研究者詳細 - 多田　周

論文 - 多田　周

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Anatomy of the left subsuperior segment for segmentectomy.

Ryunosuke Maki, Masahiro Miyajima, Keishi Ogura, Makoto Tada, Yuki Takahashi, Hirofumi Adachi, Atsushi Watanabe

Surgery today 52 ( 7 ) 1054 - 1062 2022年07月 [国内誌]

PURPOSE: The subsuperior segmental bronchi (B*) forms the subsuperior segment (S*) between the superior (S6) and basal segment (S7, S8, S9, S10) of the lung. However, the anatomical planes of S* remains undefined. The present study clarified the anatomical features of S*. METHODS: We reviewed the anatomical patterns of pulmonary vessels and the left lung bronchus in 539 patients using three-dimensional computed tomography. We report the anatomic structure in S*. RESULTS: A total of 537 patients were analyzed. B* was observed in 129 (24.0%) patients. The intersegmental vein between S6 and S* was complete in all cases. The absence of intersegmental veins of S* was observed in 77 (14.3%) patients, reaching 59.7% of B* cases. Twenty-two (4.1%) cases of B* diverged from the trunk of the basal bronchus, and about half of the B* branched to the dorsolateral (n = 77, 14.3%) or dorsal (n = 2, 0.37%) direction. CONCLUSION: Our study revealed the branching patterns of B* and anatomical intersegmental veins of S*. Our results provide useful information regarding anatomical segmentectomy including or adjusting to the left S*.

Pulmonary vessels and bronchus anatomy of the left upper lobe.

Ryunosuke Maki, Masahiro Miyajima, Keishi Ogura, Makoto Tada, Yuki Takahashi, Hirofumi Adachi, Atsushi Watanabe

Surgery today 52 ( 4 ) 550 - 558 2022年04月 [国内誌]

PURPOSES: The bronchopulmonary vascular bifurcation patterns in the upper lobe of the left lung are diverse. Therefore, it is important for general thoracic surgeons to understand the detailed anatomy of the pulmonary segments when performing thoracoscopic anatomical pulmonary resection. This study aimed to analyze the bronchovascular patterns of the left upper lobe and summarize the anatomical information associated with pulmonary anatomical pulmonary resection. METHODS: We reviewed the anatomical patterns of pulmonary vessels and the left lung bronchus of 539 patients using computed tomography imaging data including those obtained using three-dimensional computed tomography. We herein report the anatomic structure in the left upper lobe. RESULTS: Regarding the superior division bronchi, a pattern of trifurcation into B1+2, B3, lingular division bronchus was observed in nine patients (1.7%). A pattern of proximal bifurcation of B4 was found in eight patients (1.5%). Regarding the lingular veins (LV), patterns of LV drainage into the left lower pulmonary vein were observed in 22 patients (4.1%). Regarding the pulmonary artery, mediastinal lingular arteries (MLA) were found in 161 patients (29.9%). CONCLUSION: The bifurcation patterns of the bronchovascular region in the upper lobe of the left lung were clarified. These results should be carefully noted when performing anatomical pulmonary resection.

Salvage Surgery for Bronchopleural Fistula Due to Durvalumab and Chemoradiation.

Makoto Tada, Hirofumi Uehara, Takeshi Ohyu, Atsushi Watanabe

The Annals of thoracic surgery 2021年12月 [国際誌]

Herein we describe a case of salvage lobectomy for a bronchopleural fistula secondary to durvalumab after chemoradiotherapy in initially unresectable non-small cell lung cancer. A 75-year-old man with adenocarcinoma, c-stage IIIB (T4N2M0) in the upper lobe of the right lung, received durvalumab after chemoradiotherapy. Fourteen months after durvalumab was discontinued, pneumonitis developed followed by peripheral bronchopleural fistula, and he unavoidably underwent salvage right upper lobectomy. The postoperative course was uneventful, and air leakage ceased. After chemoradiotherapy and durvalumab, refractory air leakage may develop that may require salvage surgery.

Unexpected haemorrhage from lateral thoracic artery following the removal of a pleural drainage tube.

Keigo Matsuura, Makoto Tada, Toshiyuki Sumi, Koichi Osuda, Hisashi Nakata, Hirofumi Chiba

Respirology case reports 9 ( 12 ) e0882 2021年12月 [国際誌]

MCL1 inhibition enhances the efficacy of docetaxel against airway-derived squamous cell carcinoma cells.

Yuji Sakuma, Sachie Hirai, Toshiyuki Sumi, Makoto Tada, Takashi Kojima, Toshiro Niki, Miki Yamaguchi

Experimental cell research 406 ( 2 ) 112763 - 112763 2021年09月 [国際誌]

MCL1 is an anti-apoptotic BCL2 family member that is often overexpressed in various malignant tumors. However, few reports have described the role of MCL1 in squamous cell carcinoma (SqCC) derived from airways including the lung. In this study, we examined whether MCL1 could be a novel druggable target for airway-derived SqCC, for which effective molecular targeted drugs are unavailable. We searched the Kaplan-Meier Plotter database and found that high MCL1 mRNA expression was significantly associated with shorter survival in patients with lower airway (lung) or upper airway (head and neck) derived SqCC. We also explored the Expression Atlas database and learned that authentic lung SqCC cell lines expressing both TP63 and KRT5 mRNA were extremely sparse among the publicly available "lung SqCC cell lines", with an exception being HARA cells. HARA cells were highly dependent on MCL1 for survival, and MCL1-depleted cells were not able to grow, and even declined in number, upon docetaxel (DTX) exposure in vitro and in vivo. Similar in vitro experimental findings, including those in a 3D culture model, were also obtained using Detroit 562 pharyngeal SqCC cells. These findings suggested that combined treatment with MCL1 silencing plus DTX appears highly effective against airway-derived SqCC.

