Risk factors and interventions for developing recurrent pneumonia in older adults.

Background: Pneumonia is common among older adults and often recurrent. Several studies have been conducted on the risk factors for pneumonia; however, little is known about the risk factors for recurrent pneumonia. This study aimed to identify the risk factors for developing recurrent pneumonia among older adults and to investigate methods of prevention. Methods: We analysed the data of 256 patients aged 75 years or older who were admitted for pneumonia between June 2014 and May 2017. Moreover, we reviewed the medical records for the subsequent 3 years and defined the readmission caused by pneumonia as recurrent pneumonia. Risk factors for recurrent pneumonia were analysed using multivariable logistic regression analysis. Differences in the recurrence rate based on the types and use of hypnotics were also evaluated. Results: Of the 256 patients, 90 (35.2%) experienced recurrent pneumonia. A low body mass index (OR: 0.91; 95% CI: 0.83‒0.99), history of pneumonia (OR: 2.71; 95% CI: 1.23‒6.13), lung disease as a comorbidity (OR: 4.73; 95% CI: 2.13‒11.60), taking hypnotics (OR: 2.16; 95% CI: 1.18‒4.01) and taking histamine-1 receptor antagonist (H1RA) (OR: 2.38; 95% CI: 1.07‒5.39) were risk factors. Patients taking benzodiazepine as hypnotics were more likely to experience recurrent pneumonia than patients not taking hypnotics (OR: 2.29; 95% CI: 1.25-4.18). Conclusion: We identified several risk factors for recurrent pneumonia. Among them, restricting the use of H1RA and hypnotics, in particular benzodiazepines, may be useful in preventing the recurrence of pneumonia in adults aged 75 years or older.

[HUMIDIFIER LUNG WITH ORGANIZING PNEUMONIA DETECTED BY BRONCHOSCOPY: A CASE REPORT].

A 58-year-old man presented with dyspnea on exertion and diffuse ground-glass opacities with mosaicism on chest computed tomography in April 201X. A transbronchial lung biopsy revealed organizing pneumonia and lymphocytic infiltration, and steroids were administered. During steroid tapering, the shortness of breath and ground-glass opacities recurred, and a transbronchial lung re-biopsy revealed organizing pneumonia without a granuloma again. Based on the clinical history, imaging features, and amount of humidifier usage, hypersensitivity pneumonitis caused by a humidifier was suspected. The inhalation challenge test was considered positive, and the diagnosis was confirmed. There have been some reports of unidentified granuloma in patients with humidifier lungs. Therefore, this case suggests that humidifier lung should be considered as a possibility even if pathological examination does not reveal granulomas and inflammatory changes such as organizing pneumonia are the only findings.

Prognostic Model of Baseline Medications plus Neutrophil-to-lymphocyte Ratio in Patients with Advanced Non-small-cell Lung Cancer Receiving Immune Checkpoint Inhibitor plus Platinum Doublet: A Multicenter Retrospective Study.

Background: Association between baseline medications plus neutrophil-to-lymphocyte ratio (NLR) and the effectiveness of immune checkpoint inhibitor (ICI) plus platinum doublet remains unknown, despite several reported prognostic models. We used real-world data to investigate whether baseline medications plus NLR predict survival outcomes in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICI plus platinum doublet. Methods: This multicenter, retrospective, observational study conducted in Japan between December 2018 and March 2021 used real-world data of consecutive patients with advanced NSCLC who received ICI (pembrolizumab or atezolizumab) plus platinum doublet as first-line treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The prognostic score for baseline medications plus NLR was weighted by regression ß coefficients and used to categorize patients into good, intermediate, and poor prognoses groups. In addition, time-dependent receiver operating characteristic curve analyses and univariable and multivariable Cox proportional hazards models were constructed. Results: Overall, 241 patients were included. Poor prognosis was significantly associated with worse PFS (hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.08-2.94; P = 0.025) and OS (HR: 3.59; 95% CI: 2.05-6.28; P < 0.001) than good prognosis. Harrell's C-index for this prognostic model was 0.648. Conclusions: Baseline medication plus NLR could predict progressively worse survival outcomes in patients with advanced NSCLC receiving ICI plus platinum doublet and could be used as a prognostic index for poor outcomes.

Primary bronchial schwannoma: A case report.

