記述言語：英語   掲載種別：研究論文（学術雑誌）  

Thus far, there have been limited case reports on immunoglobulin G4-related autoimmune hepatitis (IgG4-AIH), and its clinical features have not been elucidated. We herein report a rare case of IgG4-AIH simultaneously concomitant with autoimmune pancreatitis (AIP). A 73-year-old female was admitted to our hospital for further investigation of elevated levels of liver transaminase and pancreatic enzymes. Her serological tests showed a high antinuclear antibody titer, and elevated IgG and IgG4 levels. Liver biopsy revealed interface hepatitis and bridging necrosis with IgG4-positive lymphoplasmacytic infiltration in the portal area. Moreover, contrast-enhanced computed tomography (CECT) showed pancreatic tail enlargement, and magnetic resonance cholangiopancreatography showed skipped narrowing of the main pancreatic duct in the pancreatic tail. Endoscopic ultrasonography-fine needle aspiration specimens showed no malignant cells. Based on these results, we diagnosed her with IgG4-AIH simultaneously concomitant with probable type 1 AIP. She was started on prednisolone (PSL) at 35 mg/d, and her symptoms and liver transaminase levels improved. One month after starting treatment, CECT showed improvement of pancreatic tail enlargement. She is maintained on 5 mg PSL/d and has been in remission for two years.

DOI： 10.1007/s12328-021-01509-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Effective management of immune-related adverse events in patients receiving immunotherapy for cancer is problematic. In this report, we present the case of a 58-year-old man with advanced clear cell renal cell carcinoma who responded well to a combination of ipilimumab and nivolumab. However, after two courses of treatment, he developed fulminant hepatitis and died. An autopsy confirmed that the primary lesion in the left kidney was more than 99% necrotic with only six small residual tumor lesions. These lesions were infiltrated by large numbers of CD8-positive/TIA-1-positive lymphocytes. However, a metastatic lesion in the right kidney harbored few lymphocytes. Furthermore, the tumor cells in the metastatic lesion and one of the residual lesions showed decreased expression of HLA class I molecules, which are a prerequisite for cytotoxic T-lymphocyte-mediated immunotherapy in tumor cells. In this patient, more than 80% of hepatocytes were destroyed and the parenchyma was infiltrated with CD8-positive/TIA-1-positive lymphocytes. The patient had polyuria, which was attributed to neurohypophysitis caused by the infiltration of CD8-positive/TIA-1-positive lymphocytes. We believe that this is an instructive case for immuno-oncologists.

DOI： 10.1080/25785826.2020.1788229

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mismatch repair protein deficiency (dMMR) is a favorable prognostic factor in colorectal cancer. It is also associated with aberrant expression of HLA class I molecules, which are required for cytotoxic T lymphocyte-mediated cancer immunotherapy. Because dMMR is frequently also found in endometrial cancers (ECs), we retrospectively investigated the expression of mismatch repair proteins and HLA class I molecules in 127 EC patients. In this study, EC patients being treated in our hospital were recruited from 2005 to 2009 and observed until December 2017. Lesion specimens were evaluated via immunohistochemistry for MSH6 and PMS2 (mismatch repair proteins) and HLA class I molecules. Expression of these molecules was statistically related to clinical and pathological factors and prognosis. dMMR was detected in 33 patients and did not correlate with the expression level of HLA class I molecules (P = 0.60). On the other hand, unexpectedly, multivariate analysis revealed that intact expression of HLA class I molecules was associated with p53 overexpression (P = 0.004). Neither dMMR nor decreased expression of HLA class I molecules were prognostic factors. These results are inconsistent with previous findings for colorectal cancer. A distinctive local tissue immune microenvironment would underlie the discrepancy in the results between EC and colorectal cancer.

DOI： 10.1007/s00795-020-00254-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.

DOI： 10.1111/cas.14773

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記述言語：英語  

Introduction: Immune checkpoint inhibitors are now a standard therapeutic option for lung adenocarcinoma. However, Immune checkpoint inhibitors often induce various immune-related adverse events. Case presentation: The patient was a 78-year-old woman with lung adenocarcinoma who had a partial response to pembrolizumab. During treatment, she complained of pollakiuria and nocturia with painful micturition. Histological analysis revealed infiltration of CD8-positive and/or TIA-1 cytotoxic granule-associated RNA binding protein-positive lymphocytes and programmed death-ligand 1 expression in the urothelium. A diagnosis of immune-related adverse event cystitis was made based on these clinical and pathological findings. The patient's subjective symptoms and findings on cystoscopy improved dramatically after treatment with prednisolone. Conclusion: Immune checkpoint inhibitors-induced cystitis is extremely rare. This report is the first to include an immunohistochemical analysis of the urothelial epithelium in immune-related adverse event cystitis and describes an instructive case.