Treatment of air leakage using the VIO soft coagulation system: a mouse pulmonary air leak model.

Yuki Takahashi, Atsushi Saito, Yuji Sakuma, Makoto Tada, Ryunosuke Maki, Motoko Takahashi, Atsushi Watanabe

Surgery today 51 ( 9 ) 1521 - 1529 2021年09月 [国内誌]

PURPOSE: We aimed to compare the efficacy of the VIO soft coagulation system (VSCS) for the treatment of air leaks by sealing with fibrin glue, and also assess the histological alterations that occur after soft coagulation. METHODS: A mouse pulmonary air leak model was designed. The pulmonary fistula was subsequently coagulated with the VSCS or sealed with fibrin glue with polyglycolic acid (PGA) sheets. The burst pressure at air leak recurrence was measured in each group, and the results were compared. We also evaluated the histological alterations in the mouse pulmonary air leak model after soft coagulation with the VSCS. RESULTS: The burst pressure in the soft coagulation group (80 W/Effect 5) (median 42.8; range 35.4-53.8 cmH2O) was similar to that in the fibrin glue group (median 41.5; range 34.6-43.9 cmH2O) (p = 0.21). Histological examinations revealed that the visceral pleura remained torn, the structure of the pulmonary alveolus was maintained, and the coagulated fistula was covered with a fibrin membrane in the soft coagulation group. CONCLUSIONS: The pressure resistance following soft coagulation was equivalent to that after sealing using fibrin glue with PGA sheets. The air leaks were likely controlled by covering the fistula with a fibrin membrane after soft coagulation with the VSCS.

Vessel sealing system for video-assisted lung resection for cancer reduces chylothorax and bleeding.

Masahiro Miyajima, Ryunosuke Maki, Makoto Tada, Kodai Tsuruta, Yuki Takahashi, Wataru Arai, Atsushi Watanabe

Journal of thoracic disease 13 ( 6 ) 3458 - 3466 2021年06月 [国際誌]

BACKGROUND: The objective of this study was to analyze the efficacy of the LigaSureTM vessel sealing system for lung cancer resection with node dissection, as this has not been sufficiently evaluated. METHODS: From 2004 to 2018, 948 patients underwent anatomical pulmonary resection with node dissection for non-small cell lung carcinoma (NSCLC) via the video-assisted thoracoscopic surgery (VATS) approach. Medical records of these patients were reviewed retrospectively. Univariate and multivariate analyses were conducted to determine the risk factors for chylothorax and blood loss. RESULTS: Of the 948 patients, 318 (33.5%) who underwent anatomical lung resection with node dissection by conventional methods without vessel sealing system and 630 (66.5%) who underwent lung resection with node dissection with the vessel sealing system were included. The median intraoperative blood loss was 100 mL. Postoperative chylothorax occurred in 9 (2.8%) patients in the conventional method group with 2 (0.3%) patients in the vessel sealing system group (P=0.001). Patients in the vessel sealing group who developed chylothorax were cured by conservative treatment. Univariate and multivariate analyses identified male sex [odds ratio (OR) 2.053; 95% confidence interval (CI): 1.494-2.820; P<0.001] and the use of vessel sealing system (OR 0.342; 95% CI: 0.256-0.457; P<0.001) as independent predictors of intraoperative blood loss. The univariate and multivariate analyses identified the use of the vessel sealing system (OR 0.108; 95% CI: 0.023-0.504; P=0.005) as an independent predictor of chylothorax incidence. CONCLUSIONS: Vessel sealing system for lung cancer resection could decrease chest tube duration, amount of intraoperative bleeding, and incidence of chylothorax in patients who undergo lung resection with node dissection.

PD-L1高発現の非小細胞肺癌に対する初回治療ペムブロリズマブの無増悪生存期間と体重減少の関連性

四十坊直貴, 角俊行, 多田周, 山田裕一, 鎌田弘毅, 上原浩文, 中田尚志, 森裕二

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 10 ( 増刊 ) 153 - 153 2021年04月

Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.

Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada, Hisashi Nakata, Yuji Mori, Hirofumi Chiba

Respirology case reports 9 ( 3 ) e00716 2021年03月 [国際誌]

Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.

Efficacy of Automatic Retention Pressure of a Double-Lumen Tube Cuff: An Artificial Intubation Model.

