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Background Diffuse alveolar hemorrhage (DAH) is a syndrome resulting from bleeding in the microcirculation of the lung, with a poor prognosis. The study aim was to identify prognostic factors of DAH, especially bronchoalveolar lavage fluids (BALF) cell pattern. Methods We conducted a single-center retrospective cohort study of patients diagnosed as having DAH and hospitalized at our hospital between October 2008 and July 2020. We performed univariate logistic regressions to identify variables associated with in-hospital death. Results Sixty-eight patients were included in our analysis. In-hospital mortality was 26.5%. Variables associated with in-hospital death were neutrophils percentage in BALF ≥ 44.5% [Odds Ratio (OR) 16.0, 95% confidence interval (CI) 4.33–58.9)], lymphocytes percentage in BALF < 14% (OR 7.44, 95% CI 2.11–26.2), idiopathic DAH (OR 0.31, 95% CI 0.10–0.95), oxygen flow ≥ 4L/min (OR 3.90, 95% CI 1.20–12.6), and estimated glomerular filtration rate < 60 mL/min (OR 5.00, 95%CI 1.29–19.4). Conclusions High neutrophils and low lymphocytes percentages in BALF were associated with poor prognosis.

Circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) is a complementary and alternative test to tissue-based NGS. We performed NGS analysis of ctDNA samples collected from patients with EGFR -mutated non-small cell lung cancer (NSCLC) who received osimertinib; the samples were collected after second-line treatment, before osimertinib treatment, one week and one month after osimertinib treatment, and at the time of resistance formation. We examinedthe correlation with osimertinib efficacy. From January to December 2018, 34 patients with EGFR -mutated NSCLC harboring EGFR T790M mutations were enrolled, and a total of 132 peripheral blood samples were collected. The fragment sizes of EGFR -mutated ctDNAs were significantly shorter than that of their corresponding normal fragments. Osimertinib treatment of patients with shorter EGFR -mutated ctDNA fragments resulted in shorter progression-free survival (PFS). The disappearance time of EGFR -mutated fragment fractions and clonal evolution patterns (new driver mutation group, additional mutation group vs. attenuation group) were each associated with the PFS achieved with osimertinib treatment; however,multivariate analysis revealed that only shorter EGFR -mutated ctDNA fragments were associated with the PFS resulting from osimertinib treatment. EGFR -mutated ctDNA fragment size, time of disappearance of these fragments, and clonal evolution pattern were related to the effects of osimertinib. In particular, short EGFR -mutated ctDNA fragmentation may be closely related to osimertinib efficacy prediction.

Mucinous adenocarcinoma, a very rare type of thymic carcinoma, is aggressive and has a poor prognosis. The optimal treatment for advanced thymic mucinous adenocarcinoma has not yet been established because of its rarity. An oral multi-tyrosine kinase inhibitor, lenvatinib, was approved for treatment of thymic carcinoma in March 2021 in Japan. However, to the best of our knowledge, there are no published reports concerning lenvatinib for thymic mucinous adenocarcinoma. Herein, we report a 39-year-old woman who presented with a 70 mm multilocular cystic tumor in her left anterior mediastinum and a massive pericardial effusion. We diagnosed a Masaoka stage IVb thymic mucinous adenocarcinoma with multiple metastases to the liver and bones, and pericardial dissemination on the basis of the pathologic findings on examination of a video-assisted thoracoscopic tumor biopsy and radiological examinations. She received paclitaxel–carboplatin-based chemotherapy, but developed a left cerebellar metastasis. Second-line chemotherapy with lenvatinib failed to suppress the tumor. She died of cancer progression 5 months after presentation. Here, we report what we believe to be the first case of a thymic mucinous adenocarcinoma treated with lenvatinib. Our patient’s thymic mucinous adenocarcinoma was refractory to both cytotoxic chemotherapy and lenvatinib. Using next-generation sequencing, we identified phosphatidylinositol 3-kinase catalytic subunit alpha mutation in the tumor. We suspected an association between this mutation and resistance to lenvatinib. We therefore recommend performing next-generation sequencing when considering introduction of lenvatinib for thymic mucinous adenocarcinoma. A surgical procedure may be necessary for accurate diagnosis and genetic analysis of this histological tumor type.

