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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.

ABSTRACT A 71‐year‐old man with diffuse idiopathic skeletal hyperostosis (DISH) underwent posterior spinal fixation for a thoracic vertebral fracture at a fused segment, sustained as a result of a fall. One month postoperatively, he was readmitted due to bilateral massive pleural effusions and increased displacement at the fracture site compared to the immediate postoperative state. The effusions were exudative and lymphocyte‐predominant. Further evaluation suggested that inflammation and pleural irritation due to spinal instability were the likely causes. Revision fixation led to the resolution of the effusions. Vertebral fractures caused by low‐energy trauma, such as a fall, rarely result in spinal instability severe enough to cause pleural effusion, even in cases of nonunion. However, patients with DISH are more prone to highly unstable fractures due to spinal ankylosis and bone fragility. Even after surgical fixation, such fractures may progress to further instability. We report a case in which this instability led to localised inflammation and pleural irritation, ultimately resulting in bilateral pleural effusions. DISH is commonly seen in older adults and has been associated with obesity and diabetes mellitus. Its prevalence is reportedly increasing. Therefore, both internists and orthopaedic surgeons should be aware of the potential for similar cases and consider spinal instability related to DISH in the differential diagnosis and management of unexplained pleural effusions. We present a case of massive bilateral pleural effusion likely caused by spinal instability due to a spinal fracture in a patient with diffuse idiopathic skeletal hyperostosis (DISH).

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.

ABSTRACT A 62‐year‐old woman with a history of papillary thyroid carcinoma presented to our hospital with fever and cough and was diagnosed with stage IV non‐small cell lung carcinoma (NSCLC). One year after chemoimmunotherapy, a re‐biopsy of the left pleural tumour lesion was performed. Histological analysis revealed papillary thyroid carcinoma. Another biopsy was performed on the primary tumour, and the histological analysis of the primary tumour lesion confirmed NSCLC. BRAF V600E mutations were detected in both left pleural metastatic lesions of papillary thyroid carcinoma and the primary tumour of NSCLC. Dabrafenib and trametinib reduced both tumour lesions. Here, we report a rare case of concomitant BRAF V600E‐mutated NSCLC and pleural metastasis from papillary thyroid carcinoma. Recent molecular characterizations of multiple cancers have enabled the identification of driver oncogenes, and multiple molecular‐targeted inhibitors have been developed. We report the first case, to our knowledge, of concomitant lung carcinoma and pleural metastasis of papillary thyroid carcinoma with BRAF V600E mutation.

A 70‐year‐old immunocompetent male with a history of insomnia presented with pneumonia and bacteremia caused by Bacillus subtilis. The patient took benzodiazepines and regularly consumed alcohol and natto (fermented soybeans). Initial antibiotic treatment was not effective, and bronchoalveolar lavage was performed. Bronchoalveolar lavage fluid (BALF) analysis revealed an increased lymphocytes fraction, and B. subtilis was detected in the BALF. Whole‐genome sequencing confirmed the congruence of the genetic sequences between the strain in the blood culture of the patient, BALF, and strain isolated from the consumed natto, confirming B. subtilis subsp. natto as the causative pathogen of pneumonia and bacteremia. Vancomycin followed by levofloxacin and systemic corticosteroid were used to treat the condition. This case highlights community‐acquired pneumonia and bacteremia caused by B. subtilis subsp. natto, particularly in individuals who consume natto. We report a rare case of pneumonia and bacteremia caused by Bacillus subtilis subsp. natto in an immunocompetent patient. B. subtilis subsp. natto is a gram‐positive spore‐forming bacteria and a subspecies of B. subtilis. Natto is a Japanese traditional food made by fermenting soybeans with B. subtilis subsp. natto which can produce nattokinase.

