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Background: In EGFR mutation-positive NSCLC, dual EGFR/VEGFR inhibition compared to EGFR alone increases anti-tumor efficacy. The Phase III RELAY trial demonstrated superior PFS for ramucirumab plus erlotinib (RAM + ERL) over placebo plus erlotinib (PBO + ERL) (HR 0.591 [95% CI 0.461–0.760], p

Background: In Japan, there are no studies comparing endotracheal intubation performed by emergency medical technicians (EMTs) during out-of-hospital cardiac arrest (OHCA) using a Macintosh laryngoscope and a video laryngoscope. Objective: The purpose of this study was to compare the success rate, complication rate, return of spontaneous circulation (ROSC), neurological prognosis (CPC1-2) and regional differences between Video laryngoscope (VL) and Macintosh laryngoscope (ML) for OHCA patients. Method: This study is a retrospective cohort study using 10,067 OHCA data extracted from the national Utstein Form and emergency medical transport data. The primary endpoint was the success rate of tracheal intubation and the complication rate and the secondary endpoints were the incidence of ROSC and CPC1-2. Results: A total of 885 tracheal Intubated OHCA patients were enrolled in this study. The success rate was 94.1% (490/521) in the VL group and 89.3% (325/364) in the ML group (RR, 1.05; 95%CI, 1.01–1.10, P = 0.01), the VL group shows significantly higher success rate than that of the ML group. In the complication rates, oesophageal intubation occurred in 0.2% (1/521) of in the VL group and in 6.0% (22/364) in the ML group, Indicating significantly higher complication rates in the ML group compared with the VL group (RR, 1.06; 95% CI, 1.03–1.09, P

Objectives: We aimed to estimate the relationship between the promotion of bystander cardiopulmonary resuscitation (CPR) with dispatcher-assistance over time and good cerebral function after out-of-hospital cardiac arrests (OHCAs). Methods: This was a retrospective observational study, using a nationwide OHCA database in Japan. The eligible 267,193 witnessed cardiogenic OHCA patients between 2005 and 2016 were analysed. Multivariable logistic regression models were performed to estimate the effect of dispatcher-assisted bystander CPR per year. In addition, we calculated the number of patients with good cerebral function, which was attributed to dispatcher-assisted bystander CPR. Results: Dispatcher-assisted bystander CPR was performed to 84,076 (31.5%), those without dispatcher-assistance were 48,389 (18.1%), and non-bystander CPR were 134,728 (50.4%). The adjusted odds ratio (AOR) of dispatcher-assisted bystander CPR vs. non-bystander CPR was significantly related to good cerebral function, regardless of the year (AOR, 1.47, 1.62; 95%CI, 1.19-1.80, 1.42-1.85, 2005 and 2016, respectively). The association of dispatcher-assisted bystander CPR with good cerebral function tended to increase (AOR, 1.11, 2.97; 95%CI, 0.99-1.24, 2.69-3.28, 2006 and 2016, based on 2005, respectively). Estimating the number of patients with good cerebral function who attributed to dispatcher-assisted bystander CPR was a significant increase from 41 in 2005 to 580 in 2016 (p < .0001, r = 0.98). Furthermore, chest compression consistently contributed to higher number of patients with good cerebral function than that with a combination of chest compression and shock with public-access-defibrillation. Conclusion: We found that the increased dispatcher-assisted bystander CPR rate was related to good cerebral function at 1-month post OHCA. Chest compression without public-access-defibrillation was most helpful to that number, explaining the effects of dispatcher-assistance and sustaining improvement.

Double electron capture is a rare nuclear decay process in which two orbital electrons are captured simultaneously in the same nucleus. Measurement of its two-neutrino mode would provide a new reference for the calculation of nuclear matrix elements whereas observation of its neutrinoless mode would demonstrate lepton number violation. A search for two-neutrino double electron capture on 124Xe is performed using 165.9 days of data collected with the XMASS-I liquid xenon detector. No significant excess above background was observed and we set a lower limit on the half-life as 4.7×1021 years at 90% confidence level. The obtained limit has ruled out parts of some theoretical expectations. We obtain a lower limit on the 126Xe two-neutrino double electron capture half-life of 4.3×1021 years at 90% confidence level as well.

Objectives: The purpose of this study was to identify a relationship between the background environment, bystander and emergency medical services intervention, and favourable neurological outcomes (CPC1-2) one-month after out-of-hospital cardiac arrest (OHCA) occurred at Tokyo train and subway stations. Methods: This retrospective observational study used OHCA data between 2014 and 2018 that occurred at train stations in Tokyo. The eligible 954 patients were analysed for correlation between background, time frame, and location. Multivariable logistic regression models were used to estimate factors associated with CPC1-2 in patients with cardiogenic OHCA. Results: A total of 886 OHCA cases, cardiogenic (n=562) and non-cardiogenic (n=324), met the inclusion criteria. Of the cardiogenic cases, 71.9% occurred at the platform and on-a-train. One-month CPC1-2 was achieved in 32.0% of cardiogenic OHCAs, which included 47.3% during morning rush hour, 24.7% during daytime hours, 40.2% during evening rush hour, and 20.5% during night-time/early morning hours. CPC1-2 had significant correlation with morning rush hour (adjusted odds ratio [AOR],4.52; 95% confidence interval [CI], 1.09–18.78), evening rush hour (AOR, 6.85; 95% CI, 1.51–31.15), public access defibrillation (AOR, 5.19; 95% CI, 1.38–19.51), and ventricular fibrillation or pulseless ventricular tachycardia (AOR, 7.56; 95% CI, 1.35–42.43). Conclusion: A total of 71.9% of cardiogenic OHCAs occurred at platforms and on trains. To improve neurological outcomes of OHCAs at stations, AED installations on train platforms are necessary. Additionally, using artificial intelligence-based platform monitoring for early detection of OHCAs and offering CPR training are required.

Hexafluoropropylene oxide dimer acid (HFPO-DA), which belongs to the class of perfluoroalkyl ether carboxylic acid (PFECA), is a new alternative to perfluorooctanoic acid (PFOA). However, whether HFPO-DA is a safer alternative to PFOA in neonates remains unclear. In this study, we evaluated neonatal hepatic toxicity on postnatal days 9-10 by orally exposing pregnant CD-1 mice to 0.3 or 3.0 mg/kg/day (low or high doses) of HFPO-DA or PFOA from gestation days 15-17. The results showed that exposure of pregnant mice to HFPO-DA and PFOA induced similar phenotypic effects, including significant decreases in neonatal body weight (BW) and significant increases in liver weight relative to BW in the high-dose. Notably, HFPO-DA exposure significantly decreased in neonatal BW in the low-dose group, whereas PFOA did not. Comprehensive gene expression analysis revealed significant alterations in 408 and 1402 differentially expressed genes (DEGs) in the liver of neonates from the low- and high-dose HFPO-DA groups, respectively, while PFOA significantly altered 0 and 292 DEGs in the corresponding groups. Gene set enrichment analysis indicated that the DEGs induced by HFPO-DA and PFOA were enriched in pathway related to "PPAR signaling", "fatty acid metabolism", and "biological oxidations". In addition, transactivation assays revealed that mouse (m)PPARα and mPPARγ activity of HFPO-DA exceeds that of PFOA and molecular docking simulations analysis predicted that the binding conformation differ between PFOA and HFPO-DA. Overall, our findings demonstrate that HFPO-DA consistently affected neonatal phenotypes, liver gene expression and the molecular initiating events involving PPARα/γ, at lower concentrations than PFOA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Introduction: RELAY, a global double-blind, placebo-controlled phase 3 study (NCT02411448) found statistically significant improvement in progression-free survival (primary end point) for ramucirumab (RAM) plus erlotinib (ERL) (RAM + ERL) in patients with untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59, 95% confidence interval [CI]: 0.46-0.76, p < 0.0001; median progression-free survival: 19.4 versus 12.4 mo). Here, we report the final overall survival (OS; secondary end point) outcomes for the intention-to-treat population., Methods: Between January 2016 and February 2018, 449 eligible patients with an EGFR exon 19del or L858R mutation and no central nervous system metastases were randomized (1:1) to ERL (150 mg/day) with RAM (10 mg/kg every two weeks, N = 224) or placebo (N = 225)., Results: At data cutoff, 297 deaths were reported (overall event rate = 66%), with a median follow-up of 45.1 months (interquartile range: 26.7-71.2), an OS HR of 0.98 (95% CI: 0.78-1.24, p = 0.864), and median OS of 51.1 months (RAM + ERL) and 46.0 months (placebo + ERL). Outcomes in subsets of patients with