Osimertinib-induced cardiotoxicity is a well-known but rare disorder. An 84-year-old woman was diagnosed with recurrence of lung adenocarcinoma showing an epidermal growth factor receptor mutation of exon 19 deletion, which was initially treated by curative-intent thoracic radiotherapy 4 years prior. She started taking osimertinib (80 mg/day). She had no history of heart disease and showed no signs of cardiac problems. However, 2 months later she presented with symptoms of cardiac failure and QT prolongation on electrocardiogram. Cardiac enzyme levels were not elevated and coronary computed tomography angiography showed no significant stenosis. On admission, sudden-onset torsade de pointes required electrocardioversion. Thus, drug-induced cardiac failure was strongly suspected and we stopped osimertinib therapy. Cardiac function and the electrocardiogram abnormality improved. To our knowledge, this is the third case of coincidence of cardiac failure and QT prolongation and the second case of sudden-onset torsade de pointes associated with osimertinib treatment. In our case, osimertinib-induced cardiac failure with QT prolongation was recovered by stopping the drug treatment. The potential for cardiotoxicity should be considered with osimertinib treatment.

Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology with few treatment options. Although tetraspanins are involved in various diseases, their roles in fibrosis have not been determined. To investigate the role of tetraspanin CD151 in pulmonary fibrosis. CD151 knockout (KO) mice were studied by histological, biochemical, and physiological analyses and compared with wild-type mice and CD9 KO mice. Further mechanistic analyses were performed in vitro, in vivo, and on samples from patients with IPF. A microarray study identified an enrichment of genes involved in connective tissue disorders in the lungs of CD151 KO mice, but not in CD9 KO mice. Consistent with this, CD151 KO mice spontaneously exhibited age-related pulmonary fibrosis. Deletion of CD151 did not affect pulmonary fibroblast functions but instead degraded epithelial integrity via attenuated adhesion strength on the basement membrane; CD151-deleted alveolar epithelial cells exhibited increased α-SMA expression with activation of p-Smad2, leading to fibrotic changes in the lungs. This loss of epithelial integrity in CD151 KO lungs was further exacerbated by intratracheal bleomycin exposure, resulting in severe fibrosis with increased mortality. We also observed decreased numbers of CD151-positive alveolar epithelial cells in patients with IPF. CD151 is essential for normal function of alveolar epithelial cells; loss of CD151 causes pulmonary fibrosis as a result of epithelial disintegrity. Given that CD151 may protect against fibrosis, this protein represents a novel target for the treatment of fibrotic diseases.

Chronic fibrosing idiopathic interstitial pneumonia (IIP) can be divided into two main types: idiopathic pulmonary fibrosis (IPF), a steroid-resistant and progressive disease with a median survival of 2–3 years, and idiopathic non-specific interstitial pneumonia (INSIP), a steroid-sensitive and non-progressive autoimmune disease. Although the clinical courses of these two diseases differ, they may be difficult to distinguish at diagnosis. We performed a comprehensive analysis of serum autoantibodies from patients definitively diagnosed with IPF, INSIP, autoimmune pulmonary alveolar proteinosis, and sarcoidosis. We identified disease-specific autoantibodies and enriched KEGG pathways unique to each disease, and demonstrated that IPF and INSIP are serologically distinct. Furthermore, we discovered a new INSIP-specific autoantibody, anti–myxovirus resistance-1 (MX1) autoantibody. Patients positive for anti-MX1 autoantibody constituted 17.5% of all cases of chronic fibrosing IIPs. Notably, patients rarely simultaneously carried the anti-MX1 autoantibody and the anti–aminoacyl-transfer RNA synthetase autoantibody, which is common in chronic fibrosing IIPs. Because MX1 is one of the most important interferon-inducible anti-viral genes, we have not only identified a new diagnostic autoantibody of INSIP but also obtained new insight into the pathology of INSIP, which may be associated with viral infection and autoimmunity.

