Efficacy and safety of macrolide therapy for adult asthma: A systematic review and meta-analysis.

BACKGROUND: The evidence for macrolide therapy in adult asthma is not properly established and remains controversial. We conducted a systematic review and meta-analysis to examine the efficacy and safety of macrolide therapy for adult asthma. METHODS: We searched randomized controlled trials from MEDLINE via the PubMed, CENTRAL, and Ichushi Web databases. The primary outcome was asthma exacerbation. The secondary outcomes were serious adverse events (including mortality), asthma-related quality of life (symptom scales, Asthma Control Questionnaire, and Asthma Quality of Life Questionnaire), rescue medication (puffs/day), respiratory function (morning peak expiratory flow, evening peak flow, and forced expiratory volume in 1 s), bronchial hyperresponsiveness, and minimum oral corticosteroid dose. Of the 805 studies, we selected seven studies for the meta-analysis, which was conducted using a random-effects model. SYSTEMATIC REVIEW REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN000050824). RESULTS: No significant difference between macrolide and placebo for asthma exacerbations was observed (risk ratio 0.71, 95 % confidence interval [CI] 0.46-1.09; p = 0.12). Macrolide therapy for adult asthma showed a significant improvement in rescue medication with short-acting beta-agonists (mean difference -0.41, 95 % CI -0.78 to -0.04; p = 0.03). Macrolide therapy did not show more serious adverse events (odd ratio 0.61, 95 % CI 0.34-1.10; p = 0.10) than those with placebo. The other secondary outcomes were not significantly different between the macrolide and placebo groups. CONCLUSIONS: Macrolide therapy for adult asthma may be more effective than placebo and could be a treatment option.

Entrectinib Response to ROS1-Fusion-Positive Non-Small-Cell Lung Cancer That Progressed on Crizotinib with Leptomeningeal Metastasis: A Case Report.

Introduction: C-ros oncogene 1 (ROS1) translocation is an oncogenic driver-mutation identified in 1-2% of non-small-cell lung cancer (NSCLC) cases. Although crizotinib, a tyrosine kinase inhibitor (TKI) against ALK/ROS1, is known to be effective against ROS1-fusion-positive NSCLC, such cases sometimes progress with brain metastases. The most frequently reported crizotinib-resistance mutation is ROS1 G2032R, and some studies have found that even newly developed ROS1 TKIs, such as entrectinib and lorlatinib, show a decreased efficacy against it. The optimal therapies for ROS1-fusion-positive NSCLC and how such cases can be sequenced have not yet been established. Case Presentation: We herein report a patient with ROS1-fusion-positive NSCLC diagnosed at 34 years old. Crizotinib was started at the diagnosis and switched after 25 months to cisplatin/pemetrexed/bevacizumab once the disease progressed with multiple brain metastases that were resistant to stereotactic radiation therapy. The cytotoxic chemotherapy stabilized the patient's condition for 17 months until he developed leptomeningeal metastasis (LM). He underwent lumboperitoneal shunting and whole-brain radiotherapy, followed by crizotinib re-administration. Despite crizotinib treatment, his neurological symptoms, such as double vision, headache, weakness in the legs, and walking difficulties, progressed. Eventually, subsequent entrectinib treatment was initiated, which resolved all of the symptoms mentioned above. Regrettably, liquid next-generation sequencing had failed to detect the resistance mechanism due to minimal ctDNA in this case. Conclusion: These findings imply that sequential entrectinib administration may be effective in patients with disease progression limited to central nervous system metastases during crizotinib administration.

Association of PD-L1 tumor proportion score ≥20% with early resistance to osimertinib in patients with EGFR-mutated NSCLC.