poor prognosis (L858R or TP53 co-mutation) suggest a directional improvement in OS (L858R: HR = 0.87, 95% CI: 0.62-1.22; exon 19del: HR = 1.13, 95% CI: 0.83-1.55; TP53 co-mutation: HR = 0.83, 95% CI: 0.58-1.19; TP53-wild-type: HR = 1.22, 95% CI: 0.87-1.72). Treatment-emergent T790M rates were similar between arms. Over 80% of patients received post-study discontinuation therapy (>50% received osimertinib in comparable numbers between arms). The safety profile for RAM + ERL was consistent with previous reports with no increased toxicity over time or new safety signals observed., Conclusion: In RELAY, OS was not significantly improved with similar long OS durations in both treatment arms., Clinical Trial Information: ClinicalTrials.gov Identifier: NCT02411448., Competing Interests: Disclosure Dr. Nakagawa reports funding from Amgen, Ascent Development Services, Astellas Pharma, AstraZeneca, Bayer Yakuhin, BMS, Chugai, CMIC, Covance Japan, Daiichi Sankyo, Eisai, Eli Lilly Japan, EPS Corporation, EPS International, EP-CRSU, GSK, IQVIA Services JAPAN, Janssen, Japan Clinical Research Operations, Kobayashi, MRS, Merck Biopharma, Mebix, Mochida, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis Pharma, Otsuka, Pfizer Japan, Pfizer R&D Japan G.K., Pra Healthsciences, Sanofi, Shionogi &, SRL, Syneos Health Clinical, Taiho, Takeda; consulting fees from Eli Lilly Japan, Ono; honoraria from Amgen, AstraZeneca, Bayer Yakuhin, BMS, Chugai, CMIC ShiftZero, CMIC, Daiichi Sankyo, Eli Lilly Japan, Global Health Consulting Japan, Hisamitsu, Incyte biosciences Japan, Japan Clinical Research Operations, Janssen Pharmaceutical Factori, Life Technologies Japan, M3, Medical Mobile Communications, Merck Biopharma, MSD, Neo Communication, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono, Pfizer Japan, Takeda, Taiho, Taiyo Pharma, The YomiuriShimbun, Yodosha; and patents planned with Daiichi Sankyo. Dr. Garon reports funding from ABL-Bio, Arrivent, AstraZeneca, BridgeBio, BMS, Daiichi Sanko, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck; Mirati Novartis, Prelude, Regeneron, Synthekine, TILT Biotherapeutics; consulting or advisory role for Abbvie, Arcus, AstraZeneca, Arrivent, Atreca, Black Diamond Therapeutics, BridgeBio, BMS, Daiichi Sankyo, EMD Serono, Eli Lilly, Gilead, GSK, Hookipa, I-Mab, LianBio, Merck, Merus, Novartis, Nuvalent, Personalis, Pfizer, Regeneron, Sanofi, Seagan, Sensei, Sumitomo, Strata, Summit, Synthekine, Xilio, Zymeworks; travel support from A2 Bio, Novartis; Sponsored Independent Medical Education for Daiichi Sankyo; and is on the scientific advisory board for LUNGevity. Dr. Seto reports honoraria from Amgen, AstraZeneca, BMS, Chugai, Eli Lilly Japan, MSD, Novartis Pharma, Ono, Pfzer Japan, Takeda, and Towa; and is an employee of Precision Medicine Asia. Dr. Nishio reports honoraria from Abbvie, AstraZeneca, Boehringer Ingelheim, BMS, Chugai, Daiichi Sankyo Healthcare, Eli Lilly, Janssen, Merck, MSD, Nippon Kayaku, Novartis Pharma, Ono, Pfizer, Taiho, Takeda. Dr. Paz-Ares reports institutional funding from AstraZeneca, BMS, MSD, Pfizer, and PharmaMar; travel support from AstraZeneca, BMS, Eli Lilly, Pfizer, and Roche, MSD; honoraria from Abbvie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BMS, Celgene, Gilead, Eli Lilly, Merck Serono, Merck & Co., Inc., S.A., MSD, Mirati, Novartis, Pfizer, PharmaMar, Roche/Genentech, Sanofi, Takeda; an advisory board member for Altum Sequencing and Stab therapeutics, and leadership roles at Altum Sequencing and Stab therapeutics. Dr. Chiu reports honoraria from AstraZeneca, Boehringer Ingelheim, BMS, Chugai, Eli Lilly, Janssen, Merck KGaA, MSD, Novartis, Ono, Pfizer, Roche, and Takeda. Dr. Park reports funding from AstraZeneca, MSD; consulting or advisory role for AstraZeneca, Daiichi Sankyo, Eli Lilly, GENIUS, IMBDx, Janssen Research & Development, Merus, Zymeworks; honoraria for BeiGene, Incyte, MSD; Scientific Advisory Board: IMBDx, GENINUS, ABION. Dr. Novello reports consulting fees from Novartis and Sanofi, honoraria from Amgen, AstraZeneca, MSD, Novartis, Pfizer, Roche, Takeda, Thermofisher, and Sanofi; and is an advisory board member for AstraZeneca, MSD, Pfizer and Roche. Dr. Nadal reports research funding from Billerica, BMS, EMD Serono Research & Development Institute, Pfizer, Roche, and MA, USA, an affiliate of Merck; consulting fees from Amgen, AstraZeneca, Billerica, Boehringer Ingelheim, BMS, Daiichi Sankyo, Eli Lilly, EMD Serono Research & Development Institute, Genmab, Janssen, Johnson and Johnson, MA, MSD, Pfizer, Pierre Fabre, Qiagen, Regeneron, Roche, Sanofi, Takeda, and MA, USA, an affiliate of Merck; travel support from AstraZeneca, MSD, Pfizer, Roche and Takeda; honoraria for lectures from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Illumina, Janssen, Johnson and Johnson, MSD, Pfizer, Qiagen, Roche, Sanofi, and Takeda; fees for participation in data safety meetings from Apollomics, Transgene and Roche. Dr. Nishino reports funding from Ono, Taiho, MSD, Abbvie, Daiichi Sankyo, Amgen, Eisai Co, Sanofi K.K., Janssen K.K., Novartis, Pfizer, Eli Lilly Japan, Merck Biopharma Co., Ltd., Takeda, Chugai, AstraZeneca; Speakers bureau for AstraZeneca, Chugai, Nippon Boehringer Ingelheim, Eli Lilly Japan, Roche Diagnostics, Novartis, Pfizer, Merk, Janssen K.K., BMS, Nippon Kayaku, Taiho; and on advisory board for AstraZeneca, Eli Lilly Japan, Pfizer. Dr. Yoh reports funding from Abbvie, Amgen, ArriVent Biopharma, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Taiho, Taked; consulting fees from Boehringer Ingelheim and Abbvie; honoraria from Amgen, AstraZeneca, BMS, Chugai, Daiichi Sankyo, Kyowa kirin, Eli Lilly, MSD, Ono, Takeda. Dr. Shih reports funding from Taipei City Thoracic Disease Academic Research and Education Foundation, and Roche; consulting fees from AstraZeneca, Pfizer, MSD, Chugai, Takeda, CStone, Janssen, TTY Biopharm, Ono, and BMS; honoraria from ACTgenomics, Amgen, Genconn Biotech, AstraZeneca, Roche, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, MSD, Chugai, Takeda, CStone, Janssen, Tshbiopharm, TTY Biopharm, Orient EuroPharma, Ono, and BMS. Dr. Moro-Sibilot reports funding from Roche, AstraZeneca, BMS, Boehringer Ingelheim, Abbvie, Pfizer; consulting fees from Roche, AstraZeneca, BMS, MSD, Eli Lilly, Takeda, Boehringer Ingelheim, Abbvie, Becton Dickinson, Pfizer, Novartis; honoraria from Roche, BMS, MSD, Takeda; non-financial support from Roche, AstraZeneca, BMS, MSD, Eli Lilly, Takeda, Boehringer Ingelheim and Pfizer. Dr. Puri is a full-time employee of Eli Lilly and Company with stock options. Mr. Varughese is a full-time employee of Eli Lilly and Company and declares no conflict of interest. Ms. Frimodt-Moller and Dr. Visseren-Grul are full-time employees of Eli Lilly and Company with stock options. Dr. Reck reports consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Beigene, Eli Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Beigene, Eli Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; meeting or travel support from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Beigene, Eli Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis; participation in Data Safety Monitoring Board or Advisory Board for Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Beigene, Eli Lilly, Mirati, MSD, Merck, Novartis, Pfizer, Sanofi, Regeneron, Roche, Takeda, and Samsung Bioepis. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The anatomical approach for the management of para-Hisian ventricular arrhythmias (VAs) with QRS morphological changes after catheter ablation (CA) has not been well investigated., Objective: We aimed to evaluate the electrocardiographic and electrophysiological findings and ablation outcomes of para-Hisian VAs with QRS morphological changes after CA., Methods: Of the 30 patients who underwent CA for para-Hisian VAs at 4 institutions, 10 (33%) had QRS morphological changes after ablation. All 10 patients underwent an anatomical approach, targeting the site anatomically opposite to the site where the QRS morphology had been changed by ablation. We investigated the safety and efficacy of the anatomical approach., Results: Of the 10 patients evaluated, the approach was switched from the right ventricular septum to the left ventricular septum/aortic root in 7 (70%) (RL group) whereas 3 (30%) underwent left-to-right switches (LR group). After CA, the precordial transition zone tended to be earlier in the RL group and later in the LR group. In the RL group, successful VA suppression was achieved, despite suboptimal pace map concordance from the left side or a relatively delayed earliest activation time. Of the 10 patients who underwent an anatomical approach, 8 (80%) had procedural success, and ablation was discontinued in 1 (10%) because of the risk of atrioventricular block., Conclusion: The anatomical approach showed promising results regarding safety and efficacy. Therefore, it should be considered when QRS morphological changes are observed during or after CA of para-Hisian VAs., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic impact of extracardiac sarcoidosis remains unknown in