Okayama University Medical School Acta Medica Okayama 0386-300X 80 3 2026 Determination of the Side Responsible for Bilateral Pneumothorax due to Pleural Communication 225 228 EN Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruchika Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kumi Nakajima Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hidejiro Torigoe Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/70859 Simultaneous bilateral spontaneous pneumothorax associated with pleuro-pleural communication is a rare but potentially life-threatening condition, most commonly occurring after major thoracic surgery. We report the case of an 81-year-old man with severe emphysema and a history of esophagectomy who presented with sudden-onset dyspnea. Chest computed tomography revealed bilateral pneumothorax with pleuro-pleural communication. Although bilateral chest tube drainage was performed, the primary side of air leakage could not be identified preoperatively. After induction of general anesthesia, a double-lumen endotracheal tube clamping test identified the right pleural cavity as the source of air leakage, thereby enabling appropriate thoracoscopic surgery. No potential conflict of interest relevant to this article was reported.

Oxford University Press (OUP) Acta Medica Okayama 2753-670X 41 5 2026 Lung Segmental Perfusion Defect Is Associated With Airway Complications After Living-Donor Lobar Lung Transplantation ivag139 EN Kentaro Imanishi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tsuyoshi Ryuko Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuaki Tomioka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences PURPOSE: Airway complications (ACs) are potentially fatal after lung transplantation (LT). Although bronchial blood flow to the graft is supplied mainly from the pulmonary circulation after LT, lung segmental perfusion defects (LSPDs) are occasionally identified on lung perfusion scintigraphy (Q-scinti) after living-donor lobar LT (LDLLT). Lung segmental perfusion defects may impair bronchial healing and contribute to the development of ACs. This study aimed to evaluate the relationship between LSPD and AC after LDLLT. METHODS: We retrospectively reviewed 86 recipients who underwent LDLLT and 163 living donors at our institution from October 1998 to December 2023. Transplanted lungs that developed AC were classified as the AC group, whereas those without AC were classified as the non-AC group. Blood flow in the transplanted lungs was evaluated using Q-scinti after LDLLT. RESULTS: AC developed in 8 (4.9%) of 163 transplanted lungs after LDLLT. Although there were no significant differences in recipient-related variables between the 2 groups, LSPD was detected significantly more frequently in the AC group (n = 8) than in the non-AC group (n = 155) (50.0% vs 6.5%, P = .002). Furthermore, transplanted lungs showing LSPD were associated with significantly higher grades of the pulmonary interlobar fissures at the time of living-donor lobectomy (P = .025). Overall survival did not differ between patients with and without AC after LDLLT. CONCLUSIONS: LSPD on Q-scinti, which may develop in grafts with incomplete interlobar fissures during living-donor lobectomy, is associated with the development of AC after LDLLT. CLINICAL REGISTRATION NUMBER: This study was approved by the Institutional Review Board of Okayama University Hospital (approval date: August 23, 2024; 2409-027). No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1432-0851 75 4 2026 Immunological effects of amivantamab in EGFR or MET-expressing non-small cell lung cancer 121 EN Ryo Yoshichika Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Fumiaki Mukohara Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kotaro Yamada Department of Respiratory Medicine, Okayama University Hospital Joji Nagasaki Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroko Watanabe Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Youki Ueda Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University Takamasa Ishino Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yosuke Togashi Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Background Epidermal growth factor receptor (EGFR) mutations represent one of the most frequent oncogenic driver in non-small cell lung cancer (NSCLC). Amivantamab, a bispecific antibody targeting EGFR and MET proto-oncogene, receptor tyrosine kinase (MET), has demonstrated clinical benefit in EGFR-mutant NSCLC through dual blockade, but its immunological role in human clinical specimens, especially tumor-infiltrating lymphocytes (TILs), has not been directly evaluated. Methods We analyzed surgically resected tumor samples from 40 patients with NSCLC to investigate immune responses and their associations with EGFR and MET expression. TILs were characterized by flow cytometry (FCM) and immunohistochemistry (IHC). To assess the immunomodulatory potential of amivantamab, fresh tumor digests containing live tumor cells and TILs were cultured ex vivo with CD3 and CD28 stimulation in the absence or presence of amivantamab, followed by FCM. EGFR and MET expression were also evaluated by IHC. Results EGFR mutations and high EGFR protein expression were associated with a trend toward reduced CD8⁺ T-cell and dendritic cell (DC) infiltration. In ex vivo TIL assays, exposure to amivantamab significantly activated CD8⁺ T cells, such as programmed cell death-1 expression and cytokine production, and promoted DC maturation. These effects were most pronounced in tumors with high EGFR or MET protein expression rather than EGFR mutations. Conclusions This study provides the first direct evidence from ex vivo fresh TIL assays using human NSCLC clinical specimens that amivantamab can activate immune responses. EGFR and MET expression may serve as potential biomarkers for amivantamab-induced immune responses. No potential conflict of interest relevant to this article was reported.

Japan Surgical Society Acta Medica Okayama 2198-7793 12 1 2026 Tailored Management of Anomalous Systemic Arterial Supply to the Basal Segment of the Lung: A Case Report and Literature Review cr.26-0288 EN Shunsuke Mori Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Koji Tomita Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruchika Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kumi Nakajima Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hidejiro Torigoe Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takao Hiraki Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences INTRODUCTION: Parenchyma-preserving strategies for anomalous systemic arterial supply to the basal segment of the lung have gained increasing attention. However, pulmonary infarction of the preserved lung has been reported, and clear criteria for selecting the optimal treatment have yet to be established. We report 2 cases in which detailed preoperative imaging informed tailored management—right posterior basal segmentectomy in 1 patient and endovascular embolization of the aberrant artery in the other—both without postoperative complications. A review of the relevant literature is also provided, with an emphasis on potential selection criteria. CASE PRESENTATION: Case 1: A 20-year-old asymptomatic woman was referred after an abnormal screening chest radiograph. CT demonstrated an aberrant artery arising from the abdominal aorta supplying the right posterior basal segment (S10) with a large intravascular thrombus. The pulmonary artery showed hypoplasia limited to A10, while the other branches were normal, and no parenchymal congestion was identified. Following resection of the aberrant artery, robot-assisted right S10 segmentectomy was performed. The postoperative course was uneventful, and the patient was discharged on POD 6. Case 2: A 27-year-old woman was incidentally diagnosed on CT for an unrelated indication. An aberrant artery arising from the descending thoracic aorta supplied the left basal segment. Pulmonary arterial branches were preserved, with only minimal congestion in S9-10. Angiography revealed no evidence of an arteriovenous fistula. As surgical lung resection was considered unnecessary, coil embolization of the aberrant artery was performed. No complications occurred, and the patient was discharged on day 3 after the procedure. CONCLUSIONS: In patients with anomalous systemic arterial supply to the basal segment of the lung, when pulmonary arterial branches are preserved and background parenchymal congestion is minimal, parenchyma-sparing approaches should be considered. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2051-3380 14 3 2026 An Atypical Surgical Case of Lung Cancer With Unilateral Absence of the Pulmonary Artery, With Only the Superior Branch Remaining e70554 EN Kazuhiro Okada Department of Thoracic Surgery, Okayama University Hospital Shin Tanaka Department of Thoracic Surgery, Okayama University Hospital Tsuyoshi Ryuko Department of Thoracic Surgery, Okayama University Hospital Yasuaki Tomioka Department of Thoracic Surgery, Okayama University Hospital Kazuhiko Shien Department of Thoracic Surgery, Okayama University Hospital Ken Suzawa Department of Thoracic Surgery, Okayama University Hospital Kentaroh Miyoshi Department of Thoracic Surgery, Okayama University Hospital Mikio Okazaki Department of Thoracic Surgery, Okayama University Hospital Seiichiro Sugimoto Department of Thoracic Surgery, Okayama University Hospital Shinichi Toyooka Department of Thoracic Surgery, Okayama University Hospital A 69-year-old woman was referred to our department for an abnormal shadow on chest radiography. Contrast-enhanced computed tomography (CT) revealed a solid nodule in the right lower lobe and defects in the branches of the middle and lower lobes of the pulmonary artery (PA). Furthermore, collateral circulation had developed via the right internal thoracic, bronchial, intercostal, inferior phrenic, and subdiaphragmatic arteries. The solid nodule was diagnosed as adenocarcinoma by CT-guided biopsy. The day before surgery, embolization was performed using interventional radiology (IVR) to mitigate the risk of bleeding during thoracotomy, resulting in minimal intraoperative bleeding during the subsequent right middle and lower lobectomies with lymph node dissection (ND2a-1). UAPA is a rare congenital abnormality characterized by unilateral pulmonary artery agenesis. The presence of recurrent infections, extensive intrathoracic adhesions, and developed collateral circulation may pose challenges during surgical procedures. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 2589-0042 29 5 2026 Wnt3-mediated fibrosis and carcinogenesis of lung squamous cell carcinoma in idiopathic pulmonary fibrosis 115667 EN Atsushi Matsuoka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Masayoshi Ohki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hidejiro Torigoe Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuya Hisamatsu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryota Fujiwara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kosei Ishimura Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shunsuke Mori Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryunosuke Fujii Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Asuka Mimata Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiro Okada Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryo Yoshichika Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mao Yoshikawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuma Fukumoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruchika Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kumi Nakajima Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hirofumi Inoue Center for Comprehensive Genomic Medicine, Okayama University Hospital Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Idiopathic pulmonary fibrosis (IPF) increases the risk of lung squamous cell carcinoma (LUSC), yet its molecular pathogenesis remains unclear. We conducted multi-omics analysis, including single-cell RNA sequencing and digital spatial profiling, on LUSC specimens from seven patients with usual interstitial pneumonia (UIP). In UIP lung tissue, metaplastic basal cells arising from the transdifferentiation of alveolar type 2 (AT2) cells were increased. LUSC tumors arising within UIP exhibited molecular profiles and trajectory dynamics suggesting derivation from these metaplastic basal cells. Both UIP-affected tissue and associated tumors showed activation of Wnt signaling, particularly WNT3 expression. Additionally, enrichment of the nuclear factor erythroid 2-related factor 2 (NRF2)-linked antioxidant response was observed in LUSC within UIP. Targeting Wnt/β-catenin signaling restored the sensitivity of these stress-adapted cancer cell lines to oxidative damage. These findings suggest that LUSC within UIP originates from AT2-derived metaplastic basal cells and involves aberrant Wnt3 activation, linking fibrosis to carcinogenesis and highlighting a potential therapeutic strategy. No potential conflict of interest relevant to this article was reported.