RATIONALE: Bronchial schwannomas are extremely rare among the benign tracheobronchial tumors and little are known about its epidemiology and optimal clinical management. Here, we report a case of bronchial schwannoma in a young Japanese man and clinical implications about epidemiology, symptom, diagnosis, and treatment of bronchial schwannoma. PATIENTS CONCERN: A 37-year-old man visited our department with a nodule incidentally found on his chest radiograph during a routine medical checkup. DIAGNOSIS: The tumor was diagnosed as a bronchial schwannoma after pathological evaluation. Microscopically, the tumor consisted of spindle cell proliferation characterized by an alternating highly ordered cellular Antoni A component with occasional nuclear palisading and a loose myxoid Antoni B component. Tumor cells were immunoreactive for S100 but not for smooth muscle actin or KIT. INTERVENTIONS: A video-assisted right middle and lower bilobectomy was performed. OUTCOME: He remains under observation without recurrence. LESSONS: In our review, many reports have come from Asian countries. Bronchial schwannoma can occur within a wide range of age groups and in both men and women. No difference in incidence was observed between right and left bronchial tree. Bronchial schwannoma is sometimes difficult to differentiate from malignant diseases. We should include bronchial schwannoma as one of the differential diagnoses of primary bronchial tumors.

Disseminated cryptococcosis in a renal transplant recipient.

Skin cryptococcosis often manifests as an umbilicated papule, and chest computed tomography findings of multiple nodules and cavities are also characteristic. The combination of characteristic cutaneous manifestations and radiological findings can help clinicians make an "at-a-glance" diagnosis of disseminated cryptococcosis.

Myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis with a unique imaging presentation of organizing pneumonia: A case report.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes a group of blood vessel inflammation diseases of autoimmune origin. Myeloperoxidase (MPO) ANCA is closely related to ANCA associated AAV. The MPO-ANCA positive AAV patients have lung involvement at high rates; however, there are only a few reported cases with organizing pneumonia (OP). A 78-year-old man was presented to our hospital due to a fever of 38 °C despite a whole month of antibiotics treatment. Chest computed tomography image revealed restricted consolidations visible in the middle lobe of the right lung and the upper lobe of the left lung, which suggested an OP pattern. MPO-ANCA and urine occult blood tests were positive. Histopathological examination of the transbronchial biopsy revealed OP and mucus plug. Histological findings on renal biopsy showed necrotizing glomerulonephritis related to AAV. The patient was diagnosed with MPO-ANCA positive AAV and was treated with systemic corticosteroid therapy, from which he recovered rapidly. Thus, when diagnosing OP, the possibility of AAV should be considered by ordering patients' serum ANCA and occult hematuria tests.

NRXN1 as a novel potential target of antibody-drug conjugates for small cell lung cancer.

Small cell lung cancer (SCLC) is a high-grade malignancy, and treatment strategies have not changed for decades. In this study, we searched for novel targets for antibody-drug conjugate (ADC) therapy for SCLC. We identified transmembrane proteins overexpressed specifically in SCLC with little or no expression in normal tissues and decided to focus on the cell adhesion molecule neurexin-1 (NRXN1). The cell surface overexpression of NRXN1 was confirmed using flow cytometry in SCLC cell lines (SHP77 and NCI-H526). The combination of a primary anti-NRXN1 monoclonal antibody and a secondary ADC exhibited anti-tumor activity in SCLC cell lines. Moreover, the knockout of NRXN1 in SHP77 cells resulted in a loss of the anti-tumor activity of NRXN1-mediated ADC therapy. Thus, NRXN1 could be a novel target for ADC therapy for the treatment of SCLC that is worth further research.

Preoperative intervention with long-acting bronchodilators for the reduction of postoperative pulmonary complications in untreated patients with obstructive lung disease.

BACKGROUND: Obstructive lung disease (OLD) is a risk factor for postoperative pulmonary complications (PPC) and is incidentally discovered during preoperative evaluation. The key treatments for OLD are inhaled long-acting bronchodilators (LAB). However, the advantage of preoperative bronchodilator treatment for patients with OLD remains unclear. The aim of this study is to elucidate the effect of preoperative LAB treatment in patients with untreated OLD on postoperative outcomes. METHODS: In this propensity-matched cohort study, we included patients who were referred to the pulmonologists for untreated OLD. The patients were either treated with LAB or left untreated. The primary outcome was the incidence of prolonged oxygen therapy (>3 days) in the postoperative period. We evaluated patients' characteristics with and without the use of LAB using propensity score (PS) matching weight. Subsequently, the outcomes in the two groups were compared. RESULTS: We analysed 614 patients; 132 patients were part of the LAB group and 482 were included in the control group. In the crude analysis, the incidence of prolonged oxygen therapy was higher in the LAB group than in the control group (odds ratio [OR] = 1.35; P = 0.04). However, after PS matching weight, no statistically significant differences in prolonged oxygen therapy (OR = 1.15), incidence of prolonged intensive care unit stay, endotracheal re-intubation postoperatively and in-hospital death between the groups were identified. CONCLUSION: There is a limited benefit of preoperative treatment with inhaled LAB for the reduction of PPC in patients with untreated OLD.

