety between granisetron alone (40 μg/kg) and the combination of granisetron and methylprednisolone (MP: 10 mg/kg) in urological cancer patients treated with cisplatin. Forty-eight courses were given with granisetron alone and 47 courses with both granisetron and MP. The antiemetic effect of nausea and vomiting was evaluated in the acute emetic phase, during the 24 hours following the CDDP administration, and in the delayed emetic phase, 2 to 7 days after the administration. Combination therapy of granisetron and MP demonstrated a greatest antiemetic effect during the 72 hours following the CDDP administration than by granisetron alone. But there was no significant difference in antiemetic effect between combination therapy and granisetron alone after the 3rd day. Combination therapy also demonstrated more efficacy in complete antiemetic effect, with no emesis and less than moderate nausea, than by granisetron alone. Both treatments showed no side effects and were safe.

An overview of clinical trials in endocrine therapy for cancer

S. Hinotsu, Y. Ohasi, H. Akaza

Japanese Journal of Cancer and Chemotherapy 23 ( 6 ) 689 - 694 1996 [Refereed]

To obtain information for published clinical trials in endocrine therapy for cancer in Japan, a computerized literature search of MEDLINE, EMBASE and IGAKU-CHUO-ZASSHI (CD-ROM) was done. We found four articles on randomized trials for prostate cancer and two for breast cancer. In order to obtain information for ongoing randomized phase III trials in endocrine therapy for cancer in the United States and Europe, a search of PDQ (Physician's Data Query) was done. In PDQ, 13 active trials started after January 1990 in endocrine therapy for breast cancer and six active trials started after January 1990 in endocrine therapy for prostate cancer were registered. Out of 13 trials for breast cancer, projected sample sizes were over 1,000 in eight trials, and QOL was selected as an end point in six trials. Out of six trials for prostate cancer, projected sample sizes were over 500 in three trials, and QOL or sexual function was selected as an end point in three trials.

精巣腫瘍導入化学療法における肺障害の検討

河合弘二, 樋之津史郎, 宮永直人, 菊池孝治, 内田克紀, 武島仁, 赤座英之

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 87 ( 2 ) 508 - 508 1996

シスプラチン併用全身および動注化学療法時の悪心・嘔吐に対する制吐剤投与法の検討

内田克紀, 佐々木明, 菊池孝治, 赤座英之, 小磯謙吉, 石川悟, 野口良輔, 大谷幹伸, 樋之津史郎, 服部一紀, 近藤福次, 岩崎明郎, 真鍋文雄

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 86 ( 3 ) 824 - 824 1995

日本泌尿器科学会雑誌掲載論文中に使用された統計学的手法の解析

樋之津史郎, 大橋靖雄

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 86 ( 3 ) 831 - 831 1995

Bellini duct carcinoma accompanied by hemorrhagic renal cyst: A case report and review of the literature

N. Sekido, S. Hinotsu, K. Kawai, K. Matsuki, H. Akaza, K. Koiso

Nishinihon Journal of Urology 57 ( 4 ) 515 - 518 1995

A 51-year-old female, who had undergone close follow-up for a right hemorrhagic renal cyst one year earlier, was admitted to our hospital in order to undergo examination of a newly developing tumor adjacent to the cyst, which had been found on ultrasonography and computed tomography. Aortography showed the downward displacement of the lower renal artery, but did not reveal any tumor vessels. Dark red fluid was aspirated from the cyst and the LDH level in the fluid was found to be very high (3042 U/ml). Urine cytological study resulted in class IV. Since small renal cell carcinoma was highly suspected according to these results, we performed right radical nephrectomy. According to the pathological findings, this tumor was not a renal cell carcinoma originating from the proximal tubules, but was a Bellini duct carcinoma originating from the collecting duct. Moreover, renal hilar lymph-node metastasis was present. She was treated with α-interferon and Tegafur postoperatively, but 4 months after surgery there was evidence of metastasis in the liver. She received chemotherapy of the M-VAC regimen, but after 1 cycle of this therapy, multiple liver metastases and retroperitoneal lymph node metastases were noted. We herein describe a case report and review the literature.

Fournier's gangrene detected at an early stage: A case report

N. Sekido, S. Hinotsu, H. Akaza, K. Koiso

Nishinihon Journal of Urology 56 ( 10 ) 1199 - 1202 1994

A 25-year-old male was admitted to our hospital complaining of pyrexia, sore throat and left hemiscrotal pain. On physical examination, a part of the left hemiscrotum showed slight redness, mild swelling and a small ulcerative lesion. Hematological study revealed marked inflammatory reaction. Intensive antibiotic chemotherapy and deep stab incision through the center of the lesion was conducted under the diagnosis of early-stage Fournier's gangrene. He rapidly recovered and the scrotal wound healed very quickly, without spreading any further across the scrotum. We conclude that early-stage Fournier's gangrene can be treated with intensive antibiotic chemotherapy and minimal debridement.

Intravesical ultrasound tomography with miniature probe for bladder cancer

K. Hattori, S. Hinotsu, T. Shimazui, K. Uchida, H. Akaza, K. Koiso

Japanese Journal of Medical Ultrasonics 20 ( 10 ) 1 - 5 1993

軟性膀胱鏡と Nd : YAGレーザーを用いた表在性膀胱腫瘍の外来治療 : 第80回日本泌尿器科学会総会

石川悟, 佐々木明, 笠谷俊也, 樋之津史郎, 鶴田敦, 小磯謙吉

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 84 ( 1 ) 105 - 106 1993

Use of ND:YAG laser and flexible cystoscope in outpatient treatment of recurrent superficial bladder tumors

Satoru Ishikawa, Akira Sasaki, Atsushi Tsuruta, Shiro Hinotsu, Kenkichi Koiso

Japanese Journal of Urology 84 ( 4 ) 707 - 710 1993 [Refereed]

Nd:YAG laser irradiation and flexible cystoscopy were used in the outpatient management of 16 cases (21 sessions) with superficial bladder tumors. Irradiation of tumors was accomplished in all cases except 3 in which the visual field was affected by bleeding after the cup biopsy of tumors. Tumors at the bladder neck were easily irradiated through the flexible cystoscope. No tumor recurred at or near the previously irradiated site. This method provided a safe and cost-effective means to treat superficial bladder tumors in selected cases. © 1993, THE JAPANESE UROLOGICAL ASSOCIATION. All rights reserved.

軟性尿道膀胱鏡による下部尿路の経尿道的操作 : 第79回日本泌尿器科学会総会

樋之津史郎, 石川悟, 鶴田敦, 小磯謙吉

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 83 ( 6 ) 1021 - 1021 1992

Effect of UFT with high dose leucovorin for transplantable bladder tumor (MBT-2) in mice

Y. Nishijima, S. Hinotsu, K. Koiso, R. Nemoto

Gan to kagaku ryoho. Cancer & chemotherapy 18 ( 13 ) 2349 - 2351 1991

進行性移行上皮癌に対するMCV療法

石川悟, 樋之津史郎, 鶴田敦, 根本良介, 小磯謙吉

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 81 ( 13 ) 2097 - 2097 1990

尿路癌の脊椎骨転移経路に関する実験的研究

西嶋由貴子, 河合弘二, 真鍋文雄, 樋之津史郎, 内田克紀, 小磯謙吉, 根本良介

日本泌尿器科学会雑誌 ( 一般社団法人日本泌尿器科学会 ) 81 ( 13 ) 2073 - 2073 1990

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