Efficacy of immune checkpoint inhibitors in non-small cell lung cancer with uncommon histology: a propensity-score-matched analysis.

BACKGROUND: Clinical efficacy of immune checkpoint inhibitors (ICIs) for non-small cell lung cancer (NSCLC) with uncommon histology (uNSCLC) is unknown. METHODS: Patients with NSCLC treated with ICI monotherapy between January 2014 and December 2018 in 10 Japanese hospitals were retrospectively evaluated. The patients were divided into: (1) NSCLC with common histology (cNSCLC), defined as adenocarcinoma and squamous cell carcinoma; and (2) uNSCLC, defined as incompatibility with morphological and immunohistochemical criteria for adenocarcinoma or squamous cell carcinoma. Propensity score matching was performed to balance the two groups. RESULTS: Among a total of 175 patients included, 44 with uNSCLC (10 pleomorphic carcinomas, 9 large cell neuroendocrine carcinomas, 2 large cell carcinomas, and 23 not otherwise specified) and 44 with matched cNSCLC (32 adenocarcinomas and 12 squamous cell carcinomas) were selected for analyses. Median progression-free survival (PFS) (4.4 months, 95% confidence interval [CI] 1.8-7.7 months) and overall survival (OS) (11.4 months, 95% CI 7.4-27.4 months) in the uNSCLC patients were not significantly different from those in matched cNSCLC patients (5.4 months, 95% CI 3.1-7.6 months, p = 0.761; and 14.1 months, 95% CI 10.6-29.6 months, p = 0.381). In multivariate analysis, Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0-1 and programmed death ligand-1 (PD-L1) expression were predictive for PFS and OS in uNSCLC. CONCLUSIONS: ICIs had similar clinical efficacy for treatment of uNSCLC and cNSCLC. Good ECOG-PS and PD-L1 expression were predictive for efficacy of ICIs in uNSCLC.

Screening and diagnosis of acute and chronic bird-related hypersensitivity pneumonitis by serum IgG and IgA antibodies to bird antigens with ImmunoCAP®.

BACKGROUND: Bird antigens are some of the most relevant antigens in hypersensitivity pneumonitis (HP). Possible sources of bird antigens are bird breeding, feather products and fertilizer with fowl droppings. For the screening and diagnosis of HP, the measurement of bird-specific antibodies should be standardized. The aim of this study was to clarify the utility of serum IgG (sIgG) and IgA (sIgA) antibodies to bird antigens in screening and diagnosing acute/chronic bird-related HP with ImmunoCAP® in multi-centre clinical research. METHODS: We executed a clinical performance test by conducting a multi-institutional study to measure the levels of sIgG/sIgA against pigeon, parrot and budgerigar antigens by the ImmunoCAP® system in 29 acute and 46 chronic bird-related HP patients. RESULTS: The levels of sIgG/sIgA against the bird antigens of the three species were significantly higher in subjects with acute bird-related HP and chronic bird-related HP with acute episodes (recurrent type) than in the control subjects. For sIgG, the optimal cutoff values by receiver operating characteristic (ROC) analysis were 24.6 mgA/L for pigeon, 14.0 mgA/L for parrot, and 8.7 mgA/L for budgerigar. By measuring multiple bird antigens and combining sIgG values of two species, the sensitivity and specificity for acute and recurrent-type chronic bird-related HP patients were 85-91% and 73-80%, respectively. For recurrent and insidious types of chronic bird-related HP, the sensitivity and specificity were 48-61% and 73-80%, respectively. CONCLUSIONS: Measurement of the levels of sIgG/sIgA against pigeon, budgerigar and parrot antigens by ImmunoCAP® was useful for screening and diagnosis in bird-related HP.

CD248 and integrin alpha-8 are candidate markers for differentiating lung fibroblast subtypes.

