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We report an angle-resolved photoemission spectroscopy study of BaFeCoAs. For x=0, above the structural and magnetic transition temperature ( T), the spectral weight near the Fermi level is considerably suppressed around the Γ point where the Fe 3d yz/ zx orbital degeneracy is expected. This observation suggests that the Jahn-Teller type instability is playing an important role in the tetragonal phase above T. Below T, the spectral weight of 0-100 meV is reconstructed to form flat bands at 70-100 meV and Fermi surfaces, consistent with the orbital-dependent excitonic coupling. In the optimally doped and overdoped regimes, the hole pocket around the Γ point and the electron pocket around the M point are apparently nested, indicating that the doping dependence of the superconducting transition temperature cannot be explained by the nesting scenario and that the unusual electron-lattice fluctuation due to the orbital degeneracy is important. [ABSTRACT FROM AUTHOR]

Abstract Background The oral multi-kinase inhibitor sunitinib malate improves the survival of patients with gastrointestinal stromal tumors (GIST) after the disease progresses or intolerance to imatinib mesylate develops. Urinary fistulae arising during treatment with sunitinib for GIST have not been described. Case presentation We describe a 62-year-old female patient diagnosed with unresectable GIST that involved the abdominal wall, urinary bladder wall, bowel, mesentery and peritoneum in the pelvic cavity. Intestinocutaneous fistulae developed on a surgical lesion after orally administered imatinib was supplemented by an arterial infusion of 5-flurouracil. Sunitinib was started after the patient developed resistance to imatinib. On day 4 of the fourth course of sunitinib, a widely dilated cutaneous fistula discharged large amounts of fluid accompanied by severe abdominal pain. Urinary communication was indicated based on the results of an intravenous injection of indigo carmine. Computed tomography findings suggested a small opening on the anterior urinary bladder wall and fistulous communication between the bladder and abdominal walls bridged by a subcutaneous cavity. The fistula closed and the amount of discharge decreased when sunitinib was discontinued. Therefore, sunitinib might have been associated with the development of the vesicocutaneous fistula in our patient. Conclusion This is the first description of a vesicocutaneous fistula forming while under sunitinib treatment. Clinicians should be aware of the possible complication of vesicocutaneous fistula formation during treatment with molecular targeting agents in patients with extravesical invasion and peritoneal dissemination of GIST.

Children who scored below the MA level on the TOM developmental test (Morinaga et al., 2003) are examined in detail. The TOM developmental test is a screening test for three to seven year olds. The test consists of three false-belief tasks, one task for the understanding of emotion, and a simple vocabulary task. It has been developed and standardised in Japan for use at day-care centres and clinics. Forty-eight children, referred to Shirayuri College Developmental Clinic, are tested with the TOM developmental test. Of these, children with high-functioning autism, Asperger syndrome, Attention Deficit Hyperactivity Disorder (ADHD), LD, and those with developmental disorders due to environmental factors (i.e., child abuse) tend to score below the average; however, their developmental courses differ. Although children with ADHD and nonverbal LD tend to score below MA when they are younger, they catch up as they grow. On the other hand, those children with high-functioning autism remain below the MA equivalent. Children with delays due to environmental factors tend to score low in TOM, but as the environment improves, their TOM scores improve rapidly. Various types of developmental courses suggest that differentiating underlying causes for developmental delays is an important step towards correct intervention. [ABSTRACT FROM AUTHOR]

Although several studies have shown that glucocorticoids exert diuretic effects in animals and humans, the underlying mechanism responsible for the acute diuretic effect remains obscure. Here we examined the mechanism in terms of gene-expression. We observed that glucocorticoids, including dexamethasone (Dex) and prednisolone (PSL), acutely induced diuresis in rats in a dose-dependent manner. Free water clearance values were negative after Dex or PSL treatment, similar to those observed after treatment with osmotic diuretics (furosemide and acetazolamide). Dex significantly increased the urinary excretion of sodium, potassium, chloride, glucose, and inorganic phosphorus. Renal microarray analysis revealed that Dex significantly altered the renal expression of genes related to transmembrane transport activity. The mRNA levels of sodium/phosphate (NaPi-2a/Slc34a1, NaPi-2b/Slc34a2, and NaPi-2c/Slc34a3) and sodium/glucose cotransporters (Sglt2/Slc5a2) were significantly reduced in the Dex-treated kidney, being negatively correlated with the urinary excretion of their corresponding solutes. Dex did not affect renal expression of the natriuretic peptide receptor 1 (Npr1) gene, or the expression, localization, and