BACKGROUND: The relationship between epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance, including osimertinib, and programmed cell death-ligand 1 (PD-L1) expression status in EGFR-mutated non-small cell lung carcinoma (NSCLC) remains unclear. PATIENTS AND METHODS: We retrospectively analyzed 64 patients with unresectable advanced or metastatic NSCLC carrying EGFR exon 19 deletions (ex19del) or EGFR exon 21 L858R substitutions (L858R) who received osimertinib as the first-line treatment. We compared progression-free survival (PFS) between eligible patients with PD-L1 tumor proportion scores (TPS) ≥20% and PD-L1 TPS <20% using the Kaplan-Meier survival plots with a log-rank test. Multivariate analysis was performed to examine the poor prognostic factors of PFS. RESULTS: The PD-L1 TPS ≥20% group included 22 cases (median [range] age: 70.5 [33-86] years; 10 women [45.5%]; 11 current or ex-smokers [50%]); ECOG performance status (PS) of 0-1/2/3/4 was noted in 16/4/1/1 patients, respectively. The PD-L1 TPS <20% group included 42 patients (median [range] age 73 [43-88] years; 29 women [69%]; 12 current or ex-smokers [28.6%]); ECOG PS of 0-1/2/3/4 was noted in 33/6/3/0 cases, respectively. The median PFS was 9.1 and 28.1 months in the PD-L1 TPS ≥20% and PD-L1 TPS <20% groups, respectively (log-rank p = 0.013). Multivariate analysis revealed that PD-L1 TPS ≥20% was associated with PFS (hazard ratio: 2.35, 95% confidence interval: 1.09-5.08, p = 0.030). CONCLUSION: PD-L1 TPS ≥20% in patients with EGFR-mutated NSCLC may be associated with early resistance to osimertinib.

The Clinical Significance of Anaerobic Coverage in the Antibiotic Treatment of Aspiration Pneumonia: A Systematic Review and Meta-Analysis.

INTRODUCTION: Aspiration pneumonia is increasingly recognised as a common condition. While antibiotics covering anaerobes are thought to be necessary based on old studies reporting anaerobes as causative organisms, recent studies suggest that it may not necessarily benefit prognosis, or even be harmful. Clinical practice should be based on current data reflecting the shift in causative bacteria. The aim of this review was to investigate whether anaerobic coverage is recommended in the treatment of aspiration pneumonia. METHODS: A systematic review and meta-analysis of studies comparing antibiotics with and without anaerobic coverage in the treatment of aspiration pneumonia was performed. The main outcome studied was mortality. Additional outcomes were resolution of pneumonia, development of resistant bacteria, length of stay, recurrence, and adverse effects. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: From an initial 2523 publications, one randomised control trial and two observational studies were selected. The studies did not show a clear benefit of anaerobic coverage. Upon meta-analysis, there was no benefit of anaerobic coverage in improving mortality (Odds ratio 1.23, 95% CI 0.67-2.25). Studies reporting resolution of pneumonia, length of hospital stay, recurrence of pneumonia, and adverse effects showed no benefit of anaerobic coverage. The development of resistant bacteria was not discussed in these studies. CONCLUSION: In the current review, there are insufficient data to assess the necessity of anaerobic coverage in the antibiotic treatment of aspiration pneumonia. Further studies are needed to determine which cases require anaerobic coverage, if any.

Programmed cell death ligand 1 measurement study in granulocyte colony-stimulating factor-producing lung cancer: an observational study.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF)-producing lung cancer induces severe inflammation and a high white blood cell (WBC) count and is associated with poor prognosis. A recent case of G-CSF-producing lung adenocarcinoma showed high expression of programmed cell death ligand 1 (PD-L1) and was treated with pembrolizumab as first-line therapy, which was extremely effective. We hypothesized that G-CSF-producing lung cancers are associated with high PD-L1 expression. METHODS: This retrospective study included patients diagnosed with lung cancer at Yokohama Municipal Citizen's Hospital (Kanagawa, Japan) between 2009 and 2019. The PD-L1 status of 13 patients with high plasma G-CSF levels (≥40 pg/mL) was assessed by conducting immunohistochemical analysis of tissue samples. RESULTS: Of the total patients, 11 were men and 2 were women, with a median age of 74 years (70-85 years). Four, five, and three patients had adenocarcinoma, squamous cell carcinoma, and others, respectively. The median G-CSF level and WBC count were 85.5 pg/mL (range, 40.8-484 pg/mL) and 15,550/µL (range, 6,190-56,800/µL), respectively. The PD-L1 tumor proportion scores (TPSs) were ≥50%, 1%-49%, and <1% in 9, 1, and 3 patients, respectively. The median overall survival time was 7.3 months. Pembrolizumab was administered in six patients as first-line treatment, with two patients showing partial response, one patient with stable disease, and three patients with progressive disease. All six patients had a PD-L1 TPS of ≥50%. CONCLUSION: G-CSF-producing lung cancers may be associated with increased PD-L1 expression. Although immune checkpoint inhibitors are an important treatment option for G-CSF-producing tumors, their effects are limited.

A case of slowly progressive malignant pericardial mesothelioma suggesting the involvement of BAP1 loss.

