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Background: Advances in minimally invasive surgery and drainage systems have caused earlier chest-tube-removal. This retrospective study aimed to assess the safety of early chest tube removal using the institution's new criteria 6 hours after thoracic surgery., Methods: Elective thoracic surgery patients from 2017 to 2023 were reviewed for meeting or not meeting the newer institutional requirement for early chest tube removal; (I) no air leak detected under the digital drainage device observation; (II) no fluid drainage of ≥100 mL/h; (III) no ≥3 combined risks [male, chronic obstructive pulmonary disease (COPD), body mass index (BMI) of <18.5 kg/m 2 , severe pleural adhesion, upper lobe lobectomy, or left upper division segmentectomy]. The incidence of adverse events, including chest tube replacement, subcutaneous tube placement, and postoperative thoracentesis, were investigated for 1 month postoperatively. Perioperative outcomes and factors involved in conventional chest tube removal were also assessed., Results: Of the 942 patient charts reviewed, 244 (25.9%) met the criteria for chest tube removal within 6 hours postoperatively. This patient group did not experience adverse events. They also demonstrated shorter postoperative hospital stay (4 vs. 6 days, P<0.001), and lesser postoperative complications (7.4% vs. 25.6%, P<0.001) compared to those for whom early chest tube removal was not done. A correlation with thoracotomy, COPD, and steroid and/or immunosuppressant use was observed for patients in the conventional chest tube removal group., Conclusions: Early chest tube removal after 6 postoperative hours was deemed safe for a selected group of patients who met the criteria for early chest tube removal. This study would support the potential expansion of our early removal criteria., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1905/coif). The authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Tracheomediastinal fistula is a rare but life-threatening complication of cancer. We report a case of tracheomediastinal fistula induced by concurrent chemoradiotherapy in limited stage small cell lung cancer. Despite the treatment response, the metastatic paratracheal lymph node increased gradually during concurrent chemoradiotherapy, resulting in the occurrence of tracheomediastinal fistula and mediastinitis. Without any surgical intervention, the patient achieved successful recovery from mediastinitis through antibiotic treatment, although the tracheomediastinal fistula remained open. In this report, we also review previous studies of tracheomediastinal and bronchomediastinal fistulas and summarize the clinical features., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Early chest tube removal should be considered to enhance recovery after surgery. The current study aimed to provide a predictive algorithm for air leak episodes (ALE) and to create a knowledge base for early chest tube removal., Methods: This retrospective study enrolled patients who underwent thoracoscopic anatomical pulmonary resections in our unit. We defined ALE as any airflow ≥ 10 mL/min recorded in the follow-up charts based on the digital thoracic drainage device. Multivariate regression analysis was used to control for preoperative and intraoperative confounding factors. The ALE prediction algorithm was constructed by combining an additive ALE risk-scoring system using the coefficients of the significant predictive factors with the intraoperative water-sealing test., Results: In 485 consecutive thoracoscopic major pulmonary resections, ALE developed in 209 (43%) patients. Statistically significant ALE-associated preoperative factors included male sex, lower body mass index, radiologically evident emphysema, lobectomy, and upper lobe surgery. Significant ALE-associated intraoperative factors were incomplete fissure and pleural adhesion. The ALE risk scoring demonstrated an average area under the receiver operating characteristic curve of 0.72 in the fivefold cross-validation test. The ALE prediction algorithm correctly predicted ALE-absent patients at a negative predictive value of 80%., Conclusions: The algorithm may promote the optimization of the chest tube-dwelling duration by identifying potential ALE-absent patients for accelerated tube removal., (© 2024. The Author(s).)

We report on the synthesis and selective adsorption property of a novel threefold interpenetrated Zr-based metal-organic framework (MOF), [Zr 12 O 8 (OH) 8 (HCOO) 15 (BPT) 3 ] (BPT 3- = [1,1'-biphenyl]-3,4',5-tricarboxylate) (abbreviated as Zr-BPT). This MOF shows a high tolerance to acidic conditions and has permanent pores, the size of which (approx. <5.6 Å) is the smallest ever reported among porous Zr-based MOFs with high acid tolerance. Zr-BPT selectively adsorbs aryl acids due to its strong affinity for them and exhibits separation ability, even between strong acid molecules, such as sulfonic and phosphonic acids. This is the first demonstration of a MOF exhibiting selective adsorption and separation ability for strong acids., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Ingested sharp foreign bodies rarely migrate extraluminally into adjacent organs such as the pharynx, lungs, and liver. Herein, we report a case of fish bone ingestion where the foreign body followed a unique migration trajectory. Computed tomography revealed a fish bone extraluminally located in the aortopulmonary space in the left mediastinum and peri-esophageal pneumomediastinum. Endoscopic examination indicated no injury to the esophageal mucosa but showed mucosal lacerations in the left hypopharynx. Accordingly, we reasoned that the fish bone penetrated the laryngopharynx and then descended in the mediastinum.