phosphorylation of aquaporin-2 (AQP2), a water channel protein. These findings suggest that the acute diuretic effects of glucocorticoids might be mediated by reduced expression of sodium-dependent cotransporter genes., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Intracellular potassium ion (K + ) concentration is higher than extracellular K + concentration. Some cells maintain intracellular potassium levels by taking up extracellular potassium. However, investigating these details requires techniques to measure intracellular potassium concentrations. We established a method to easily measure intracellular potassium concentrations using a simpler electrode. The LAQUAtwin K-11 was capable of linearly quantifying potassium concentrations and was not affected by cellular constituents other than nucleic acids; however, it did not tolerate low temperatures. Interference caused by a high concentration of nucleic acids was eliminated by the addition of cations. It was also suggested that the concentration of nucleic acids in the cell suspension was not sufficiently high to interfere with the measurements. Intracellular potassium concentrations increased and decreased in response to extracellular potassium concentrations. Exposure to valinomycin did not decrease the potassium concentration, suggesting that re-uptake of the potassium released outside the cells occurred immediately. Additionally, potassium concentrations could be measured in the brain tissue homogenates using the device. This measurement method can track the relative changes in potassium concentration in cells under various conditions and in tissues of various disease models., Competing Interests: Conflict of interests: All authors declare no conflicts of interest in this paper., (© 2024 the Author(s), licensee AIMS Press.)

Introduction: Combined treatment using anti-programmed death-ligand 1 antibody (anti-PD-L1) and platinum-etoposide is the current standard first-line treatment for patients with extensive-stage (ES) small cell lung cancer (SCLC). However, the best treatment for relapsed ES-SCLC after the first-line treatment remains unclear. There are some approved chemotherapeutic agents that can be used against ES-SCLC, and treatment with irinotecan is well established as both a monotherapy and a combined therapy, in combination with platinum. Therefore, we conduct a phase II study with irinotecan in the second- or later-line setting for patients with ES-SCLC who have been previously treated with combined treatment., Methods: Our study will enroll total 30 patients who are diagnosed with ES-SCLC and have experienced disease progression after the combined treatment. Patients will receive irinotecan on days 1, 8, and 15, which will be repeated every 4 weeks. Doses of irinotecan (100/80/60 mg/m 2 ) will be determined according to the type of UGT1A1 gene polymorphism, and the treatment will be discontinued following disease progression, intolerance, withdrawal of patient consent, and based on the investigator's decision. The primary endpoint of the study is the response rate, and the secondary endpoints are overall survival, progression-free survival, and safety., Discussion: Since the present first-line treatment has been changed to the combined treatment, the second- or later-line treatment should be re-evaluated for patients with relapsed SCLC. Irinotecan is a major chemotherapeutic agent used for SCLC. This study demonstrates and re-evaluates the clinical benefits of irinotecan after combined treatment with anti-PD-L1 and platinum-etoposide for patients with ES-SCLC., Registration Details: This study was registered in the Japan Registry of Clinical Trials (no. jRCT s071210090) on November 4, 2021., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Studies elucidating detailed characteristics of pneumonitis in association with chemo-immunotherapy are limited. We aimed to investigate the characteristics of images, prognostic factors, and clinical course of combination therapy associated with pneumonitis. A multicenter, retrospective cohort study of patients with non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed, and pembrolizumab was conducted. Patients with confirmed pneumonitis established by an independent multidisciplinary team were enrolled. For 53 patients with pneumonitis, radiographic features at diagnosis predominantly comprised an organizing pneumonia pattern (62%, 33/53). Twelve (23%) patients experienced a worsening respiratory status during pneumonitis management, which was associated with a high mortality rate (58%, 7/12) during treatment. Severe grade at pneumonitis diagnosis (p < 0.001), diffuse alveolar damage (DAD) pattern (p = 0.002), and disease extent ≥ 25% in the lungs (p = 0.009) were significantly associated with worsening respiratory status. Furthermore, post-diagnosis survival was significantly worse in severe pneumonitis (p = 0.02) than in mild and in patients with the DAD pattern than in those without (p < 0.0001). We showed detailed clinical course of patients with pneumonitis and reported several important influencing factors. Given the small number of trials on pneumonitis, our findings provide valuable information to guide the development of appropriate management guidelines and improve pneumonitis treatment., (© 2023. The Author(s).)