Ovid Technologies (Wolters Kluwer Health) Acta Medica Okayama 1743-9159 112 2 2025 Total thymectomy is oncologically superior to partial thymectomy in patients with thymic carcinoma: insights from a multicenter real-world data analysis 2301 2310 EN Tatsuya Hayashi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiharu Mitsuhashi Center of Innovative Clinical Medicine, Okayama University Hospital Hidetaka Yamamoto Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomohiro Habu Okayama University Thoracic Surgery Study Group (OUTSSG) Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Okayama University Thoracic Surgery Study Group (OUTSSG) Tomoaki Otsuka Okayama University Thoracic Surgery Study Group (OUTSSG) Mototsugu Watanabe Okayama University Thoracic Surgery Study Group (OUTSSG) Takeshi Kurosaki Okayama University Thoracic Surgery Study Group (OUTSSG) Eiji Yamada Okayama University Thoracic Surgery Study Group (OUTSSG) Eisuke Matsuda Okayama University Thoracic Surgery Study Group (OUTSSG) Tatsurou Hayashi Okayama University Thoracic Surgery Study Group (OUTSSG) Toshiya Fujiwara Okayama University Thoracic Surgery Study Group (OUTSSG) Makio Hayama Okayama University Thoracic Surgery Study Group (OUTSSG) Hiroyuki Tao Okayama University Thoracic Surgery Study Group (OUTSSG) Masaomi Yamane Okayama University Thoracic Surgery Study Group (OUTSSG) Hidetoshi Inokawa Okayama University Thoracic Surgery Study Group (OUTSSG) Yuji Hirami Okayama University Thoracic Surgery Study Group (OUTSSG) Kazuhiro Washio Okayama University Thoracic Surgery Study Group (OUTSSG) Takahiko Misao Okayama University Thoracic Surgery Study Group (OUTSSG) Motohiro Yamashita Okayama University Thoracic Surgery Study Group (OUTSSG) Yoshifumi Sano Okayama University Thoracic Surgery Study Group (OUTSSG) Masao Nakata Okayama University Thoracic Surgery Study Group (OUTSSG) Osamu Kawamata Okayama University Thoracic Surgery Study Group (OUTSSG) Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background: Although total thymectomy has been the standard surgical approach for thymic epithelial tumors, an increasing number of recent reports suggest that partial thymectomy for early-stage thymomas may yield outcomes comparable to those of total thymectomy. However, whether partial thymectomy is a viable alternative for thymic carcinoma remains unclear. Materials and methods: A total of 106 patients with thymic carcinoma underwent curative intended resection at 19 institutions between January 2010 and December 2021. Excluding 14 patients with incomplete resection, 92 patients with thymic carcinoma who underwent total (n = 73) or partial thymectomy (n = 19) were compared. Overall survival (OS) and recurrence-free survival (RFS) were analyzed using Kaplan–Meier curves and Cox proportional hazard models. Overlap weighting was applied to adjust for potential confounding factors. Results: Among patients with clinical stage I disease, 79.3% were upstaged to stage II or higher postoperatively. Unadjusted analyses revealed no statistically significant differences in OS and RFS between the total and partial thymectomy groups, although a trend toward poorer outcomes in the partial thymectomy group was observed. After overlap weighting, partial thymectomy was associated with significantly poorer OS (P = 0.0027) and higher recurrence risk (P < 0.0001). Early postoperative recurrence occurred more frequently in the partial thymectomy group. Conclusion: Partial thymectomy was associated with significantly worse survival and recurrence outcomes in thymic carcinoma. Given the limitations of preoperative diagnosis, total thymectomy should remain the preferred surgical approach for undiagnosed thymic epithelial tumors to achieve optimal oncologic control and minimize the risk of recurrence. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 2399-3642 8 1 2025 Single-cell and spatial transcriptomic characterization of pulmonary pleomorphic carcinoma 1773 EN Atsushi Matsuoka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Masayoshi Ohki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuya Hisamatsu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryota Fujiwara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kosei Ishimura Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryunosuke Fujii Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoaki Higashihara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naohiro Hayashi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiro Okada Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryo Yoshichika Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumiaki Mukohara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mao Yoshikawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuma Fukumoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuaki Tomioka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yusuke Otani Department of Pathology, Beth Israel Deaconess Medical Center Atsushi Tanaka Department of Pathology, Beth Israel Deaconess Medical Center Hirofumi Inoue Center for Comprehensive Genomic Medicine, Okayama University Hospital Yosuke Togashi Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hidetaka Yamamoto Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Pulmonary pleomorphic carcinoma (PPC) is a rare subtype of lung cancer that comprises both epithelial and sarcomatoid components. The molecular basis of PPC, including the cellular dynamics of its components, remains largely unknown. To elucidate potential therapeutic targets for PPC, we perform a multi-omics analysis incorporating digital spatial profiling and single-cell RNA sequencing (scRNA-seq). PPC exhibits diverse driver gene alterations, including MET exon 14 skipping mutation (METex14) and ALK fusion. In spatial transcriptomics, MET gene and protein are overexpressed exclusively within the epithelial component and not in the sarcomatoid component, even in patients harboring METex14. Epithelial-mesenchymal transition (EMT)-related transcriptional changes, along with extracellular matrix (ECM) remodeling between the epithelial and sarcomatoid components, are observed. scRNA-seq identifies cell populations within the epithelial component that contribute to the malignant transformation and differentiation of the sarcomatoid component. They are characterized by an intermediate EMT state with ECM remodeling signature, suggesting their potential as novel therapeutic targets for PPC. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 2950-1334 8 2025 Downward hyperinflation of the native lung after right single lung transplantation for COPD: A case report highlighting diaphragmatic mobility 100268 EN Shin Tanaka Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tsuyoshi Ryuko Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuaki Tomioka Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences A 60-year-old male with COPD underwent right single lung transplantation. Despite progressive hyperinflation of the native left lung, the transplanted lung maintained function, as downward expansion of the left lung displaced the diaphragm without compressing the mediastinum. This suggests diaphragm mobility, aided by the absence of the liver beneath the left diaphragm, contributes to favorable outcomes in right single lung transplantation by preventing mechanical compression of the transplanted lung. No potential conflict of interest relevant to this article was reported.