Background: Actionable tumor genomic alterations, primarily EGFR mutations, occur in nearly 70% of Japanese advanced nonsquamous non-small cell lung cancer (NSCLC) patients. Standard assessment of tumor tissue includes rapid testing for EGFR mutations, ALK fusions and ROS1 fusions. We conducted a prospective observational study (WJOG13620L) of follow-on next-generation sequencing of circulating tumor DNA (ctDNA) in patients without driver alterations after EGFR testing., Methods: Patients with untreated advanced (Stage IIIB-IV or relapsed) nonsquamous NSCLC without EGFR mutations according to single-plex testing of tumor tissue, were enrolled into this study. Patients with other known driver mutations or who underwent comprehensive genomic profiling were excluded. Plasma was analyzed by Guardant360, and the primary endpoint was the proportion of patients with pathogenic gene alterations in at least one of nine genes., Results: Among the 72 patients enrolled, ALK and ROS1 fusions were tested in 86.1% and 65.2%, respectively. Alterations in pre-defined genes were detected in 21 patients (29.2%; 95% confidence interval: 19.0-41.1, p < 0.001 [one-sided null hypothesis proportion of 10%]), including RET fusion (n = 1) and mutations in KRAS (n = 11), EGFR (n = 5), ERBB2 (n = 3), and BRAF (n = 1). Median time from sample submission to results was 8 days (range, 5-17 days)., Conclusion: Rapid follow-on comprehensive testing of ctDNA should be considered prior to first-line treatment for patients with advanced nonsquamous NSCLC when no alterations are detected after single-plex tissue testing., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Brillouin optical correlation-domain analysis (BOCDA) utilizing low-coherence light sources offers high-resolution distributed strain and temperature sensing. However, conventional BOCDA requires dual-end injection of pump and probe light into the sensing fiber. To overcome this limitation, low-coherence Brillouin optical correlation-domain reflectometry (BOCDR) based on spontaneous Brillouin scattering has emerged, enabling single-end light injection. While a pilot demonstration has shown a spatial resolution of 19 cm, a comparison of its measurement accuracy with standard BOCDR systems is yet to be explored. This study presents a distributed measurement with ~ 3 cm spatial resolution and demonstrates that low-coherence BOCDR eliminates systematic errors caused by direct sinusoidal modulation, offering enhanced measurement precision., (© 2023. Springer Nature Limited.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive lung scarring. IPF-related pulmonary vascular remodeling and pulmonary hypertension (PH) result in a particularly poor prognosis. Objectives: To study the pathogenesis of vascular remodeling in fibrotic lungs and its contribution to progression of fibrosis. Methods: We used an experimental model of lung fibrosis associated with PH by transient overexpression of active TGF-β1 (transforming growth factor-β1). Samples from patients with fibrotic lung diseases were analyzed in depth using immunostaining, gene expression, and gene mutations. Measurements and Main Results: We found a reduction in endothelial cells (ECs) and activation of vascular smooth muscle cells (VSMCs) in fibrotic lungs. Coculturing fibroblasts with VSMCs or ECs from fibrotic lungs induced fibrotic phenotypes in fibroblasts. IPF fibroblasts induced EC death and activation of VSMCs in coculture systems. Decreased concentrations of BMPR2 (bone morphogenic protein receptor 2) and its signaling were observed in ECs and VSMCs from fibrotic lungs in both rats and humans. On fibroblasts treated with media from VSMCs, BMPR2 suppression in VSMCs led to fibrogenic effects. Tacrolimus activated BMPR2 signaling and attenuated fibrosis and PH in rodent lungs. Whole-exome sequencing revealed rare mutations in PH-related genes, including BMPR2 , in patients with IPF undergoing transplantation. A unique missense BMPR2 mutation (p.Q721R) was discovered to have dysfunctional effects on BMPR2 signaling. Conclusions: Endothelial dysfunction and vascular remodeling in PH secondary to pulmonary fibrosis enhance fibrogenesis through impaired BMPR2 signaling. Tacrolimus may have value as a treatment of advanced IPF and concomitant PH. Genetic abnormalities may determine the development of PH in advanced IPF.

Objective: Terror management theory posits that when mortality is salient, individuals attempt to defend their cultural worldviews. Although numerous studies have confirmed this hypothesis, some recent studies have suggested that East Asians do not engage in worldview defense. We conducted a pre-registered experiment with 895 Japanese adults to investigate whether they exhibited worldview defense at an unconscious level. Participants performed the Implicit Association Test using Japanese and Korean surnames as stimuli after being primed with thoughts about mortality., Results: The results revealed that mortality salience had no influence on implicit ethnic bias. These findings support the notion that East Asians do not engage in worldview defense, in accord with recent criticism of the validity of terror management theory. We discuss the limitations and implications of our findings., (© 2023. The Author(s).)

Phytophthora colocasiae is an important pathogen that causes great economic losses in taro production in tropical and subtropical regions, especially in Japan. Understanding the genetic variations in P. colocasiae populations and their transmission patterns in Japan is essential for effective disease control. Here, the genetic diversity of 358 P. colocasiae isolates, including 348 from Japan, 7 from China, and 3 from Indonesia, was assessed using 11 simple sequence repeat (SSR) primer pairs with high polymorphism. The phylogenetic tree of the SSR locus showed that the isolates from Japan could be divided into 14 groups, with group A being the dominant group. Among foreign isolates, only six from mainland China were similar to those from Japan and clustered in groups B and E. Analysis of molecular variance (AMOVA), principal components analysis (PCA), and cluster analysis (K = 3) results revealed a moderate level of genetic diversity, mainly within individuals. Populations showed high heterozygosity, a lack of regional differentiation, and frequent gene flow. Analysis of mating types and ploidy levels revealed that A2 and self-fertile (SF) A2 types and tetraploids were dominant across populations. Explanations and hypotheses for the results can provide more effective strategies for disease management of taro leaf blight.