DOI： 10.1002/iju5.12211

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: The tumor microenvironment (TME) balances tumor growth and suppression through humoral factors and cell-cell interactions. In oral squamous cell carcinoma (OSCC), TMEs have been associated with prognosis of cancer patients and are evaluated by microscopy; however, these methods of evaluation vary among studies. MATERIALS AND METHODS: To evaluate the TME, borderline microenvironment fibrosis (bMF) was evaluated histologically in 236 OSCC cases and used to determine the clinicopathological status. RESULTS: bMF was observed in 47% (110 in 236 cases) of OSCC cases and associated with higher T category, N category, stage, histological grade and mode of invasion. bMF-positive was related to overall survival (OS) and progression-free survival (PFS). Multivariate analysis revealed that bMF-positive was an independent factor for OS in all cases [n=226; HR=1.683 (1.018-2.781); p=0.042], especially in T1+T2 cases [n=186; HR=1.926 (1.079-3.440); p=0.024], and PFS in all cases [n=226; HR=2.254 (1.397-3.637); p=0.001]. CONCLUSION: bMF may act as a novel biomarker for OSCC.

DOI： 10.21873/anticanres.14434

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The surgical resection of craniovertebral junction(CVJ)meningioma is challenging because of the neighboring brainstem, lower cranial nerves, and vertebral artery(VA). Moreover, encasement of the VA by the tumor can raise the risk of complications and require cautious manipulation during surgery. CASE: A 46-year-old woman presented with a one-year history of neck pain. She had temporal hemiplegia and numbness on her left side. Magnetic resonance imaging(MRI)showed a CVJ meningioma pushing the brainstem from the right vertebral side and encasing the right VA. Digital subtraction angiography(DSA)showed two feeding arteries arising from the right VA and a sunburst sign. The right VA was the dominant side but did not have the right posterior inferior cerebellar artery(PICA). The anterior spinal artery(ASA)was dominant in the left VA. We performed a balloon test occlusion(BTO)for 20 min and it did not cause any complications;therefore, we occluded the VA using endovascular coils. After 4 days, we removed the meningioma in the prone position, using a far-lateral approach and C1-laminectomy. The laterally located meningioma pushed the brainstem. After detaching the tumor from the dura, we cut the encased VA and the tumor was resected safely(Simpson grade II). Postoperatively, she developed temporal thermal hypoalgesia on the left side of her body. Magnetic resonance imaging showed a microinfarction in the medulla. CONCLUSION: If the VA test occlusion provides a clear result, pre-operative endovascular sacrifice of the VA encased by CVJ meningioma is a feasible treatment strategy.

DOI： 10.11477/mf.1436204220

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Langerhans cell sarcoma (LCS) and quintuple cancers are extremely rare. In this report, a case of quintuple cancers including LCS was described. An 80-year-old man had squamous cell carcinoma of the nasal skin, colon and rectum adenocarcinomas, and T-cell/histiocyte-rich large B-cell lymphoma. As swelling of multiple submental lymph nodes was observed, fine-needle aspiration was carried out. Many large cells with high-grade nuclear atypia and abundant cytoplasm were observed. Lymphocytes and eosinophils were observed in the background. Although a malignant tumor was suspected, a definite diagnosis could not be made. In a biopsy sample, the tumor cells were positive for vimentin, CD68, S-100, CD1a, and CD163 and negative for epithelial, lymphocyte, and melanoma markers in immunohistochemistry. A diagnosis of LCS was made from the immunohistochemical findings and high mitotic rate with atypical forms. The patient died about 2 months after the first medical examination. Metastasis of LCS was confirmed in many organs by autopsy. LCS has a poor prognosis. In cases with the above-described cytological findings, LCS should be added to the list of differential diagnosis. The cytological findings presented here may be useful for determining appropriate clinical management such as staging of the disease and follow-up of the neoplasm. Diagn. Cytopathol. 2017;45:441-445. © 2017 The Authors Diagnostic Cytopathology Published by Wiley Periodicals, Inc.