Oxford University Press (OUP) Acta Medica Okayama 2753-670X 38 2 2024 Plasma concentrations of histidine-rich glycoprotein in primary graft dysfunction after lung transplantation ivae021 EN Toshio Shiotani Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Seiichiro Sugimoto Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Yasuaki Tomioka Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Shin Tanaka Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Toshiharu Mitsuhashi Center for Innovative Clinical Medicine, Okayama University Hospital Ken Suzawa Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Kazuhiko Shien Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Kentaroh Miyoshi Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Hiromasa Yamamoto Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Mikio Okazaki Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital OBJECTIVES: Histidine-rich glycoprotein has been reported as an anti-inflammatory glycoprotein that inhibits acute lung injury in mice with sepsis and as a prognostic biomarker in patients with sepsis. We investigated the relationship between plasma concentrations of histidine-rich glycoprotein and the risk of occurrence of primary graft dysfunction. METHODS: According to the primary graft dysfunction grade at post-transplant 72 h, patients who underwent lung transplantation were divided into three groups: non-primary graft dysfunction group (grade 0–1), moderate primary graft dysfunction group (grade 2), and severe primary graft dysfunction group (grade 3). The plasma concentrations of histidine-rich glycoprotein measured daily during the first post-transplant 7 days were compared among the three groups. Appropriate cutoff values of the concentrations were set for survival analyses after lung transplantation. RESULTS: A total of 68 patients were included. The plasma histidine-rich glycoprotein concentration at post-transplant 72 h was significantly lower in the severe primary graft dysfunction group (n = 7) than in the other two groups [non-primary graft dysfunction group (n = 43), P = 0.042; moderate primary graft dysfunction group (n = 18), P = 0.040]. Patients with plasma histidine-rich glycoprotein concentration ≥34.4 µg/ml at post-transplant 72 h had significantly better chronic lung allograft dysfunction-free survival (P = 0.012) and overall survival (P = 0.037) than those with the concentration <34.4 µg/ml. CONCLUSIONS: Plasma histidine-rich glycoprotein concentrations at post-transplant 72 h might be associated with the risk of development of primary graft dysfunction. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0003-4975 120 1 2025 Comparable Clinical Outcomes Between Segmentectomy and Lobectomy for NSCLC With Unsuspected N1/N2: A Multicenter Real-World Data Study 87 98 EN Tsuyoshi Ryuko Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiharu Mitsuhashi Center for Innovative Clinical Medicine, Okayama University Hospital Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tsuyoshi Ueno Okayama University Thoracic Surgery Study Group Toshiya Fujiwara Okayama University Thoracic Surgery Study Group Mototsugu Watanabe Okayama University Thoracic Surgery Study Group Hidetoshi Inokawa Okayama University Thoracic Surgery Study Group Takahiko Misao Okayama University Thoracic Surgery Study Group Hidejiro Torigoe Okayama University Thoracic Surgery Study Group Kazuhiro Washio Okayama University Thoracic Surgery Study Group Hiroyuki Tao Okayama University Thoracic Surgery Study Group Daisuke Okutani Okayama University Thoracic Surgery Study Group Makio Hayama Okayama University Thoracic Surgery Study Group Masashi Uomoto Okayama University Thoracic Surgery Study Group Eiji Yamada Okayama University Thoracic Surgery Study Group Shinji Otani Okayama University Thoracic Surgery Study Group Takeshi Kurosaki Okayama University Thoracic Surgery Study Group Yuji Yaginuma Okayama University Thoracic Surgery Study Group Eito Niman Okayama University Thoracic Surgery Study Group Osamu Kawamata Okayama University Thoracic Surgery Study Group Hitoshi Nishikawa Okayama University Thoracic Surgery Study Group Tomoaki Otsuka Okayama University Thoracic Surgery Study Group Takeshi Yoshikawa Okayama University Thoracic Surgery Study Group Tatsuro Hayashi Okayama University Thoracic Surgery Study Group Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background Segmentectomy for lung cancer has been increasingly performed. However, evidence regarding the necessity of additional surgical resection after the diagnosis of unsuspected N1 or N2 lymph node metastasis is limited. Methods We conducted a multicenter, real-world data study of patients with any clinical T and N0 non-small cell lung cancer (NSCLC) who underwent lobectomy or segmentectomy between 2012 and 2021 and who subsequently received a diagnosis of pathologic N1 or N2 lymph node metastasis. Patients were categorized into lobectomy and segmentectomy groups. We analyzed overall survival (OS), recurrence-free survival (RFS), cumulative recurrence rates, and recurrence patterns using both unadjusted and propensity score–adjusted cohorts. Results A total of 736 patients were in the lobectomy group, and 70 were in the segmentectomy group. In the unadjusted cohort, segmentectomy-treated patients were older, had a lower preoperative percentage of vital capacity, had smaller tumors, and received less postoperative adjuvant chemotherapy. The 5-year OS was significantly worse in the segmentectomy group (P = .011), with no significant differences in 5-year RFS or cumulative recurrence rates. In the propensity score–adjusted cohort, there were no significant differences in OS, RFS, or recurrence rates; however, the segmentectomy group had a higher rate of local recurrence. Conclusions In patients with unsuspected N1 or N2 NSCLC, analysis using a cohort adjusted for patient background with propensity scores revealed no differences in OS, RFS, or cumulative recurrence rates between segmentectomy and lobectomy. This finding suggests that additional resection of the remaining segments may not be necessary for these patients. However, the higher rate of local recurrence in the segmentectomy group warrants careful consideration. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 1201-9712 156 2025 Recurrent diffuse panbronchiolitis after lung transplantation: Off-label use of inhaled tobramycin for Pseudomonas aeruginosa control in a transplant recipient 107913 EN Shin Tanaka Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tuyoshi Ryuko Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuaki Tomioka Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideharu Hagiya Department of Infectious Diseases, Okayama University Hospital Mikio Okazaki Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Objectives: This report highlights a clinical case of recurrent diffuse panbronchiolitis (DPB) after bilateral lung transplantation (LTx), with a focus on the therapeutic impact of off-label inhaled tobramycin solution for inhalation (TSI) in managing Pseudomonas aeruginosa colonization. Methods: A Japanese woman with a history of DPB experienced disease recurrence following bilateral LTx. Persistent colonization by P. aeruginosa and recurrent respiratory symptoms were observed. Off-label TSI therapy, commonly used in cystic fibrosis, was introduced. Clinical response was assessed through radiologic imaging, bronchoscopy, and microbiological cultures. Results: TSI administration led to significant clinical and radiological improvement. P. aeruginosa was eradicated from sputum cultures within one month and remained absent throughout six months of follow-up. No hospitalizations or adverse events were reported during therapy. Conclusion: This case suggests the potential of TSI as a therapeutic approach for managing recurrent DPB and indicates its role in stabilizing post-transplant outcomes. Further studies may clarify its efficacy and expand its application in broader DPB management strategies. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1471-2466 25 1 2025 Co-occurrence of interstitial lung disease and pulmonary embolism as adverse events of adjuvant osimertinib treatment for EGFR mutant non-small cell lung cancer: a case report 311 EN Kenta Manabe Department of Thoracic Surgery, Okayama University Hospital Kazuhiko Shien Department of Thoracic Surgery, Okayama University Hospital Shinichi Furukawa Department of Thoracic Surgery, Okayama University Hospital Tomoya Seno Department of Thoracic Surgery, Okayama University Hospital Kousei Ishimura Department of Thoracic Surgery, Okayama University Hospital Shin Tanaka Department of Thoracic Surgery, Okayama University Hospital Ken Suzawa Department of Thoracic Surgery, Okayama University Hospital Mikio Okazaki Department of Thoracic Surgery, Okayama University Hospital Seiichiro Sugimoto Department of Thoracic Surgery, Okayama University Hospital Shinichi Toyooka Department of Thoracic Surgery, Okayama University Hospital Background Postoperative osimertinib for EGFR mutant non-small cell lung cancer has become the standard of care. However, its adverse events in clinical practice remain unclear. We report a case of interstitial lung disease and pulmonary embolism occurring simultaneously as adverse events during adjuvant osimertinib treatment. Case presentation A 74-year-old woman, diagnosed with left lower lobe lung adenocarcinoma harboring an EGFR mutation, underwent a left lower lobectomy with lymph node dissection. During adjuvant osimertinib therapy, the patient developed respiratory distress with hypoxia, leading to the diagnosis of interstitial lung disease. Despite immediate steroid therapy, respiratory distress persisted, the patient developed leg edema. She was diagnosed with deep vein thrombosis and pulmonary embolism via contrast-enhanced computed tomography scan. Following treatment with steroid and anticoagulation, her clinical symptoms improved rapidly, and she showed no recurrence of interstitial lung disease, pulmonary embolism, or lung cancer over the following nine months. Conclusions We encountered a case of interstitial lung disease and pulmonary embolism occurring simultaneously as adverse events during adjuvant osimertinib treatment. In patients with osimertinib-induced interstitial lung disease, particularly when respiratory symptoms show poor improvement with steroid treatment, the possibility of pulmonary embolism complications should be suspected. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1432-1068 35 1 2025 Primary chest wall sarcoma: advances in surgical management and outcomes 141 EN Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Eiji Nakata Tsuyoshi Ryuko Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takuto Itano Department of Orthopedic Surgery, Okayama University Hospital Yasuaki Tomioka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshifumi Ozaki Department of Orthopedic Surgery, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Purpose Although rare, primary chest wall sarcomas are complex malignancies necessitating optimal local control and comprehensive treatment. This study aimed to review 9 years of cases of primary chest wall sarcomas at a single institution, focusing on their histology, surgical management, and prognosis. Methods A retrospective analysis was performed on 19 patients undergoing chest wall resection for sarcoma from 2012 to 2020. Data on demographics, tumor specifics, resection extent, and adjuvant therapies were collected. Surgical and postoperative outcomes were also assessed. Results The median patient age was 64 years. Chondrosarcoma was the most common histology. R0 resection was achieved in all patients, with early postoperative complications occurring in 11% of the patients. Robust chest wall reconstruction was performed, resulting in minimal respiratory complications. The 5-year overall survival and disease-free survival rates were 94% and 68%, respectively. Tumor size and patient age were significant prognostic factors for local recurrence. Conclusion Comprehensive surgical resection, coupled with multidisciplinary preoperative planning, achieves favorable outcomes. Patients aged ≥ 70 years and with tumor size ≥ 5 cm (P = .047) should be carefully followed up for local recurrence. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 2212-5345 62 5 2024 Augmented humoral response to third and fourth dose of SARS-CoV-2 mRNA vaccines in lung transplant recipients 804 810 EN Shinichi Kawana Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kei Matsubara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruki Choshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Megumi Ishihara Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Tomohiro Habu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kohei Hashimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masanori Nakayama Office of Innovative Medicine, Organization for Research Strategy and Development, Okayama University Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background: Since lung transplant recipients (LTRs) exhibit low immunogenicity after two doses of SARS-CoV-2 mRNA vaccines, optimal vaccine strategies for SARS-CoV-2 are required in LTRs. This study aimed to investigate the efficacy and safety of the third and fourth doses of the SARS-CoV-2 mRNA vaccines in LTRs. Methods: We conducted a single-center study of 73 LTRs and 23 healthy controls (HCs). Participants received two-to-four doses of SARS-CoV-2 mRNA vaccines. The LTRs were divided into three groups based on the number of vaccine dose. IgG titers against SARS-CoV-2 spike protein were measured, and adverse events were assessed. Factors associated with humoral response were analyzed using univariate and multivariate analyses. Results: The Dose 4 group (n = 27) had a higher humoral response rate (P = 0.018) and higher levels of anti-SARS-CoV-2 IgG antibody (P = 0.04) than the Dose 2 group (n = 14). The Dose 3 group (n = 32) had lower humoral response rates (P = 0.005) and levels of anti-SARS-CoV-2 IgG antibody (P = 0.0005) than the HCs (n = 23) even after the same dose. Systemic adverse events were milder in the LTRs than in the HCs (P < 0.05). Increased number of vaccine dose was identified as a predictor of positive humoral response (P = 0.021). Conclusion: Booster doses of SARS-CoV-2 mRNA vaccines may enhance humoral response with mild adverse events in LTRs. Repeated vaccination might be warranted for LTRs to prevent SARS-CoV-2 infection. No potential conflict of interest relevant to this article was reported.