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease implicated as an independent risk factor for lung cancer. However, optimal treatment for advanced lung cancer with IPF remains to be established. We performed a randomised phase 3 trial (J-SONIC) to assess the efficacy and safety of nintedanib plus chemotherapy (experimental arm) compared with chemotherapy alone (standard-of-care arm) for advanced nonsmall cell lung cancer (NSCLC) with IPF., Methods: Chemotherapy-naïve advanced NSCLC patients with IPF were allocated to receive carboplatin (area under the curve of 6 on day 1) plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) (100 mg·m -2 on days 1, 8 and 15) every 3 weeks with or without nintedanib (150 mg twice daily, daily). The primary end-point was exacerbation-free survival (EFS)., Results: Between May 2017 and February 2020, 243 patients were enrolled. Median EFS was 14.6 months in the nintedanib plus chemotherapy group and 11.8 months in the chemotherapy group (hazard ratio (HR) 0.89, 90% CI 0.67-1.17; p=0.24), whereas median progression-free survival was 6.2 and 5.5 months, respectively (HR 0.68, 95% CI 0.50-0.92). Overall survival was improved by nintedanib in patients with nonsquamous histology (HR 0.61, 95% CI 0.40-0.93) and in those at GAP (gender-age-physiology) stage I (HR 0.61, 95% CI 0.38-0.98). Seven (2.9%) out of 240 patients experienced acute exacerbation during study treatment., Conclusions: The primary end-point of the study was not met. However, carboplatin plus nab-paclitaxel was found to be effective and tolerable in advanced NSCLC patients with IPF. Moreover, nintedanib in combination with such chemotherapy improved overall survival in patients with nonsquamous histology., Competing Interests: Conflict of interest: K. Otsubo has received honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Boehringer Ingelheim, ONO Pharmaceutical, AstraZeneca, Novartis, Merck and Thermo Fisher Scientific. H. Kenmotsu has received grants from Chugai Pharmaceutical, Novartis, Daiichi Sankyo, AstraZeneca and Loxo Oncology; and honoraria from Chugai Pharmaceutical, ONO Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Kyowa Kirin, Bristol-Myers Squibb, MSD, Novartis, Daiichi Sankyo, AstraZeneca, Pfizer and Taiho Pharmaceutical. Y. Minegishi has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, ONO Pharmaceutical, Taiho Pharmaceutical and Chugai Pharmaceutical. H. Horinouchi has received grants from MSD, AbbVie, AstraZeneca, Bristol-Myers Squibb, ONO Pharmaceutical, Merck, Daiichi Sankyo, Janssen, Genomic Health, Chugai Pharmaceutical, Roche and Novartis; honoraria from AstraZeneca, MSD, Eli Lilly, ONO Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Roche, Kyowa Kirin and Novartis; and fees for membership of an advisory board from Roche, AstraZeneca, Eli Lilly, Chugai Pharmaceutical, Roche, ONO Pharmaceutical, Bristol-Myers Squibb and MSD. T. Kato received grants from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck, MSD, Novartis, ONO Pharmaceutical, Pfizer and Regeneron; honoraria from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck, MSD, Novartis, Pfizer and Boehringer Ingelheim; fees for membership of an advisory board from AbbVie, AstraZeneca, Daiichi Sankyo, MSD, Merck, Amgen, Chugai Pharmaceutical, Eli Lilly, Novartis and Nippon Kayaku; and fees for membership of an independent data monitoring committee from Chugai Pharmaceutical, Taiho Pharmaceutical, Takeda and ONO Pharmaceutical. E. Ichihara has received grants from Eli Lilly and MSD; and honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Bristol-Myers Squibb, Novartis, ONO Pharmaceutical, Taiho Pharmaceutical, Takeda and Chugai Pharmaceutical. M. Kondo has received consulting fees from Takeda; and honoraria from Chugai Pharmaceutical, Eli Lilly, Pfizer, AstraZeneca, ONO Pharmaceutical, Bristol-Myers Squibb and MSD. S. Atagi has received grants from AstraZeneca, Eli Lilly, ONO Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, MSD, Chugai Pharmaceutical, Merck and Roche; and honoraria from AstraZeneca, Eli Lilly, ONO Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Hisamitsu Pharmaceutical, MSD, Chugai Pharmaceutical, Kyowa Kirin, Merck, Novartis and Thermo Fisher Scientific. M. Tamiya has received grants and honoraria from Boehringer Ingelheim. S. Ikeda has received grants from AstraZeneca and Chugai Pharmaceutical; and honoraria from Chugai Pharmaceutical, ONO Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Bristol-Myers Squibb, AstraZeneca, Pfizer and Taiho Pharmaceutical. H. Hayashi has received reports grants from AstraZeneca, Astellas, MSD, ONO Pharmaceutical, Boehringer Ingelheim, Novartis, Pfizer, Bristol-Myers Squibb, Eli Lilly, Chugai Pharmaceutical, Daiichi Sankyo, Merck, Takeda, Taiho Pharmaceutical, SymBio Pharmaceuticals, AbbVie, inVentiv Health Japan, ICON Japan, Gritsone Oncology, Parexel, Kissei Pharmaceutical, EPS Corporation, Syneos Health, Pfizer R&D Japan, A2 Healthcare, IQVIA, EP-CRSU, Eisai, CMIC Shift Zero, Kyowa Kirin, Bayer Yakuhin, EPS and Otsuka Pharmaceutical; consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Pfizer, Shanghai Haihe Biopharm, Takeda and Merck; and honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyorin, Merck, Ltd, MSD, Novartis, ONO Pharmaceutical, Taiho Pharmaceutical and Takeda. Y. Kimura has received honoraria from AstraZeneca, Boehringer Ingelheim and Taiho Pharmaceutical. Y. Kondoh has received honoraria from Asahi Kasei Pharma, Shionogi, Boehringer Ingelheim, AstraZeneca, Eisai, Kyorin, Mitsubishi Tanabe Pharma and Novartis; and fees for membership of a data safety monitoring board or an advisory board from Asahi Kasei Pharma, Shionogi, Boehringer Ingelheim, Janssen, Healios, Chugai Pharmaceutical and Taiho Pharmaceutical. M. Kusumoto has received grants from Canon medical systems; and honoraria from AstraZeneca and Daiichi Sankyo. N. Yamamoto has received honoraria from MSD, AstraZeneca, ONO Pharmaceutical, Thermo Fisher Scientific, Daiichi Sankyo, Taiho Pharmaceutical, Takeda, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Novartis, Pfizer, Bristol-Myers Squibb, Nippon Kayaku, GlaxoSmithKline, Sanofi, Hisamitsu Pharmaceutical and Merck; and fees for membership of a data safety monitoring board or an advisory board from MSD, AstraZeneca, ONO Pharmaceutical, Taiho Pharmaceutical, Takeda, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Novartis, Pfizer, Bristol-Myers Squibb, Life Technologies Japan, Nippon Kayaku, Amgen, Guardant Health and Janssen. K. Nakagawa has received grants from Takeda, Taiho Pharmaceutical, SymBio Pharmaceuticals, AbbVie, ICON, Parexel, Kissei Pharmaceutical, EPS, Syneos Health, Pfizer R&D Japan, A2 Healthcare, IQVIA, Eisai, CMIC Shift Zero, Kyowa Kirin, Bayer Yakuhin, Otsuka Pharmaceutical, PRA Health Sciences, Covance, Medical Research Support, Sanofi, PPD-SNBL, Japan Clinical Research Operations, Sysmex, Mochida Pharmaceutical and GlaxoSmithKline; honoraria from AstraZeneca, Chugai Pharmaceutical, Takeda, Roche, MSD, Eli Lilly, Nippon Kayaku, ONO Pharmaceutical, Astellas, Bayer Yakuhin, Merck, Nanzando, Daiichi Sankyo, Novartis, Kyowa Kirin, Medical Mobile Communications, Yomiuri Telecasting Corporation, Nikkei Business Publications, Boehringer Ingelheim, Medicus Shuppan, Taiho Pharmaceutical, Pfizer, AbbVie, Bristol-Myers Squibb, CareNet, Amgen, Medical Review, Yodosha, 3H Clinical Trial, Thermo Fisher Scientific, Hisamitsu Pharmaceutical, Nichi-Iko Pharmaceutical and Kyorin; and payment for expert testimony from Astellas, Takeda, Eli Lilly, Pfizer, Kyorin and ONO Pharmaceutical. Y. Nakanishi has received grants from ONO Pharmaceutical; and honoraria from MSD, ONO Pharmaceutical, AstraZeneca, Pfizer and Boehringer Ingelheim. I. Okamoto has received grants from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, ONO Pharmaceutical, MSD, Eli Lilly, Astellas, Bristol-Myers Squibb, Novartis, Chugai Pharmaceutical, Pfizer and AbbVie; consulting fees from AstraZeneca, Bristol-Myers Squibb and AbbVie; and honoraria from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, ONO Pharmaceutical, MSD, Eli Lilly, Bristol-Myers Squibb, Novartis, Chugai Pharmaceutical and Pfizer. All other authors declare no competing interests., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Many studies have recently reported the association of concomitant medications with the response and survival in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy. However, the clinical impact of statin therapy on the outcome of cancer immunotherapy in patients with NSCLC is poorly understood., Methods: In our database, we retrospectively identified and enrolled 390 patients with advanced or recurrent NSCLC who were treated with anti-programmed cell death-1 (PD-1) monotherapy in clinical practice between January 2016 and December 2019 at 3 medical centers in Japan to examine the clinical impact of statin therapy on the survival of patients with NSCLC receiving anti-PD-1 monotherapy. A propensity score-matched analysis was conducted to minimize the bias arising from the patients' backgrounds., Results: The Kaplan-Meier curves of the propensity score-matched cohort showed that the overall survival (OS), but not the progression-free survival (PFS), was significantly longer in patients receiving statin therapy. However, a Cox regression analysis in the propensity score-matched cohort revealed that statin therapy was not an independent favorable prognostic factor, although it tended to be correlated with a favorable outcome., Conclusions: Statin therapy may be a combination tool for cancer immunotherapy in patients with NSCLC. These findings should be validated in further prospective studies with larger sample sizes., (© 2022. The Author(s).)