DOI： 10.1002/dc.23628

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Cancer-initiating cells (CICs) are thought to be essential for tumor maintenance, recurrence, and distant metastasis, and they are therefore reasonable targets for cancer therapy. Cancer immunotherapy is a novel approach to target cancer. In this study, we aimed to establish novel CIC-targeting immunotherapy. EXPERIMENTAL DESIGN: Colorectal cancer (CRC) CICs were isolated as side population (SP) cells. The gene expression profile of CRC CICs was analyzed by cDNA microarray and RT-PCR. Protein expression of olfactory receptor family 7 subfamily C member 1 (OR7C1) were analyzed by Western blot and immunohistochemical staining. The functions of OR7C1 were analyzed by gene overexpression and gene knockdown using siRNAs. OR7C1-positive cells were isolated by a flow cytometer and analyzed. CTLs specific for OR7C1 peptide were generated, and the antitumor effect was addressed by mice adoptive transfer model. RESULTS: OR7C1 has essential roles in the maintenance of colon CICs, and the OR7C1-positive population showed higher tumorigenicity than that of the OR7C1-negative population, indicating that OR7C1 is a novel functional marker for colon CIC. Immunohistochemical staining revealed that OR7C1 high expression was correlated with poorer prognosis in CRC patients. OR7C1-derived antigenic peptide-specific CTLs showed specific cytotoxicity for CICs, and an OR7C1-specific CTL clone showed a greater antitumor effect than did a CTL clone targeting all cancer cells in a CTL adoptive transfer mouse model. CONCLUSIONS: OR7C1 is a novel marker for colon CICs and can be a target of potent CIC-targeting immunotherapy. Clin Cancer Res; 22(13); 3298-309. ©2016 AACR.

DOI： 10.1158/1078-0432.CCR-15-1709

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Human cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be isolated as side population (SP) cells, aldehyde dehydrogenase high (ALDHhigh) cells or cell surface marker-positive cells including CD44+ cells and CD133+ cells. CSCs/CICs and non-CSCs/CICs are unstable in in vitro culture, and CSCs/CICs can differentiate into non-CSCs/CICs and some non-CSCs/CICs can dedifferentiate into CSCs/CICs. Therefore, experiments using a large amount of CSCs/CICs are technically very difficult. In this study, we isolated single cell clones from SP cells and main population (MP) cells derived from the human colon cancer cell line SW480. SP analysis revealed that SP clone cells had relatively high percentages of SP cells, whereas MP clone cells showed very few SP cells, and the phenotypes were sustainable for more than 2 months of in vitro culture. Xenograft transplantation revealed that SP clone cells have higher tumor-initiating ability than that of MP clone cells and SP clone cell showed higher chemo-resistance compared with MP clone cells. These results indicate that SP clone cells derived from SW480 cells are enriched with CSCs/CICs, whereas MP clone cells are pure non-CSCs/CICs. SP clone cells and MP clone cells are a very stable in vitro CSC/CIC-enriched and non-CSC/CIC model for further analysis.

DOI： 10.1371/journal.pone.0158903

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aim of the present study was to establish cancer stem-like cell/cancer-initiating cell (CSC/CIC)-targeting immunotherapy. The CSC/CIC are thought to be essential for tumor maintenance, recurrence and distant metastasis. Therefore they are reasonable targets for cancer therapy. In the present study, we found that a heat shock protein (HSP) 40 family member, DnaJ (Hsp40) homolog, subfamily B, member 8 (DNAJB8), is preferentially expressed in CSC/CIC derived from colorectal cancer (CRC) cells rather than in non-CSC/CIC. Overexpression of DNAJB8 enhanced the expression of stem cell markers and tumorigenicity, indicating that DNAJB8 has a role in CRC CSC/CIC. A DNAJB8-specific cytotoxic T lymphocyte (CTL) response could be induced by a DNAJB8-derived antigenic peptide. A CTL clone specific for DNAJB8 peptide showed higher killing activity to CRC CSC/CIC compared with non-CSC/CIC, and CTL adoptive transfer into CRC CSC/CIC showed an antitumor effect in vivo. Taken together, the results indicate that DNAJB8 is expressed and has role in CRC CSC/CIC and that DNAJB8 is a novel target of CRC CSC/CIC-targeting immunotherapy.