Integrin α11 in non-small cell lung cancer is associated with tumor progression and postoperative recurrence.

Integrins are transmembrane proteins that mediate cell adhesion to the extracellular matrix. Integrin α11 (ITGA11) is not expressed in normal alveolar epithelial cells and is a known receptor for collagen. While integrin α11ß1 overexpression in the tumor stroma has been associated with tumor growth and metastatic potential of non-small cell lung cancer (NSCLC), little is known about the role of ITGA11 in tumor cells. Thus, we examined the RNA expression of ITGA11 by quantitative RT-PCR in 80 samples collected from NSCLC patients who had undergone surgical resection and analyzed the clinical outcomes. We found that high expression of ITGA11 was associated with lower recurrence-free survival in all NSCLC patients (P = 0.043) and in stage I NSCLC patients (P = 0.049). These results were consistent with in silico analyses of the Cancer Genome Atlas database. We also analyzed cell proliferation, migration and invasion capacity in lung cancer cell lines after overexpression of ITGA11. Overexpression of ITGA11 in lung cancer cell lines had little effect on cell proliferation but resulted in increased migration and invasion capacity. Our findings suggest that ITGA11 plays a significant role in cancer migration and invasion, leading to higher recurrence. ITGA11 expression may be a predictor of poor prognosis in patients with surgically resected NSCLC.

Small lung tumor biopsy samples are feasible for high quality targeted next generation sequencing.

Next-generation sequencing (NGS) has been implemented in clinical oncology to analyze multiple genes and to guide therapy. In patients with advanced lung cancer, small biopsies such as computed tomography-guided needle biopsy (CTNB), endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and transbronchial biopsy (TBB) are less invasive and are preferable to resection to make a pathological diagnosis. However, the quality of DNA/RNA and NGS from small lung tumor biopsy samples is unknown. Between April 2017 and March 2018, 107 consecutive samples were obtained from thoracic tumors or metastatic sites for targeted NGS analysis. Fifteen samples were obtained through CTNB, 11 through EBUS-TBNA, 11 through TBB and 70 through surgical resection. All samples were formalin-fixed and paraffin-embedded. DNA and RNA quality was measured using the ddCq method and the percentage of RNA fragments above 200 nucleotides (DV200), respectively. Our custommade probes were designed to capture exon sequences of 464 cancer-related genes and transcripts of 463 genes. DNA and RNA yield from the 3 biopsy methods were similar, and less than the yield obtained from resected samples. The quality of DNA and RNA was similar across all methods. Overall, 12 of 15 CTNB samples (80%), all 11 EBUS-TBNA samples, and 9 of 11 TBB samples (82%) underwent successful NGS assays from DNA. NGS analysis from RNA was successful in all 12 CTNB samples, 9 of 11 EBUS-TBNA samples (82%), and 8 of 11 TBB samples (73%). CTNB, EBUS-TBNA and TBB mostly resulted in adequate DNA and RNA quality and enabled high-quality targeted NGS analysis.

CADM1 associates with Hippo pathway core kinases; membranous co-expression of CADM1 and LATS2 in lung tumors predicts good prognosis.

Cell adhesion molecule-1 (CADM1) is a member of the immunoglobulin superfamily that functions as a tumor suppressor of lung tumors. We herein demonstrated that CADM1 interacts with Hippo pathway core kinases and enhances the phosphorylation of YAP1, and also that the membranous co-expression of CADM1 and LATS2 predicts a favorable prognosis in lung adenocarcinoma. CADM1 significantly repressed the saturation density elevated by YAP1 overexpression in NIH3T3 cells. CADM1 significantly promoted YAP1 phosphorylation on Ser 127 and downregulated YAP1 target gene expression at confluency in lung adenocarcinoma cell lines. Moreover, CADM1 was co-precipitated with multiple Hippo pathway components, including the core kinases MST1/2 and LATS1/2, suggesting the involvement of CADM1 in the regulation of the Hippo pathway through cell-cell contact. An immunohistochemical analysis of primary lung adenocarcinomas (n = 145) revealed that the histologically low-grade subtype frequently showed the membranous co-expression of CADM1 (20/22, 91% of low-grade; 61/91, 67% of intermediate grade; and 13/32, 41% of high-grade subtypes; P < 0.0001) and LATS2 (22/22, 100% of low-grade; 44/91, 48% of intermediate-grade; and 1/32, 3% of high-grade subtypes; P < 0.0001). A subset analysis of disease-free survival revealed that the membranous co-expression of CADM1 and LATS2 was a favorable prognosis factor (5-year disease-free survival rate: 83.8%), even with nuclear YAP1-positive expression (5-year disease-free survival rate: 83.7%), whereas nuclear YAP1-positive cases with the negative expression of CADM1 and LATS2 had a poorer prognosis (5-year disease-free survival rate: 33.3%). These results indicate that the relationship between CADM1 and Hippo pathway core kinases at the cell membrane is important for suppressing the oncogenic role of YAP1.