cardiac sarcoidosis (CS). We aimed to evaluate the influence of extracardiac sarcoidosis on clinical outcomes and the effect of continued outpatient visits for screening of cardiac involvement., Methods: Ninety-nine patients with CS were divided into two groups: patients with systemic CS who had prior extracardiac sarcoidosis, patients with isolated CS who had no prior extracardiac sarcoidosis. Patients with systemic CS were divided according to the continuation of outpatient visits. The endpoint was cardiac death, fatal ventricular arrhythmia, or hospitalization for heart failure., Results: At the time of diagnosing CS, patients with isolated CS had a higher prevalence of high-grade atrioventricular block or fatal ventricular arrhythmia, and left ventricular contractile dysfunction than those with systemic CS. Over a median follow-up of 42 months, cardiac events occurred in 19 (37%) of 52 patients with systemic CS and in 27 (57%) of 47 patients with isolated CS. The event-free survival rate was worse in patients with isolated CS than in those with systemic CS. Cox proportional hazard analysis showed that the absence of prior extracardiac sarcoidosis was an independent predictor of adverse outcomes. Patients with systemic CS who ceased outpatient visits had a lower left ventricular ejection fraction with severe heart failure symptoms and a worse event-free survival rate than those who continued outpatient visits., Conclusions: The presence of extracardiac sarcoidosis is associated with clinical outcomes. The cessation of screening for cardiac involvement after diagnosing extracardiac sarcoidosis is associated with adverse outcomes., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Patient safety is crucial in high-risk specialties such as orthopedic surgery due to the significant incidence of preventable adverse events. Analyzing extensive databases of orthopedic surgery-related incidents in operating rooms is vital for enhancing medical safety and identifying targeted interventions. This study analyzed orthopedic surgery-related incidents in operating rooms using a nationwide incident reporting database in Japan to identify risk factors associated with severe harm., Methods: We extracted orthopedic surgery-related incidents in the operating room from the Japan Council for Quality Health Care's database, which contained 127,207 near-miss and adverse event reports recorded between January 1, 2010 and September 30, 2022. We analyzed 882 incident cases, focusing on patient demographics, incident timing, surgical site, incident causes, and severity levels., Results: The most incidents involved surgeons (93.3 %) with an average of 16.0 ± 8.5 years of experience. The frequent causes were "failure to check" (48.0 %) and "misjudgment" (24.0 %), which were non-technical errors. "Errors in methods/procedures" accounted for 37.1 % of incidents, possibly due to a wide variety of surgical approaches and implants used in orthopedic surgeries. Regarding severity, 86 % were critical incidents that threatened patients' livelihoods or lives. Surgeries involving surgeons had a significantly higher risk of severe harm than those involving healthcare professionals other than surgeons (odds ratio: 3.311, 95 % confidence interval: 1.858-5.901)., Conclusions: This study revealed that most of orthopedic surgery-related incidents in operating rooms involved experienced surgeons and resulted in severe patient harm. The frequent causes were failure to check, misjudgment, and errors in methods/procedures. These highlight the crucial role of orthopedic surgeons in actively contributing to medical safety databases and fostering a culture of reporting within their field., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Introduction: The JCOG0802/WJOG4607L trial revealed superior overall survival in segmentectomy compared with lobectomy for small-peripheral NSCLC. Nevertheless, locoregional relapse (LR) is a major issue for segmentectomy. An ad hoc supplementary analysis aimed to determine the risk factors for LR and the degree of advantages of segmentectomy on the basis of primary tumor sites., Methods: Participants in multi-institutional and intergroup, open-label, phase 3 randomized controlled trial in Japan were enrolled from August 10, 2009, to October 21, 2014. Risk factors for LR after segmentectomy and clinical features following the primary tumor site were investigated., Results: Of 1105 patients, 576 and 529 underwent lobectomy and segmentectomy, respectively. The primary tumor site for segmentectomy was the left upper division, left lingular segment, left S6, left basal segment, right upper lobe, right S6, or right basal segment. Multivariable analysis in the segmentectomy group revealed that pure-solid appearance on thin-section computed tomography (OR = 3.230; 95% confidence interval [CI]: 1.559-6.690; p = 0.0016), margin distance less than the tumor size (OR = 2.682; 95% CI: 1.350-5.331; p = 0.0049), and male sex (OR = 2.089; 95% CI: 1.047-4.169; p = 0.0366) were significantly associated with LR. Patients with left lingular segment tumors (OR = 4.815; 95% CI: 1.580-14.672) tended to experience LR more frequently than those with left upper division tumors, although primary tumor sites were not statistically significant., Conclusions: Thin-section computed tomography findings and margin distance are important factors to avoid LR in segmentectomy., Competing Interests: Disclosure The authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Several signs of malignant early repolarizations have been proposed in patients with early repolarization syndrome (ERS). However, reports have challenged the efficacy of these signs in predicting future ventricular fibrillation (VF) in patients with ERS., Objective: This study aimed to assess the predictive value of various electrocardiogram (ECG) markers for future VF events in patients with ERS., Methods: We retrospectively evaluated the clinical characteristics of 44 patients with ERS to identify risk factors for VF during follow-up., Results: After the initial event, 16 patients experienced VF (VF group), whereas 28 did not (non-VF group). The VF group had a longer QRS interval, more fragmented QRS (fQRS), and a higher T/R voltage ratio than the non-VF group. Wide J waves were more prevalent in the VF group; however, other J-wave markers did not differ between the groups. Positive late potentials recorded on signal-averaged ECGs were more frequent in the VF group. Whereas none of the patients showed spontaneous Brugada syndrome on ECG, the VF group frequently exhibited pilsicainide-induced ST-segment elevation. These ECG markers were significantly associated with the occurrence of VF during follow-up. Patients with multiple ECG factors, including QRS abnormalities (wide QRS or fQRS), wide J waves, and a high T/R ratio, had a worse prognosis than patients without multiple factors, effectively stratifying patient risk., Conclusion: The occurrence of VF in patients with ERS may be associated with conduction abnormalities such as QRS widening, fQRS, high T/R ratio, positive late potentials, and pilsicainide test results. Therefore, ECG factors could be useful in identifying high-risk patients., Competing Interests: Disclosures H.M. and N.N. are affiliated with the endowed department by Japan Medtronic Inc., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: There is limited data on the impact of COVID-19 epidemic on the number of orthopaedic surgeries in Japan., Methods: We conducted a nationwide hospital survey asking for the monthly number of orthopaedic surgeries performed at each facility from January 2019 to June 2021. Those facilities that had performed at least 100 surgeries in 2019 were included for analyses. The facilities were further grouped by prefecture and by hospital characteristics. A brief health economic evaluation was also performed. Risk ratios were compared using univariate analyses with P < 0.05 considered statistically significant., Results: Questionnaire was sent to 1988 hospitals with 1671 hospitals (84%) responding. The survey data indicated a total number of orthopaedic surgeries decreased in 2020 compared to 2019 (1,061,541 vs 1,119,955 P < 0.01), and also for the first six months of 2021 compared to the same period in 2019 (530,388 vs 550,378 P < 0.01). In 2020, over 50% of all facilities in nearly all of the prefectures saw a decline in surgical procedures. The risk of incurring more than a 25% decease in the number of surgeries was significantly higher in 2020 for class I designated medical institutions compared to those that were not designated for any types of infectious diseases among the institutions with a tertiary emergency medical center in 2020 (crude risk ratio 2.9: 95% CI 1.2-7.4, p = 0.02) and in 2021 (crude risk ratio 4.7: 95% CI 1 0.9-12.1, p < 0.01). The estimated total nationwide decrease of revenue were in the range of approximately ¥29.2 to ¥116.8 billion per year for orthopaedic surgeries alone., Conclusion: There was a statistically significant decrease in the number of orthopaedic surgeries in Japan. The magnitude of the decline varied by