DOI： 10.1111/cas.12362

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Identification of antigenic peptides derived from tumor-associated antigens (TAA) enables cancer vaccine therapy using antigenic peptides. Here, we summarize the design of antigenic peptides and induction of cytotoxic T lymphocytes (CTL) using antigenic peptides and validation of CTL.

DOI： 10.1007/978-1-4939-0345-0_28

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5045/br.2013.48.2.154

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DNA methyltransferase 1 (Dnmt1) is essential for the maintenance of hematopoietic and somatic stem cells in mice; however, its roles in human cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are still elusive. In the present study, we investigated DNMT1 functions in the maintenance of human colon CSCs/CICs using the human colon cancer cell line HCT116 (HCT116 w/t) and its DNMT1 knockout cell line (DNMT1(-/-)). The rates of CSCs/CICs were evaluated by side population (SP) analysis, ALDEFLUOR assay and expression of CD44 and CD24. SP, ALDEFLUOR-positive (ALDEFLUOR(+)) and CD44-positive and CD24-positive (CD44(+)CD24(+)) cell rates were lower in DNMT1(-/-) cells than in HCT116 w/t cells. Since CSCs/CICs have higher tumor-initiating ability than that of non-CSCs/CICs, the tumor-initiating abilities were addressed by injecting immune deficient (NOD/SCID) mice. DNMT1(-/-) cells showed less tumor-initiating ability than did HCT116 w/t cells, whereas the growing rate of DNMT1(-/-) cells showed no significant difference from that of HCT116 cells both in vitro and in vivo. Similar results were obtained for cells in which DNMT1 had been transiently knocked-down using gene-specific siRNAs. Taken together, these results indicate that DNMT1 is essential for maintenance of colon CSCs/CICs and that short-term suppression of DNMT1 might be sufficient to disrupt CSCs/CICs.

DOI： 10.1016/j.yexmp.2012.10.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer stem-like cells (CSCs)/cancer-initiaiting cells (CICs) are defined as a small population of cancer cells that have self-renewal capacity, differentiation potential and high tumor-initiating ability. CSCs/CICs of ovarian cancer have been isolated by side population (SP) analysis, ALDEFLUOR assay and using cell surface markers. However, these approaches are not definitive markers for CSCs/CICs, and it is necessary to refine recent methods for identifying more highly purified CSCs/CICs. In this study, we analyzed SP cells and aldehyde dehydrogenese bright (ALDH(Br)) cells from ovarian cancer cells. Both SP cells and ALDH(Br) cells exhibited higher tumor-initiating ability and higher expression level of a stem cell marker, sex determining region Y-box 2 (SOX2), than those of main population (MP) cells and ALDH(Low) cells, respectively. We analyzed an SP and ALDH(Br) overlapping population (SP/ALDH(Br)), and the SP/ALDH(Br) population exhibited higher tumor-initiating ability than that of SP cells or ALDH(Br) cells, enabling initiation of tumor with as few as 10(2) cells. Furthermore, SP/ADLH(Br) population showed higher sphere-forming ability, cisplatin resistance, adipocyte differentiation ability and expression of SOX2 than those of SP/ALDH(Low), MP/ALDH(Br) and MP/ALDH(Low) cells. Gene knockdown of SOX2 suppressed the tumor-initiation of ovarian cancer cells. An SP/ALDH(Br) population was detected in several gynecological cancer cells with ratios of 0.1% for HEC-1 endometrioid adenocarcinoma cells to 1% for MCAS ovary mucinous adenocarcinoma cells. Taken together, use of the SP and ALDH(Br) overlapping population is a promising approach to isolate highly purified CSCs/CICs and SOX2 might be a novel functional marker for ovarian CSCs/CICs.