Yuki Takahashi, Yasuyuki Tokinaga, Michitaka Edanaga, Kenichiro Kikuchi, Makoto Tada, Ryunosuke Maki, Michiaki Yamakage, Atsushi Watanabe

The Journal of surgical research 257 344 - 348 2021年01月 [国際誌]

BACKGROUND: The movement of a double-lumen endotracheal tube (DLT) out of its appropriate position during thoracic surgery can result in the loss of one-lung ventilation (OLV), especially during pulmonary resection and node dissection. Our study aimed to validate the efficacy of automatic retention pressure control of the DLT bronchial cuff in maintaining OLV in an artificial intubation model. MATERIALS AND METHODS: A 35-Fr left-sided DLT was intubated to the left main bronchus in an intubation simulator and connected to an anesthesia machine. The inspiratory volume, respiratory rate, and inspiratory-expiratory ratio were set at 500 mL, 12 times/min, and 1:2, respectively. A 1-kg right main bronchial traction in the lateral right was provided after OLV was established. SmartCuff (Smiths Medical, Minneapolis, Minnesota, USA) was used to maintain cuff pressure. The efficacy of retention pressure with SmartCuff (Group S) and without SmartCuff (Group WS) was compared. The primary outcome was the rate of tidal volume (TV) reduction following bronchial traction in the two groups. RESULTS: The TVs were 289.8 ± 28.9 mL and 242.8 ± 31.9 mL in Group S and Group WS, respectively (P = 0.003). The rate of TV reduction after bronchial traction was significantly lower in Group S (29 ± 5%) than in Group WS (43 ± 6%) (P < 0.001). CONCLUSIONS: Automatic retention pressure control of the DLT bronchial cuff improves the rate of TV reduction during right main bronchial traction in an artificial intubation model. Continuous retention cuff pressure may be useful in maintaining OLV during thoracic surgery.

右肺下葉切除後に中葉温存残存右上葉切除を行った異時性肺癌の1例

佐藤太軌, 佐藤太軌, 上原浩文, 多田周, 多田周, 計良淑子, 渡辺敦

日本臨床外科学会雑誌 82 ( 9 ) 2021年

縦隔腫瘍との鑑別を要した準確定診断免疫グロブリンG4(IgG4)関連大動脈周囲炎

千葉慶宜, 新井航, 大川美穂, 多田周, 槙龍之輔, 三品泰二郎, 宮島正博, 渡辺敦, 杉田真太朗

胸部外科 74 ( 2 ) 2021年

Lung adenocarcinoma with tumor resolution and dystrophic calcification after salvage surgery following immune checkpoint inhibitor therapy: A case report.

Toshiyuki Sumi, Hirofumi Uehara, Toshiaki Masaoka, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada, Hisashi Nakata, Yuji Mori, Hirofumi Chiba

Thoracic cancer 11 ( 11 ) 3396 - 3400 2020年11月 [国際誌]

A clinical trial of immune checkpoint inhibitors for advanced non-small cell lung cancer reported an overall survival plateau with a long tail to the survival curve, suggesting that immune checkpoint inhibitors prolong survival. However, little evidence supports the efficacy of immune checkpoint inhibitors as neoadjuvant chemotherapy. We performed salvage surgery on a patient who was treated with an anti-programmed cell death protein-1 (PD-1) antibody and whose tumor size had not changed over time. A 69-year-old Japanese female with advanced lung adenocarcinoma was initially administered pembrolizumab therapy; however, owing to the development of various immune-related adverse events (irAEs), the patient was switched to chemotherapy following steroid therapy. The tumor continued to shrink and calcification within the tumor increased. We performed salvage surgery following which the tumor cells disappeared and necrosis and calcification were detected in the tumor. We concluded that if calcification develops within the tumor and tumor shrinkage is maintained after treatment with anti-PD-1 drugs, the calcification may be dystrophic owing to drug-induced tumor necrosis, and salvage surgery might be beneficial in removing the tumor. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: If calcification develops within the tumor and tumor shrinkage is maintained after treatment with anti-PD-1 drugs, the calcification may be dystrophic owing to tumor necrosis caused by drug effects, and salvage surgery might be beneficial in removing the tumor. WHAT THIS STUDY ADDS: This study showed the efficacy of immune checkpoint inhibitors as neoadjuvant chemotherapy to be followed by salvage surgery for unresectable advanced lung adenocarcinoma.

Pulmonary vessels and bronchial anatomy of the left lower lobe.

Ryunosuke Maki, Masahiro Miyajima, Keishi Ogura, Makoto Tada, Yuki Takahashi, Wataru Arai, Hirofumi Adachi, Atsushi Watanabe

Surgery today 50 ( 9 ) 1081 - 1090 2020年09月 [国内誌]

PURPOSE: To identify and clarify the comprehensive anatomic patterns in the left lower lobe (LLL). METHODS: Using computed tomography (CT) imaging data, including that obtained using three-dimensional CT, we reviewed the anatomic patterns of the pulmonary vessels and bronchi in the left lungs of 539 patients, focusing on the LLL. RESULTS: The two-stem type in A6 was observed in 131 (24.7%) patients and the three-stem type in A6 was observed in 11 (2.1%) patients. The independent two-stem type in B6 was observed in four (0.75%) patients. The B7 with independent branching from the basal bronchi was observed in 42 (7.9%) patients. B* was observed in 129 (24.0%) patients and B* was accompanied by A* in all patients. An extrapericardial common trunk of the left pulmonary veins was identified in five patients (0.93%). CONCLUSION: We identified various bronchovascular patterns in the LLL of a large number of patients. Our results provide useful information for anatomic pulmonary resection, especially segmentectomy.