Background: The standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC study. Although multiple Japanese phase II studies have shown high efficacy and tolerability of CRT with cisplatin plus S-1 (SP), no prospective study using durvalumab after SP-based CRT has been reported., Objectives: We conducted a multicenter phase II study of this approach, the interim analysis of which showed a high transition rate to durvalumab consolidation therapy. Here, we report the primary analysis results., Design: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m 2 , day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab (10 mg/kg) every 2 weeks for up to 1 year., Methods: The primary endpoint was 1-year progression-free survival (PFS). The expected 1-year PFS and its lower limit of the 80% confidence interval (CI) were set as 63% and 47%, respectively, based on the results of TORG1018 study., Results: In all, 59 patients were enrolled, with 51 (86.4%) proceeding to durvalumab. The objective response rate throughout the study was 72.9% (95% CI: 59.7-83.6%). After median follow-up of 21.9 months, neither median PFS nor OS was reached. The 1-year PFS was 72.5% (80% CI: 64.2-79.2%, 95% CI: 59.1-82.2%), while the 1-year overall survival was 91.5% (95% CI: 80.8-96.4%). No grade 5 adverse events were observed throughout the study. The most common adverse event during the consolidation phase was pneumonitis (any grade, 78.4%; grade ⩾3, 2.0%). Eventually, 52.5% of patients completed 1-year durvalumab consolidation therapy from CRT initiation., Conclusion: This study of durvalumab after SP-based CRT met its primary endpoint and found a 1-year PFS of 73% from CRT initiation. This study provides the first prospective data on the prognosis and tolerability of durvalumab consolidation from the initiation of CRT., Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127., Competing Interests: H.T. received personal fees as honoraria from Boehringer Ingelheim, AstraZeneca, Pfizer, Chugai Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. S.T. received research funding from AstraZeneca, and personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly. T.Misu. received personal fees as honoraria from Chugai Pharmaceutical and AstraZeneca. S.K. received personal fees as honoraria from Chugai Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, MSD, Taiho Pharmaceutical, Sanofi, Kyowa Kirin, Hisamitsu Pharmaceutical, Daiichi Sankyo, Nippon Kayaku, and Novartis. N.I. received personal fees as honoraria from AstraZeneca. K.Kusa. received personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, and Nippon Kayaku. N.F. received personal fees as honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Boehringer Ingelheim, and AstraZeneca. Y.F. received personal fees as honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Novartis, Merck Biopharma, MSD, Boehringer Ingelheim, Taiho Pharmaceutical, and Daiichi Sankyo. T.T. received personal fees as honoraria from Chugai Pharmaceutical. K.Shib. received personal fees as honoraria from AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. A.B. received research funding from AstraZeneca and personal fees as honoraria from AstraZeneca and Taiho Pharmaceutical. K.Kair. received research funding from AstraZeneca and Nihon Medi-Physics and personal fees as honoraria from Ono Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, and Pfizer. N.S. received research funding from Ono Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Eisai, Daiichi Sankyo, Takeda Pharmaceutical, Shionogi, Nippon Kayaku, and Pfizer, and personal fees as honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Boehringer Ingelheim, MSD, Daiichi Sankyo, Novartis, Bristol-Myers Squibb, Pfizer, Takeda Pharmaceutical, and Nippon Kayaku. No potential conflicts of interest were disclosed by the other authors., (© The Author(s), 2022.)