Chiral sulfoximines have recently been considered as promising bioisosteres in medicinal chemistry. However, methods for preparing chiral sulfoximines in a stereoselective manner are underdeveloped. Herein, we demonstrate an asymmetric synthesis of chiral sulfoximines through a stereospecific S -alkylation of readily accessible chiral sulfinamides under practical conditions. A key to establishing the practical conditions was the identification of the intermediate structure in our previously reported S -alkylation by X-ray crystallographic analysis.

Metal-organic frameworks (MOFs), made from various metal nodes and organic linkers, provide diverse research platforms for proton conduction. Here, we report on the superprotonic conduction of a Pt dimer based MOF, [Pt 2 (MPC) 4 Cl 2 Co(DMA)(HDMA)·guest] (H 2 MPC, 6-mercaptopyridine-3-carboxylic acid; DMA, dimethylamine). In this framework, a protic dimethylammonium cation (HDMA + ) is trapped inside a pore through hydrogen bonding with an MPC ligand. Proton conductivity and X-ray measurements revealed that trapped HDMA + works as a preinstalled switch, where HDMA + changes its relative position and forms an effective proton-conducting pathway upon hydration, resulting in more than 10 5 times higher proton conductivity in comparison to that of the dehydrated form. Moreover, the anisotropy of single-crystal proton conductivity reveals the proton-conducting direction within the crystal. The present results offer insights into functional materials having a strong coupling of molecular dynamic motion and transport properties., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non-small-cell lung cancer (NSCLC). Next-generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real-world clinical data using the Oncomine Dx Target Test Multi-CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%-83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36-6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Minichromosome maintenance (MCM) protein deregulation is associated with tumor formation, progression and malignant transformation. MCM2 is frequently expressed during premalignant lung cell proliferation and is a sensitive marker for the early detection of pulmonary malignant lesions. The present study was undertaken to investigate whether MCM2 expression is of clinical and prognostic value in patients who have undergone lung adenocarcinoma resection. Between January 2009 and December 2010, 102 consecutive patients underwent complete pulmonary resection (involving lobectomy or more extensive resection) for lung adenocarcinoma at St. Marianna Medical University Hospital (Kanagawa, Japan). Among those, 73 patients, who had a final pathological diagnosis of lung adenocarcinoma measuring ≥10 mm, were enrolled in the present study. High MCM2 expression was found in 35 patients (48.0%). Univariate analysis of the overall survival (OS) revealed that pathological stage and MCM2 expression were significant prognostic factors in lung adenocarcinoma (P<0.001 and P<0.002, respectively). Univariate analysis of the recurrence-free survival (RFS), the significant prognostic factors included pathological stage, EGFR mutation status and MCM2 expression (P<0.001, P<0.034 and P<0.003, respectively). On multivariate survival analysis, high MCM2 expression and pathological stage II-III were identified as independent strong prognostic factors (OS: HR=5.084, 95% CI: 1.715-15.080, P=0.003; RFS: HR=2.761, 95% CI: 1.090-6.998, P=0.032). Therefore, the findings of the present study demonstrated that MCM2 may serve as a potential biomarker and therapeutic target for lung adenocarcinoma., Competing Interests: All authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