Pericyte-myofibroblast transition in the human lung.

Miki Yamaguchi, Sachie Hirai, Yusuke Tanaka, Toshiyuki Sumi, Makoto Tada, Hiroki Takahashi, Atsushi Watanabe, Yuji Sakuma

Biochemical and biophysical research communications 528 ( 2 ) 269 - 275 2020年07月 [国際誌]

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease that includes fibroblastic foci (FF). It has been increasingly appreciated that the origin of collagen-overproducing cells such as pathological myofibroblasts in FF is pericytes. However, neither pericytes derived from the lung nor FF in the IPF lung have not been fully characterized. Human lung pericytes (HuL-P) examined in this study expressed two representative pericyte markers; platelet-derived growth factor receptor β (PDGFRB) and chondroitin sulfate proteoglycan 4 (CSPG4), and were able to migrate and cover endothelial tubes in 3D conditions, indicating that they retain characteristics of pericytes. Moreover HuL-P cells transitioned to myofibroblast-like cells in the presence of transforming growth factor (TGF)-β signaling or to pericyte-like cells in the absence of TGF-β signaling (pericyte-myofibroblast transition). On the other hand, the FF detected in this study were invariably localized between peripheral lung epithelia and capillary endothelia, the basement membranes of which are physiologically fused. The localization is highly specific in that the only cells that exist between the gap are pericytes. As expected, FF were immunohistochemically positive for PDGFRB and CSPG4, suggesting that pericytes are activated to form FF. We also found that HuL-P cells were difficult to eradicate by dual silencing of Bcl-xL plus MCL1. It would be more sensible to suppress pericyte-myofibroblast transition than to kill activated myofibroblasts for the treatment of IPF.

EGFR-independent EGFR-mutant lung adenocarcinoma cells depend on Bcl-xL and MCL1 for survival.

Sachie Hirai, Makoto Tada, Miki Yamaguchi, Toshiro Niki, Yuji Sakuma

Biochemical and biophysical research communications 526 ( 2 ) 417 - 423 2020年05月 [国際誌]

Although most EGFR-mutant lung adenocarcinomas initially respond to EGFR inhibitors, disease progression almost inevitably occurs. We previously reported that two EGFR-mutant lung adenocarcinoma cell lines, HCC827 and H1975, contain subpopulations of cells that display an epithelial-to-mesenchymal phenotype and can thrive independently of EGFR signaling. In this study, we explored to what extent these two sublines, HCC827 GR2 and H1975 WR7, depended on the anti-apoptotic BCL2 family members, Bcl-xL and/or MCL1, for survival. Although HCC827 GR2 cells were hardly affected by Bcl-xL or MCL1 knockdown alone, dual inhibition of Bcl-xL and MCL1 caused the cells to undergo apoptosis, resulting in decreased viability. In H1975 WR7 cells, not only dual inhibition, but also MCL1 silencing alone, induced the cells to undergo apoptosis. Interestingly, the two sublines markedly declined in number when autophagy flux was suppressed, because they depend, in part, on active autophagy for survival. However, autophagy inhibition was inferior to dual inhibition of Bcl-xL plus MCL1 for GR2 cells, or MCL1 inhibition alone, for decreasing the viability of WR7 cells. Collectively, these findings suggest that inhibiting Bcl-xL plus MCL1, or MCL1 alone, may represent a new approach to treat EGFR-independent EGFR-mutant cancer cells.

Cerebral infarction after left upper lung lobectomy with central vascular ligation.

Yasushi Mizukami, Makoto Tada, Hirofumi Adachi

Journal of thoracic disease 12 ( 5 ) 2210 - 2219 2020年05月 [国際誌]

BACKGROUND: Thrombus of the pulmonary vein (PV) stump is reportedly more frequent after left upper lobectomy than after other lobectomies, risking postoperative cerebral infarction (PCI). We have performed central vascular ligation before vascular dissection to improve the safety of surgical stapling. The effects of central vascular ligation in terms of PV stump thrombus and PCI are uncertain. METHODS: This study retrospectively reviewed the records of patients who underwent left upper lobectomy at a single center (Hokkaido Cancer Center, Sapporo, Japan) between November 1, 2008 and July 31, 2018. Relationships between PCI, PV stump thrombus and background characteristics were investigated and analyzed. RESULTS: All 208 cases of left upper lobectomy underwent central vascular ligation of the PV during this study. PCI occurred in 8 of the 208 patients. PV stump thrombus was detected in 14 of the 132 patients. In comparison with no-PCI cases, PCI cases showed significantly higher rates of comorbidity with cardiovascular disease (P=0.02), double cancer within 5 years (P=0.04), intraoperative hyperthermic chemotherapy (P=0.02), postoperative intrapleural inflammation (P=0.02) and postoperative PV stump thrombus (P=0.04). Presence of both comorbid cardiovascular disease (odds ratio, 18.4) and intraoperative hyperthermic chemotherapy (odds ratio, 30.4) was associated with higher risk of PV stump thrombus than presence of none of these factors. Cerebral infarction within 30 days postoperatively was seen in only 2 of the 208 cases (1.0%). CONCLUSIONS: Central ligation of the PV may prevent postoperative early cerebral infarction. Further study of the effectiveness of this method for preventing PV stump thrombus is needed.

