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Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.

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.

Background Helicobacter cinaedi is a microaerobic Gram-negative spiral-shaped bacterium that causes enteritis, cellulitis, and bacteremia in both immunocompromised and immunocompetent patients. While there have been increasing numbers of reported H. cinaedi infections recently, there has been no thyroid abscess case caused by H. cinaedi presenting with thyroid storm. Case presentation A 50-year-old Japanese man presented with a 9-day history of high fever associated with palpitations, dry cough, and chronic diarrhea. The patient had a history of Basedow’s disease that had been treated with thiamazole in the past. During the current episode, the patient was diagnosed with thyroid storm and treated accordingly. The blood culture taken on admission was positive for H. cinaedi . This finding was confirmed by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOFMS). A systemic computed tomography (CT) scan revealed a thyroid abscess as the site of infection and cause of the bacteremia. The 16S rRNA gene sequencing identified the pathogen of thyroid abscess as H. cinaedi . Clinical symptoms and laboratory data normalized on admission day 7 after treatment with both effective antibiotics and antithyroid drugs. Conclusions The case study described a patient with a history of Basedow’s disease that presented with a thyroid abscess caused by H. cinaedi with symptoms similar to those of thyroid storm. While this bacterium has been implicated in other infections, we believe this is the first time the bacteria has been documented to have caused a thyroid abscess.

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.

PurposeContinuous positive airway pressure (CPAP) therapy improves subjective symptoms in obstructive sleep apnea syndrome (OSAS) patients; however, factors predicting symptom improvement post-CPAP therapy and the CPAP duration necessary for improving subjective symptoms are unclear. This study aimed to identify these factors and the appropriate nightly CPAP duration for improving subjective symptoms.MethodsWe recruited 359 subjects who completed both overnight polysomnography and subjective symptom assessments using the Epworth Sleepiness Scale (ESS), Zung Self-Depression Scale (SDS), and Pittsburgh Sleep Quality Index (PSQI). Firstly, we analyzed subject characteristics, and the associations between each assessment score and the Apnea-Hypopnea Index. These assessments were then repeated for 138 subjects who could continue for 3 months after starting CPAP. Secondly, associations between changes in self-reported outcome measures and nightly CPAP duration were analyzed. We identified subjects with abnormal initial ESS, PSQI, and SDS scores and divided them into “improvement” and “non-improvement” groups to examine factors associated with a positive outcome after CPAP therapy.ResultsSubjective symptom scores and proportions of subjects exceeding the cutoff values of each symptom score were not significantly related to OSAS severity. ESS, SDS, and PSQI scores improved 3 months after CPAP treatment, and factors involved in each improvement were found. Remarkably, longer CPAP nightly duration resulted in improvements in all subjective symptom scores. Furthermore, minimum durations between 4.75 and 5.40 h were necessary for improvements in subjective symptoms based on ROC curve analysis.ConclusionsLonger nightly CPAP use significantly improved OSAS subjective symptoms.

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.

BackgroundNo consensus has been reached regarding the treatment order and timing of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and cytotoxic chemotherapy administration for EGFR mutation-positive non-small cell lung cancer (NSCLC) patients.MethodsIn this phase II trial, chemotherapy-naïve patients harboring activating EGFR mutations with stage IIIB/IV or post-surgical recurrent non-squamous NSCLC were enrolled. Patients were treated with erlotinib induction at 150 mg/day for 3 months. This was followed by cytotoxic chemotherapy with platinum plus pemetrexed, with or without bevacizumab, when the induction erlotinib achieved a CR or PR. The primary end point was the 1-year progression-free survival (PFS) rate, while the secondary end points were the response rate (RR), PFS, safety, and overall survival (OS).ResultsTwenty patients were enrolled in this study. The median age was 63 years. Eighteen patients had stage IV disease, and 2 patients had recurrent disease. Eleven patients achieved a PR after induction of erlotinib and 9 out of 11 patients were switched to chemotherapy. The 1-year PFS rate was 45.0% (90% CI 26.8–63.2), the overall RR was 55.0%, and the median PFS was 10.7 months in the intention-to-treat (ITT) population. Grade 3–4 adverse events were reported for 40% of the patients, including patients with leukopenia (10%), neutropenia (20%), and interstitial pneumonitis, bacterial pneumonia, rash, and nausea (all 5%).ConclusionsThe primary end point of this study was not achieved. However, the therapy was well tolerated and may be a treatment option for a future study with patients responsive to short-term erlotinib treatment.Clinical trials registration numberUMIN ID: 000013125.