Public Library of Science Acta Medica Okayama 1932-6203 19 5 2024 PAI-1 mediates acquired resistance to MET-targeted therapy in non-small cell lung cancer e0300644 EN Yin Min Thu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Kosuke Ochi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shimpei Tsudaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumiaki Takatsu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keiichi Date Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naoki Matsuda Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuma Iwata Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaro Nakata Department of Surgery, Division of Cardiovascular and Thoracic Surgery, Duke University School of Medicine Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 0941-1291 54 11 2024 Effective division of the intersegmental plane using a robotic stapler in robotic pulmonary segmentectomy 1319 1328 EN Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kohei Hashimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Purposes Robot-assisted thoracoscopic (RATS) segmentectomy is becoming increasingly common because of the expanded indications for segmentectomy and the widespread adoption of robotic surgery. The precise division of the intersegmental plane is necessary to ensure oncologic margins from the tumor and to preserve the lung function. In this study, we present a strategy for accurately dividing the intersegmental plane using a robotic stapler and review the surgical outcomes. Methods RATS portal segmentectomy was performed using the Da Vinci Xi system and the intersegmental plane was dissected using a robotic stapler. We evaluated the perioperative outcomes in 92 patients who underwent RATS portal segmentectomy between May 2020 and January 2023. These results were compared with those of 82 patients who underwent complete video-assisted thoracoscopic surgery (CVATS) during the same period. Results The operative and console times were 162 and 97 min, respectively. No intraoperative complications occurred, and postoperative complications were observed in four cases (4.3%). The operative time, blood loss, postoperative complications, and maximum incision size were significantly lower in the RATS group than in the CVATS group. However, RATS requires a significantly higher number of staplers than CVATS. Conclusions The division of the intersegmental plane using a robotic stapler in RATS portal segmentectomy was, therefore, found to be safe and effective. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 115 7 2024 Adrenergic microenvironment driven by cancer-associated Schwann cells contributes to chemoresistance in patients with lung cancer 2333 2345 EN Yusuke Otani Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruyoshi Katayama Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yidan Zhu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Rongsheng Huang Department of Trauma Orthopedics, The Second Hospital of Dalian Medical University Takafumi Shigehira Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadahiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsushi Fujimura Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Doublecortin (DCX)-positive neural progenitor-like cells are purported components of the cancer microenvironment. The number of DCX-positive cells in tissues reportedly correlates with cancer progression; however, little is known about the mechanism by which these cells affect cancer progression. Here we demonstrated that DCX-positive cells, which are found in all major histological subtypes of lung cancer, are cancer-associated Schwann cells (CAS) and contribute to the chemoresistance of lung cancer cells by establishing an adrenergic microenvironment. Mechanistically, the activation of the Hippo transducer YAP/TAZ was involved in the acquisition of new traits of CAS and DCX positivity. We further revealed that CAS express catecholamine-synthesizing enzymes and synthesize adrenaline, which potentiates the chemoresistance of lung cancer cells through the activation of YAP/TAZ. Our findings shed light on CAS, which drive the formation of an adrenergic microenvironment by the reciprocal regulation of YAP/TAZ in lung cancer tissues. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1068-9265 30 11 2023 EGFR Mutation is a Prognostic Factor in Lung Cancer Patients with Pleural Dissemination Detected During or After Surgery 6697 6702 EN Toshiya Fujiwara Okayama University Thoracic Surgery Study Group (OUTSSG) Kazuhiko Shien Okayama University Thoracic Surgery Study Group (OUTSSG) Motoki Matsuura Okayama University Thoracic Surgery Study Group (OUTSSG) Junichi Soh Okayama University Thoracic Surgery Study Group (OUTSSG) Hiromasa Yamamoto Okayama University Thoracic Surgery Study Group (OUTSSG) Soshi Takao Department of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yuho Maki Okayama University Thoracic Surgery Study Group (OUTSSG) Tsuyoshi Ueno Okayama University Thoracic Surgery Study Group (OUTSSG) Ryujiro Sugimoto Okayama University Thoracic Surgery Study Group (OUTSSG) Ken Suzawa Okayama University Thoracic Surgery Study Group (OUTSSG) Mikio Okazaki Okayama University Thoracic Surgery Study Group (OUTSSG) Hiroyuki Tao Okayama University Thoracic Surgery Study Group (OUTSSG) Makio Hayama Okayama University Thoracic Surgery Study Group (OUTSSG) Masafumi Kataoka Okayama University Thoracic Surgery Study Group (OUTSSG) Yoshifumi Sano Okayama University Thoracic Surgery Study Group (OUTSSG) Hidetoshi Inokawa Okayama University Thoracic Surgery Study Group (OUTSSG) Motohiro Yamashita Okayama University Thoracic Surgery Study Group (OUTSSG) Osamu Kawamata Okayama University Thoracic Surgery Study Group (OUTSSG) Kazuhiko Kataoka Okayama University Thoracic Surgery Study Group (OUTSSG) Shinichi Toyooka Okayama University Thoracic Surgery Study Group (OUTSSG) Background. Primary lung tumors are sometimes resected when either pleural dissemination (PD) or malignant pleural effusion (MPE) exists. This study clarified the prognostic factors for non-small cell lung cancer (NSCLC) with either PD and MPE, or both, detected during or after surgery. Patients and Methods. We examined patients with NSCLC from a multicenter database who had either PD, MPE, or both, detected during or after surgery between 2005 and 2015. Hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model adjusted for potential confounding factors. Results. Among 9463 registered patients, PD, MPE, or both, were found in 114 patients with NSCLC during or after surgery. Primary tumor resection and exploratory thoracotomy were performed in 65 and 49 patients, respectively. In univariate analysis, adenocarcinoma, clinically undetected lymph node metastasis (c-N0 or unknown), EGFR mutation, and combination of chemotherapy or tyrosine kinase inhibitors after surgery were better prognostic factors for overall survival (OS), whereas in the multivariate analysis, adenocarcinoma, clinically undetected lymph node metastasis, and EGFR mutation were favorable independent prognostic factors in OS. Additionally, limited to patients with EGFR mutation, patients with primary lung tumor resection showed a significantly better 5-year OS than those with exploratory thoracotomy (86.4 vs. 44.8%; p < 0.001). Conclusion. Our findings show that surgical resection of primary tumors could improve the prognosis of patients with PD, MPE, or both, detected during or after surgery when the tumors harbor an EGFR mutation. No potential conflict of interest relevant to this article was reported.

Oxford University Press (OUP) Acta Medica Okayama 1873-734X 63 3 2023 Surgical outcome of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy ezad048 EN Mikio Okazaki Department of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ken Suzawa Department of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kazuhiko Shien Department of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiromasa Yamamoto Department of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kota Araki Okayama University Thoracic Surgery Study Group (OUTSSG) Mototsugu Watanabe Okayama University Thoracic Surgery Study Group (OUTSSG) Masanori Okada Okayama University Thoracic Surgery Study Group (OUTSSG) Yuho Maki Okayama University Thoracic Surgery Study Group (OUTSSG) Tsuyoshi Ueno Okayama University Thoracic Surgery Study Group (OUTSSG) Shinji Otani Okayama University Thoracic Surgery Study Group (OUTSSG) Ryujiro Sugimoto Okayama University Thoracic Surgery Study Group (OUTSSG) Hitoshi Nishikawa Okayama University Thoracic Surgery Study Group (OUTSSG) Riki Okita Okayama University Thoracic Surgery Study Group (OUTSSG) Makio Hayama Okayama University Thoracic Surgery Study Group (OUTSSG) Hiroyuki Tao Okayama University Thoracic Surgery Study Group (OUTSSG) Toshiya Fujiwara Okayama University Thoracic Surgery Study Group (OUTSSG) Hidetoshi Inokawa Okayama University Thoracic Surgery Study Group (OUTSSG) Yuji Hirami Okayama University Thoracic Surgery Study Group (OUTSSG) Yoshifumi Sano Okayama University Thoracic Surgery Study Group (OUTSSG) Motohiro Yamashita Okayama University Thoracic Surgery Study Group (OUTSSG) Osamu Kawamata Okayama University Thoracic Surgery Study Group (OUTSSG) Motoki Matsuura Okayama University Thoracic Surgery Study Group (OUTSSG) Shinichi Toyooka Department of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University OBJECTIVES: Ipsilateral reoperation after pulmonary lobectomy is often challenging because of adhesions from the previous operation. We retrospectively examined the surgical outcome and prognosis of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy using a multicentre database. METHODS: We evaluated the perioperative outcomes and overall survival of 51 patients who underwent pulmonary lobectomy followed by ipsilateral anatomical resection for lung cancer between January 2012 and December 2018. In addition, patients with stage I non-small-cell lung cancer (NSCLC) were compared with 3411 patients with stage I lung cancer who underwent pulmonary resection without a prior ipsilateral lobectomy. RESULTS: Ipsilateral anatomical resections included 10 completion pneumonectomies, 19 pulmonary lobectomies and 22 pulmonary segmentectomies. Operative time was 312.2 ± 134.5 min, and intraoperative bleeding was 522.2 ± 797.5 ml. Intraoperative and postoperative complications occurred in 9 and 15 patients, respectively. However, the 5-year overall survival rate after anatomical resection followed by ipsilateral lobectomy was 83.5%. Furthermore, in patients with c-stage I NSCLC, anatomical resection followed by ipsilateral lobectomy was not associated with worse survival than anatomical resection without prior ipsilateral lobectomy. CONCLUSIONS: Anatomical resection following ipsilateral lobectomy is associated with a high frequency of intraoperative and postoperative complications. However, the 5-year overall survival in patients with c-stage I NSCLC who underwent ipsilateral anatomical resection after pulmonary lobectomy is comparable to that in patients who underwent anatomical resection without prior pulmonary lobectomy. No potential conflict of interest relevant to this article was reported.