A 64‐year‐old man was diagnosed with small cell lung cancer (SCLC) with multiple bone and liver metastases and bone marrow metastases. Spontaneous tumour lysis syndrome (TLS) was observed before starting chemotherapy with carboplatin, etoposide, and atezolizumab. The tumour further collapsed, and the patient developed disseminated intravascular coagulation (DIC) on day 4 of chemotherapy. The patient was successfully treated with intravenous hydration and rasburicase for TLS and subcutaneous unfractionated heparin for DIC. A large amount of tissue factor may be released in TLS, which could induce DIC. However, to the best of our knowledge, this is the first report of DIC following TLS in a case of SCLC. DIC following TLS in SCLC is a rare but life‐threatening oncologic complication. Therefore, clinicians should be aware of this possibility when treating patients with advanced SCLC. Disseminated intravascular coagulation (DIC) following tumour lysis syndrome (TLS) is a rare but serious life‐threatening complication that clinicians need to be aware of when treating patients with advanced small cell lung cancer (SCLC). To the best of our knowledge, this is the first report of DIC following TLS in a case of SCLC.

A 76-year-old man was admitted to our hospital with Guillain-Barré syndrome (GBS), presenting with facial palsy, dysarthria, and dysphagia as Grade 3 immune-related adverse events (irAEs) due to pembrolizumab administration for Stage IV lung adenocarcinoma. Although prednisolone (1 mg/kg) was started for GBS due to the irAE, dark erythema and skin eruptions appeared on the patient’s torso. Then erosion was observed on 18% of the body surface area and skin biopsy was performed. Finally, the patient was diagnosed with Stevens-Johnson syndrome/toxic epidermal necrosis overlap. Intravenous immunoglobulin therapy was started, and the skin symptoms improved, with the erosion becoming epithelial. He died of aspiration pneumonia related to GBS, although his neurological symptoms had improved after steroid and intravenous immunoglobulin therapy. This is the first reported case of pembrolizumab-induced GBS and Stevens–Johnson syndrome/toxic epidermal necrosis overlap. It is necessary to be careful that the possibility of other severe irAEs may occur simultaneously.

Five cases of anti‐melanoma differentiation‐associated gene 5 antibody‐positive dermatomyositis‐associated rapidly progressive interstitial lung diseases (anti‐MDA5‐positive DM‐RPILD) following COVID‐19 vaccination have been reported previously. We present the first case of the disease that developed following the sequence of COVID‐19 infection, COVID‐19 vaccination, and 23‐valent pneumococcal polysaccharide vaccine (PPSV23) administration. A 75‐year‐old‐Japanese man received the third dose of Pfizer COVID‐19 vaccine 4 weeks after he had a mild COVID‐19 infection. Eleven weeks after vaccination, he received PPSV23 for the first time. He developed fever, malaise, and anorexia the day after the PPSV23, rash a week later, and shortness of breath 2 weeks later. He was then admitted to a local hospital and treated with antibiotics, but his condition worsened. He was transferred to our hospital 4 weeks after the PPSV23 and was diagnosed with anti‐MDA5‐positive DM‐RPILD. Despite intensive treatment, the patient died on the 10th hospital day. Five cases of anti‐melanoma differentiation‐associated gene 5 antibody‐positive dermatomyositis‐associated rapidly progressive interstitial lung diseases (anti‐MDA5‐positive DM‐RPILD) following COVID‐19 vaccination have been reported previously. We present the first case of the disease that developed following the sequence of COVID‐19 infection, COVID‐19 vaccination, and 23‐valent pneumococcal polysaccharide vaccine (PPSV23) administration.

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.

Background Fungal infections are rarely reported as a complication of bronchial thermoplasty (BT) in patients without immunosuppressive comorbidity. Case presentation A 19-year-old woman college student was admitted to our hospital owing to uncontrolled severe asthma despite using the maximum dose of steroid inhalation. She experienced asthmatic attacks more frequently while cheerleading, which is an extracurricular activity. She received BT because she wanted to continue cheerleading. After the second BT session, she developed more sputum and cough. During the third session, white secretion and saccular bronchodilation appeared in the left lower bronchus. Aspergillus fumigatus was detected in the culture of the bronchial lavage sample, and saccular bronchodilation in the affected bronchus was observed on computed tomography (CT). Five months after the start of oral itraconazole, her subjective symptoms as well as her CT findings improved. Her asthma condition improved enough for the patient to continue cheerleading without exacerbation. Conclusions It is necessary to consider the possibility of respiratory tract infections including fungal infections after BT. Detailed observations of the entire bronchus and sample collection for microbial culture are highly recommended.