Comprehensive assay for the molecular profiling of cancer by target enrichment from formalin-fixed paraffin-embedded specimens.

Tumor molecular profiling is becoming a standard of care for patients with cancer, but the optimal platform for cancer sequencing remains undetermined. We established a comprehensive assay, the Todai OncoPanel (TOP), which consists of DNA and RNA hybridization capture-based next-generation sequencing panels. A novel method for target enrichment, named the junction capture method, was developed for the RNA panel to accurately and cost-effectively detect 365 fusion genes as well as aberrantly spliced transcripts. The TOP RNA panel can also measure the expression profiles of an additional 109 genes. The TOP DNA panel was developed to detect single nucleotide variants and insertions/deletions for 464 genes, to calculate tumor mutation burden and microsatellite instability status, and to infer chromosomal copy number. Clinically relevant somatic mutations were identified in 32.2% (59/183) of patients by prospective TOP testing, signifying the clinical utility of TOP for providing personalized medicine to cancer patients.

Identification of a metastatic lung adenocarcinoma of the palate mucosa through genetic and histopathological analysis: a rare case report and literature review.

BACKGROUND: Cancers of unknown primary origin (CUPs) are reported to be the 3-4th most common causes of cancer death. Recent years have seen advances in mutational analysis and genomics profiling. These advances could improve accuracy of diagnosis of CUPs and might improve the prognosis of patients with CUPs. CASE PRESENTATION: A 76-year old male with an adenocarcinoma of unknown primary origin in the lung presented with another tumor of the palate mucosa. The tumor cells in the pleural effusion were all negative for immunohistochemical markers (TTF-1 and Napsin A) and lung-specific oncogenic driver alterations (EGFR mutation and ALK translocation). The tumor of the palate mucosa was likewise identified as an adenocarcinoma, and the cells showed cytological similarities with the tumor cells in the pleural effusion; TTF-1, Napsin A, EGFR mutation and ALK translocation were all negative. This result suggested that origins of the tumors of the palate mucosa and in the lung were the same, even though the origin had not yet been determined. Next, we addressed whether the tumor of the palate mucosa was a primary tumor or not. Secretory carcinoma (SC), which is a common type of minor salivary gland tumor (MSGT), was suspected; however, mammaglobin was negative and ETV6-NTRK3 (EN) fusion was not observed. Other MSGTs were excluded based on histological and immunohistochemical findings. Furthermore, an additional examination demonstrated an oncogenic KRAS mutation at codon 12 (p.G12D) in both palate tumor and in pleural effusion. KRAS mutation is known to exist in one-third of lung adenocarcinomas (LUADs), but quite rare in MSGTs. The possibility of metastasis from other organs was considered unlikely from the results of endoscopic and imaging studies. This result indicated that the primary site of the CUP was indeed the lung, and that the tumor of the palate mucosa was a metastasis of the LUAD. CONCLUSIONS: A tumor of the palate mucosa that showed diagnostic difficulties was determined to be a metastatic LUAD by genomic alterations and histopathological findings.

Effect of normal saline flush injection into a bronchus on lung decellularization.

BACKGROUND: The aim of this study was to evaluate effect of normal saline flush injection into bronchus on creation of decellularized lung scaffolds. METHODS: Pigs were used: 3 lung grafts for decellularization with pre-treatment of normal saline injection into a bronchus, 3 for decellularization without pre-treatment and 3 treated as normal controls. We compared the characteristics of lung scaffolds created by each method. RESULTS: The pretreatment procedure significantly reduced the DNA content of lung grafts, suggesting effective removal of cellular components. However, this pretreatment also reduced the elastin contents of lung grafts. CONCLUSIONS: Considering this characteristic of saline pretreatment, we must continue to look for better methods to produce ideal decellularized lung grafts.