Malignant pericardial mesothelioma (MPM) is a rare tumour that arises from the mesothelial cells of the pericardium. No standard treatment has been established owing to a poor treatment response; therefore, MPM has a poor prognosis. We herein report a rare case of MPM in a 70-year-old man that was diagnosed immunohistopathologically using cell block sections of pericardial fluid and in which long-term survival for more than 3 years was achieved with only periodic pericardial drainage. Immunohistopathological staining investigations, especially BRCA1-associated protein 1 (BAP1) immunostaining using cell block sections of pericardial effusion, are effective in making a diagnosis of MPM. Well-differentiated papillary mesothelioma (WDPM) with BAP1 loss progresses to MPM in the long term, showing that BAP1 loss may induce phenotypical evolution of WDPM. BAP1 loss may also progress to malignant mesothelioma in situ and then to invasive mesothelioma. BAP1 immunohistochemistry should be considered for the early diagnosis of MPM.

Acute pancreatitis or severe increase in pancreatic enzyme levels following remdesivir administration in COVID-19 patients: an observational study.

Remdesivir has been shown to reduce recovery time and mortality among patients with coronavirus disease 2019 (COVID-19). However, data regarding the efficacy and safety of remdesivir use are limited in Japan. We conducted a single-center retrospective cohort study at Yokohama Municipal Citizen's Hospital, Kanagawa, Japan. Patients with COVID-19 pneumonia treated with remdesivir were included. The onset of acute pancreatitis and increased pancreatic enzyme levels and clinical, laboratory, treatment, and outcome data were collected and analyzed. A total of 201 patients were included. Among the 201 patients treated with remdesivir, 177 recovered from COVID-19. Increased pancreatic enzyme levels of grade 3 or higher or acute pancreatitis developed in 23 of the 201 patients. The potential etiopathogenetic effects of remdesivir on increased pancreatic enzyme levels of grade 3 or higher or acute pancreatitis were ascertained by reviewing the characteristics of patients hospitalized for COVID-19 who did not receive remdesivir treatment. Only 3 of 159 patients had increased pancreatic enzyme levels of grade 3 or higher during the treatment course. Multivariate analysis indicated remdesivir administration and severe COVID-19 infection by National Institute of Health standards as independent risk factors. Acute pancreatitis and severe increases in pancreatic enzyme levels were observed among patients with COVID-19 treated with remdesivir.

A case of pulmonary tumor thrombotic microangiopathy following lymphedema on the lower extremities.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare manifestation of malignancy. The antemortem diagnosis is difficult, since patients present with rapidly progressive symptoms. We recently observed a case of PTTM following lymphedema of the lower extremities. We did not reach a diagnosis, even after performing BAL and TBLB. The patient manifested pulmonary hypertension and died on the 9th day of admission. Autopsy revealed a tumor embolism in the pulmonary arterioles accompanied by fibrocellular epithelial cell proliferation, but the primary organ was not identified. To our knowledge, this is the first reported case of PTTM with lymphedema.

High variability in results and methodological quality among overlapping systematic reviews on the same topics in surgery: a meta-epidemiological study.

BACKGROUND: Redundant publication of systematic reviews and meta-analyses (SRs/MAs) on the same topic presents an increasing burden for clinicians. The aim of this study was to describe variabilities in effect size and methodological quality of overlapping surgery-related SRs/MAs and to investigate factors associated with their postpublication citations. METHODS: PubMed/MEDLINE was searched to identify SRs/MAs of RCTs on thoracoabdominal surgeries published in 2015. Previous SRs/MAs on the same topics published within the preceding 5 years (2011-2015) were identified and 5-year citation counts (through to 2020) were evaluated. Discrepancies in pooled effect sizes and their methodological quality using A Measurement Tool to Assess Systematic Reviews (AMSTAR) among overlapping SRs/MAs were assessed. The SR/MA-level factors associated with 5-year citation counts were explored, using a mixed-effects regression model with a random intercept for surgical topics. RESULTS: A total of 57 surgery-related SRs/MAs (48 topics) published in 2015 were identified, and 146 SRs/MAs had overlapping publications on 29 topics (60.4 per cent of all topics) in the preceding 5 years. There was considerable variability in methodological quality of SRs/MAs and coverage probability for relevant RCTs, resulting in discrepant effect size estimates for the same topic. High quality (AMSTAR score 8-11) was independently associated with higher 5-year citation counts (coefficient = 32.82; 95 per cent c.i. 15.63 to 50.02; P < 0.001). CONCLUSION: Overlapping SRs/MAs with high variability in results and methodological quality were common in surgery. A high-quality SR/MA score was an independent predictor of more frequent citations. Researchers and journal editors should concentrate their efforts on limiting publications to higher-quality reviews.