Background Epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) therapy is the standard treatment for advanced non‐small cell lung cancer (NSCLC) harboring common EGFR mutations, such as exon 19 deletion or L858 point mutation. However, the effectiveness of EGFR‐TKIs for patients with uncommon EGFR mutations remains unclear. Methods We retrospectively surveyed a consecutive database of NSCLC patients with EGFR mutations at five participating institutions. Data from NSCLC patients with uncommon mutations (including single or compound mutations), who were treated with systemic therapy between May 2016 and October 2018, were collected and analyzed. Results A total of 23 of the 524 patients whose data were collected had uncommon EGFR mutations. Of these, 22 received EGFR‐TKIs (gefitinib = 6, erlotinib = 4, and afatinib = 12). Patients who received first EGFR‐TKIs had overall response and disease control rates of 59.1% and 81.8%, respectively. The median progression‐free survival (PFS) of patients with G719X mutation (n = 13, median PFS = 32.9 months) was favorable, compared with those of patients with L861Q mutation (n = 4, median PFS = 6.4 months) and compound mutations (n = 4, median PFS = 7.3 months). The PFS of patients who received first‐ and second‐generation EGFR‐TKIs was 14.0 months (n = 10) and 7.3 months (n = 12), respectively. The median cumulative duration of treatment (DOT) with EGFR‐TKIs was 30.4 months, which was longer than those of cytotoxic chemotherapy (median DOT = 10.7 months) or immune checkpoint inhibitors (median DOT = 6.6 months). Conclusions EGFR‐TKIs elicit favorable responses and contribute to long‐term disease control in NSCLC patients with uncommon EGFR mutations. Key points Significant findings of the study: Our results demonstrate that both first‐ and second‐generation EGFR‐TKIs elicit favorable responses in NSCLC patients with uncommon EGFR mutations. What this study adds This study revealed all clinical courses for NSCLC patients with uncommon EGFR mutations. In addition to EGFR‐TKIs, CCT and ICIs were found to contribute to long‐term disease control in this cohort. This study revealed all clinical courses for NSCLC patients with uncommon EGFR mutations. In addition to EGFR‐TKIs, cytotoxic chemotherapy (CCT) and immune checkpoint inhibitors (ICIs) contributed to long‐term disease control in this cohort.

Small-cell lung cancer (SCLC) easily recurs with a multidrug resistant phenotype. However, standard therapeutic strategies for relapsed SCLC remain unestablished. We found that human epidermal growth factor receptor 2 (HER2) is not only expressed in pretreated human SCLC specimens, but is also upregulated when HER2-positive SCLC cells acquire chemoresistance. Trastuzumab induced differential levels of antibody-dependent cell-mediated cytotoxicity (ADCC) to HER2-positive SCLC cells. Furthermore, as a mechanism of the differential levels of ADCC, we have revealed that coexpression of intracellular adhesion molecule (ICAM)-1 on SCLC cells is essential to facilitate and accelerate the trastuzumab-mediated ADCC. Although SN-38–resistant SCLC cells lacking ICAM-1 expression were still refractory to trastuzumab, their in vivo growth was significantly suppressed by bevacizumab treatment due to dependence on their distinctive and abundant production of vascular endothelial growth factor. Collectively, stepwise treatment with trastuzumab and bevacizumab is promising for the treatment of chemoresistant SCLC.

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of surfactants in the alveoli. It has been suggested that immunosuppressants contribute to the development and exacerbation of PAP. Here, we report the case of a 73-year-old man who developed secondary PAP after intensive immunosuppressive treatment for acute exacerbation of interstitial pneumonia (IP). In this case, despite the improvement of the inflammatory response after immunosuppressive treatment, Krebs von den Lungen-6 (KL-6) continued to increase, leading to the diagnosis of PAP. De-escalation of immunosuppressive treatment improved the PAP, allowing him to be discharged from the hospital. Although KL-6 is a useful marker of IP, when IP appears to be refractory and KL-6 increases despite the improvement of other inflammatory markers, physicians should consider the development of PAP and perform proactive bronchoscopic evaluation.

Abstract We report the case of a 68-year-old woman with Stage III and Class II rheumatoid arthritis (RA) that was resistant to prednisolone, methotrexate, and infliximab. After treatment with etanercept or tocilizumab, suspicious allergic bronchopulmonary aspergillosis (ABPA) repeatedly occurred and then rapidly improved after the withdrawal of each drug. We suspect that administration of etanercept and tocilizumab caused suspicious ABPA in this patient. The relevance to the pathogenesis of ABPA under these biological drugs is also discussed.