prefectures and hospital characteristics, with the greater impact imposed on medical institutions with higher classification functions. The estimated immediate health economic impact was sizable., Competing Interests: Declaration of competing interest No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. The first author reports personal speaker fees from Johnson & Johnson K·K., Pfizer Japan, 3 M Japan, Stryker Japan, Taisho Toyama Pharmaceutical, MSD K.K., Hisamitsu Pharmaceutical, Kaken Pharmaceutical, Astellas Pharma, Smith＆Nephew, Daiichi Sankyo Company, outside the submitted work., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: In patients with Brugada syndrome, myocardial fibrosis can be identified through epicardial biopsy or cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE). However, the myocardial alterations in patients with early repolarization syndrome (ERS) remain poorly elucidated., Objective: The objective of this study was to investigate the presence of myocardial fibrosis in patients with ERS by LGE in CMR., Methods: We retrospectively evaluated 20 patients with ERS, all of whom exhibited J waves in the contiguous 2 leads. The location of J waves was classified as in the septum (V 1 -V 2 ), anterior (V 3 -V 4 ), lateral (I, aVL, V 5 -V 6 ), inferior (II, III, aVF), or posterior (V 7 -V 9 ) regions. To compare the distribution of LGE on CMR imaging with J waves, sections on short-axis view of the left ventricle (LV) were categorized as located in the septum, anterior, lateral, inferior, and posterior regions., Results: Overall, 85% of ERS patients displayed LGE, which was more prevalent in the septum and posterior regions, followed by the inferior and lateral regions. The presence or absence of J waves and LGE coincided in 61% of LV areas, whereas discordance between the distributions of J waves and LGE was observed in 38%. LGE was most frequent in the septum (75%), where its reflection in J waves may be less robust. The appearance of LGE was not associated with symptoms, electrical storm, or ventricular fibrillation occurrence during follow-up., Conclusion: LGE is common in patients with ERS, and the distribution of J waves and LGE coincides in approximately 60% of LV areas., Competing Interests: Disclosure H.M. and N.N. are affiliated with a department endowed by Japan Medtronic Inc., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Meniscal stabilization with saucerization has recently been recommended for discoid lateral meniscus (DLM) to preserve the meniscus shape and prevent the progression of osteoarthritis. However, axial alignment of the lower limb causes a significant valgus change after arthroscopic partial meniscectomy and can lead to progressive lateral osteoarthritic changes. Thus, valgus knees in patients with DLM are a suspected predictive factor for poor outcomes after DLM surgery. Valgus malalignment in pediatric patients can be corrected by temporarily tethering one side of the open physis using implant-mediated guided growth to generate differential growth in the coronal plane. This Technical Note describes simultaneous arthroscopic meniscal surgery and temporary hemiepiphysiodesis to treat DLM with valgus deformities to reduce the risk of future chondral damage to the lateral knee compartment., Competing Interests: H.N. reports a relationship with Department of Orthopaedic Surgery, Osaka Metropolitan University. All other authors (Y.H., Ke.N., Ka.N., T.T., D.T., and H.K.) declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Percutaneous left atrial appendage closure (LAAC) has increased for those who need alternative to long-term anticoagulation with non-valvular atrial fibrillation (NVAF)., Methods and Results: From September 2019, after initiating WATCHMAN (Boston Scientific, Maple Grove, MN, USA) device implantation, we established Transcatheter Modification of Left Atrial Appendage by Obliteration with Device in Patients from the NVAF (TERMINATOR) registry. Utilizing 729 patients' data until January 2022, we analyzed percutaneous LAAC data regarding this real-world multicenter prospective registry. A total of 729 patients were enrolled. Average age was 74.9 years and 28.5 % were female. Paroxysmal AF was 37.9 % with average CHADS 2 3.2, CHA 2 DS 2 -VASc 4.7, and HAS-BLED score of 3.4. WATCHMAN implantation was successful in 99.0 %. All-cause deaths were 3.2 %, and 1.2 % cardiovascular or unexplained deaths occurred during follow-up [median 222, interquartile range (IQR: 93-464) days]. Stroke occurred in 2.2 %, and the composite endpoint which included cardiovascular or unexplained death, stroke, and systemic embolism were counted as 3.4 % [median 221, (IQR: 93-464) days]. Major bleeding defined as BARC type 3 or 5 was seen in 3.7 %, and there was 8.6 % of all bleeding events in total [median 219, (IQR: 93-464) days]., Conclusions: These preliminary data demonstrated percutaneous LAAC with WATCHMAN device might have a potential to reduce stroke and bleeding events for patients with NVAF. Further investigation is mandatory to confirm the long-term results of this strategy using this transcatheter local therapy instead of life-long systemic anticoagulation., Competing Interests: Declaration of competing interest The following authors have received lecture and consultancy fees outside of the submitted work broadly related to LAA closure technology: H. Hara has received lecture fees and consultancy fees from Boston Scientific; M. Fukunaga has received lecture fees and consultancy fees from Boston Scientific; S. Kubo has received lecture fees and consultancy fees from Boston Scientific; Y. Nakajima has received lecture fees and consultancy fees from Boston Scientific; T. Matsumoto has received lecture fees and consultancy fees from Boston Scientific; Yusuke Kondo has received lecture fees and consultancy fees from Boston Scientific. The other authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Early repolarization syndrome (ERS) is an idiopathic ventricular fibrillation (VF) associated with inferolateral J waves. While electrical storm (ES) in ERS is not rare, their characteristics and risk factors are not fully understood., Objective: This study aimed to clarify the significance of ES in ERS., Methods: We evaluated 44 patients with ERS who experienced VF/sudden cardiac death or arrhythmic syncope. We assessed clinical characteristics to identify the risk factors for ES., Results: In total, 13 patients (30%) experienced ES (ES group). Of these, 11 patients (85%) experienced ES during the acute phase of initial VF episodes and 2 patients (2%) experienced ES during follow-up. VF associated with ES occurred during therapeutic hypothermia in 6 of 13 patients (46%). The J-wave voltage during therapeutic hypothermia was higher in the ES group than that in the patients without ES. Isoproterenol was used in 5 patients (38%), which decreased J-wave voltage and relieved ES. Among the clinical markers, shorter QT and QTp intervals (the interval from QRS onset to the peak of T wave), pilsicainide-induced ST elevation, and high scores on the Shanghai Score System were associated with ES. Although pilsicainide induced ST elevation in 6 of 34 patients (18%), spontaneous Brugada electrocardiographic patterns did not appear to be associated with VF. Therapeutic hypothermia was also a risk factor for acute phase ES., Conclusion: Patients with ERS in the ES group frequently had short QT and QTp intervals, pilsicainide-induced ST elevations, and high Shanghai Score System scores. Therapeutic hypothermia was also associated with acute phase ES., Competing Interests: Disclosures Drs Morita and Nishii are affiliated with the endowed department of Japan Medtronic Inc., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Dietary vitamin K 1 (phylloquinone: PK) and menaquinone (MK-n) are converted to menadione (MD) in the small intestine and then translocated to various tissues where they are converted to vitamin K 2 (menaquinone-4: MK-4) by UbiA prenyltransferase domain containing protein 1 (UBIAD1). MK-4 is effective in bone formation and is used to treat osteoporosis in Japan. UBIAD1 is expressed in bone and osteoblasts and shows conversion to MK-4, but the role of UBIAD1 in osteogenesis is unknown. In this study, we investigated the function of UBIAD1 in osteogenesis using a tamoxifen-dependent UBIAD1-deficient mouse model. When UBIAD1 deficiency was induced from the first week of life, the femur was significantly shortened, and bone mineral density (BMD) was reduced. In addition, the expression of bone and chondrocyte matrix proteins and chondrocyte differentiation factors was significantly decreased. In primary cultured chondrocytes, chondrocyte differentiation was significantly reduced by UBIAD1 deficiency. These results suggest that UBIAD1 is an important factor for the regulation of chondrocyte proliferation and differentiation during osteogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Efficacy of necitumumab [recombinant human monoclonal antibody that blocks the ligand binding epidermal growth factor receptor (EGFR)] in patients with squamous (SQ) non-small-cell lung