Legionella pneumophila pneumonia with rapid clinical course in a lung cancer patient.

We report an acute clinical course of pneumonia caused by Legionella pneumophila in a patient receiving chemotherapy for lung cancer and corticosteroid therapy. A 57-year-old man presented with fever and dyspnoea and was admitted to our hospital. Chest computed tomography revealed a new left lower lung infiltrate, tumour progression in the right upper lung region, metastases to lymph nodes and pleural effusion. The urinary antigen test for Legionella was positive. The patient's oxygen requirement increased on the day of admission, and he died the day after hospitalization. Legionnaires' disease may manifest with an acute presentation, and patients in Japan with physical risk factors for this disease could get infected despite the absence of environmental risk factors. Early treatment for suspected Legionnaire's disease should be considered.

Examination of endobronchial ultrasound-guided transbronchial needle aspiration using a puncture needle with a side trap.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is useful for diagnosing hilar and mediastinal lymph node enlargement; however, specimens obtained are often small and inadequate for pathologic diagnosis. In June 2017, EchoTip ProCore, a puncture needle with a side trap, was launched in Japan. In this single-center prospective interventional study, 57 patients with lymph nodes, intrapulmonary tumor or pleural mass were diagnosed using EBUS-TBNA with EchoTip ProCore between June 2017 and February 2020. EBUS-TBNA was performed for 57 patients and 53 patients had sufficient specimen for histologic diagnosis. The following pathologic subtypes were diagnosed: non-small cell lung cancer, 22; small cell lung cancer, 8; cancer of unknown primary, 2; neuroendocrine tumor (G2) recurrence, 1; lymphoma, 2; metastatic renal cell carcinoma, 3; thymoma recurrence, 1; sarcoidosis, 4; tuberculosis, 1; and non-malignancy, 9. In addition, the cytology showed Class V in 31 out of 57 cases (54.4%). In total, a definitive pathological diagnosis was obtained in 50 out of 57 cases (87.7%). The only complication was pneumonia caused by BAL simultaneously combined with EBUS-TBNA in one patient. Among 13 patients with inadequate specimens or without malignancy, only one patient was subsequently diagnosed with malignancy, and the median follow-up period was 300 days. EBUS-TBNA using EchoTip ProCore can obtain a sufficient specimen size for pathologic diagnosis.

Association of early antibiotic therapy and in-hospital mortality in adult mild-to-moderate acute aspiration pneumonitis: a cohort study.

BACKGROUND: Patients with aspiration pneumonitis often receive empiric antibiotic therapy despite it being due to a non-infectious, inflammatory response. OBJECTIVE: To study the benefits of early antibiotic therapy in patients with suspected aspiration pneumonitis in an acute care hospital. DESIGN: Retrospective cohort study using electronic medical records from Teine Keijinkai Hospital. PARTICIPANTS: Adults aged over 18 years admitted with a diagnosis of aspiration pneumonitis to the Department of General Internal Medicine or Emergency Department between January 1, 2008, and May 31, 2019. A diagnosis of aspiration pneumonitis was defined as a documented macro-aspiration event and a chest radiograph demonstrating new radiographic infiltrates. MAIN MEASURES: Patients were classified into the "early antibiotic treatment" group and the "no or late treatment" group depending on whether they received antibiotic therapy for respiratory bacterial pathogens within 8 h of arrival. The primary outcome was in-hospital all-cause mortality. Secondary outcomes included length of hospital stay, antibiotic-free days, duration of fever, readmission within one month, and incidence of complications. KEY RESULTS: Of the 146 patients enrolled, 52 (35.6%) did not receive early antibiotic therapy, while the remaining 94 (64.4%) did. There was no difference in in-hospital mortality rates between the groups after adjustment for potential confounding variables using Cox proportional hazards analysis (hazard ratio 2.78; 95% confidence interval, 0.57-13.50, p = 0.20). Patients in the no or late treatment group had more antibiotic-free days (p < 0.001) and a shorter length of hospital stay among survivors (p = 0.040) than did those in the early antibiotic treatment group. There were no statistically significant differences between the groups with respect to other secondary outcomes. CONCLUSIONS: Early antibiotic therapy for acute aspiration pneumonitis was not associated with in-hospital mortality, but was associated with a longer hospital stay and prolonged use of antibiotics.