MCL1 inhibition enhances the therapeutic effect of MEK inhibitors in KRAS-mutant lung adenocarcinoma cells.

Makoto Tada, Toshiyuki Sumi, Yusuke Tanaka, Sachie Hirai, Miki Yamaguchi, Masahiro Miyajima, Toshiro Niki, Hiroki Takahashi, Atsushi Watanabe, Yuji Sakuma

Lung cancer (Amsterdam, Netherlands) 133 88 - 95 2019年07月 [国際誌]

OBJECTIVES: MCL1 is an anti-apoptotic BCL2 family member that is highly expressed in various malignant tumors. However, little is known about the role of MCL1 in KRAS-mutant lung adenocarcinomas. In this study, we aimed to clarify whether MCL1 could be a therapeutic target in KRAS-mutant lung adenocarcinomas for which no effective molecular targeted drugs are available. MATERIALS AND METHODS: We examined to what extent MCL1 knockdown either alone or in combination with MEK inhibitor trametinib suppressed growth or induced apoptosis in the KRAS-mutant lung adenocarcinoma cell line H441 and EGFR-mutant lung adenocarcinoma cell line H1975. Furthermore, we investigated the therapeutic effects of dual inhibition of MCL1 and Bcl-xL, another anti-apoptotic BCL2 family member, in these two cell lines. RESULTS: MCL1 knockdown alone did not induce apoptosis in H441 or H1975 cells. However, MCL1-depleted H441 and H1975 cells underwent apoptosis and decreased in number in the presence of trametinib. We also confirmed that combined therapy by MCL1 knockdown and trametinib almost completely suppressed the growth of H441 cells in vivo. Moreover, dual knockdown of MCL1 and Bcl-xL induced extensive apoptosis in H441 and H1975 cells. CONCLUSION: These findings suggest that combined treatments of MCL1 knockdown and trametinib or dual inhibition of MCL1 and Bcl-xL would be effective therapies for lung adenocarcinomas including the KRAS-mutant subtype.

Outcomes of completion lobectomy long after segmentectomy.

Yuki Takahashi, Masahiro Miyajima, Makoto Tada, Ryunosuke Maki, Taijiro Mishina, Atsushi Watanabe

Journal of cardiothoracic surgery 14 ( 1 ) 116 - 116 2019年06月 [国際誌]

BACKGROUND: Completion lobectomy long after segmentectomy in the same lobe is extremely difficult because of severe adhesions around hilar structures, especially in cases involving video-assisted thoracoscopic surgery (VATS) completion lobectomy. We report and compare the surgical outcomes of patients who underwent VATS or thoracotomy completion lobectomy long after radical segmentectomy for lung cancer. METHODS: We retrospectively evaluated the surgical outcomes of completion lobectomies performed at our institute long after radical segmentectomies for lung cancer in the same lobe. The efficacy and safety of VATS completion lobectomy was compared to that of thoracotomy completion lobectomy. RESULTS: Ten of 228 patients who underwent radical segmentectomy for lung cancer between 2009 and 2018 underwent completion lobectomy at least a month after segmentectomy; five patients underwent VATS completion lobectomy. None of the patients underwent VATS left upper completion lobectomy, and conversion to thoracotomy was required in one patient. There were no significant differences between VATS and thoracotomy completion lobectomies in the median operative times (VATS 295 min, thoracotomy 339 min, p = 0.55), intraoperative blood loss volumes (VATS 350 mL, thoracotomy 500 mL, p = 0.84), intervals between initial segmentectomy and completion lobectomy (VATS 40 months, thoracotomy 48 months, p = 0.55), and number of patients with pulmonary artery injury (VATS 1, thoracotomy 2, p = 0.49). There was no operation-related mortality. CONCLUSIONS: VATS completion lobectomy long after segmentectomy for lung cancer could be performed without fatal complications unless severe adhesions are observed around each main pulmonary artery.

パラフィン充填術40年後に起きた脊髄麻痺

新井航, 大川美穂, 高橋有毅, 多田周, 槙龍之介, 三品泰二郎, 宮島正博, 渡辺敦

胸部外科 72 ( 5 ) 344 - 347 2019年05月 [国内誌]

Paraffin had been used for pleural plombage in the treatment of tuberculosis. However, paraffin use has been reported to cause late postoperative complications. A 79-year-old man was presented with an extramedullary tumor and spinal paralysis. Forty-seven years ago, he had undergone pleural plombage using paraffin for the treatment of pulmonary tuberculosis. Since the extramedullary tumor was found to be paraffinoma, paraffin in the vertebral canal and thoracic cavity was removed surgically. All the paraffin in the vertebral canal and thoracic cavity was removed. After surgery, the patient remains well, without spinal paralysis.