cancer (NSCLC) has been confirmed in two randomized clinical trials (SQUIRE and JFCM). This study evaluated the association between efficacy and initial skin toxicity with necitumumab treatment by analyzing pooled data from two clinical trials (SQUIRE and JFCM)., Materials and Methods: Data of 635 patients with SQ-NSCLC (intent-to-treat population) treated with necitumumab plus gemcitabine and cisplatin (N + GC) were pooled from two clinical trials (SQUIRE and JFCM). The relationship between skin toxicities developed by the end of the second cycle and efficacy was evaluated. Efficacy endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Univariate and multivariate analyses were carried out for these endpoints., Results: OS and ORR were associated with skin toxicity, whereas PFS was not. Patients with grade ≥2 or grade 1 skin toxicity had significantly longer OS compared to patients without skin toxicity (grade 0) in the N + GC group [median = 15.0 (grade ≥2); 12.7 (grade 1); 9.4 (grade 0) months; hazard ratio (HR) = 0.51 (grade ≥2 to grade 0); 95% confidence interval (CI) 0.40-0.64, P < 0.001 and HR = 0.64 (grade 1 to grade 0); 95% CI 0.52-0.80, P < 0.001]. In multivariate analysis, OS was significantly associated with skin toxicity., Conclusions: A significant association was found between necitumumab-induced skin toxicity and efficacy. These results are consistent with the previously reported association between other EGFR inhibitors-induced skin toxicity and efficacy., Competing Interests: Disclosure SW reports receiving personal fees from Novartis Pharma, Chugai Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, MSD, and Daiichi Sankyo. HY reports receiving personal fees from Delta Fly Pharma, Chugai Pharmaceutical, MSD, AstraZeneca, Boehringer Ingelheim, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Novartis Pharma, Kyowa Kirin, Nippon Kayaku, Eli Lilly, Otsuka Pharmaceutical, Daiichi Sankyo, Amgen, Pfizer, and Nipro Pharma. HS reports receiving personal fees from Merck, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, and AstraZeneca. KH reports receiving grants from MSD, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Bristol-Myers Squibb, and AbbVie; and personal fees from Pfizer, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Takeda Pharmaceutical, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, and Boehringer Ingelheim. MT reports receiving grants from Chugai Pharmaceutical, Ono Pharmaceutical, and Pfizer. KY reports personal fees from Healios, Chugai Pharmaceutical, AstraZeneca, and Bristol-Myers Squibb. SS reports receiving personal fees from MSD, Nippon Kayaku, Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Taiho Pharmaceutical, Eli Lilly, Novartis Pharma, Kyowa Kirin, Yakult Honsha, Takeda Pharmaceutical, Pfizer, Merck, Amgen, AbbVie, Otsuka Pharmaceutical, Thermo Fisher Scientific, and Towa Pharmaceutical. YT reports receiving grants from Ono Pharmaceutical, AstraZeneca, MSD, AbbVie, Bristol-Meyers Squib, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Eisai, Nippon Kayaku, and Takeda Pharmaceutical; and personal fees from Ono Pharmaceutical, AstraZeneca, Bristol-Meyers Squib, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Eisai, MSD, Takeda Pharmaceutical, Amgen, Novartis Pharma, Merck BioPharma, and Kyowa Kirin. YH reports receiving personal fees from AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda Pharmaceutical, Eisai, Novartis Pharma, and Pfizer. KT reports receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Kyowa Kirin, MSD, and Taiho Pharmaceutical. SN reports receiving grants from AstraZeneca, Merck BioPharma, Chugai Pharmaceutical, and GlaxoSmithKline; and personal fees from AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, Pfizer, Eli Lilly, Takeda Pharmaceutical, Merck BioPharma, Boehringer Ingelheim, Taiho Pharmaceutical, Novartis Pharma, Daiichi Sankyo, KYORIN Pharmaceutical, and MSD. MN reports receiving personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Astellas Pharma, Boehringer Ingelheim, MSD, Novartis Pharma, Daiichi Sankyo Healthcare, Taiho Pharmaceutical, and Merck Serono. TK reports receiving grants from AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Haihe Biopharma, Merck, MSD, Novartis Pharma, Pfizer, Regeneron Pharmaceuticals, Takeda Pharmaceutical, and Turning Point Therapeutics; and personal fees from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Merck, MSD, Novartis Pharma, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical. TT reports receiving grants from AstraZeneca, Amgen, Boehringer Ingelheim, Merck Biopharma, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, MSD, and Pfizer; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, MSD, Pfizer, Boehringer Ingelheim, Roche Diagnostics, Takeda Pharmaceutical, and Yakult Honsha. HE reports receiving personal fees from Nippon Kayaku. MA reports receiving personal fees from Nippon Kayaku. NY reports receiving grants from Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Shionogi Pharma, Eli Lilly, Daiichi Sankyo, Tsumura, Nippon Kayaku, Asahikasei-pharma, AstraZeneca, Janssen Pharmaceutical, Sanofi, Amgen, Novartis Pharma, Astellas Pharma, MSD, Eisai, Bristol-Myers Squibb, AbbVie, and Tosoh; and personal fees from MSD, AstraZeneca, Amgen, Ono Pharmaceutical, Otsuka Pharmaceutical, Guardant Health, Tsumura, Kyowa Kirin, KYORIN Pharmaceutical, GlaxoSmithKline, Sanofi, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Kayaku, Boehringer Ingelheim, Novartis Pharma, Pfizer, Bristol-Myers Squibb, Miyarisan Pharmaceutical, Merck, and Janssen Pharmaceutical. YO reports receiving grants from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, KYORIN Pharmaceutical, Sumitomo Pharma, Pfizer, Taiho Pharmaceutical, Novartis Pharma, Takeda Pharmaceutical, Kissei Pharmaceutical, Daiichi Sankyo, and Janssen Pharmaceutical; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Yakuhin, Pfizer, MSD, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Kirin, and Eisai. KN reports receiving grants from AstraZeneca, MSD, Ono Pharmaceutical, Boehringer Ingelheim, Novartis Pharma, Pfizer, Bristol-Myers Squibb, Eli Lilly, Chugai Pharmaceutical, Daiichi Sankyo, Merck Biopharma, PAREXEL International, PRA HEALTHSCIENCES, EPS, Kissei Pharmaceutical, EPS International, Taiho Pharmaceutical, PPD-SNBL, SymBio Pharmaceuticals, IQVIA Services, SYNEOS HEALTH CLINICAL, Nippon Kayaku, EP-CRSU, Mebix, Janssen Pharmaceutical, AbbVie, Bayer Yakuhin, Eisai, Mochida Pharmaceutical, Covance, Japan Clinical Research Operations, Takeda Pharmaceutical, GlaxoSmithKline, Sanofi, Sysmex, Medical Research Support, Otsuka Pharmaceutical, SRL, Pfizer R&D, and Amgen; and personal fees from Eli Lilly, KYORIN Pharmaceutical, Ono Pharmaceutical, Pfizer, Amgen, Nippon Kayaku, AstraZeneca, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, Taiho Pharmaceutical, Bayer Yakuhin, CMIC ShiftZero, Life Technologies, Neo Communication, Roche Diagnostics, AbbVie, Merck Biopharma, Kyowa Kirin, Takeda Pharmaceutical, 3H Clinical Trial, Care Net, Medical Review, Medical Mobile Communications, YODOSHA, Nikkei Business Publications, Japan Clinical Research Operations, CMIC, Novartis Pharma, TAIYO Pharma, and Bristol-Myers Squibb., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Preoperative difference in lumbar lordosis (DiLL) was associated with surgical outcomes after single-level transforaminal lumbar interbody fusion (TLIF). Patients with DiLL>0 (DiLL (+)) tended to show worse clinical outcomes and postoperative greater restoration of lumbar lordosis (LL). However, some patients with DiLL (+) showed relatively good outcomes and no postoperative LL restration. This study aimed to elucidate whether the lumbar intervertebral disc vacuum phenomenon (VP) influences clinical course after single-level TLIF in patients with DiLL (+) and DiLL (-)., Methods: Patients with lumbar spinal stenosis and degenerative spondylolisthesis treated with single-level TLIF were included. Pre- and postoperative LL were measured, and postoperative LL improvement was calculated. Preoperative DiLL was calculated as preoperative supine LL minus standing LL. Severity of VP at the non-fused discs (SVP (non-FS)) was evaluated using preoperative reconstructed computed tomography imaging. Clinical outcomes were assessed using the Oswestry disability index, visual analogue scale (VAS; low back pain (LBP), lower-extremity pain, numbness, and the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire. Patients were stratified by the median preoperative SVP (non-FS) score into severe and mild VP groups in patients with DiLL (+) or DiLL (-), and their surgical outcomes were compared., Results: Overall, 89 patients were included. In patients with DiLL (+) (n = 37), patients with severe VP showed worse clinical outcomes, particulary for LBP and DiLL (+) patients with mild VP showed greater LL improvement (6.5° ± 10.0°). In patients with DiLL(-) (n = 52), patients with severe VP showed worse clinical outcomes, particularly for LBP and no differences in preoperative, postoperative, and improvement of LL were observed between two