Background: The standard of care for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC trial. Disease progression and pneumonitis were reported as the main reasons to preclude the initiation of durvalumab in multiple retrospective studies. However, the transition rate and the reasons for failure to proceed to consolidation therapy with durvalumab after CRT were not evaluated prospectively. Although phase II studies in Japan have shown high efficacy and tolerability of CRT with cisplatin + S-1 (SP), no prospective study using durvalumab after SP-based CRT has yet been reported. We therefore conducted a phase II study to verify the efficacy and safety of durvalumab following SP-based CRT. In this interim analysis, we report the transition rate and the reasons for its failure., Methods: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m 2 , day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab every 2 weeks for up to 12 months. The primary endpoint was 12 month progression-free survival rate., Results: Fifty-nine patients were enrolled, of whom 86.4% (51/59) proceeded to durvalumab. All of them initiated durvalumab within 42 days after CRT [median 18 days (range: 3-38)], including 27.5% (14/51) in <14 days. Common reasons for failure to proceed to durvalumab were disease progression (2/59, 3.4%) and adverse events (6/59, 10.2%). Among the latter cases, four resumed treatment and proceeded to durvalumab within 42 days on off-protocol. The objective response rate and the disease control rate were 62.7% and 93.2%, respectively. The incidences of ⩾grade 3 pneumonitis, febrile neutropenia, and esophagitis were 0%, 8.5%, and 3.4%, respectively., Conclusion: Regarding durvalumab after CRT, this interim analysis of the SAMURAI study clarified the high transition rate, early introduction, and reasons for failure to proceed to consolidation therapy, which were not determined in the PACIFIC trial., Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127., Competing Interests: Competing Interests: ST received research funding from AstraZeneca and personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly. SK received personal fees as honoraria from Chugai Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, MSD, Taiho Pharmaceutical, Sanofi, Kyowa Kirin, Hisamitsu Pharmaceutical, DAIICHI SANKYO, Nippon Kayaku, and Novartis. NI received personal fees as honoraria from AstraZeneca. KK received personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, and Nippon Kayaku. TY received research funding from Bristol-Myers Squibb, MSD, Chugai Pharmaceutical, Takeda Pharmaceutical, and Delta-Fly Pharma and personal fees as honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Nippon Kayaku, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Novartis, and Takeda Pharmaceutical. TT received personal fees as honoraria from Chugai Pharmaceutical. KS received personal fees as honoraria from AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. AB received research funding from AstraZeneca and personal fees as honoraria from AstraZeneca and Taiho Pharmaceutical. KK received research funding from AstraZeneca, and Nihon Medi-Physics and personal fees as honoraria from Ono Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, and Pfizer. TM received personal fees as honoraria from Chugai Pharmaceutical and AstraZeneca. NS received research funding from Ono Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Eisai, DAIICHI SANKYO, Takeda Pharmaceutical, SHIONOGI, Nippon Kayaku, and Pfizer and personal fees as honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Boehringer Ingelheim, MSD, DAIICHI SANKYO, Novartis, Bristol-Myers Squibb, Pfizer, Takeda Pharmaceutical, and Nippon Kayaku. No potential conflicts of interest were disclosed by other authors., (© The Author(s), 2022.)