DOI： 10.1371/journal.pone.0068187

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cancer cells that have high tumorigenicity. Furthermore, CSCs/CICs are resistant to several cancer therapies, and CSCs/CICs are therefore thought to be responsible for cancer recurrence after treatment and distant metastasis. In epithelial ovarian cancer (EOC) cases, disease recurrence after chemotherapy is frequently observed, suggesting ovarian CSCs/CICs are involved. There are four major histological subtypes in EOC, and serous adenocarcinoma and clear cell adenocarcinoma are high-grade malignancies. We therefore analyzed ovarian CSCs/CICs from ovarian carcinoma cell lines (serous adenocarcinoma and clear cell adenocarcinoma) and primary ovarian cancer cells in this study. We isolated ovarian CSCs/CICs as an aldehyde dehydrogenase 1 high (ALDH1(high)) population from 6 EOC cell lines (3 serous adenocarcinomas and 3 clear cell adenocarcinomas) by the ALDEFLUOR assay. ALDH1(high) cells showed greater sphere-forming ability, higher tumorigenicity and greater invasive capability, indicating that ovarian CSCs/CICs are enriched in ALDH1(high) cells. ALDH1(high) cells could also be isolated from 8 of 11 primary ovarian carcinoma samples. Immunohistochemical staining revealed that higher ALDH1 expression levels in ovary cancer cases are related to poorer prognosis in both serous adenocarcinoma cases and clear cell adenocarcinoma cases. Taken together, the results indicate that ALDH1 is a marker for ovarian CSCs/CICs and that the expression level of ALDH1 might be a novel biomarker for prediction of poor prognosis.

DOI： 10.1371/journal.pone.0065158

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Evaluation of: Rech AJ, Mick R, Martin S et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patents. Sci. Transl. Med. 4(134), 134ra62 (2012). Tregs are involved in the maintenance of immunological self-tolerance. Recent studies have revealed that Tregs suppress antitumor immunity and that they are major obstacles for cancer immunotherapy. Various approaches have been carried out to cancel immunological suppression by Tregs in clinical settings; however, side effects such as autoimmunity occurred and expected antitumor effects were not achieved. In a recent study, Rech et al. evaluated daclizumab, a US FDA-approved humanized anti-CD25 antibody, for regulation of Treg cells in a peptide vaccination trial of breast cancer patients. Daclizumab caused long-lasting depletion of CD25(+) Tregs, reprogramming of CD25(+) Tregs, and enhancement of antipeptide immune response. Of note, major autoimmune responses were not observed in daclizumab-treated patients. This study provides a possible safe and promising approach to regulate Tregs in cancer vaccine therapy.

DOI： 10.2217/imt.12.116

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer stem-like cells (CSC) are a small population of cancer cells with superior tumor initiating, self-renewal, and differentiation properties. In this study, we show that the cancer-testis antigen and HSP40 family member DNAJB8 contributes to the CSC phenotype in renal cell carcinoma (RCC). DNAJB8 overexpression increased the percentage of side population (SP) cells representing CSCs in RCC cells, enhancing their tumor-initiating ability. Conversely, attenuation of DNAJB8 decreased SP cells and reduced tumor-initiating ability. The utility of DNAJB8 as an immunologic target was established in DNA vaccination experiments. Compared with immunization with the tumor-associated antigen survivin, which was expressed in both CSCs and non-CSCs in RCC, immunization with Dnajb8 expression plasmids yielded stronger antitumor effects. Together, our findings suggest that DNAJB8 plays a role in CSC maintenance and that it offers a candidate for CSC-targeting immunotherapy in RCC.

DOI： 10.1158/0008-5472.CAN-11-3062

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer stem cells (CSCs)/cancer-initiating cells (CICs) are characterized as a small population of cancer cells that have high tumor-initiating ability. CSCs/CICs are resistant to several cancer therapies, and eradication of CSCs/CICs is essential to cure cancer. How can we eradicate CSCs/CICs? Cytotoxic T lymphocytes (CTLs) might be a promising answer.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, the SOX2 gene has been reported to be amplified in human lung squamous cell carcinomas. However, its roles in human lung adenocarcinomas are still elusive. In this study, we analyzed the functions of SOX2 in cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) derived from human lung adenocarcinoma. Human lung CSCs/CICs were isolated as higher tumorigenic side population (SP) cells using Hoechst 33342 dye from several lung cancer cell lines. Four of nine lung cancer cell lines were positive for SP cells (LHK2, 1-87, A549, Lc817). The ratios of SP cells ranged from 0.4% for Lc817 to 2.8% for LHK2. To analyze the molecular aspects of SP cells, we performed microarray screening and RT-PCR analysis, and isolated SOX2 as one of a SP cell-specific gene. SOX2 was expressed predominantly in LHK2 and 1-87 SP cells, and was also expressed in several other cancer cell lines. The expression of SOX2 protein in primary human lung cancer tissues were also confirmed by immunohistochemical staining, and SOX2 was detected in more than 80% of primary lung cancer tissues. To address SOX2 molecular functions, we established a SOX2-overexpressed LHK2 and A549 cell line (LHK2-SOX2 and A549-SOX2). LHK2-SOX2 cells showed higher rates of SP cells and higher expression of POU5F1 compared with control cells. LHK2-SOX2 and A549-SOX2 cells showed relatively higher tumorigenicity than control cells. On the other hand, SOX2 mRNA knockdown of LHK2 SP cells by gene-specific siRNA completely abrogated tumorigenicity in vivo. These observations indicate that SOX2 has a role in maintenance of stemness and tumorigenicity of human lung adenocarcinoma CSCs/CICs and is a potential target for treatment.