groups., Conclusion: Patients with DiLL (+) and DiLL (-) showed different clinical courses depending on VP severity at the non-fused discs after single-level TLIF., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Ever since the proposal of ferroptosis, it has been studied as a nonapoptotic cell death caused by iron ion-dependent phospholipid (PL) peroxidation. We previously showed that treatment of human hepatoma cell line HepG2 with prepared PL hydroperoxide (PLOOH) resulted in ferroptosis. However, in human sebum, the major hydroperoxide is not PLOOH but squalene hydroperoxide (SQOOH), and to our knowledge, it is not established yet whether SQOOH induces ferroptosis in the skin. In this study, we synthesized SQOOH and treated human keratinocyte HaCaT cells with SQOOH. The results showed that SQOOH induces ferroptosis in HaCaT cells in the same way that PLOOH causes ferroptosis in HepG2 cells. Some natural antioxidants (botanical extracts) could inhibit the ferroptosis in both the cell types. Consequently, future research focus would revolve around the involvement of SQOOH-induced ferroptosis in skin pathologies as well as the prevention and treatment of skin diseases through inhibition of ferroptosis by botanical extracts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kiyotaka Nakagawa reports financial support was provided by Amway I&S. Hirono Totsuka is an employee of Amway Japan G.K. Arun Rajgopal and Jina Hong are employees of Amway I&S. The remaining authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Object: To clarify the involvement of clock genes in the production of inflammatory mediators from RA-FLS, we examined the role of Bmal1, one of the master clock genes., Methods: RA-FLSs were stimulated with IL-1β (0, 20 ng/mL), IL-6 (0, 20 ng/mL), IL-17 (0, 20 ng/mL), TNF-α (0, 20 ng/mL) or IFN-γ (0, 20 ng/mL) to examine the expression of Bmal1, MMP-3, CCL2, IL-6, IL-7 and IL-15 by qPCR and immunofluorescence staining. After silencing Bmal1, RA-FLSs were stimulated with IL-1β (0, 20 ng/mL), TNF-α (0, 20 ng/mL) or IFN-γ (0, 20 ng/mL) to examine the expressions of inflammatory mediators; MMP-3, CCL2, IL-6 and IL-15 by qPCR, ELISA and immunofluorescence staining., Results: Bmal1 expressions were increased by IL-1β, TNF-α and IFN-γ stimulations. Under stimulations with TNF-α, IL-1β, and IFN-γ, mRNA and protein expressions of MMP-3, CCL2 and IL-6 were suppressed by siBmal1., Conclusion: Results indicate that Bmal1 contributes the production of MMP-3, CCL2, and IL-6 from RA-FLS, implying Bmal1 is involved in the pathogenesis of RA by regulating the inflammation., Competing Interests: Declaration of competing interest There is no conflict of interests regarding the publication of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: J waves in the inferior or lateral leads are characteristic electrocardiographic (ECG) changes in patients with early repolarization syndrome (ERS). However, the presence of J waves in the left posterior region has not yet been evaluated., Objective: The purpose of this study was to clarify the significance of J waves in the posterior left ventricle using leads V 7 -V 9 and a body surface mapping (BSM) system., Methods: Forty patients diagnosed with ERS were included. All patients exhibited J waves in either the contiguous inferior, lateral, or posterior leads. We evaluated the incidence of J waves in the inferolateral and posterior leads using a 15-lead ECG with synthesized V 7 -V 9 and an 87-lead BSM. Additionally, we assessed the arrhythmogenicity of the posterior regions based on the morphology of the premature ventricular complexes (PVCs) associated with ventricular fibrillation (VF)., Results: J waves were observed in the lateral, inferior, and posterior leads of 26 (65%), 31 (78%), and 39 (97%) patients, respectively. J waves were found only in the posterior leads of 5 patients. BSM was evaluated in 9 patients, all of whom exhibited a positive area on the posterior region. PVCs associated with VF were recorded in 5 patients. Among patients with inferolateral and posterior J waves, all except 1 patient who displayed left bundle branch block morphology showed PVCs originating from the posterior left ventricular region., Conclusion: Posterior J waves are common in ERS patients. This abnormality can be detected using leads V 7 -V 9 and the BSM system and may be associated with arrhythmogenesis., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE)., Methods: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers., Results: The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8 + tumor-infiltrating lymphocyte density and the high CD73 + cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8 + tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity., Conclusions: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Although osimertinib or afatinib alone induced drug-resistant clones with EGFR secondary mutation in a preclinical model, its combination prevented the appearance of these mutations. We investigated alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC in a single-arm Phase II trial., Methods: Treatment-naïve patients with stage IV NSCLC harboring an activating EGFR mutation were enrolled. Alternating cycles of osimertinib (80 mg/day) followed by afatinib (20 mg/day) were administered every 8 weeks. Genomic analysis was performed using circulating tumor DNA obtained before and after the treatment., Results: Among the 46 enrolled patients, the median progression-free survival was 20.2 months. The overall response rate was 69.6%. The median overall survival was not reached. Among the 26 plasma samples obtained after the acquisition of resistance, 3 showed an increased MET gene copy number, and 1 showed BRAF mutation. Meanwhile, no EGFR secondary mutation was detected., Conclusion: The efficacy of our treatment was not significantly different from osimertinib alone, as reported previously in untreated advanced NSCLC patients with EGFR mutations. Although the sample size was limited, this treatment may prevent the emergence of EGFR secondary mutations that trigger drug resistance. Further studies are warranted to establish the significance of this treatment., Clinical Trial Registration: jRCTs051180009., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) over placebo + ERL (PBO + ERL) in the phase III RELAY study of patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (EGFR+ mNSCLC; NCT02411448). Next-generation sequencing (NGS) was used to identify clinically relevant alterations in circulating tumor DNA (ctDNA) and explore their impact on treatment outcomes., Patients and Methods: Eligible patients with EGFR+ mNSCLC were randomized 1 : 1 to ERL (150 mg/day) plus RAM (10 mg/kg)/PBO every 2 weeks. Liquid biopsies were to be prospectively collected at baseline, cycle 4 (C4), and postdiscontinuation follow-up. EGFR and co-occurring/treatment-emergent (TE) genomic alterations in ctDNA were analyzed using Guardant360 NGS platform., Results: In those with valid baseline samples, detectable activating EGFR alterations in ctDNA (aEGFR+) were associated with shorter PFS [aEGFR+: 12.7 months (n = 255) versus aEGFR-: 22.0 months (n = 131); hazard ratio (HR) = 1.87, 95% confidence interval (CI) 1.42-2.51]. Irrespective of detectable/undetectable baseline aEGFR, RAM + ERL was associated with longer PFS versus PBO + ERL [aEGFR+: median PFS (mPFS) = 15.2 versus 11.1 months, HR = 0.63, 95% CI 0.46-0.85; aEGFR-: mPFS = 22.1 versus 19.2 months, HR = 0.80, 95% CI 0.49-1.30]. Baseline alterations co-occurring with aEGFR were identified in 69 genes, most commonly TP53 (43%), EGFR (other than aEGFR; 25%), and PIK3CA (10%). PFS was longer in RAM + ERL, irrespective of baseline co-occurring alterations. Clearance of baseline aEGFR by C4 was associated with longer PFS (mPFS = 14.1 versus 7.0 months, HR = 0.481, 95% CI 0.33-0.71). RAM + ERL improved PFS outcomes, irrespective of aEGFR mutation clearance. TE gene alterations were most commonly in EGFR [T790M (29%), other (19%)] and TP53 (16%)., Conclusions: Baseline aEGFR alterations in ctDNA were associated with shorter mPFS. RAM + ERL was associated with improved PFS outcomes, irrespective of detectable/undetectable aEGFR, co-occurring baseline alterations, or aEGFR+ clearance by C4. aEGFR+ clearance by C4 was associated with improved PFS outcomes. Monitoring co-occurring alterations and aEGFR+ clearance may provide insights into mechanisms of EGFR tyrosine kinase inhibitor resistance and the patients who may benefit from intensified treatment schedules., Competing Interests: Disclosure EBG declares grants from ABL-Bio, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Dynavax Technologies, EMD Serono, Eli Lilly and Company, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis; consulting fees from AbbVie, ABL-Bio, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly and Company, Gilead, GlaxoSmithKline, Ipsen, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio; payment for expert testimony from UCLA relating to motif neoepitopes for cancer immunotherapy; leadership/fiduciary role with LUNGevity and Jonsson Comprehensive