Lippincott, Williams & Wilkins Acta Medica Okayama 2373-8731 10 5 2024 Postoperative Complications in Living Donors for Lung Transplantation e1617 EN Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kento Fujii Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Megumi Ishihara Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Haruki Choshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kei Matsubara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kohei Hashimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuji Okahara Department of Anesthesiology and Resuscitology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background. Living donor lobar lung transplantation is a life-saving procedure for critically ill patients. This requires 2 healthy donors exposed to risks and without medical benefit. Therefore, the donor's safety and minimal postoperative complications are crucial. This study aimed to investigate the short-term outcomes and identify the risk factors affecting these outcomes. Methods. The data of 175 living donors enrolled between 1998 and 2022 were analyzed. Donors were divided into era 1 (1998-2009) and era 2 (2010-2022). Results. The overall incidence of postoperative complications was 39%, of which 7% were major complications. Donors who underwent surgery on the right side had a higher incidence of delayed pulmonary fistulae (P = 0.01) and elevated liver enzyme levels (P = 0.028). Living donor surgery on the right side (P = 0.01), era 2 (P = 0.01), and the need for plasty (P = 0.04) were predictors of postoperative complications. Conclusions. Updated data on complications and their correlation with postoperative quality of life from this study could aid in the selection of potential donors and facilitate informed consent. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0003-4975 117 1 2024 Clinical Features of Patients With Second Primary Lung Cancer After Head and Neck Cancer 181 188 EN Fumiaki Takatsu Department of Thoracic Surgery, Okayama University Hospital Ken Suzawa Department of Thoracic Surgery, Okayama University Hospital Mikio Okazaki Department of Thoracic Surgery, Okayama University Hospital Kazuhiko Shien Department of Thoracic Surgery, Okayama University Hospital Hiromasa Yamamoto Department of Thoracic Surgery, Okayama University Hospital Mototsugu Watanabe Okayama University Thoracic Surgery Study Group Makio Hayama Okayama University Thoracic Surgery Study Group Tsuyoshi Ueno Okayama University Thoracic Surgery Study Group Ryujiro Sugimoto Okayama University Thoracic Surgery Study Group Yuho Maki Okayama University Thoracic Surgery Study Group Toshiya Fujiwara Okayama University Thoracic Surgery Study Group Riki Okita Okayama University Thoracic Surgery Study Group Hidetoshi Inokawa Okayama University Thoracic Surgery Study Group Hiroyuki Tao Okayama University Thoracic Surgery Study Group Yuji Hirami Okayama University Thoracic Surgery Study Group Eisuke Matsuda Okayama University Thoracic Surgery Study Group Kazuhiko Kataoka Okayama University Thoracic Surgery Study Group Motohiro Yamashita Okayama University Thoracic Surgery Study Group Yoshifumi Sano Okayama University Thoracic Surgery Study Group Motoki Matsuura Okayama University Thoracic Surgery Study Group Hisao Mizutani Okayama University Thoracic Surgery Study Group Shinichi Toyooka Department of Thoracic Surgery, Okayama University Hospital Background In survivors of head and neck cancer (HNC), second primary lung cancer (SPLC) often develop as a result of a common risk factor, that is, smoking. A multicenter experience was reviewed to evaluate how the history of a diagnosis of HNC affects the outcomes of patients undergoing pulmonary resection for SPLC. Methods A multicenter retrospective analysis of patients hospitalized between January 2012 and December 2018 was performed. From a cohort of 4521 patients undergoing therapeutic pulmonary resection for primary non-small cell lung cancer, 100 patients with a previous history of HNC (HNC group) were identified. These patients were compared with a control group consisting of 200 patients without an HNC history from the same cohort pair-matched with operating facility, age, sex, and pathologic stage of lung cancer. Results At the time of surgery for SPLC, the HNC group showed malnutrition with a lower prognostic nutritional index compared with the control group (P < .001). The HNC group was determined to have postoperative complications more frequently (P = .02). The 5-year overall survival rates in the HNC and control groups were 59.0% and 83.2%, respectively (P < .001). Statistically, HNC history, lower prognostic nutritional index, squamous cell lung cancer, and TNM stage were identified to be independently associated with poor survival. Conclusions Patients with SPLC after primary HNC often present with malnutrition and are predisposed to postoperative complications and poor survival after pulmonary resection. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1068-9265 30 13 2023 Prognostic Impact of Tumor-Infiltrating Lymphocytes, Tertiary Lymphoid Structures, and Neutrophil-to-Lymphocyte Ratio in Pulmonary Metastases from Uterine Leiomyosarcoma 8727 8734 EN Naoki Matsuda Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomohiro Habu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuma Iwata Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kei Matsubara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kohei Hashimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomohiro Toji Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuhito Takahashi Department of Sarcoma Medicine, Center for Sarcoma Multidisciplinary Treatment, Kameda Medical Center Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background　The presence of tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) in tumor tissue has been related to the prognosis in various malignancies. Meanwhile, neutrophil-to-lymphocyte ratio (NLR) as a systemic inflammation marker also has been associated with the prognosis in them. However, few reports have investigated the relationship between pulmonary metastases from sarcoma and these biomarkers. Methods　We retrospectively recruited 102 patients undergoing metastasectomy for pulmonary metastases from uterine leiomyosarcoma at Okayama University Hospital from January 2006 to December 2019. TILs and TLSs were evaluated by immunohistochemical staining of surgically resected specimens of pulmonary metastases using anti-CD3/CD8/CD103/Foxp3/CD20 antibodies. NLR was calculated from the blood examination immediately before the most recent pulmonary metastasectomy. We elucidated the relationship between the prognosis and these factors. Because we considered that the status of tumor tissue and systemic inflammation were equally valuable, we also assessed the impact of the combination of TILs or TLSs and NLR on the prognosis. Results　As for TILs, CD3-positive cells and CD8-positive cells were correlated with the prognosis. The prognosis was significantly better in patients with CD3-high group, CD8-high group, TLSs-high group, and NLR-low group, respectively. The prognosis of CD8-high/NLR-low group and TLSs-high/NLR-low group was significantly better than that of CD8-low/NLR-high group and TLSs-low/NLR-high group, respectively. Conclusions　CD3-positive TILs, CD8-positive TILs, TLSs, and NLR are correlated with the prognosis, respectively. The combination of CD8-positive TILs or TLSs and NLR may be the indicators to predict the prognosis of patients with pulmonary metastases from uterine leiomyosarcoma. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0902-0063 37 11 2023 Percentage of low attenuation area on computed tomography detects chronic lung allograft dysfunction, especially bronchiolitis obliterans syndrome, after bilateral lung transplantation e15077 EN Yujiro Kubo Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Seiichiro Sugimoto Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Toshio Shiotani Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Kei Matsubara Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Kohei Hashimoto Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Shin Tanaka Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Kazuhiko Shien Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Ken Suzawa Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Kentaroh Miyoshi Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Hiromasa Yamamoto Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Mikio Okazaki Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital Introduction: The percentage of low attenuation area (%LAA) on computed tomography (CT) is useful for evaluating lung emphysema, and higher %LAA was observed in patients with chronic lung allograft dysfunction (CLAD). This study investigated the relationship between the %LAA and the development of CLAD after bilateral lung transplantation (LT). Methods: We conducted a single-center retrospective study of 75 recipients who underwent bilateral LT; the recipients were divided into a CLAD group (n = 30) and a non-CLAD group (n = 45). The %LAA was calculated using CT and compared between the two groups from 4 years before to 4 years after the diagnosis of CLAD. The relationships between the %LAA and the percent baseline values of the pulmonary function test parameters were also calculated. Results: The %LAA was significantly higher in the CLAD group than in the non-CLAD group from 2 years before to 2 years after the diagnosis of CLAD (P < .05). In particular, patients with bronchiolitis obliterans syndrome (BOS) exhibited significant differences even from 4 years before to 4 years after diagnosis (P < .05). Significant negative correlations between the %LAA and the percent baseline values of the forced expiratory volume in 1 s (r = −.36, P = .0031), the forced vital capacity (r = −.27, P = .027), and the total lung capacity (r = −.40, P < .001) were seen at the time of CLAD diagnosis. Conclusion: The %LAA on CT was associated with the development of CLAD and appears to have the potential to predict CLAD, especially BOS, after bilateral LT. No potential conflict of interest relevant to this article was reported.

nature portfolio Acta Medica Okayama 2045-2322 13 1 2023 Identification of genetic loci associated with renal dysfunction after lung transplantation using an ethnic-specific single-nucleotide polymorphism array 8912 EN Yasuaki Tomioka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruchika Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Toshio Shiotani Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinji Otani Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masaomi Yamane Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Renal dysfunction is a long-term complication associated with an increased mortality after lung transplantation (LT). We investigated the association of single-nucleotide polymorphisms (SNPs) with the development of renal dysfunction after LT using a Japanese-specific SNP array. First, eligible samples of 34 LT recipients were genotyped using the SNP array and divided into two groups, according to the presence of homozygous and heterozygous combinations of mutant alleles of the 162 renal-related SNPs. To identify candidate SNPs, the renal function tests were compared between the two groups for each SNP. Next, we investigated the association between the candidate SNPs and the time course of changes of the estimated glomerular filtration rate (eGFR) in the 99 recipients until 10 years after the LT. Delta eGFR was defined as the difference between the postoperative and preoperative eGFR values. Eight SNPs were identified as the candidate SNPs in the 34 recipients. Validation analysis of these 8 candidate SNPs in all the 99 recipients showed that three SNPs, namely, rs10277115, rs4690095, and rs792064, were associated with significant changes of the Delta eGFR. Pre-transplant identification of high-risk patients for the development of renal dysfunction after LT based on the presence of these SNPs might contribute to providing personalized medicine. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 2405-8440 9 4 2023 Diagnostic value of circulating microRNA-21 in chronic lung allograft dysfunction after bilateral cadaveric and living-donor lobar lung transplantation e14903 EN Toshio Shiotani Organ Transplant Center, Okayama University Hospital Seiichiro Sugimoto Organ Transplant Center, Okayama University Hospital Yasuaki Tomioka Organ Transplant Center, Okayama University Hospital Haruchika Yamamoto Department of General Thoracic Surgery, Okayama University Hospital Shin Tanaka Organ Transplant Center, Okayama University Hospital Kentaroh Miyoshi Department of General Thoracic Surgery, Okayama University Hospital Ken Suzawa Department of General Thoracic Surgery, Okayama University Hospital Kazuhiko Shien Department of General Thoracic Surgery, Okayama University Hospital Hiromasa Yamamoto Department of General Thoracic Surgery, Okayama University Hospital Mikio Okazaki Department of General Thoracic Surgery, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery, Okayama University Hospital Background: MicroRNAs (miRNAs) involved in the pathogenesis of pulmonary fibrosis have been shown to be associated with the development of chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). We investigated the role of circulating miRNAs in the diagnosis of CLAD after bilateral LT, including cadaveric LT (CLT) and living-donor lobar LT (LDLLT). Methods: The subjects of this retrospective study were 37 recipients of bilateral CLT (n = 23) and LDLLT (n = 14), and they were divided into a non-CLAD group (n = 24) and a CLAD group (n = 13). The plasma miRNA levels of the two groups were compared, and correlations between their miRNAs levels and percent baseline forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and total lung capacity (TLC) values were calculated from one year before to one year after the diagnosis of CLAD. Results: The plasma levels of both miR-21 and miR-155 at the time of the diagnosis of CLAD were significantly higher in the CLAD group than in the non-CLAD group (miR-21, P = 0.0013; miR155, P = 0.042). The miR-21 levels were significantly correlated with the percent baseline FEV1, FVC, and TLC value of one year before and at the time of diagnosis of CLAD (P < 0.05). A receiver operating characteristic curve analysis of the performance of miR-21 levels in the diagnosis of CLAD yielded an area under the curve of 0.89. Conclusion: Circulating miR-21 appears to be of potential value in diagnosing CLAD after bilateral LT. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2306-5354 9 11 2022 Functional Blockage of S100A8/A9 Ameliorates Ischemia-Reperfusion Injury in the Lung 673 EN Kentaro Nakata Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomohisa Sakaue Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine Rie Kinoshita Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuhei Komoda Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine Dai Shimizu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruchika Yamamoto Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiaki Ohara Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masaomi Yamane Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihiro Matsukawa Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masakiyo Sakaguchi Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences (1) Background: Lung ischemia-reperfusion (IR) injury increases the mortality and morbidity of patients undergoing lung transplantation. The objective of this study was to identify the key initiator of lung IR injury and to evaluate pharmacological therapeutic approaches using a functional inhibitor against the identified molecule. (2) Methods: Using a mouse hilar clamp model, the combination of RNA sequencing and histological investigations revealed that neutrophil-derived S100A8/A9 plays a central role in inflammatory reactions during lung IR injury. Mice were assigned to sham and IR groups with or without the injection of anti-S100A8/A9 neutralizing monoclonal antibody (mAb). (3) Results: Anti-S100A8/A9 mAb treatment significantly attenuated plasma S100A8/A9 levels compared with control IgG. As evaluated by oxygenation capacity and neutrophil infiltration, the antibody treatment dramatically ameliorated the IR injury. The gene expression levels of cytokines and chemokines induced by IR injury were significantly reduced by the neutralizing antibody. Furthermore, the antibody treatment significantly reduced TUNEL-positive cells, indicating the presence of apoptotic cells. (4) Conclusions: We identified S100A8/A9 as a novel therapeutic target against lung IR injury. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2075-4426 12 8 2022 Robotic Mediastinal Tumor Resections: Position and Port Placement 1195 EN Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science This study aimed to determine the optimal position and port placement during robotic resection for various mediastinal tumors. For anterior mediastinal tumors, total or extended thymectomy is commonly performed in the supine position using the lateral or subxiphoid approach. Although it is unclear which approach is better during robotic thymectomy, technical advantages of subxiphoid approach are beneficial for patients with myasthenia who require extended thymectomy. Partial thymectomy is performed in the supine position using a lateral approach. Superior, middle, and posterior mediastinal tumors are resected in the decubitus position using the lateral approach, whereas dumbbell tumor resection, which requires a posterior approach, can be performed in the prone position. The position and port placement should be chosen depending on the size, location, and aggressiveness of the tumor. In this study, we describe how to choose which of these different robotic approaches can be used based on our experience and previous reports. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 2022 2022 Drug repositioning of tranilast to sensitize a cancer therapy by targeting cancer-associated fibroblast EN Kosuke Ochi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yin Min Thu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumiaki Takatsu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shimpei Tsudaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yidan Zhu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaro Nakata Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsuaki Takeda Departments of Pharmacy, Okayama University Hospital Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadahiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshiharu Okamoto Department of Veterinary Clinical Medicine, Joint School of Veterinary Medicine, Tottori University Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines, and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were cocultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer-CAF interaction. No potential conflict of interest relevant to this article was reported.

