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The next-generation sequencing (NGS)–based Oncomine Dx Target Test (ODxTT) is the standard tool for guiding postoperative adjuvant therapy in patients with non-small cell lung cancer (NSCLC) in Japan. To advance precision oncology, we evaluated the clinical utility of an in-house comprehensive genomic profiling (CGP) assay, Rapid-Neo, as a complementary approach to ODxTT in surgically resected NSCLC. Patients with pathological stage II–III NSCLC who underwent anatomical surgical resection between December 2019 and May 2024 were included. Resected specimens underwent genomic analysis using both ODxTT and Rapid-Neo CGP. We evaluated the mutational concordance and the frequency of additional actionable alterations identified by CGP. Among 68 eligible patients, driver mutation results were concordant in 64 (94.1%) cases. Crucially, CGP rescued one patient for targeted therapy by detecting an EGFR mutation where ODxTT failed due to insufficient DNA. CGP also identified rare EGFR variants not covered by ODxTT in two cases, although it failed to detect a RET fusion in one patient. Furthermore, CGP revealed additional actionable alterations, such as tumor suppressor gene mutations, in 57 patients (83.8%). Our in-house CGP shows high concordance with ODxTT and serves as a powerful complementary tool. These findings support a strategic testing algorithm where CGP is incorporated for patients with negative or inconclusive ODxTT results, or at the time of recurrence, to maximize opportunities for individualized therapy in resected NSCLC.

RNA splicing dysregulation has emerged as a hallmark of cancer and a promising therapeutic target; however, its full landscape in human solid cancer remains poorly characterized. To address this, we perform alternative splicing analyses using RNA-sequencing data from 751 lung adenocarcinoma samples from our cohort integrated with 519 samples from The Cancer Genome Atlas. Visualization of splicing patterns using t-distributed stochastic neighbor embedding reveals substantial inter-tumor heterogeneity driven by distinct molecular subtypes and histological differentiation. We identify a unique molecular subtype associated with inactivating mutations in CMTR2 , which encodes Cap-specific mRNA (nucleoside-2’-O-)-methyltransferase 2. CMTR2 mutations are observed in 3.8% of cases and are predominantly truncating mutations, which form an isolated cluster within the splicing landscape. Intrinsic and CRISPR-Cas9-engineered CMTR2 mutations disrupt alternative splicing and sensitize cancer cells to sulfonamide-based RNA splicing modulators and immune checkpoint blockade therapy. Retrospective patient data confirm the increased sensitivity of CMTR2 -deficient tumors to immune checkpoint blockade therapy. These findings uncover a previously unrecognized RNA splicing deficiency in human cancers and define a molecular subtype of lung adenocarcinoma driven by RNA splicing dysregulation, suggesting targets for therapeutic intervention in lung cancer. RNA splicing dysregulation is a hallmark of cancer but remains poorly understood in solid tumors. Here, the authors map splicing patterns in lung adenocarcinoma, uncover a CMTR2-mutant subtype, and show its vulnerability to splicing modulators and immunotherapy.

Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) are effective for EGFR -mutant lung adenocarcinoma (LUAD), resistance inevitably develops through diverse mechanisms, including secondary genetic mutations, amplifications and as-yet undefined processes. To comprehensively unravel the mechanisms of EGFR-TKI resistance, we establish a biobank of patient-derived EGFR -mutant lung cancer organoids, encompassing cases previously treated with EGFR-TKIs. Through comprehensive molecular profiling including single-cell analysis, here we identify a subgroup of EGFR-TKI-resistant LUAD organoids that lacks known resistance-related genetic lesions and instead exhibits a basal-shift phenotype characterized by the hybrid expression of LUAD- and squamous cell carcinoma-related genes. Prospective gene engineering demonstrates that NKX2-1 knockout induces the basal-shift transformation along with EGFR-target therapy resistance. Basal-shift LUADs frequently harbor CDKN2A/B loss and are sensitive to CDK4/6 inhibitors. Our EGFR -mutant lung cancer organoid library not only offers a valuable resource for lung cancer research but also provides insights into molecular underpinnings of EGFR-TKI resistance, facilitating the development of therapeutic strategies. Resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) is prevalent. Here the authors establish a biobank of patient-derived EGFR-mutant lung cancer organoids and identify a subgroup of EGFR-TKI-resistant lung adenocarcinoma organoids, which exhibit a basal-shift phenotype and vulnerability to CDK4/6 inhibitors.