PubMed J-GLOBAL

膵液瘻に伴う膿気胸に対する外科治療

大川美穂, 新井航, 高橋有毅, 槇龍之輔, 多田周, 三品泰二郎, 宮島正博, 渡辺敦

胸部外科 72 ( 3 ) 209 - 212 2019年03月 [国内誌]

A 46-year-old woman with cervical cancer with multiorgan metastasis visited our hospital. She underwent a total gastrectomy, splenectomy, distal pancreatectomy, left adrenalectomy, and left partial diaphragmatic resection. Postoperatively, she developed pleural effusion with high level of amylase secondary to a pancreatic ﬁstula, consequently causing left-sided empyema. She developed acute respiratory distress syndrome. Urgent surgical treatment was scheduled, and left lower lobectomy, with diaphragmatic partial resection were performed under the venovenous extracorporeal membrane oxygenation. After surgery, intensive care for 45 days was necessary and she was discharged home 6 months post operatively.

PubMed J-GLOBAL

Thoracoscopic Right Basilar Segmentectomy After Right Upper Lobectomy.

Makoto Tada, Masahiro Miyajima, Taijiro Mishina, Yuki Takahashi, Ryunosuke Maki, Atsushi Watanabe

The Annals of thoracic surgery 107 ( 2 ) e123-e125 2019年02月 [国際誌]

This report describes a case of thoracoscopic right basilar segmentectomy after upper lobectomy. A 76-year-old man who underwent right upper lobectomy for lung tuberculosis 50 years earlier had a diagnosis of squamous cell carcinoma, stage IB (T2a N0 M0), in the right lower lobe and underwent right basilar segmentectomy for limited resection. The postoperative course was uneventful. The patient showed no recurrence clinically, and the 1-year postoperative chest computed tomographic scan showed adequate volume of the middle and residual right lower lobe without emphysematous changes.

Characterization of distal airway stem-like cells expressing N-terminally truncated p63 and thyroid transcription factor-1 in the human lung.

Yusuke Tanaka, Miki Yamaguchi, Sachie Hirai, Toshiyuki Sumi, Makoto Tada, Atsushi Saito, Hirofumi Chiba, Takashi Kojima, Atsushi Watanabe, Hiroki Takahashi, Yuji Sakuma

Experimental cell research 372 ( 2 ) 141 - 149 2018年11月 [国際誌]

Distal airway stem cells (DASCs) in the mouse lung can differentiate into bronchioles and alveoli. However, it remains unclear whether the same stem cells exist in the human lung. Here, we found that human lung epithelial (HuL) cells, derived from normal, peripheral lung tissue, in monolayer, mostly express both the N-terminally truncated isoform of p63 (∆Np63), a marker for airway basal cells, and thyroid transcription factor-1 (TTF-1), a marker for alveolar epithelial cells, even though these two molecules are usually expressed in a mutually exclusive way. Three-dimensionally cultured HuL cells differentiated to form bronchiole-like and alveolus-like organoids. We also uncovered a few bronchiolar epithelial cells expressing both ∆Np63 and TTF-1 in the human lung, suggesting that these cells are the cells of origin for HuL cells. Taken together, ΔNp63+ TTF-1+ peripheral airway epithelial cells are possibly the human counterpart of mouse DASCs and may offer potential for future regenerative medicine.

左肺全摘後，体外式肺補助下に胸腔鏡下右肺区域切除を行った1例

多田周, 高橋有毅, 槙龍之輔, 三品泰二郎, 宮島正博, 渡辺敦

肺癌 ( 特定非営利活動法人日本肺癌学会 ) 58 ( 4 ) 298 - 302 2018年08月

背景．異時性多発肺癌に対する3回以上の解剖学的肺切除や，片肺全摘後の残肺解剖学的切除例の報告はいまだ少ない．症例．66歳男性．50歳時に左上葉肺癌（肺癌取扱い規約第8版：微小浸潤性腺癌，stage IA1）に対して左上葉切除術，61歳時に左下葉異時性多発肺癌（微小浸潤性腺癌，stage IA1）に対して左下葉切除術の既往があった．定期検診で胸部異常陰影を指摘された．術前残存肺呼吸機能は肺活量2.32 l，1秒量1.59 lであった．組織学的な確定診断は得られなかったが，CT所見から原発性肺癌が強く疑われたため，体外式肺補助（ECLA）下に胸腔鏡下右S⁶区域切除を施行した．術後合併症はなく，術後14日目に退院した．組織学的診断は上皮内腺癌であった．結論．ECLAの使用により，左肺全摘後，右肺に出現した異時性肺癌（3重癌）に対し，安全に胸腔鏡下区域切除を施行することが可能であった．

Thoracoscopic one-stage lobectomy and diaphragmatic plication for T3 lung cancer.