DOI： 10.1038/labinvest.2011.140

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer stem-like cells (CSCs) and tumor-initiating cells (TICs) are a small population of cancer cells that share three properties: tumor initiating ability, self-renewal, and differentiation. These properties suggest that CSCs/TICs are essential for tumor maintenance, recurrence, and distant metastasis. Here, we show that cytotoxic T lymphocytes (CTLs) specific for the tumor-associated antigen CEP55 can efficiently recognize colon CSCs/TICs both in vitro and in vivo. Using Hoechst 33342 dye staining, we isolated CSCs/TICs as side population (SP) cells from colon cancer cell lines SW480, HT29, and HCT15. The SP cells expressed high levels of the stem cell markers SOX2, POU5F1, LGR5, and ALDH1A1 and showed resistance to chemotherapeutic agents such as irinotecan or etoposide.To evaluate the susceptibility of SP cells to CTLs, we used CTL clone 41, which is specific for the CEP55-derived antigenic peptide Cep55/c10orf3_193 (10) (VYVKGLLAKI). The SP cells expressed HLA class I and CEP55 at the same level as the main population cells. The SP cells were susceptible to CTL clone 41 at the same level as main population cells. Furthermore, adoptive transfer of CTL clone 41 inhibited tumor growth of SW480 SP cells in vivo. These observations suggest that Cep55/c10orf3_193(10) peptide-based cancer vaccine therapy or adoptive cell transfer of the CTL clone is a possible approach for targeting chemotherapy-resistant colon CSCs/TICs.

DOI： 10.1016/j.ajpath.2011.01.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In our previous study, we demonstrated that a peptide derived from the novel centrosome residing protein Cep55/c10orf3 can be targeted by the cytotoxic T lymphocytes (CTLs) in peripheral blood mononuclear cells (PBMCs) of breast carcinoma patients. In this report, we evaluated the feasibility of cancer immunotherapy using Cep55/c10orf3 peptide for colorectal carcinoma (CRC). To evaluate the expression of Cep55/c10orf3 in CRC tissues, we performed immunohistochemical staining of using anti-Cep55/c10orf3 monoclonal antibody. Sixty-three percent cases showed weak positive for Cep55/c10orf3 in total 70 CRC cases. The Cep55/c10orf3 expression intention was collated with high histological grade of CRC. Thus, we hypothesized that Cep55/c10orf3 can also be the target of CTLs in CRC cases. We generated CTLs from PBMCs of human leukocyte antigen (HLA)-A24-positive colorectal carcinoma patients using HLA-A24-restricted Cep55/c10orf3 peptides. Two of 6 colorectal cancer patients were reactive for the Cep55/c10orf3_193(10) peptide, which was the only immunogenic peptide in breast carcinoma patients. CTL clone specific for Cep55/c10orf3_193(10) recognized and lysed HLA-A24 (+) and Cep55/c10orf3 (+) colorectal carcinoma cell lines. In addition, 1 of 6 colorectal carcinoma patients was reactive for the Cep55/c10orf3_402(11) and Cep55/c10orf3_283(12) peptides, but not for Cep55/c10orf3_193(10) with the ELISPOT assay. These observations suggest that the antigenic peptide repertoire presented by HLA-A24 in colorectal carcinoma might be different from that in breast carcinoma. Thus, these peptide vaccination peptide mixture of Cep55/c10orf3_193(10), Cep55/c10orf3_402(11) and Cep55/c10orf3_283(12) might be more effective than a single peptide in the treatment of colorectal carcinoma patients.