Background: In this study we aimed to clarify the PD-L1 positive expression in lung adenocarcinoma, including various adenocarcinoma subtypes paying particular attention to its component., Methods: A total of 307 lung adenocarcinoma patients who underwent lobectomy or segmentectomy, as well as systematic lymph node dissection (ND2a), from February 2008 to March 2020 at our hospital, were enrolled into the study. A final diagnosis of adenocarcinoma was obtained from the resected lung specimens of all 307 patients to determine the histological type, adenocarcinoma subtype, and component of adenocarcinoma by ethics of 5%. PD-L1 was immunohistochemically stained using the murine monoclonal antibody clone 22C3., Results: When PD-L1 expression-positive was defined by tumor proportion score (TPS) ≥1%, the positive cases were 6/33 in adenocarcinoma (Ad) in situ (AIS), 2/26 in minimally invasive Ad (MIA), 12/60 in lepidic predominant Ad (LPA), 44/91 in papillary predominant Ad (PPA), 24/49 in acinar predominant Ad (APA), 23/28 in solid predominant Ad (SPA), 4/7 in micropapillary predominant Ad (MPA), and 0/13 in invasive mucinous Ad (IMA). In the high proportion group (APA, PPA, SPA, and MPA) of PD-L1 expression, SPA was the only subtype which was statistically significant when both PD-L1 expression-positive was defined by TPS ≥ 1% (p < 0.0001) and TPS ≧ 50% (p < 0.0001). We then considered the solid component. We investigated 279 cases of the other subtype group excluding SPA. The group containing a solid component (≥5%) tended to be PD-L1 expression-positive both when defined by TPS ≥1% (p < 0.0001) and TPS ≧50% (p = 0.0049)., Conclusions: The PD-L1 expression tended to be positive when a solid component was confirmed (≥5%) in specimens of lung adenocarcinoma patients., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: The real-world effectiveness of combination treatment with cytotoxic chemotherapy and programmed cell death protein-1 or programmed death-ligand 1 inhibitor for NSCLC, especially for the elderly (aged ≥75 y) or those with poor performance status (≥2), has not been fully elucidated. We investigated the real-world effectiveness and safety of this combination therapy in these populations., Methods: This multicenter retrospective study evaluated patients who are chemo-naïve with advanced NSCLC who received a combination of platinum, pemetrexed, and pembrolizumab between December 2018 and June 2019. This was an updated prespecified secondary analysis with the primary objective of investigating the safety and effectiveness in this cohort., Results: Overall, 299 patients were included. Multivariate analysis identified performance status (0-1) and programmed death-ligand 1 tumor proportion score (≥50%) as significant independent predictors of progression-free survival ( p = 0.007, and p = 0.003, respectively). The incidence of severe adverse events (AEs) was higher in the elderly and those with poor performance status than in their younger and good performance status counterparts. A total of 71 patients developed AEs that led to treatment discontinuation, and AE-related treatment discontinuation occurred at a significantly higher rate in older patients (median [range]) (70 [46-82] y) than in younger patients (68 [31-84] y) ( p <0.001)., Conclusions: Combination treatment with pembrolizumab plus chemotherapy had low real-world effectiveness for poor performance status patients. Severe AEs occurred at a higher rate in the elderly and poor performance status patients, and the AE-related treatment discontinuation rate increased with age. Physicians should be cautious about using this regimen, especially in the elderly and poor performance status patients., (© 2021 The Authors.)

Background: The current study aimed to evaluate the significance of clinicopathological factors, particularly the immunohistochemistry of programed cell death ligand-1 (PD-L1), in eight cases each of pulmonary sarcomatoid carcinoma (PSC) and malignant pleural mesothelioma (MPM) at our hospital., Methods: From January 2004 to December 2020, a total of 16 consecutive patients (eight with PSC and eight with MPM diagnosed via surgical resection or biopsy) were included in this study. After retrospectively reviewing the patient characteristics, the associations between PD-L1 status and age, sex, stage, histological type, and prognosis were investigated., Results: PD-L1-positive staining was observed in four (50%) PSC cases and one (12.5%) MPM case. Among the four PD-L1-positive PSC cases, two showed high PD-L1 expression in the vimentin-positive sarcomatoid compartment. Moreover, among those with PSC, two survived for about 10 years, whereas the others died within 5 years. No clear correlation was found between PD-L1 expression and prognosis. Among the patients with MPM, four survived for more than 2 years, with the longest being 9 years. Among MPM cases who received nivolumab, one patient with positive PD-L1 staining in the sarcomatoid survived, whereas the other with negative PD-L1 staining did not., Conclusion: The present study showed that sarcomatoid carcinoma had a higher PD-L1 expression compared to non-small-cell lung cancer and that both PSC and MPM tended to exhibit PD-L1 positivity in the sarcomatoid compartment. Moreover, while immune checkpoint inhibitors may somewhat prolong the prognosis of both tumors, further studies with a larger cohort are necessary to confirm our results., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Although the risk factors for coronavirus disease 2019 (COVID-19) mortality have been identified, there is limited information about the risk factors for disease progression after hospitalization among Japanese patients with COVID-19 exhibiting no or mild symptoms., Methods: All 302 consecutive patients who were admitted to our institutions and diagnosed with COVID-19 between March and December 2020 were retrospectively assessed. Ultimately, 210 adult patients exhibiting no or mild symptoms on admission were included in the analysis. They were categorized into the stable (no oxygen needed) and worsened (oxygen needed) groups, and their characteristics and laboratory data were compared., Results: Among 210 patients, 49 progressed to a severe disease stage, whereas 161 did not. The mean patient age was 52.14 years, and 126 (60.0%) patients were male. The mean body mass index (BMI) was 23.0 kg/m 2 , and 71 patients were overweight (BMI ≥ 25 kg/m 2 ). Multivariate logistic analysis showed that old age, overweight, diabetes mellitus (DM), and high serum ferritin levels were independent risk factors for disease progression., Conclusions: Clinicians should closely observe patients with COVID-19, especially those with risk factors such as old age, overweight, DM, and high serum ferritin levels, regardless of whether they have no or mild symptoms., (© 2021. The Author(s).)