Yuki Takahashi, Masahiro Miyajima, Taijiro Mishina, Ryunosuke Maki, Makoto Tada, Kodai Tsuruta, Atsushi Watanabe

Journal of cardiothoracic surgery 13 ( 1 ) 86 - 86 2018年07月 [国際誌]

BACKGROUND: Combined resection of a phrenic nerve is occasionally required in T3 primary lung carcinomas invading the phrenic nerve to completely remove a malignant tumour, resulting in diaphragmatic paralysis. We describe the first case of thoracoscopic lobectomy and diaphragmatic plication as a one-stage surgery for lung cancer invading the phrenic nerve. CASE PRESENTATION: A 56-year-old woman with a T3N0M0 primary adenosquamous carcinoma in the left upper lobe presented with suspicious invasion to the anterior mediastinal fat tissue and left phrenic nerve and underwent left upper lobectomy, node dissection, and partial resection of the anterior mediastinal fat tissue with the left phrenic nerve. Furthermore, thoracoscopic diaphragmatic plication was performed as a concomitant procedure. The patient's postoperative course was favourable, without any complications, and respiratory function was preserved for 1 year postoperatively. CONCLUSIONS: Thoracoscopic one-stage lobectomy and diaphragmatic plication for T3 lung cancer invading the phrenic nerve is effective for preservation of postoperative pulmonary function.

Survivin knockdown induces senescence in TTF‑1-expressing, KRAS-mutant lung adenocarcinomas.

Toshiyuki Sumi, Sachie Hirai, Miki Yamaguchi, Yusuke Tanaka, Makoto Tada, Gen Yamada, Tadashi Hasegawa, Yohei Miyagi, Toshiro Niki, Atsushi Watanabe, Hiroki Takahashi, Yuji Sakuma

International journal of oncology 53 ( 1 ) 33 - 46 2018年07月 [国際誌]

Survivin plays a key role in regulating the cell cycle and apoptosis, and is highly expressed in the majority of malignant tumors. However, little is known about the roles of survivin in KRAS-mutant lung adenocarcinomas. In the present study, we examined 28 KRAS-mutant lung adenocarcinoma tissues and two KRAS-mutant lung adenocarcinoma cell lines, H358 and H441, in order to elucidate the potential of survivin as a therapeutic target. We found that 19 (68%) of the 28 KRAS-mutant lung adenocarcinomas were differentiated tumors expressing thyroid transcription factor‑1 (TTF‑1) and E-cadherin. Patients with tumors immunohistochemically positive for survivin (n=18) had poorer outcomes than those with survivin-negative tumors (n=10). In the H358 and H441 cells, which expressed TTF‑1 and E-cadherin, survivin knockdown alone induced senescence, not apoptosis. However, in monolayer culture, the H358 cells and H441 cells in which survivin was silenced, underwent significant apoptosis following combined treatment with ABT-263, a Bcl‑2 inhibitor, and trametinib, a MEK inhibitor. Importantly, the triple combination of survivin knockdown with ABT-263 and trametinib treatment, clearly induced cell death in a three-dimensional cell culture model and in an in vivo tumor xenograft model. We also observed that the growth of the H358 and H441 cells was slightly, yet significantly suppressed in vitro when TTF‑1 was silenced. These findings collectively suggest that the triple combination of survivin knockdown with ABT-263 and trametinib treatment, may be a potential strategy for the treatment of KRAS-mutant lung adenocarcinoma. Furthermore, our findings indicate that the well‑differentiated type of KRAS-mutant lung tumors depends, at least in part, on TTF‑1 for growth.

p40陰性肺類基底細胞型扁平上皮癌の1例

槙龍之輔, 杉田真太朗, 小野祐輔, 宮島正博, 多田周, 高橋有毅, 三品泰二郎, 渡辺敦

胸部外科 71 ( 7 ) 547 - 550 2018年07月 [国内誌]

Immunohistochemical staining is important for the differential diagnosis of basaloid squamous cell carcinoma(BSC)and other similar carcinomas, such as small-cell carcinomas and large-cell neuroendocrine carcinomas. p40 is a useful marker of squamous cell carcinoma that can be used for the diagnosis of BSC. We present the case of a 64-year-old man who was referred to our hospital for investigation of an abnormal shadow revealed on chest radiography. Computed tomography(CT) revealed a 16×11 mm nodule in the left lung(S1+2), and a thoracoscopic left upper lobectomy was performed. Histologically, lobular pattern with peripheral palisading was observed and the immunohistochemical staining revealed the tumor cells to be positive for p63 and negative for both p40 and neuroendocrine markers, leading to the diagnosis of BSC.

PubMed J-GLOBAL

Trametinib downregulates survivin expression in RB1-positive KRAS-mutant lung adenocarcinoma cells.

Toshiyuki Sumi, Sachie Hirai, Miki Yamaguchi, Yusuke Tanaka, Makoto Tada, Toshiro Niki, Hiroki Takahashi, Yuji Sakuma

Biochemical and biophysical research communications 501 ( 1 ) 253 - 258 2018年06月 [国際誌]

High expression levels of survivin in KRAS-mutant lung adenocarcinomas are linked with unfavorable patient outcomes, suggesting that survivin is a promising target for tumor treatment. We found that trametinib, a MEK inhibitor, downregulates survivin expression in the RB1-positive KRAS-mutant lung adenocarcinoma cell lines H358 and H441. In these cell lines, trametinib treatment induced p21 expression and dephosphorylated RB1, leading to sustained suppression of survivin. Knockdown of p21 or RB1 restored survivin expression in trametinib-treated cells, at least partially, which supports the contribution of these molecules to trametinib-mediated survivin suppression. In RB1-negative KRAS-mutant lung adenocarcinoma H2009 cells, survivin downregulation by trametinib was only slight and transient, and trametinib-resistant (TR) cells developed within 1 month of treatment. H2009 TR cells depended much more on survivin for survival than its parental cells, as evidenced by apoptosis induction when survivin was depleted. These findings collectively suggest that trametinib is effective for the treatment of RB1-positive KRAS-mutant lung adenocarcinomas through sustained survivin suppression, but not for RB1-negative lung adenocarcinomas. Thus, the RB1 status could be a biomarker for trametinib application in KRAS-mutant lung adenocarcinomas.