Background Multiple prolonged symptoms are observed in patients who recover from acute coronavirus disease 2019 (COVID-19), defined as long COVID. Cough and sputum are presented by patients with long COVID during the acute and post-acute phases. This study aimed to identify specific risk factors for cough and sputum in patients with long COVID. Methods Hospitalized patients with COVID-19 aged 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. Results At the 3-, 6-, and 12-month follow-ups, there were no differences in the incidence rates of wet and dry coughs. In contrast, the proportion of patients presenting sputum without coughing increased over time compared to those with sputum and coughing. Univariate analyses of cough and sputum at all follow-up visits identified intermittent mandatory ventilation (IMV), smoking, and older age as risk factors for prolonged symptoms. At the 12-month follow-up, persistent cough and sputum were associated with the characteristics of severe COVID-19 based on imaging findings, renal and liver dysfunction, pulmonary thromboembolism, and higher serum levels of LDH, KL-6, and HbA1C. The Kaplan–Meier curves showed that the severity of acute COVID-19 infection was correlated with prolonged cough and sputum production. Multivariable logistic regression analysis showed that IMV ventilator management were independent risk factors for prolonged cough and sputum at 12 months. Conclusions In a Japanese population with long COVID, prolonged cough and sputum production were closely associated with severe COVID-19. These findings emphasize that a preventive approach including appropriate vaccination and contact precaution and further development of therapeutic drugs for COVID-19 are highly recommended for patients with risk factors for severe infection to avoid persistent respiratory symptoms.

ABT‐263 (Navitoclax) is a BH3‐mimetic drugs targeting anti‐apoptotic B‐cell lymphoma‐2 (BCL‐2) family proteins, including BCL‐2, BCL‐xL, and BCL‐w, thereby inducing apoptosis. In small‐cell lung cancer (SCLC) cells, the response to ABT‐263 is associated with the expression of myeloid cell leukemia‐1 (MCL‐1) protein, however the efficacy of ABT‐263 in non‐small‐cell lung cancer (NSCLC) has not been thoroughly evaluated. There are currently no established biomarkers for predicting the efficacy of ABT‐263 treatment in NSCLC. We screened a panel of different NSCLC cell lines and found that ABT‐263 inhibited cell proliferation and induced apoptosis in Calu‐1, Calu‐3, and BID007 cells. Inconsistent with previous reports on SCLC, low levels of MCL‐1 did not predict the response to ABT‐263 in NSCLC cells, however we found that intracellular levels of reactive oxygen species (ROS) in cancer cells were associated with sensitivity to ABT‐263 in NSCLC cells. We also showed that increasing the level of intracellular ROS could enhance the sensitivity to ABT‐263 in NSCLC cells. In summary, we propose that the intracellular levels of ROS could be used as a potential novel biomarker for predicting a response to ABT‐263 in NSCLC. Furthermore, we show some evidence supporting the further assessment of ABT‐263 as a new therapeutic strategy in patients with NSCLC combined with agents regulating ROS levels. We believe that our findings and follow‐up studies on this matter would lead to novel diagnostic and treatment strategies in patients with NSCLC. This article clarified the potential relationship between intracellular ROS and sensitivity to BH3‐mimetic drug, ABT‐263 in non‐small‐cell lung cancer.

With the rising numbers of patients infected with severe acute respiratory syndrome coronavirus 2, long coronavirus disease 2019 (COVID-19)-a sequelae of COVID-19-has become a major problem. Different sexes and age groups develop different long COVID symptoms, and the risk factors for long COVID remain unclear. Therefore, we performed subgroup analyses of patients with COVID-19, classifying them into different groups. In this multicenter cohort study, using an original questionnaire, we examined patients (≥18 years old) diagnosed with COVID-19 from November 2020 to March 2022 and hospitalized at participating medical facilities. In total, 1066 patients were registered (361 female, 620 male). Hypertension was the most common comorbidity (n = 344; 32.5%). Females with hypertension were significantly less likely to develop long COVID symptoms than those without hypertension (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.27-0.98; p = 0.043). In females, Ca channel blocker administration, rather than having hypertension, was significantly associated with reductions in the frequency of alopecia (OR 0.14, 95% CI 0.03-0.67, p = 0.015), memory impairment (OR 0.14, 95% CI 0.02-0.82, p = 0.029), sleeping disorders (OR 0.17, 95% CI 0.04-0.67, p = 0.012), tinnitus (OR 0.23, 95% CI 0.05-0.98, p = 0.047), sputum (OR 0.31, 95% CI 0.10-0.92, p = 0.035), and fever (OR 0.33, 95% CI 0.12-0.93, p = 0.036). Several long COVID symptoms, including alopecia, were significantly negatively associated with Ca channel-blocker administration in female patients with long COVID. Calcium channel blockers may reduce the development of long COVID in females.