Cancer Center at UCLA. JVH declares advisory board/committee membership with Genentech, Mirati Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, DAVA Oncology, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Immunocore, and Novartis; research support from AstraZeneca, Boehringer-Ingelheim, Spectrum, and Takeda; royalties and licensing fees from Spectrum. MR declares consulting fees from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; honoraria from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; support for meetings/travel from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; board participation for Daiichi and Sanofi. KN declares grants from Nippon Boehringer-Ingelheim, West Japan Oncology Group, Thoracic Oncology Research Group, North East Japan Study Group, Clinical Research Support Center Kyushu, Nichirei Biosciences Inc., Eli Lilly and Company, Hitachi, Sysmex, and Otsuka Pharmaceutical; consulting fees from SymBio Pharmaceuticals, Solasia Pharma, Eli Lilly and Company, and Otsuka Pharmaceutical; honoraria from Chugai, Pfizer, Eli Lilly and Company, MSD, Novartis Pharma, AstraZeneca, Amgen, Merck Biopharma, Roche Diagnostics, Yakult Honsha, Guardant Health, Takeda Pharmaceuticals, Boehringer-Ingelheim Japan, FUJIREBIO, Bristol-Myers Squibb, Merck Biopharma, Janssen Pharmaceutical Daiichi-Sankyo, and Ono Pharmaceutical. MN declares honoraria from Ono Pharmaceuticals, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly and Company, AstraZeneca, MSD, AbbVie, Takeda, Pfizer, Boehringer-Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen. SN declares grants from Eli Lilly and Company; consulting fees from BMS, Eli Lilly and Company, Takeda, Roche, Pfizer, AstraZeneca, BI, MSD, AbbVie, PharmaMar, and BeiGene; support for meetings and/or travel from Eli Lilly and Company, Thermo Fisher, and Takeda; participation on advisory boards for Guardant Health, GSK, Novocure, Amgen, AstraZeneca, Janssen, and Eli Lilly and Company; and declares leadership/fiduciary roles as President of WALCE (Women against Lung Cancer in Europe) Onlus. LPA declares grants from MSD, AstraZeneca, Pfizer, and BMS; consulting fees from Eli Lilly and Company, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, and Daiichi-Sankyo; honoraria from AstraZeneca, Janssen, Merck, and Mirati; member of the board of directors of Altum Sequencing and Genomica; principal investigator for studies sponsored by Alkermes, Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, IO Biotech, Janssen-Cilag, Eli Lilly and Company, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Takeda, and Tesaro. SP declares consulting fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly and Company, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; honoraria from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, Takeda, and Pfizer; payment for expert testimony from Roche and Merck Serono; support for attending meetings and/or travel from Janssen and Roche; unpaid leadership/fiduciary roles in British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP-IBCSG Partners Foundation Board. SPA declares no conflicts of interest. HG was an employee and stockholder of Eli Lilly and Company during the time of study analysis and manuscript preparation; contributions to the manuscript were made as part of the roles at Eli Lilly and Company. BDB and CVG are full-time employees and minor shareholders of Eli Lilly and Company. KN declares grants to institution from AstraZeneca, MSD, Ono Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis, Pfizer Japan Inc., Bristol-Myers Squibb, Eli Lilly and Company, Chugai Pharmaceutical, Daiichi-Sankyo, Merck, Paraxel International Corp., PRA Health Sciences, EPS Corporation, Kissei Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., PPD-SNBL K.K., SymBio Pharmaceuticals Limited, IQVIA Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku Co. Ltd., EP-CRSU Co. Ltd., Mebix, Janssen Pharmaceutical K.K., AbbVie Inc., Bayer Yakuhin Ltd., Eisai, Mochida Pharmaceutical Co. Ltd. Covance Japan Inc., Japan Clinical Research Operations, Takeda Pharmaceutical Co. Ltd., GlaxoSmithKline, Sanofi, Sysmex Corporation, Medical Research Support, Otsuka Pharmaceutical Co. Ltd., SRL Inc., Pfizer R&D Japan G.K., and Amgen Inc.; consulting fees from Eli Lilly and Company, KYORIN Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., and Pfizer Japan Inc.; honoraria from Ono Pharmaceutical Co. Ltd., Amgen Inc. Nippon Kayaku Co. Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly and Company, MSD, Pfizer Japan Inc., Nippon Boehringer-Ingelheim Co. Ltd., Taiho Pharmaceutical Co. Ltd., Bayer Yakuhin, CMIC ShiftZero K.K., Life Technologies Japan Ltd., Neo Communication, Roche Diagnostics K.K., AbbVie Inc, Merck Biopharma Co. Ltd., Kyowa Kirin Co. Ltd., Takeda Pharmaceutical Co. Ltd., 3H Clinical Trial Inc., Care Net Inc., Medical Review Co. Ltd., Medical Mobile Communications Co. Ltd., Yodosha Co. Ltd., Nikkei Business Publications Inc., Japan Clinical Research Operations, CMIC Co. Ltd., Novartis, TAIYO Pharma Co. Ltd., KYORIN Pharmaceutical Co. Ltd., and Bristol-Myers Squibb K.K.; patents planned, issued, or pending with Daiichi-Sankyo. Data sharing Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Perfluorooctanoic acid (PFOA), a synthetic perfluorinated eight-carbon organic chemical, induces hepatotoxicity in rodents, indicated increased liver weight, hepatocellular hypertrophy, necrosis, and peroxisome proliferation. Epidemiological studies have demonstrated the association between serum PFOA levels and various adverse effects. In this study, we investigated the gene expression profiles of human HepaRG cells exposed to 10 and 100 μM PFOA for 24 h. Treatment with 10 and 100 μM PFOA significantly modulated the expression of 190 and 996 genes, respectively. Genes upregulated or downregulated by 100 µM PFOA included peroxisome proliferator-activated receptor (PPAR) signaling genes related to lipid metabolism, adipocyte differentiation, and gluconeogenesis. Moreover, we identified the "Nuclear receptors-meta pathways" following the activation of other nuclear receptors: constitutive androstane receptor (CAR), pregnane X receptor (PXR) and farnesoid X receptor (FXR), as well as the transcription factor nuclear factor E2-related factor 2 (Nrf2). The expression levels of some target genes (CYP4A11, CYP2B6, CYP3A4, CYP7A1, and GPX2) of these nuclear receptors and Nrf2 were confirmed using quantitative reverse transcription polymerase chain reaction. Next, we performed transactivation assays using COS-7 and HEK293 cells to investigate whether these signaling-pathways were activated by the direct effects of PFOA on human PPARα, CAR, PXR, FXR and Nrf2. PFOA concentration-dependently activated PPARα, but not CAR, PXR, FXR, or Nrf2. Taken together, these results suggest that PFOA affects the hepatic transcriptomic responses of HepaRG cells through the direct activation of PPARα and indirect activation of CAR, PXR, FXR, and Nrf2. Our finding indicates that PPARα activation in the "Nuclear receptors-meta pathways" functions as a molecular initiating event for PFOA, and indirect activation of alternative nuclear receptors and Nrf2 also induce important molecular mechanisms in PFOA-induced human hepatotoxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Ramucirumab plus erlotinib (RAM+ERL) demonstrated superior progression-free survival (PFS) in RELAY, a randomised Phase III trial in patients with untreated, metastatic, EGFR-mutated, non-small-cell lung cancer (EGFR+ NSCLC). Here, we present the relationship between TP53 status and outcomes in RELAY., Materials and Methods: Patients received oral ERL plus intravenous RAM (10 mg/kg IV) or placebo (PBO+ERL) every 2 weeks. Plasma was assessed by Guardant 360 next-generation sequencing and patients with any gene alteration detected at baseline were included in this exploratory analysis. Endpoints included PFS, overall response rate (ORR), disease control rate (DCR), DoR, overall survival (OS), safety, and biomarker analysis. The association between TP53 status and outcomes was evaluated., Results: Mutated TP53 was detected in 165 (42.7%; 74 RAM+ERL, 91 PBO+ERL) patients, wild-type TP53 in 221 (57.3%; 118 RAM+ERL, 103 PBO+ERL) patients. Patient and disease characteristics and concurrent gene alterations were comparable between those with mutant and wildtype TP53. Independent of treatment, TP53 mutations, most notably on exon 8, were associated with worse clinical outcomes. In all patients, RAM+ERL improved PFS. While ORR and DCR were comparable across all patients, DoR was superior with RAM+ERL. There were no clinically meaningful differences in the safety profiles between those with baseline TP53 mutation and wild-type., Conclusion: This analysis indicates that while TP53 mutations are a negative prognostic marker in EGFR+ NSCLC, the addition of a VEGF inhibitor improves outcomes in those with mutant TP53. RAM+ERL is an efficacious first-line treatment option for patients with EGFR+ NSCLC, independent of TP53 status., Competing Interests: Disclosure This work was supported by Eli Lilly and