左肺全摘後,体外式肺補助下に胸腔鏡下右肺区域切除を行った1例

多田周, 高橋有毅, 槙龍之輔, 三品泰二郎, 宮島正博, 渡辺敦

肺癌(Web) 58 ( 4 ) 2018年

Video-assisted thoracoscopic surgery node dissection for lung cancer treatment.

Atsushi Watanabe, Masahiro Miyajima, Taijiro Mishina, Kodai Tsuruta, Yuki Takahashi, Ryunosuke Maki, Makoto Tada

Surgery today 47 ( 12 ) 1419 - 1428 2017年12月 [国内誌]

PURPOSE: Mediastinal node dissection (MND) is an integral component of the surgical treatment for non-small cell lung cancer (NSCLC). Although video-assisted thoracoscopic surgery (VATS) has been used increasingly for lung cancer treatment, the accuracy of by VATS MND still remains controversial. We reviewed the surgical results of VATS MND for NSCLC. METHODS: A systematic review of literature was performed, and articles that fully described the surgical procedure, devices, and results of VATS MND were selected to compare the efficacy of MND by VATS and thoracotomy. RESULTS: Various techniques and equipments have been shown to perform adequate MND, but there is an argument as to the method of estimation of the accuracy of MND. Most of the recent studies showed that the nodal upstaging and number of dissected nodes are significantly lower by VATS than after thoracotomy. Oppositely, some studies showed VATS noninferiority in these issues. Complications such as chylothorax, pleural effusion, bleeding, and nerve damage were similar in both groups. CONCLUSIONS: Although ND by VATS remains controversial, VATS MND is becoming easier and more feasible owing to the development of more advanced endoscopic cameras and equipments. We should learn further to become more adept at performing adequate ND by VATS.

Angiotensin-converting enzyme 2 is a potential therapeutic target for EGFR-mutant lung adenocarcinoma.

Miki Yamaguchi, Sachie Hirai, Toshiyuki Sumi, Yusuke Tanaka, Makoto Tada, Yukari Nishii, Tadashi Hasegawa, Hiroaki Uchida, Gen Yamada, Atsushi Watanabe, Hiroki Takahashi, Yuji Sakuma

Biochemical and biophysical research communications 487 ( 3 ) 613 - 618 2017年06月 [国際誌]

EGFR-mutant lung adenocarcinomas contain a subpopulation of cells that have undergone epithelial-to-mesenchymal transition and can grow independently of EGFR. To kill these cancer cells, we need a novel therapeutic approach other than EGFR inhibitors. If a molecule is specifically expressed on the cell surface of such EGFR-independent EGFR-mutant cancer cells, it can be a therapeutic target. We found that a mesenchymal EGFR-independent subline derived from HCC827 cells, an EGFR-mutant lung adenocarcinoma cell line, expressed angiotensin-converting enzyme 2 (ACE2) to a greater extent than its parental cells. ACE2 was also expressed at least partially in most of the primary EGFR-mutant lung adenocarcinomas examined, and the ACE2 expression level in the cancer cells was much higher than that in normal lung epithelial cells. In addition, we developed an anti-ACE2 mouse monoclonal antibody (mAb), termed H8R64, that was internalized by ACE2-expressing cells. If an antibody-drug conjugate consisting of a humanized mAb based on H8R64 and a potent anticancer drug were produced, it could be effective for the treatment of EGFR-mutant lung adenocarcinomas.

高齢者気管腺様嚢胞癌に対し気管管状切除・再建術を施行した1例

多田周, 高橋有毅, 槙龍之輔, 三品泰二郎, 宮島正博, 渡辺敦

肺癌 ( 特定非営利活動法人日本肺癌学会 ) 57 ( 7 ) 870 - 874 2017年

背景．高齢者に対する気管切除・再建術の報告はいまだ少ない．症例．84歳女性．検診で胸部異常陰影を指摘された．胸部CT検査で胸部中部気管前壁の結節性病変を認めた．前医で行われた経気管支鏡生検で腺様嚢胞癌の診断であった．胸骨正中切開で気管管状切除・再建術を施行した．術後合併症はなく，術後33日目に退院した．結論．80歳代女性患者の気管原発腺様嚢胞癌に対して気管切除・再建術を施行した．切除後12か月無再発生存中である．

高齢者気管腺様嚢胞癌に対し気管管状切除・再建術を施行した1例

多田周, 高橋有毅, 槙龍之輔, 三品泰二郎, 宮島正博, 渡辺敦

肺癌(Web) 57 ( 7 ) 2017年

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