Hypercapnia in addition to hypoxia affects the mammalian cardiorespiratory system and has been suggested to exert its effects on cardiorespiratory function by slightly different mechanisms to hypoxia. In the present study, we examined cardiorespiratory changes in urethane-anesthetized rats under hypocapnic (Hypo, 10% O 2 ), isocapnic (Iso, 10% O 2 and 4% CO 2 ), and hypercapnic (Hyper, 10% O 2 and 8% CO 2 ) hypoxia for 2 h to clarify the effects of CO 2 on sustained hypoxia-induced cardiorespiratory responses. Respiratory frequency increased the most in Hypo and tidal volume in Hyper. Minute ventilation, a product of respiratory frequency and tidal volume, increased the most in the latter group. Regarding cardiovascular variables during the hypoxic exposure period, heart rate and mean blood pressure both markedly decreased in Hypo. However, decreases in these parameters were small in Iso, and both increased over the pre-exposure level in Hyper. The present results suggest that CO 2 interferes with the hypoxia-activated neural pathway via another pathway under sustained exposure to hypoxia., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: This study aimed to determine the incidence and clinical course of epidermal growth factor receptor (EGFR)-mutated lung cancer with histologic transformation (HT)., Patients and Methods: We conducted a multicentre, retrospective, cohort study of patients with advanced EGFR-mutated lung cancer who received EGFR-tyrosine kinase inhibitors (TKIs) between 2012 and 2019. The primary outcome was the incidence of HT. The secondary outcome was treatment efficacy in patients with HT., Results: In total, 6356 patients were enrolled. In 2624 patients, the histological type was proven by rebiopsy after acquiring resistance to EGFR-TKIs. Among them, 74 patients had HT (incidence rate: 2.8% [95% confidence interval: 2.3%-3.5%]). The median progression-free survival after EGFR-TKIs and first-line therapy after confirming HT was 10.4 and 4.4 months, respectively, which was not significantly different between patients with transformation to high-grade neuroendocrine carcinoma and those with transformation to another subtype of non-small cell lung cancer. Overall survival after confirming HT was 12.2 months. Twenty-seven patients received immune checkpoint inhibitors: 6 and 21 received immune checkpoint inhibitors before and after confirming HT, respectively. No patients achieved 1-year progression-free survival. The median progression-free survival after immune checkpoint inhibitor therapy after confirming HT was 1.6 months., Conclusion: HT occurred in approximately 3% of EGFR-mutated patients who developed resistance to EGFR-TKIs. Cytotoxic agents are likely to be effective in patients with HT. However, the therapeutic effectiveness of immune checkpoint inhibitors was limited in these patients. Given the rarity of HT and absence of prospective trials, our findings are important to inform the treatment of these patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Few clinical studies have been designed for elderly patients with locally advanced non-small cell lung cancer (NSCLC). We conducted a phase I study to evaluate the tolerability of carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy in elderly patients with locally advanced NSCLC. The eligibility criteria were: unresectable stage III NSCLC, performance status 0 or 1, and age ≥ 75 years. Eligible patients received 6 weeks of weekly carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy with a total dose of 64 Gy in 32 fractions. Carboplatin was fixed to an area under the plasma concentration time curve (AUC) of 2 mg/mL/min, and the recommended dose of nab-paclitaxel was evaluated using a dose-escalation study (30 or 40 mg/m 2 ). Tolerability at the recommended dose was evaluated in an expansion study. Nineteen patients were enrolled at four institutions, all of whom were eligible and assessable. The recommended nab-paclitaxel dose was set at 30 mg/m 2 because two patients experienced dose-limiting toxicity at 40 mg/m 2 . The treatment completion rate of the 17 patients analyzed at the recommended dose was 100% (80% confidence interval (CI), 83.8-100%). The overall response rate was 76.5%, and the median progression free survival was 13.4 months (95% CI, 4.2-21.4 months). Common grade 3 and 4 toxicities included leukopenia (23.5%), neutropenia (17.6%), anemia (5.9%), and infection (5.9%). One treatment-related death due to pneumonitis was observed six months after the end of the study. In conclusion, carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy show good tolerability and exhibit promising efficacy in elderly patients with locally advanced NSCLC. This trial was registered with the Japan Registry of Clinical Trials on March 11, 2019 (trial no. jRCTs042180077)., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.)