DOI： 10.1016/j.yexmp.2010.10.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer stem-like cells (CSCs)/tumor-initiating cells (TICs) are a small population of cancer cells that have the properties of tumor-initiating ability, self-renewal and differentiation. These properties suggest that CSCs/TICs are essential for tumor maintenance, recurrence and distant metastasis. Thus, elimination of CSCs/TICs is essential to cure malignant diseases. However, there are several studies reporting that CSCs/TICs are more resistant to standard cancer therapies, including chemotherapy and radiotherapy, than non-CSC/TIC populations. How then, can we eliminate CSCs/TICs? Immunotherapy might be the possible answer. In recent analysis, innate immunity (natural killer cells and gammadeltaT cells) and also adaptive immunity (cytotoxic T lymphocyte-based cellular immunity and antibody-based humoral immunity) can recognize CSCs/TICs in vitro efficiently. Furthermore, CSC/TIC-specific monoclonal antibody therapies are also efficient in vivo. In this article, we describe the potency, possibilities and problems of CSC/TIC-targeting immunotherapy.

DOI： 10.2217/imt.10.10

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 53-year-old woman had demonstrated idiopathic thrombocytopenic purpura (ITP) and iron deficiency anemia (IDA) since 1978. Although she was treated with prednisolone for ITP and oral iron compounds for IDA, neither ITP nor IDA showed any improvement. Since her (13)C-urea breath test was positive, Helicobacter pylori (H. pylori) eradication therapy was performed in 2001. The therapy was effective for IDA but not for ITP. Analysis of cases such as this will be useful for clarifying the mechanisms underlying the development of ITP and IDA associated with H. pylori.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 30-year-old man consulted a local hospital because of upper abdominal pain and tarry stool and was admitted because of duodenal ulcer and hepatic dysfunction. On the fifth hospital day, he developed fever and erythema on the upper body. Liver biopsy demonstrated giant cell hepatitis, and interferon alpha was therefore administered. Liver function improved, though total bilirubin increased to 22.3 mg/dl. The eruption and fever improved in the 3rd hospital week, deteriorated again in the 5th hospital week, and then improved again in the 8th hospital week. Thereafter, he was transferred to our hospital for detailed examination of atypical lymphocytosis, lymphopenia, and hypogammaglobulinemia. Many lymph nodes measuring about 1 cm were detected by palpation. After admission to our hospital, lymphoadenopathy and fever improved. We measured the level of HHV-6 antibody since the clinical course was similar to that of drug-induced hypersensitivity syndrome (DIHS). HHV-6 IgG was x2,560, although it had been x160 at the previous hospital. The clinical course appeared similar to that of DIHS, but drugs known to cause DIHS had not been administered.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/bmt.2008.340

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatitis B virus (HBV)-reverse seroconversion (RS) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a frequent late-onset complication in recipients with previous HBV infection. We followed 38 allo-HSCT recipients with previous HBV infection, and conducted posttransplant HB vaccine intervention in 13 recipients. First, we followed the recipients without any intervention (historic control) until 2003; hence, we commenced HB vaccination. Out of the patients who underwent transplantation after 2003, 13 recipients were immunized by a standard three-dose regimen after immunosuppressant cessation (vaccine group), whereas 12 recipients were observed without any intervention (nonvaccine group). Eight of the 13 historic control group recipients and 3 of the 12 nonvaccine group recipients, but none of the 13 vaccine group recipients, suffered HBV-RS. Cumulative risks of HBV-RS at 3 years post-HSCT in the historic control, nonvaccine and vaccine groups were 41%, 39%, and 0% respectively (P=.022). We therefore conclude that intervention with HB vaccines is significantly effective in preventing post-HSCT HBV-RS.

DOI： 10.1016/j.bbmt.2008.08.007

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記述言語：英語  

DOI： 10.1007/s12185-008-0140-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Adult T cell leukemia/lymphoma (ATL) is a highly aggressive T cell malignancy, and has a poor prognosis. Recently, allogeneic-hematopoietic stem cell transplantation (allo-HSCT) has been suggested to improve the outcome. We retrospectively analyzed 15 patients with ATL who had received allo-HSCT in 2 institutions in Hokkaido, Japan. The median age of the patients was 57 years. The estimated 3-year overall survival (OS) and progression-free survival (PFS) rates were 73.3% and 66.7%, respectively. Calcineurin inhibitor dosage was reduced and administration was discontinued abruptly in 6 of the 15 patients for disease control; as a result, 4 (66.7%) of the 6 patients achieved complete response (CR) or partial response. Therefore, a graft-versus-leukemia/lymphoma (GVL) effect might be induced by discontinuation of immunosuppression. Thirteen of the 15 patients were followed up by monitoring HTLV-1 proviral DNA levels. In 10 of the 11 patients with positive HTLV-1 proviral DNA before allo-HSCT, HTLV-1 proviral DNA became undetectable at least once after allo-HSCT, and only 1 of the 5 patients in whom HTLV-1 proviral DNA became detectable after allo-HSCT relapsed. Compared to the results of past studies, these results show that allo-HSCT greatly improved the prognosis of ATL and suggest a contribution of the induction of a GVL effect.