Nature Portfolio Acta Medica Okayama 2045-2322 12 1 2022 One-step nucleic acid amplification for intraoperative diagnosis of lymph node metastasis in lung cancer patients: a single-center prospective study 7297 EN Kei Namba Department of Pathology, Memorial Sloan Kettering Cancer Center Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Akihiro Miura Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yuta Takahashi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shunsaku Miyauchi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kota Araki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kentaro Nakata Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shinji Otani Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Junichi Soh Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Masaomi Yamane Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences One-step nucleic acid amplification (OSNA) is a rapid intraoperative molecular detection technique for sentinel node assessment via the quantitative measurement of target cytokeratin 19 (CK19) mRNA to determine the presence of metastasis. It has been validated in breast cancer but its application in lung cancer has not been adequately investigated. 214 LNs from 105 patients with 100 primary lung cancers, 2 occult primary lung tumors, and 3 metastatic lung tumors, who underwent surgical lung resection with LN dissection between February 2018 and January 2020, were assessed. Resected LNs were divided into two parts: one was snap-frozen for OSNA and the other underwent rapidly frozen histological examination. Intraoperatively collected LNs were evaluated by OSNA using loop-mediated isothermal amplification and compared with intraoperative pathological diagnosis as a control. Among 214 LNs, 14 were detected as positive by OSNA, and 11 were positive by both OSNA and intraoperative pathological diagnosis. The sensitivity and specificity of OSNA was 84.6% and 98.5%, respectively. The results of 5 of 214 LNs were discordant, and the remainder all matched (11 positive and 198 negative) with a concordance rate of 97.7%. Although the analysis of public mRNA expression data from cBioPortal showed that CK19 expression varies greatly depending on the cancer type and histological subtype, the results of the five cases, except for primary lung cancer, were consistent. OSNA provides sufficient diagnostic accuracy and speed and can be applied to the intraoperative diagnosis of LN metastasis for non-small cell lung cancer. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1477-7819 20 1 2022 Survival and prognostic factors in patients undergoing pulmonary metastasectomy for lung metastases from retroperitoneal sarcoma 114 EN Fumiaki Takatsu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuaki Tomioka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Tanaka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaroh Miyoshi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinji Otani Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masaomi Yamane Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuhito Takahashi Center for Sarcoma Multidisciplinary Treatment, Department of Sarcoma Medicine, Kameda Medical Center Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background Soft-tissue sarcomas are rare malignancies that consist of many different histologic subtypes and arise in various locations in the body. In patients with lung metastases from retroperitoneal sarcomas, the long-term outcomes and prognostic factors are unknown. This study is a retrospective review of patients undergoing pulmonary metastasectomy for retroperitoneal sarcoma metastases at one institution, with the purpose of determining prognostic factors and clinical outcomes. Methods This is a single-center, retrospective cohort study of patients undergoing pulmonary metastasectomy for lung metastases from various sarcomas at Okayama University Hospital from January 2006 to December 2018. The Kaplan-Meier method and log-rank test were used for the analyses, and cut-off values of continuous variables were determined by a receiver operating characteristic curve analysis. Results Twenty-four patients underwent the first pulmonary metastasectomy for lung metastases from retroperitoneal sarcoma in our hospital. Leiomyosarcoma was the most common histologic subtype of retroperitoneal sarcoma (79.2%, n = 19). Median overall survival was 49.9 months, and the 3-year and 5-year survival rates after the first pulmonary metastasectomy were 62.5% and 26.4% respectively. In univariate analysis, age >= 56 years, disease-free interval < 15 months, and size of metastasis (>= 27 mm) were associated with poor survival. Conclusion Pulmonary metastasectomy can be considered as an effective management strategy in retroperitoneal sarcoma patients with lung metastases in appropriately selected cases, just as it is for other sarcomas. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 22 23 2021 YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development 12809 EN Miwa Fujihara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Tadahiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Tatsuaki Takeda Departments of Pharmacy, Okayama University Hospital Yidan Zhu Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Tomoka Mamori Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yusuke Otani Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Ryo Yoshioka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Maya Uno Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yoko Suzuki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yuko Abe Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Minami Hatono Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Takahiro Tsukioki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Yuko Takahashi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Mariko Kochi Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Takayuki Iwamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Naruto Taira Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Hiroyoshi Doihara Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1. No potential conflict of interest relevant to this article was reported.

Oxford Univ Press Acta Medica Okayama 2042-8812 2021 8 2021 Robot-assisted thoracoscopic lobectomy for severe incomplete interlober fissure rjab336 EN Mikio Okazaki Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine Ken Suzawa Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine Kazuhiko Shien Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine Kentaroh Miyoshi Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine Shinji Otani Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine Hiromasa Yamamoto Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine Seiichiro Sugimoto Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine Masaomi Yamane Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine Shinichi Toyooka Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine An incomplete interlobar fissure makes thoracoscopic lobectomy difficult and is predictive of morbidity after thoracoscopic lobectomy. This report demonstrates the robot-assisted thoracoscopic (RATS) lobectomy technique for patients with severe incomplete interlobar fissures. A fissureless approach was chosen for pulmonary resection. Near-infrared fluorescence imaging with intravenous indocyanine green (ICG) was used to detect the interlobar line after transection of the bronchus, pulmonary artery and vein. Interlobar fissure was identified and divided by robotic staplers. This combined technique using ICG and fissureless lobectomy made RATS lobectomy safe for patients with severe incomplete interlobar fissures. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 00219258 296 2021 Covalent N-arylation by the pollutant 1,2-naphthoquinone activates the EGF receptor 100524 EN Kengo Nakahara Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kyohei Hamada Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomoki Tsuchida Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Nobumasa Takasugi Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yumi Abiko Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba Kazuhiko Shien Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshito Kumagai Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba Takashi Uehara Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University The epidermal growth factor receptor (EGFR) is the most intensively investigated receptor tyrosine kinase. Several EGFR mutations and modifications have been shown to lead to abnormal self-activation, which plays a critical role in carcinogenesis. Environmental air pollutants, which are associated with cancer and respiratory diseases, can also activate EGFR. Specifically, the environmental electrophile 1,2-naphthoquinone (1,2-NQ), a component of diesel exhaust particles and particulate matter more generally, has previously been shown to impact EGFR signaling. However, the detailed mechanism of 1,2-NQ function is unknown. Here, we demonstrate that 1,2-NQ is a novel chemical activator of EGFR but not other EGFR family proteins. We found that 1,2-NQ forms a covalent bond, in a reaction referred to as N-arylation, with Lys80, which is in the ligand-binding domain. This modification activates the EGFR–Akt signaling pathway, which inhibits serum deprivation–induced cell death in a human lung adenocarcinoma cell line. Our study reveals a novel mode of EGFR pathway activation and suggests a link between abnormal EGFR activation and environmental pollutant–associated diseases such as cancer. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 5 2020 A Giant Thymic Cyst Accompanied by Acute Mediastinitis 431 433 EN Akihiro Miura Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Hospital Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Hospital Tomohiro Toji Department of Pathology, Okayama University Hospital Shinji Otani Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Hospital Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Hospital Mikio Okazaki Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Hospital Seiichiro Sugimoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Hospital Junichi Soh Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Hospital Masaomi Yamane Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Hospital Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Hospital Case Report 10.18926/AMO/60804 We encountered a rare case of thymic cyst accompanied by mediastinitis. A 39-year-old Japanese male presented with fever and chest pain. The chest CT revealed a mass composed of a lobular cystic lesion with inflammation, suggesting the onset of mediastinitis. A definitive histological diagnosis was not obtained, and we performed a thymectomy. Pathologically, the thymic cyst was accompanied by multiple cavities, mimicking thymic cysts, caused by the inflammatory abscess. The surrounding adipose tissue showed inflammatory cell infiltrations with chronic fibrosis. These findings indicate that clinicians should be aware that thymic cysts may cause severe mediastinitis. No potential conflict of interest relevant to this article was reported.