Introduction: Although treatment with osimertinib confers survival benefits in patients with lung cancer with the EGFR T790M mutation, the mechanism of acquired resistance to osimertinib remains poorly understood. We conducted a prospective observational study to identify the mechanism on the basis of repeated tissue biopsies., Methods: Patients with EGFR -mutated advanced lung cancer with a T790M mutation detected on a tissue biopsy underwent a rebiopsy after developing acquired resistance to osimertinib. Nucleic acids extracted from the biopsy samples were subjected to targeted resequencing (Oncomine Comprehensive Assay), and circulating cell-free DNA (ccfDNA) was analyzed by CAncer Personalized Profiling by deep Sequencing (AVENIO ctDNA Surveillance Kit)., Results: Between November 2016 and March 2020, a total of 87 patients were screened. Among them, 44 developed acquired resistance. Of these, 19 samples from rebiopsies and 12 from preosimertinib biopsies were able to be analyzed by an Oncomine Comprehensive Assay. A ccfDNA analysis was performed in 16 patients. Regarding the mechanisms of acquired resistance, structural change in EGFR, namely, C797S, G796S, or L792V, was the most frequent alteration, being observed in 57.9% of the cases. MET gain was observed in 31.6% of the cases, and gains in cell cycle genes were observed in 26.3% of the cases. In addition, we identified GAS6 gain and an ATM mutation in a patient with small-cell transformation and a BRAF V600E mutation in a patient with oligoprogressive disease., Conclusions: A repeated tissue biopsy and a ccfDNA analysis were useful in analyzing the mechanisms underlying acquired resistance. A long treatment history of EGFR TKIs may result in a high percentage of EGFR structural change., (© 2021 The Authors.)

Background: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study., Methods: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80-120 mg/body, Days 1-14) + cisplatin (60 mg/m 2 , Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate., Discussion: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab., Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127., Competing Interests: Conflict of interest statement: S.T. received research funding from AstraZeneca K.K. N.S. received personal fees as honoraria from Lily Japan, AstraZeneca K.K., MSD Oncology, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Japan Inc., Ono Pharmaceutical, Nippon Boehringer Ingelheim Co., Ltd., and Bristol-Myers Squibb Japan, and research funding from Nippon Boehringer Ingelheim Co., Ltd., (© The Author(s), 2021.)

Lessons Learned: Updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy were collected. In the group of 58 patients who were enrolled at 14 institutions in Japan, the median overall survival was not reached and the 2-year overall survival rate was 66.1% (95% confidence interval, 52.1%-76.8%). Results reveal encouraging feasibility and activity for this regimen., Background: We report the updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel (nab-P/C) and concurrent radiotherapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC)., Methods: Individuals between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. Patients received weekly nab-paclitaxel at 50 mg/m 2 for 6 weeks together with weekly carboplatin at an area under the curve (AUC) of 2 mg/ml/min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel (100 mg/m 2 on days 1, 8, and 15) plus carboplatin (AUC of 6 on day 1). After the treatment, patients were observed off therapy. The primary endpoint of the phase II part of the study was progression-free survival (PFS)., Results: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0-49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1%-76.8%). The median PFS was 11.8 months (95% CI, 8.2-21.0 months), and the 2-year PFS rate was 35.9% (95% CI, 23.1%-48.9%). Subgroup analysis according to tumor histology or patient age revealed no differences in median PFS or OS. Long-term follow-up of toxicities did not identify new safety signals, and no treatment-related deaths occurred during the study period., Conclusion: Concurrent chemoradiation with nab-P/C was safe and provided a long-term survival benefit for patients with locally advanced NSCLC., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Lessons Learned: Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status. Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases., Background: We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients., Methods: Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study., Results: The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1-30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8-64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886)., Conclusion: Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)