DOI： 10.1016/j.bbmt.2008.04.014

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report that granulocyte transfusion (GTX) was effective for prolonged pneumonia at allogeneic bone marrow transplantation. A 58-year-old man with MDS-RAEB-2 was admitted to our hospital for allogeneic bone marrow transplantation. He was complicated with pneumonia, which was not improved with G-CSF and antibiotics. We therefore decided to perform a GTX transplantation. During the period of neutropenia, pneumonia did not deteriorate. A combination of allogeneic stem cell transplantation and GTX is expected not only to improve transplantation results but also to expand the adaptation for transplantation. However, detailed investigation of the effect of GTX in allogeneic stem cell transplantation should be performed, and more cases should be accumulated.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Invasive fungal infection is one of the major causes of death in neutropenic patients undergoing allogeneic stem cell transplantation (SCT). Although prophylactic antifungal therapy with fluconazole (FLCZ) has become the standard care for these patients, there remains a need for more effective and cost-beneficial alternative drugs. We conducted a prospective study to evaluate the usefulness of the administration of micafungin (MCFG) as a prophylactic antifungal therapy for patients undergoing allogeneic SCT. The results were compared with previous data for patients who had received FLCZ. A total of 44 patients who underwent allogeneic SCT were enrolled in the study. Data from 29 patients who received allogeneic SCT using prophylactic FLCZ before this study were used as historical control data. Underlying diseases included acute leukemia (n = 16), non-Hodgkin's lymphoma (n = 11), myelodysplastic syndrome (n = 6), and others (n = 11) in the MCFG group and acute leukemia (n = 18), chronic myelogenous leukemia (n = 6), and others (n = 5) in the FLCZ group. The median durations of administration of MCFG and FLCZ were 36 and 34 days, respectively. Prophylactic success, defined as the absence of proven, probable, and possible invasive fungal infection (IFI) until the end of prophylactic therapy was achieved in 36 (87.8%) of the 41 evaluated patients in the MCFG group and in 65.5% of the patients in the FLCZ group (P = 0.038). No patients in the MCFG group showed proven or probable IFI, whereas proven or probable IFI was observed in three patients in the FLCZ group. Four patients in the MCFG group required dose escalation due to febrile neutropenia. Although one patient in the MCFG group required the discontinuation of MCFG due to allergic skin eruption (grade 2), none of the other patients in either group required dose reduction due to adverse effects. Although the study design was not a prospective randomized trial, our results indicate that the administration of MCFG at a daily dose of 100 mg is promising for prophylactic antifungal therapy in patients undergoing allogeneic SCT.

DOI： 10.1007/s12185-007-0011-1

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 56-year-old mentally retarded Japanese woman (intelligence quotient: 49) was admitted to our hospital with the chief complaints of headache, dizziness, vomiting, and lower limb paralysis. Laboratory tests showed severe hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. These findings suggested a diagnosis of Gitelman's syndrome (GS). We examined the thiazide-sensitive Na-Cl cotransporter (TSC) gene for the mutations that can be responsible for Gitelman's syndrome, and confirmed the diagnosis. After potassium and magnesium supplementation, her paralysis improved dramatically. The marriage of her parents was consanguineous. She had nine siblings (all with mental retardation), among whom five had died of unknown causes during childhood. Familial mental retardation has never been detected before in Gitelman's syndrome. Here we report a rare case of Gitelman's syndrome with familial mental retardation.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Imatinib mesylate (imatinib) has shown significant effects in patients with chronic myelogenous leukemia. However, hematological toxicity often occurs and requires dosage reduction or discontinuation of imatinib treatment. A patient with chronic myelogenous leukemia in the blastic crisis received granulocyte-colony stimulating factor (G-CSF) simultaneously with imatinib. The patient was continuously treated with imatinib and G-CSF and achieved remission without any severe infection or neutropenia. There are a few reports on the efficacy of combined therapy with G-CSF and imatinib; however, the results in our case are rare suggesting that the use of G-CSF is effective for preventing severe infection. G-CSF enables continuous treatment with high-dose imatinib.

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

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