Company. M. Ceccarelli and C. Visseren-Grul are full-time employees of Eli Lilly and Company. H. Graham was a full-time employee of Eli Lilly and Company at the time of this work. M. Ceccarelli and H. Graham are minor stockholders of Eli Lilly and Company. M. Nishio has received honoraria from Ono Pharmaceuticals, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, AstraZeneca, MSD, AbbVie, Takeda, Pfizer, Boehringer Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen. L. Paz-Ares has received grants from MSD, AstraZeneca, Pfizer, and Bristol Myers Squibb, consulting fees from Eli Lilly and Company, MSD, Roche, Pharmamar, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, bayer, BMS, Mirati, GSK, Janssen, Takeda, and Merck, honoraria from Roche/Genentech, Eli Lilly and Company, Pfizer, Bristol-Myers Squibb, MSD, BMS, AstraZeneca, Merck Serono, PharmaMar, Novartis, Celgene, Amgen, Mirati, and Abbvie, travel expenses from Roche, AstraZeneca, MSD, Bristol-Myers Squibb, Eli Lilly and Company, and Pfizer, and is an advisory board member for Altum Sequencing and Genomica. M. Reck has received consulting fees, honoraria, and travel expenses from Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Beigene, Eli Lilly and Company, GSK, Daiichi-Sankyo, Merck, MSD, Mirati, Novartis, Pfizer, Sanofi, Roche, and Samsung Bioepis, and is an advisory board member for Daiichi-Sankyo and Sanofi. K. Nakagawa has received grants from AstraZeneca K.K., MSD K.K., Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma K.K., Pfizer Japan Inc., Bristol Myers Squibb, Eli Lilly Japan K.K., Chugai Pharmaceutical, Daiichi Sankyo, Merck Biopharma, PAREXEL International Corp., Pra Healthsciences, EPS Corporation, Kissei Pharmaceutical, EPS International, Taiho Pharmaceutical, PPD-SNBL K.K, SymBio Pharmaceuticals, IQVIA Services JAPAN K.K., Syneos Health Clinical K.K., Nippon Kayaku, EP-CRSU, Mebix, Janssen, AbbVie, Bayer Yakuhin, Eisai, Mochida Pharmaceutical, Covance Japan Inc., Japan Clinical Research Operations, Takeda, GlaxoSmithKline K.K., Sanofi K.K., Sysmex Corporation, Medical Research Support, Otsuka Pharmaceutical, SRL Inc., Pfizer R&D Japan G.K., and Amgen, consulting feed from Eli Lilly Japan K.K., KYORIN Pharmaceutical, Ono Pharmaceutical, Pfizer Japan, honoraria from Ono Pharmaceutical, Amgen, Nippon Kayaku, AstraZeneca K.K., Chugai Pharmaceutical, Eli Lilly Japan K.K., MSD K.K., Pfizer Japan, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Bayer Yakuhin, CMIC ShiftZero K.K., Life Technologies Japan, Neo Communication, Roche Diagnostics K.K., AbbVie, Merck Biopharma, Kyowa Kirin, Takeda, 3H Clinical Trial, Care Net, Medical Review, Medical Mobile Communications, Yodosha, Nikkei Business Publications, Japan Clinical Research Operations, CMIC, Novartis Pharma K.K., Taiyo Pharma, Kyorin Pharmaceutical, and Bristol-Myers Squibb K.K., and has patents planned with Daiichi Sankyo. E. Garon has received funding from Eli Lilly and Company, grants from ABL-Bio; AstraZeneca, Bristol Myers Squibb, Dynavax Technologies, EMD Serono, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis, consulting fees from ABL-Bio, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly and Company, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio, and has a leadership role on the scientific advisory board for Lungevity. S. Popat has received consulting fees from Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly and Company, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx, honoraria from AstraZeneca, BAey, Guardant Health, Janssen, Merck Serono, Roche, Takeda, and Pfizer, payment for expert testimony from Roche and Merck Serono, travel expenses from Janssen and Roche, and has a leadership role on a board for British Thoracic Oncology Group, ALK Positive UK, Lung Caner Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETO-IBCSG Partners Foundation. S. Novello has received consulting fees from Sanofi and Novartis, honoraria from AstraZeneca, Amgen, MSD, Takeda, Roche, Pfizer, Thermofisher, Novartis, and Sanofi, and is an advisory board member for AstraZeneca, Roche, Pfizer and MSD., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although segmentectomy is a widely used surgical procedure, lobectomy is the standard procedure for resectable non-small-cell lung cancer (NSCLC). This study aimed to evaluate the efficacy and safety of segmentectomy for NSCLC up to 3 cm in size, including ground-glass opacity (GGO) and predominant GGO., Methods: A multicentre, single-arm, confirmatory phase 3 trial was conducted across 42 institutions (hospitals, university hospitals, and cancer centres) in Japan. Segmentectomy with hilar, interlobar, and intrapulmonary lymph node dissection was performed as protocol surgery for patients with a tumour diameter of up to 3 cm, including GGO and dominant GGO. Eligible patients were those aged 20-79 years with an Eastern Cooperative Oncology Group performance score of 0 or 1 and clinical stage IA tumour confirmed by thin-sliced CT. The primary endpoint was 5-year relapse-free survival (RFS). This study is registered with the University Hospital Medical Information Network Clinical Trials (UMIN000011819), and is ongoing., Findings: A total of 396 patients were registered from Sept 20, 2013, to Nov 13, 2015, of whom 357 underwent segmentectomy. At a median follow-up of 5·4 years (IQR 5·0-6·0), the 5-year RFS was 98·0% (95% CI 95·9-99·1). This finding exceeded the 87% of the pre-set threshold 5-year RFS and the primary endpoint was met. Grade 3 or 4 early postoperative complications occurred in seven patients (2%), but no grade 5 treatment-related deaths occurred., Interpretation: Segmentectomy should be considered as part of standard treatment for patients with predominantly GGO NSCLC with a tumour size of 3 cm or less in diameter, including GGO even if it exceeds 2 cm., Funding: National Cancer Centre Research and Development Fund and Japan Agency for Medical Research and Development., Competing Interests: Declaration of interests KA, AH, HI, TK, HK, TMiy, RN, YO, MO, JO, YT, and SW report research funding from the National Cancer Center Research and Development Fund by the National Cancer Center and Practical Research for Innovative Cancer Control Fund by Japan Agency for Medical Research and Development. HF reports lecture fees from Chugai Pharmaceuticals, outside of the submitted work. MW reports honoraria from Nihon Medi-Physics outside of the submitted work. MTs reports research funding from Boehringer-Ingelheim Japan and commissioned research for clinical trials from MSD, Astrazeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Eli Lilly Japan, Novartis, and BMG; lecture fees from Johnson & Johnson Japan, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, MSD, Bristol-Myers Squibb, Teijin Pharma, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical, Daiichi-Sankyo, and Novartis, outside of the submitted work; is on the advisory board of AstraZeneca, Chugai Pharmaceutical, MSD, Novartis, and Eli Lilly, outside of the submitted work; and also is on the committee of Japan Lung Cancer Society and Japanese Association of Chest Surgery, Cancer Net Japan, Japanese Organization for Research, and Treatment of Cancer, outside of the submitted work. TMim reports research funding from the Japan Society for the Promotion of Science KAKENHI (grant number 20K09177) by the Japan Society for Promotion of Science, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: This study aimed to examine whether preoperative severity and location of lumbar intervertebral disc vacuum phenomenon (VP) influence surgical outcomes after single-level transforaminal lumbar interbody fusion., Methods: We included 106 patients (age, 67.4 ± 10.4 years; 51 male/55 female) with lumbar degenerative diseases, who were treated with single-level transforaminal lumbar interbody fusion. Severity of VP (SVP) score was measured preoperatively. SVP score at fused disc was used as SVP (FS) score and at nonfused discs was used as SVP (non-FS) score. Surgical outcomes were assessed using the Oswestry Disability Index (ODI) and visual analog scale (VAS; low back pain (LBP), lower extremity pain, numbness, LBP in motion, in standing, and in sitting). The patients were divided into severe VP (FS or non-FS) and mild VP (FS or non-FS) groups, and surgical outcomes were compared between the 2 groups. Correlations between each SVP score and surgical outcomes were analyzed., Results: There were no differences in surgical outcomes between the severe VP (FS) and mild VP (FS) groups. Postoperative ODI, VAS score for LBP, lower extremity pain, numbness, and LBP in standing were significantly worse in the severe VP (non-FS) group than in the mild VP (non-FS) group. SVP (non-FS) scores significantly correlated with postoperative ODI, VAS score for LBP, lower extremity pain, numbness, and LBP in standing; however, SVP (FS) scores did not correlate with any surgical outcomes., Conclusions: Preoperative SVP at fused disc is not associated with surgical outcomes; however, SVP at nonfused discs is correlated with clinical outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)