Academic Press Acta Medica Okayama 0006-291X 529 3 2020 Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer 760 765 EN Kosuke Ochi Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Kazuhiko Shien Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jui Takano Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shunsaku Miyauchi Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsuaki Takeda Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihiro Miura Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kota Araki Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaro Nakata Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mikio Okazaki Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Sugimoto Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadahiko Shien Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masaomi Yamane Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuo Azuma Department of Veterinary Clinical Medicine, Joint School of Veterinary Medicine, Tottori University Yoshiharu Okamoto Department of Veterinary Clinical Medicine, Joint School of Veterinary Medicine, Tottori University Shinichi Toyooka Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. Materials and methods A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. Results TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. Conclusion Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance. No potential conflict of interest relevant to this article was reported.

Springer Acta Medica Okayama 0941-1291 2020 The neutrophil-to-lymphocyte ratio as a novel independent prognostic factor for multiple metastatic lung tumors from various sarcomas EN Hiromasa Yamamoto Department of Thoracic Surgery, Okayama University Hospital Kei Namba Department of Thoracic Surgery, Okayama University Hospital Haruchika Yamamoto Department of Thoracic Surgery, Okayama University Hospital Tomohiro Toji Department of Diagnostic Pathology, Okayama University Hospital Junichi Soh Department of Thoracic Surgery, Okayama University Hospital Kazuhiko Shien Department of Thoracic Surgery, Okayama University Hospital Ken Suzawa Department of Thoracic Surgery, Okayama University Hospital Takeshi Kurosaki Department of Thoracic Surgery, Okayama University Hospital Shinji Otani Department of Thoracic Surgery, Okayama University Hospital Mikio Okazaki Department of Thoracic Surgery, Okayama University Hospital Seiichiro Sugimoto Department of Thoracic Surgery, Okayama University Hospital Masaomi Yamane Department of Thoracic Surgery, Okayama University Hospital Katsuhito Takahashi Center for Multidisciplinary Treatment of Sarcoma, Department of Sarcoma Medicine, Kameda Medical Center Toshiyuki Kunisada Department of Orthopedic Surgery, Okayama University Hospital Takahiro Oto Department of Thoracic Surgery, Okayama University Hospital Shinichi Toyooka Department of Thoracic Surgery, Okayama University Hospital Purpose Sarcomas are among the most refractory malignant tumors and often recur as pulmonary metastasis. Although the presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with the prognosis of several malignancies, the relationship between the NLR and sarcoma with pulmonary metastasis is unclear. We investigated the impact of the NLR in patients who underwent surgical resection for metastatic lung tumors from various sarcomas. Methods The subjects of this retrospective study were 158 patients with metastatic lung tumors from various sarcomas, who underwent initial pulmonary metastasectomy between 2006 and 2015. We examined the clinicopathological variables, including the NLR and the characteristics of surgical procedures. Survival was estimated by the Kaplan–Meier method and prognostic factors were evaluated by multivariate analysis. Results Multivariate analysis revealed significantly better survival of the group with an NLR < 2.26 immediately before the most recent pulmonary metastasectomy, in addition to such factors as the largest resected lesion being < 22 mm, a disease-free interval of > 2 years, and 3 or more pulmonary metastasectomies. Conclusion The NLR immediately before the most recent pulmonary metastasectomy is a novel independent prognostic factor, which may be helpful when considering repeated pulmonary metastasectomy. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 111 3 2019 YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers 849 856 EN Tatsuaki Takeda Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Shunsaku Miyauchi Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kota Araki Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaro Nakata Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihiro Miura Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kei Namba Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junichi Soh Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadahiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshihisa Kitamura Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences Toshiaki Sendo Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome. No potential conflict of interest relevant to this article was reported.

Wiley Open Access Acta Medica Okayama 1347-9032 110 8 2019 Acquired resistance mechanisms to afatinib in HER2-amplified gastric cancer cells 2549 2557 EN Takahiro Yoshioka Departments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsuaki Takeda Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuta Takahashi General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Eisuke Kurihara General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yusuke Ogoshi General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kei Namba General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hidejiro Torigoe General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroki Sato General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Bioinformatics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junichi Soh General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiyoshi Fujiwara Departments of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Cancer treatment, especially that for breast and lung cancer, has entered a new era and continues to evolve, with the development of genome analysis technology and the advent of molecular targeted drugs including tyrosine kinase inhibitors. Nevertheless, acquired drug resistance to molecular targeted drugs is unavoidable, creating a clinically challenging problem. We recently reported the antitumor effect of a pan-HER inhibitor, afatinib, against human epidermal growth factor receptor 2 (HER2)-amplified gastric cancer cells. The purpose of the present study was to identify the mechanisms of acquired afatinib resistance and to investigate the treatment strategies for HER2-amplified gastric cancer cells. Two afatinib-resistant gastric cancer cell lines were established from 2 HER2-amplified cell lines, N87 and SNU216. Subsequently, we investigated the molecular profiles of resistant cells. The activation of the HER2 pathway was downregulated in N87-derived resistant cells, whereas it was upregulated in SNU216-derived resistant cells. In the N87-derived cell line, both MET and AXL were activated, and combination treatment with afatinib and cabozantinib, a multikinase inhibitor that inhibits MET and AXL, suppressed the cell growth of cells with acquired resistance both in vitro and in vivo. In the SNU216-derived cell line, YES1, which is a member of the Src family, was remarkably activated, and dasatinib, a Src inhibitor, exerted a strong antitumor effect in these cells. In conclusion, we identified MET and AXL activation in addition to YES1 activation as novel mechanisms of afatinib resistance in HER2-driven gastric cancer. Our results also indicated that treatment strategies targeting individual mechanisms of resistance are key to overcoming such resistance. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1522-8002 21 7 2019 Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness 627 640 EN Youyi Chen Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences I Wayan Sumardika Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nahoko Tomonobu Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Rie Kinoshita Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yusuke Inoue Faculty of Science and Technology, Division of Molecular Science, Gunma University Hidekazu Iioka Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences Yosuke Mitsui Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Saito Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences I Made Winarsa Ruma Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroki Sato Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akira Yamauchi Department of Biochemistry, Kawasaki Medical School Hitoshi Murata Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-ichi Yamamoto Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Department of Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junichi Soh Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junichiro Futami Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University Miyoko Kubo Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Endy Widya Putranto Department of Pediatrics, Dr. Sardjito Hospital/Faculty of Medicine, Universitas Gadjah Mada Takashi Murakami Department of Microbiology, Faculty of Medicine, Saitama Medical University Ming Liu Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University Toshihiko Hibino Department of Dermatology, Tokyo Medical University Masahiro Nishibori Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Eisaku Kondo Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences Shinichi Toyooka Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masakiyo Sakaguchi Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 70 4 2016 Study about the Efficacy of Metformin to Immune Function in Cancer Patients 327 330 EN Mototsugu Watanabe Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shingo Eikawa Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadahiko Shien Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junichi Soh Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Hotta Center for Innovative Clinical Medicine, Okayama University Hospital Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shiro Hinotsu Center for Innovative Clinical Medicine, Okayama University Hospital Toshiyoshi Fujiwara Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyoshi Doihara Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichiro Miyoshi Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Heiichiro Udono Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Clinical Study Protocols 10.18926/AMO/54514 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. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 68 1 2014 Preclinical Evaluation of MicroRNA-34b/c Delivery for Malignant Pleural Mesothelioma 23 26 EN Tsuyoshi Ueno Shinichi Toyooka Takuya Fukazawa Takafumi Kubo Junichi Soh Hiroaki Asano Takayuki Muraoka Norimitsu Tanaka Yuho Maki Kazuhiko Shien Masashi Furukawa Masakiyo Sakaguchi Hiromasa Yamamoto Kazunori Tsukuda Shinichiro Miyoshi Original Article 10.18926/AMO/52140 The microRNA-34s (miR-34s) have p53 response elements in their 5ʼ-flanking regions and demonstrate tumor-suppressive functions. In malignant pleural mesothelioma (MPM), we previously reported that expression of miR-34b and miR-34c (miR-34b/c) was frequently downregulated by methylation in MPM cell lines and primary tumors. The forced overexpression of miR-34b/c showed significant antitumor effects with the induction of apoptosis in MPM cells. In this study, we examined the in vivo antitumor effects of miR-34b/c using adenovirus vector on MPM. We subcutaneously transplanted NCI-H290, a human MPM cell line, into BALB/C mice and injected adenovirus vector expressing miR-34b/c, luciferase driven by the cytomegalovirus promoter (Ad-miR-34b/c or Ad-Luc), or PBS control into tumors over 5mm in diameter. A statistically significant growth inhibition of the tumor volume was observed in the Ad-miR-34b/c group from day 6 onward compared to the Ad-Luc group. The inhibition rate of Ad-miR-34b/c, compared to the tumor volume treated with Ad-Luc, was 58.6% on day 10 and 54.7% on day13. Our results indicate that adenovirus-mediated miR-34b/c gene therapy could be useful for the clinical treatment of MPM. No potential conflict of interest relevant to this article was reported.