Mean platelet volume and lymphocyte-to-monocyte ratio are associated with shorter progression-free survival in EGFR-mutant lung adenocarcinoma treated by EGFR tyrosine kinase inhibitor.

BACKGROUND: A growing body of evidence supports the role of platelets in cancer metastasis, escape from immune surveillance, and angiogenesis. Mean platelet volume (MPV), which reflects platelet turnover, is reported routinely as part of automated complete blood count. Accumulating evidence suggests that MPV is a useful biomarker in several diseases including cancer. However, its role in cancer patients receiving molecular targeted therapy has not been described in the literature. MATERIALS AND METHODS: We retrospectively analysed the prognostic impact of MPV in advanced or recurrent EGFR mutant lung adenocarcinoma treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). Lymphocyte-to-monocyte ratio (LMR) has been previously reported to be a poor prognostic factor in EGFR mutant non-small cell lung cancer and was also included as a covariate. RESULTS: Using the previously described Cutoff Finder algorithm, the cut-off points for MPV and LMR that best predicted progression free survival (PFS) of EGFR-TKI were determined as 10.3 and 2.8, respectively. The median PFS was 14.7 and 8.2 months in MPV low and high groups (p = 0.013, log-rank test). The median PFS was 13.5 and 6.2 months in LMR high and low groups (p < 0.001, log-rank test). MPV and LMR were independently distributed (chi square test) and the multivariate analysis using Cox's proportional hazards regression model revealed that high MPV, low LMR, and pleural effusion were significant predictors for shorter PFS. CONCLUSION: MPV and LMR, measured as part of routine complete blood count, can be utilized to predict the outcome of EGFR-TKI therapy with no additional costs. Our results suggest a mechanism of EGFR-TKI resistance which is associated with the functional status of the platelets.

Altered editing level of microRNAs is a potential biomarker in lung adenocarcinoma.

Adenosine-to-inosine (A-to-I) microRNA editing is associated with tumor phenotypes in various cancer types. Recent analyses of The Cancer Genome Atlas (TCGA) dataset have shown several microRNAs that undergo A-to-I editing in human cancers, some of which have been reported to be associated with prognosis. Herein, we examined published small RNA deep sequencing data of 74 cases of lung adenocarcinoma (AD) and the corresponding normal counterpart (NC) specimen in silico in order to identify A-to-I microRNA editing events. Editing levels of miR-379-5p, miR-99a-5p, and miR-497-5p were lower in AD than in NC and, in a large number of cases, the editing level of miR-200b-3p was higher in AD than in NC. Difference in the editing level between AD and NC was largest for miR-99a-5p. Then, we examined the editing level of miR-99a-5p in 50 surgically resected lung adenocarcinoma cases at our institution by a conventional sequence-based method, and its association with clinical outcomes. The editing level of miR-99a-5p was significantly lower in 19 cases of AD (38%) than in corresponding NC. These cases showed a shorter overall survival as assessed using the log-rank test (P = .047). This trend was consistent with previous analyses of TCGA dataset. The altered editing level of microRNAs in lung adenocarcinoma could serve as a potential biomarker.

MicroRNA-21 in cancer-associated fibroblasts supports lung adenocarcinoma progression.

Cancer-associated fibroblasts (CAFs) interact closely with cancer cells, supporting their growth and invasion. To investigate the role of microRNA-21 (miR-21) in lung adenocarcinoma, and especially in its CAF component, in situ hybridisation was applied to samples from 89 invasive lung adenocarcinoma cases. MiR-21 expression was observed in both cancer cells and CAFs. When the patients were stratified by expression, miR-21 levels in CAFs (n = 9), but not in cancer cells (n = 21), were inversely correlated with patient survival; patients with miR-21high CAFs exhibited lower survival than those with miR-21low CAFs. The underlying mechanism was investigated in vitro. Conditioned medium (CM) from A549 lung cancer cells increased miR-21 expression in MRC-5 and IMR-90 lung fibroblasts through the transforming growth factor-ß pathway, and induced CAF-like morphology and migratory capacity. MiR-21 up-regulation in lung fibroblasts induced a novel CAF-secreted protein, calumenin, as well as known CAF markers (periostin, α-smooth muscle actin, and podoplanin). Moreover, CM from the lung fibroblasts increased A549 cell proliferation in a calumenin-dependent manner. Thus, miR-21 expression in lung fibroblasts may trigger fibroblast trans-differentiation into CAFs, supporting cancer progression. Therefore, CAF miR-21 represents a pivotal prognostic marker for this scar-forming cancer of the lungs.