ABSTRACT Background Uncommon EGFR mutations, including G719X, L861Q, S768I, and compound mutations, present therapeutic challenges due to limited prospective evidence and variable drug sensitivity. Although later‐generation (i.e., second‐ and third‐) EGFR‐TKIs have shown benefit in some subtypes, real‐world data is limited. Methods We retrospectively analyzed patients with advanced or recurrent NSCLC harboring uncommon EGFR mutations diagnosed between 2014 and 2019 at Keio University Hospital and affiliated hospitals. Clinical data were updated through May 2023. EGFR mutations were detected using commercial assays. Common mutations and exon 20 insertions were excluded unless coexisting as compound mutations. Survival outcomes were estimated using the Kaplan–Meier method and compared by log‐rank test; hazard ratios were calculated using the Cox proportional hazards model. Swimmer plots depicted treatment duration by subtype and EGFR‐TKI agents. Results Among 35 patients, G719X was the most frequently detected mutation, followed by L861Q and S768I. In addition to these single mutations, various compound mutations involving combinations of G719X, L861Q, S768I, and other rare variants were also observed. While first‐generation EGFR‐TKIs were frequently used initially, 71% of patients eventually received a later‐generation EGFR‐TKI. These patients had significantly longer OS (47.7 vs. 15.5 months; p = 0.0177). Multivariate analysis identified non‐use of later‐generation EGFR‐TKIs, liver metastases, and poor performance status as independent poor prognostic factors. Afatinib showed favorable treatment duration in G719X and compound mutations. Conclusions Later‐generation EGFR‐TKIs were associated with improved outcomes in patients with uncommon EGFR mutations, with afatinib showing favorable treatment duration in G719X and compound subtypes. In this multicenter real‐world study, the use of later‐generation EGFR‐TKIs improved clinical outcomes, including overall survival, in patients with uncommon EGFR mutations.

We identified transmembrane protease, serine 4 (TMPRSS4) as a putative, druggable target by screening surgically resected samples from 90 Japanese non‐small‐cell lung cancer (NSCLC) patients using cDNA microarray. TMPRSS4 has two druggable domains and was upregulated in 94.5% of the lung cancer specimens. Interestingly, we found that TMPRSS4 expression was associated with tissue factor pathway inhibitor 2 (TFPI‐2) expression in these clinical samples. In contrast to TMPRSS4, TFPI‐2 expression was downregulated in NSCLC samples. The in vitro induction of TFPI‐2 in lung cancer cell lines decreased the expression of TMPRSS4 mRNA levels. Reporter assay showed that TFPI‐2 inhibited transcription of TMPRSS4, although partially. Knockdown of TMPRSS4 reduced the proliferation rate in several lung cancer cell lines. When lung cancer cell lines were treated with 5‐aza‐2′‐deoxycytidine or trichostatin A, their proliferation rate and TMPRSS4 mRNA expression levels were also reduced through the upregulation of TFPI‐2 by decreasing its methylation in vitro. The TFPI‐2 methylation level in the low TMPRSS4 group appeared to be significantly low in NSCLC samples (P = 0.02). We found a novel molecular mechanism that TFPI‐2 negatively regulates cell growth by inhibiting transcription of TMPRSS4. We suggest that TMPRSS4 is upregulated by silencing of TFPI‐2 through aberrant DNA methylation and contributes to oncogenesis in NSCLC. TMPRSS4 was up‐regulated by silencing of TFPI‐2 through aberrant DNA methylation and contributed to oncogenesis in NSCLC. It will provide novel therapeutic potential for NSCLC patients by suppressing TMPRSS4 through inhibiting TMPRSS4 directly or indirectly through demethylating TFPI‐2.

ABSTRACT Immune checkpoint inhibitors (ICIs) are essential treatments for lung cancer, but their safety following allogeneic haematopoietic stem cell transplantation (allo‐HSCT) remains unclear. We report a case of a 66‐year‐old man who underwent umbilical cord blood transplantation for acute lymphoblastic leukaemia and later developed lung adenocarcinoma. Pembrolizumab monotherapy was initiated, but the patient developed severe steroid‐refractory immune‐related pneumonitis, leading to mortality 56 days after treatment initiation. Given the scarcity of reports on ICI use in lung cancer patients with prior HSCT, this case highlights critical safety considerations. We report a case of a 66‐year‐old man who underwent umbilical cord blood transplantation for acute lymphoblastic leukaemia and later developed lung adenocarcinoma. Pembrolizumab monotherapy was initiated, but the patient developed severe steroid‐refractory immune‐related pneumonitis, leading to mortality 56 days after treatment initiation. Given the scarcity of reports on ICI use in lung cancer patients with prior HSCT, this case highlights critical safety considerations.

ABSTRACT Immune‐checkpoint inhibitors (ICIs) have become one of the main strategies for advanced cancers. ICIs are associated with many immune side effects, called immune‐related adverse events (irAEs). Since irAE has various variations, it is important to carefully examine each individual case that develops irAE. We experienced a case of polymyalgia rheumatica (PMR)‐like irAE after three courses of administration of Ipilimumab and Nivolumab for stage IV lung adenocarcinoma. We also confirmed that the activity of this irAE was detectable on the PET‐CT scan performed to assess lung cancer progression. Given the limited reports of PMR‐like irAE occurring after treatment with two immune checkpoint inhibitors, we present this case along with a review of the literature. We present a case of polymyalgia rheumatica (PMR)‐like irAE after three courses of administration of Ipilimumab and Nivolumab for Stage IV lung adenocarcinoma. We also confirmed that the activity of this irAE was detectable on the PET‐CT scan performed to assess lung cancer progression.