Elsevier Ireland Ltd. Acta Medica Okayama 0169-5002 82 3 2013 The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma 485 490 EN Takayuki Muraoka Junichi Soh Shinichi Toyooka Keisuke Aoe Nobukazu Fujimoto Shinsuke Hashida Yuho Maki Norimitsu Tanaka Kazuhiko Shien Masashi Furukawa Hiromasa Yamamoto Hiroaki Asano Kazunori Tsukuda Takumi Kishimoto Takemi Otsuki Shinichiro Miyoshi Objectives: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. microRNA-34b/c (miR-34b/c), which plays an important role in the pathogenesis of MPM, is frequently downregulated by DNA methylation in approximately 90% of MPM cases. In this study, we estimated the degree of miR-34b/c methylation in serum-circulating DNA using a digital methylation specific PCR assay (MSP). Materials and methods: A real-time MSP assay was performed using the SYBR Green method. The melting temperature (Tm) of each PCR product was examined using a melting curve analysis. For a digital MSP assay, 40 wells were analyzed per sample. A total of 110 serum samples from 48 MPM cases, 21 benign asbestos pleurisy (BAP) cases, and 41 healthy volunteers (HVs) were examined. Results: Positive range of Tm value for miR-34b/c methylation was defined as 77.71-78.79 degrees C which was the mean 3 standard deviations of 40 wells of a positive control. The number of miR-34b/c methylated wells was counted per sample according to this criterion. The number of miR-34b/c methylated wells in MPM cases was significantly higher than that in BAP cases (P = 0.03) or HVs (P < 0.001). Advanced MPM cases tended to have higher number of miR-34b/c methylated wells than early MPM cases. Receiver-operating characteristic (ROC) curve analysis revealed that three number of miR-34b/c methylated wells per sample was the best cut-off of positivity of MPM with a 67% of sensitivity and a 77% specificity for prediction. The area under the ROC curve was 0.77. Conclusions: Our digital MSP assay can quantify miR-34b/c methylation in serum-circulating DNA. The degree of miR-34b/c methylation in serum-circulating DNA is associated with MPM, suggesting that this approach might be useful for the establishment of a new detection system for MPM. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1021-335X 29 1 2013 Impact of GLUT1 and Ki-67 expression on early-stage lung adenocarcinoma diagnosed according to a new international multidisciplinary classification 133 140 EN Yuho Maki Junichi Soh Kouichi Ichimura Kazuhiko Shien Masashi Furukawa Takayuki Muraoka Norimitsu Tanaka Tsuyoshi Ueno Hiromasa Yamamoto Hiroaki Asano Kazunori Tsukuda Shinichi Toyooka Shinichiro Miyoshi High expression levels of glucose transporter isoform 1 (GLUT1) and Ki-67 are reportedly associated with malignancy-related clinicopathological factors in malignant tumors. Recently, a new histological IASLC/ATS/ERS classification for lung adenocarcinoma was proposed. In this study, we investigated the clinicopathological impact of GLUT1 and Ki-67 expression on early-stage lung adenocarcinoma classified according to the IASLC/ATS/ERS classification. One hundred and five patients with completely resected stage IA lung adenocarcinoma were retrospectively classified into two groups, a 'non-invasive type' (n=31) or an 'invasive type' (n=74), based on the IASLC/ATS/ERS classification. GLUT1 and Ki-67 expression status was evaluated using immunohistochemistry. The epidermal growth factor receptor (EGFR) and KRAS mutation status was determined using PCR-based assays. Positive GLUT1 and Ki-67 expression and EGFR and KRAS mutations were detected in 28 (27%), 33 (31%), 51 (49%) and 5 (8%) cases, respectively. Positive GLUT1 expression was significantly associated with a wild-type EGFR and mutant KRAS status. A multivariate analysis revealed that positive GLUT1 expression was independently associated with the 'invasive type'. In multivariate analyses for overall survival (OS) and disease-free survival (DFS), positive Ki-67 and GLUT1 expression was the only independent factor for a poor OS (P=0.012) and DFS (P=0.040), respectively. In addition, when stratified according to the GLUT1 and Ki-67 status, double-positive cases had the poorest DFS and OS times, compared with the other categories. Positive GLUT1 expression is associated with the invasive character of early-stage lung adenocarcinoma and with early disease relapse. Our results strongly suggest that GLUT1 and Ki-67 play important roles in acquiring biological malignant potential in early-stage lung adenocarcinoma. No potential conflict of interest relevant to this article was reported.

Elsevier Ireland Ltd. Acta Medica Okayama 0169-5002 76 1 2012 Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer 26 31 EN Tsuyoshi Ueno Kazunori Tsukuda Shinichi Toyooka Midori Ando Munenori Takaoka Junichi Soh Hiroaki Asano Yuho Maki Takayuki Muraoka Norimitsu Tanaka Kazuhiko Shien Masashi Furukawa Tomoki Yamatsuji Katsuyuki Kiura Yoshio Naomoto Shinichiro Miyoshi The anti-tumor activity of a newly developed Hsp90 inhibitor, NVP-AUY922 (AUY922), against non-small cell lung cancer (NSCLC) was examined. Twenty-one NSCLC cell lines were used, the somatic alterations of which were characterized. Cell proliferation was analyzed using a modified MTS assay. Expression of the client proteins was assessed using Western blotting. The cell cycle was analyzed using flow cytometry. The IC50 value of AUY922 for the NSCLC cell lines ranged from 5.2 to 860 nM (median, 20.4 nM). Based on previous data, cells with an IC50 of less than 50 nM were classified as sensitive cells and 19 of the 21 NSCLC cell lines were judged to be sensitive. The IC50 of five malignant pleural mesothelioma (MPM) cell lines revealed that the MPM cells had a significantly higher IC50 value (median, 89.2 nM; range, 22.2-24, 100 nM) than the NSCLC cells (p = 0.015). There was significant depletion of both the total and phosphorylated client proteins - EGFR, MET, HERZ and ART - at low drug concentrations (50-100 nM) in drug-sensitive cell lines. Cell-cycle analysis was performed for two sensitive cell lines, H1975 and H838. Following AUY922 treatment, an increase in the sub-G(0)-G(1) cell population, as well as appearance of cleaved PARP expression, indicated the induction of apoptosis. In conclusion, AUY922 was effective against most NSCLC cell lines, independent of the type of known molecular alteration, and appears to be a promising new drug for the treatment of NSCLC. (C) 2011 Elsevier Ireland Ltd. All rights reserved. No potential conflict of interest relevant to this article was reported.

Elsevier Ireland Ltd. Acta Medica Okayama 0169-5002 76 1 2012 Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer 32 38 EN Norimitsu Tanaka Shinichi Toyooka Junichi Soh Takafumi Kubo Hiromasa Yamamoto Yuho Maki Takayuki Muraoka Kazuhiko Shien Masashi Furukawa Tsuyoshi Ueno Hiroaki Asano Kazunori Tsukuda Keisuke Aoe Shinichiro Miyoshi Small-cell lung cancer (SCLC) is an aggressive tumor with a dismal prognosis among primary lung cancers. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family is comprised of tumor-suppressive miRNAs, and its reduced expression by methylation has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the alteration and tumor-suppressive impact of miR-34s in SCLC. The methylation of miR-34a and miR-34b/c was observed in 4 (36%) and 7 (64%) of 11 SCLC cell lines, respectively. Among the 27 SCLC clinical specimens, miR-34a and miR-34b/c were methylated in 4(15%) and 18 (67%), respectively. In contrast, 13 (28%) miR-34a methylated cases and 12 (26%) miR-34b/c methylated cases were found in 47 NSCLC primary tumors. The frequency of miR-34b/c methylation was significantly higher in SCLC than in NSCLC (p < 0.001). The expressions of miR-34s were reduced in methylated cell lines and tumors and restored after 5-aza-2'-deoxycytidine treatment, indicating that methylation was responsible for the reduced expression of miR-34s. Because the frequency of methylation was higher in miR-34b/c, we focused on miR-34b/c for a functional analysis. We examined the effect of miR-34b/c introduction on cell proliferation, migration and invasion. The transfection of miR-34b/c to two SCLC cell lines (H1048 and SBC5) resulted in the significant inhibition of cell growth, migration, and invasion, compared with control transfectants. Our results indicate that the aberrant methylation of miR-34b/c plays an important role in the pathogenesis of SCLC, implying that miR-34b/c may be a useful therapeutic target for SCLC. No potential conflict of interest relevant to this article was reported.

Elsevier Ireland Ltd. Acta Medica Okayama 0169-5002 77 1 2012 Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy 162 167 EN Kazuhiko Shien Shinichi Toyooka Kouichi Ichimura Junichi Soh Masashi Furukawa Yuho Maki Takayuki Muraoka Norimitsu Tanaka Tsuyoshi Ueno Hiroaki Asano Kazunori Tsukuda Masaomi Yamane Takahiro Oto Katsuyuki Kiura Shinichiro Miyoshi The expression of several cancer stem cell (CSC)-related markers has been confirmed in non-small cell lung cancer (NSCLC). The aim of this study was to clarify the clinical role of CSC-related markers in patients with NSCLC undergoing induction chemoradiotherapy (CRT). Fifty patients with clinically diagnosed N2 or N3 NSCLC who underwent induction CRT with docetaxel and cisplatin concurrently with thoracic radiation followed by surgery were examined in this study. The expressions of CSC related markers (CD133, ALDH1, ABCG2, and Bmi-1) were examined using immunohistochemical staining in surgically resected specimens. Among the 50 patients, 20 patients had no residual tumor cells in the resected specimen when examined pathologically; CSC-related marker expressions and their correlation to survival were evaluated in the other 30 patients. After a median follow-up period of 72 months, the 5-year overall survival rate of the patients with CD133-positive or ALDH1-positive specimens was significantly worse than that of the patients with both CD133-negative and ALDH1-negative expressions (449% vs. 90.0%, respectively; P=0.042). In a multivariate analysis. CD133 and ALDH1 negativity (P=0.047) and cN2-3 single station metastasis (P=0.03) were significant independent prognostic factors for prolonged survival. The expressions of CSC-related markers after CRT were significantly correlated with a poor prognosis in patients with NSCLC. The development of therapeutic strategies including adjuvant therapy that take CSC-related marker positivity into consideration is likely to be a key factor in further improvements of the prognosis of patients undergoing trimodality therapy. No potential conflict of interest relevant to this article was reported.