Background: This study aimed to determine the relationship of programmed death-ligand 1 (PD-L1) expression and standardized uptake values in fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) with prognosis in non-small-cell lung cancer (NSCLC)., Methods: We retrospectively analyzed 328 NSCLC patients who underwent lobectomy/segmentectomy with lymph node dissection. PD-L1 expression was detected by immunohistochemically stained using the murine monoclonal antibody clone 22C3. The preoperative maximum standardized uptake value (SUV max ) of FDG-PET/CT at the primary lesion; pathological factors including histological type, microscopic lymphatic, venous, and pleural invasion; and lymph node metastases in resected specimens was determined. Significant prognostic clinicopathologic factors were analyzed by univariate and multivariate analyses., Results: PD-L1 expression was higher in men, smokers, squamous cell carcinoma, advanced pathologic stages, positive venous invasion, positive pleural invasion, and high preoperative SUV max (≥3). Postoperative survival analysis showed that both PD-L1 expression and preoperative SUV max were significantly negative prognostic factors in univariate analysis for overall survival (OS) ( P = 0.0123 and P < 0.0001) and relapse-free survival (RFS) ( P = 0.0012 and P < 0.0001). Kaplan-Meier survival curves showed that the OS and RFS were the best in patients with negative PD-L1 expression and SUV max < 3, intermediate in patients with positive PD-L1 expression and SUV max < 3 and those with negative PD-L1 expression and SUV max ≥ 3, and poor in patients with positive PD-L1 expression and SUV max ≥ 3., Conclusion: Combining PD-L1 expression and preoperative FDG-PET/CT SUV max in primary tumor might help in accurate prediction of postoperative prognosis in NSCLC patients.

Phytophthora species cause destructive plant diseases worldwide. All Phytophthora species, except for one, are listed as plant quarantine organisms in Japan. The exception, Phytophthora nicotianae is considered to be a domestic species. The injurious pests Phytophthora ramorum, Phytophthora lateralis, and Phytophthora kernoviae are invasive pathogens that cause tree mortality worldwide, mainly in the United States and the United Kingdom. To effectively control Phytophthora diseases, we established detection methods that utilize the loop-mediated isothermal amplification (LAMP) of the genus Phytophthora and the four species P. ramorum, P. lateralis, P. kernoviae, and P. nicotianae. LAMP primers for P. ramorum, P. lateralis, and P. kernoviae were newly designed in the present study. Our multiplex assay includes the detection of plant DNA as an internal control. When the optimum ratio between plant and pathogen primers was used in multiplex LAMP assays, 1 pg to 100 fg of pathogen DNA was detected with similar sensitivity to that in simplex LAMP assays. The detection of plant DNA in the absence of pathogens enables us to check for and avoid undesirable negative results caused by enzyme inactivation or the contamination of amplification inhibitors from plant tissues. The total time from sample collection to results is approximately 120‍ ‍min, and, thus, our multiplex LAMP assay may be used as an accurate and time-saving detection method for Phytophthora pathogens.

Background: Mps one binder kinase activator 1 (MOB1) is a core component of the Hippo signaling pathway and has been implicated as a tumor suppressor. Here, we evaluated the possible relationship of MOB1 expression in non-small cell lung cancer (NSCLC) to prognosis., Methods: We retrospectively analyzed 205 lung adenocarcinoma patients treated at Kyushu University Hospital between November 2007 and October 2012. MOB1 expression in tumor cells of surgical specimens was evaluated by immunohistochemistry. Invasive activity of NSCLC cell lines in vitro was measured with a transwell assay., Results: Expression of MOB1 was classified as high in 105 of the 205 (51.2%) tumor specimens, and such high expression was significantly associated with poor disease-free survival (P = 0.0161). Among the various clinicopathologic parameters examined, high MOB1 expression was significantly associated only with intratumoral vascular invasion (P = 0.0005). Multivariate analysis also identified high MOB1 expression as a significant independent risk factor for disease-free survival (P = 0.0319). The invasiveness of H1299 cells in vitro was increased or attenuated by overexpression or knockdown of MOB1, respectively., Conclusions: Our results suggest that MOB1 might promote early recurrence of NSCLC by increasing vascular invasion by tumor cells., Key Points: SIGNIFICANT FINDINGS OF THE STUDY: We found that high MOB1 expression in surgical specimens of lung adenocarcinoma was associated with poor disease-free survival and with intratumoral vascular invasion. MOB1 expression also promoted the invasiveness of NSCLC cells in vitro., What This Study Adds: Our results thus suggest that high MOB1 expression is a risk factor for early postoperative recurrence in lung adenocarcinoma., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Phytophthora is an oomycete genus with worldwide distribution, and many of its species cause destructive diseases. In Japan, Phytophthora species are listed as quarantine organisms with the exception of Phytophthora nicotianae . For effective quarantine control, we designed a Phytophthora genus-specific loop-mediated isothermal amplification (LAMP) primer set and a P. nicotianae species-specific quenching probe (QProbe) to establish a simultaneous LAMP-based detection method. We confirmed the specificity of the genus-specific primers, and all 161 taxa were detected. No other species in the closely related genera Pythium and Phytopythium gave positive results with the exception of two species, Phytopythium delawarense and Phytopythium fagopyri . These two species gave inconsistent results. We used annealing curve analysis with the QProbe to demonstrate that P. nicotianae could be distinguished from other species. DNA from inoculated and naturally infected plants was extracted using a time-saving extraction kit and subjected to the simultaneous detection method. We confirmed that all Phytophthora DNAs in the plant samples were detected, and P. nicotianae was specifically identified. This simultaneous detection method will make quarantine inspections faster and easier.

Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes and are becoming a standard treatment for many cancer types. However, these drugs also induce immune-related adverse events, among which interstitial lung disease (ILD) is potentially fatal. The underlying mechanism of ILD induction by ICIs is largely unknown. With the use of flow cytometry, we determined the expression levels of the immune-checkpoint proteins PD-1, TIM-3, TIGIT, LAG-3 and PD-L1 in T cells of bronchoalveolar lavage fluid (BALF) from patients with ICI-related ILD and compared them with those for patients with sarcoidosis or with ILD related to connective tissue disease or cytotoxic drug use. The proportions of CD8+ T cells positive for both PD-1 and TIM-3 or for TIGIT in BALF were significantly higher for ICI-related ILD patients than for those with other types of ILD. A prominent increase in the proportion of PD-1+PD-L1+ cells among CD8+ T cells was also apparent in BALF of a patient with a fatal case of ICI-related ILD, and the proportion of such cells was positively correlated with the grade of ICI-related ILD. Our data reveal the immune-checkpoint profiles of T cells in ICI-related ILD and may provide mechanistic insight into the development of this adverse event., (© The Japanese Society for Immunology. 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The pathogenesis of lung cancer associated with idiopathic pulmonary fibrosis (IPF) has remained largely uncharacterized. To provide insight into this condition, we undertook genomic profiling of IPF-associated lung cancer as well as of adjacent fibrosing lung tissue in surgical specimens. Isolated DNA and RNA from 17 IPF-associated non-small cell lung cancer and 15 paired fibrosing lung tissue specimens were analyzed by next-generation sequencing with a panel that targets 161 cancer-related genes. Somatic genetic alterations were frequently identified in TP53 (n = 6, 35.3%) and PIK3CA (n = 5, 29.4%) genes in tumor samples as well as in EGFR (n = 7, 46.7%), PIK3CA (n = 5, 33.3%), ERBB3 (n = 4, 26.7%), and KDR (n = 4, 26.7%) in IPF samples. Genes related to the RAS-RAF signaling pathway were also frequently altered in tumor (n = 7, 41.2%) and IPF (n = 3, 20.0%) samples. The number of somatic alterations identified in IPF samples was almost as large as that detected in paired tumor samples (81 vs 90, respectively). However, only 6 of the 81 somatic alterations detected in IPF samples overlapped with those in paired tumor samples. The accumulation of somatic mutations was thus apparent in IPF tissue of patients with IPF-associated lung cancer, and the RAS-RAF pathway was implicated in lung tumorigenesis. The finding that somatic alterations were not frequently shared between tumor and corresponding IPF tissue indicates that IPF-associated lung cancer does not develop through the stepwise accumulation of somatic alterations in IPF., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Autophagy is an intracellular process that regulates the degradation of cytosolic proteins and organelles. Dying cells often accumulate autophagosomes. However, the mechanisms by which necroptotic stimulation induces autophagosomes are not defined. Here, we demonstrate that the activation of necroptosis with TNF-α plus the cell-permeable pan-caspase inhibitor Z-VAD induces LC3-II and LC3 puncta, markers of autophagosomes, via the receptor-interacting protein kinase 3 (RIPK3) in intestinal epithelial cells. Surprisingly, necroptotic stimulation reduces autophagic activity, as evidenced by enlarged puncta of the autophagic substrate SQSTM1/p62 and its increased colocalization with LC3. However, necroptotic stimulation does not induce the lysosomal-associated membrane protein 1 (LAMP1) nor syntaxin 17, which mediates autophagosome-lysosome fusion, to colocalize with LC3. These data indicate that necroptosis attenuates autophagic flux before the lysosome fusion step. Our findings may provide insights into human diseases involving necroptosis., (© 2020 Federation of European Biochemical Societies.)

Water confined within one-dimensional (1D) hydrophobic nanochannels has attracted significant interest due to its unusual structure and dynamic properties. As a representative system, water-filled carbon nanotubes (CNTs) are generally studied, but direct observation of the crystal structure and proton transport is difficult for CNTs due to their poor crystallinity and high electron conduction. Here, we report the direct observation of a unique water-cluster structure and high proton conduction realized in a metal-organic nanotube, [Pt(dach)(bpy)Br] 4 (SO 4 ) 4 ·32H 2 O (dach: (1R, 2R)-(-)-1,2-diaminocyclohexane; bpy: 4,4'-bipyridine). In the crystalline state, a hydrogen-bonded ice nanotube composed of water tetramers and octamers is found within the hydrophobic nanochannel. Single-crystal impedance measurements along the channel direction reveal a high proton conduction of 10 -2 Scm -1 . Moreover, fast proton diffusion and continuous liquid-to-solid transition are confirmed using solid-state 1 H-NMR measurements. Our study provides valuable insight into the structural and dynamical properties of confined water within 1D hydrophobic nanochannels.

Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP-Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first- or second-generation EGFR-TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP-Seq successfully. Original activating EGFR mutations were detected in 23 patients, with the remaining patient showing MET amplification. With regard to known mechanisms of EGFR-TKI resistance, the T790M mutation of EGFR was detected in 17 of the 24 patients, MET amplification in 9 patients (6 of whom also harbored T790M), ERBB2 amplification in 2 patients (1 of whom also harbored T790M), and EGFR amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first- or second-generation EGFR-TKIs. Patients positive for the T790M mutation of EGFR were also found to constitute a molecularly heterogeneous population. KEY POINTS: CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations.The T790M mutation of EGFR is associated with amplification of MET , ERBB2 , or EGFR in NSCLC patients resistant to EGFR-TKIs.T790M-positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first-generation or second-generation EGFR-TKIs., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Although immune-related adverse events (irAEs) of treatment with immune-checkpoint inhibitors may be due to cellular immunity mediated by T lymphocytes, their pathogenesis has remained unknown. Here we collected bronchoalveolar lavage fluid (BALF) from a cancer patient with nivolumab-induced pneumonitis and isolated mononuclear cells for next-generation sequencing of the complementarity-determining region of the T cell receptor (TCR) β chain. Mononuclear cells in peritumoral pleural effusion isolated from the patient were similarly analyzed, and the results obtained for the two specimens were compared. A substantial number of TCRβ clones in BALF were also identified among lymphocytes in the peritumoral pleural effusion. Such a correlation was not apparent between TCRβ clones in BALF and those in peripheral blood. Moreover, many tumor-associated clones with a read frequency of ≥0.10% were also present in BALF. Our data suggest that irAEs might be induced by drug-activated lymphocytes originating from tumor tissue. Deep sequencing will thus be indispensable for investigations of the immune-based pathogenesis of, and the development of optimal treatments for, irAEs., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Ubiquitin chains are formed with 8 structurally and functionally distinct polymers. However, the functions of each polyubiquitin remain poorly understood. We developed a polyubiquitin-mediated fluorescence complementation (PolyUb-FC) assay using Kusabira Green (KG) as a split fluorescent protein. The PolyUb-FC assay has the advantage that monoubiquitination is nonfluorescent and chain-specific polyubiquitination can be directly visualized in living cells without using antibodies. We applied the PolyUb-FC assay to examine K33-linked polyubiquitin. We demonstrated that SQSTM1/p62 puncta colocalized with K33-linked polyubiquitin and this interaction was modulated by the ZRANB1/TRABID-K29 and -K33 linkage-specific deubiquitinase (DUB). We further showed that the colocalization of K33-linked polyubiquitin and MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) puncta was impaired by SQSTM1/p62 deficiency. Taken together, these findings provide novel insights into how atypical polyubiquitin is recruited by SQSTM1/p62. Finally, we developed an inducible-PolyUb-FC system for visualizing chain-specific polyubiquitin. The PolyUb-FC will be a useful tool for analyzing the dynamics of atypical polyubiquitin chain generation.

Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(-) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin-pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin-pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objectives: Activation of the epidermal growth factor receptor (EGFR) results from receptor homodimerization and autophosphorylation and confers sensitivity to tyrosine kinase inhibitors in some tumors. However, the visual detection and quantitation of activated EGFR in the clinical setting has not been established., Materials and Methods: A proximity ligation assay (PLA) was applied to detect EGFR homodimers in non-small cell lung cancer (NSCLC) cell lines and tissue specimens., Results: PLA signals corresponding to EGFR homodimers were higher in NSCLC cell lines and tissue specimens positive for activating EGFR mutations than in those wild type (WT) for EGFR . Stimulation with EGF in NSCLC cells WT for EGFR or forced overexpression of EGFR in Ba/F3 cells resulted in marked EGFR homodimerization. The extent of EGFR homodimerization appeared related to that of EGFR autophosphorylation in NSCLC cells WT for EGFR ., Conclusion: PLA may provide a new tool for detection and quantitation of EGFR homodimers in NSCLC and other tumors., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

The T790M secondary mutation of the epidermal growth factor receptor (EGFR) gene accounts for 50% to 60% of cases of resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. The prevalence of T790M in EGFR mutation-positive patients who acquire resistance to the irreversible, second-generation EGFR-TKI afatinib has remained unclear, however. We here determined the frequency of T790M acquisition at diagnosis of progressive disease in patients with EGFR -mutated non-small cell lung cancer (NSCLC) treated with afatinib as first-line EGFR-TKI. Among 56 enrolled patients, 37 individuals underwent molecular analysis at rebiopsy. Of these 37 patients, 16 individuals (43.2%) had acquired T790M, including 11/21 patients (52.4%) with an exon 19 deletion of EGFR and 5/13 patients (38.5%) with L858R. None of three patients with an uncommon EGFR mutation harbored T790M. T790M was detected in 14/29 patients (48.3%) with a partial response to afatinib, 1/4 patients (25%) with stable disease, and 1/4 patients (25%) with progressive disease as the best response. Median progression-free survival after initiation of afatinib treatment was significantly ( P = 0.043) longer in patients who acquired T790M (11.9 months; 95% confidence interval, 8.7-15.1) than in those who did not (4.5 months; 95% confidence interval, 2.0-7.0). Together, our results show that EGFR -mutated NSCLC patients treated with afatinib as first-line EGFR-TKI acquire T790M at the time of progression at a frequency similar to that for patients treated with gefitinib or erlotinib. They further underline the importance of rebiopsy for detection of T790M in afatinib-treated patients., Competing Interests: CONFLICTS OF INTERESTS Kentaro Tanaka has received honoraria from Nippon Boehringer Ingelheim. Kaname Nosaki has received research funding from MSD and Novartis Pharma as well as honoraria from AstraZeneca, Chugai, Eli Lilly, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Nippon Kayaku, ONO, and MSD. Kohei Otsubo has received honoraria from Nippon Boehringer Ingelheim. Hiroshi Wataya has received honoraria from Nippon Boehringer Ingelheim. Taishi Harada has received honoraria from Nippon Boehringer Ingelheim. Yoichi Nakanishi has received research funding and honoraria from Nippon Boehringer Ingelheim. Isamu Okamoto has received research funding and honoraria from Nippon Boehringer Ingelheim.

Ubiquitination is a crucial post-translational modification; however, the functions of ubiquitin-coding genes remain unclear. UBA52 encodes a fusion protein comprising ubiquitin at the N-terminus and ribosomal protein L40 (RPL40) at the C-terminus. Here we showed that Uba52-deficient mice die during embryogenesis. UBA52-deficient cells exhibited normal levels of total ubiquitin. However, UBA52-deficient cells displayed decreased protein synthesis and cell-cycle arrest. The overexpression of UBA52 ameliorated the cell-cycle arrest caused by UBA52 deficiency. Surprisingly, RPL40 expression itself is insufficient to regulate cyclin D expression. The cleavage of RPL40 from UBA52 was required for maintaining protein synthesis. Furthermore, we found that RPL40 formed a ribosomal complex with ubiquitin cleaved from UBA52. UBA52 supplies RPL40 and ubiquitin simultaneously to the ribosome. Our study demonstrated that the ubiquitin-coding gene UBA52 is not just an ubiquitin supplier to the ubiquitin pool but is also a regulator of the ribosomal protein complex. These findings provide novel insights into the regulation of ubiquitin-dependent translation and embryonic development.

A cardiac mass (3 × 5 × 3 cm) was detected at the base between the right auricular wall and right vena cava of a slaughtered 6-month-old female mixed-breed pig during a meat inspection. The tumor comprised infiltrative prominent interweaving fascicles of Schwann cells with Verocay bodies. Moreover, the ganglion cells were scattered or aggregated throughout the neoplastic tissue. The ganglion and Schwann cells had neither cellular atypism nor mitosis. On the basis of the bearing site as well as the morphological and immunohistochemical features, this is the first case of a cardiac ganglioneuroma in a pig.