BACKGROUND: Lung fibrosis is a serious life-threatening condition whose manifestation varies according to the localization and characteristics of fibroblasts, which are considered heterogeneous. Therefore, to better understand the pathology and improve diagnosis and treatment of this disease, it is necessary to elucidate the nature of this heterogeneity and identify markers for the accurate classification of human lung fibroblast subtypes. METHODS: We characterized distinct mouse lung fibroblast subpopulations isolated by fluorescence-activated cell sorting (FACS) and performed microarray analysis to identify molecular markers that could be useful for human lung fibroblast classification. Based on the expression of these markers, we evaluated the fibroblast-like cell subtype localization in normal human lung samples and lung samples from patients with idiopathic pulmonary fibrosis (IPF). RESULTS: Mouse lung fibroblasts were classified into Sca-1high fibroblasts and Sca-1low fibroblasts by in vitro biological analyses. Through microarray analysis, we demonstrated CD248 and integrin alpha-8 (ITGA8) as cell surface markers for Sca-1high fibroblasts and Sca-1low fibroblasts, respectively. In mouse lungs, Sca-1high fibroblasts and Sca-1low fibroblasts were localized in the collagen fiber-rich connective tissue and elastic fiber-rich connective tissue, respectively. In normal human lungs and IPF lungs, two corresponding major fibroblast-like cell subtypes were identified: CD248highITGA8low fibroblast-like cells and CD248lowITGA8high fibroblast-like cells, localized in the collagen fiber-rich connective tissue and in the elastic fiber-rich connective tissue, respectively. CONCLUSION: CD248highITGA8low fibroblast-like cells and CD248lowITGA8high fibroblast-like cells were localized in an almost exclusive manner in human lung specimens. This human lung fibroblast classification using two cell surface markers may be helpful for further detailed investigations of the functions of lung fibroblast subtypes, which can provide new insights into lung development and the pathological processes underlying fibrotic lung diseases.

Podoplanin-positive myofibroblasts: a pathological hallmark of pleuroparenchymal fibroelastosis.

Pathological differential diagnoses of pleuroparenchymal fibroelastosis (PPFE) include usual interstitial pneumonia (UIP) and pulmonary apical cap (PAC); however, there are no specific immunostaining makers to distinguish between these diseases. We performed immunohistochemistry using several pleural mesothelial cell-related markers, including cytokeratin-5/6, CAM5.2, WT-1, calretinin, desmin and podoplanin, for PPFE (n = 4), UIP (n = 10) and PAC (n = 3) lung sections. Among the examined markers, in PPFE and PAC lungs podoplanin commonly showed positivity for spindle cells both in thickened pleura and subpleural fibroelastosis lesions; these cells were also stained with α-smooth muscle actin, a marker of myofibroblasts. However, even in elastic fibre-rich cases, UIP lungs did not show such podoplanin-positive myofibroblasts in pleura/subpleura and fibroblastic foci. These findings were also verified using immunofluorescence. By contrast, immunohistochemically as well as morphologically, the difference between PPFE and PAC was not apparent. The presence of podoplanin-positive myofibroblasts could be a pathological hallmark of PPFE, suggesting a pathogenic process distinct from UIP but common to PAC.

LTBP2 is secreted from lung myofibroblasts and is a potential biomarker for idiopathic pulmonary fibrosis.

Although differentiation of lung fibroblasts into α-smooth muscle actin (αSMA)-positive myofibroblasts is important in the progression of idiopathic pulmonary fibrosis (IPF), few biomarkers reflecting the fibrotic process have been discovered. We performed microarray analyses between FACS-sorted steady-state fibroblasts (lineage (CD45, TER-119, CD324, CD31, LYVE-1, and CD146)-negative and PDGFRα-positive cells) from untreated mouse lungs and myofibroblasts (lineage-negative, Sca-1-negative, and CD49e-positive cells) from bleomycin-treated mouse lungs. Amongst several genes up-regulated in the FACS-sorted myofibroblasts, we focussed on Ltbp2, the gene encoding latent transforming growth factor-ß (TGF-ß) binding protein-2 (LTBP2), because of the signal similarity to Acta2, which encodes αSMA, in the clustering analysis. The up-regulation was reproduced at the mRNA and protein levels in human lung myofibroblasts induced by TGF-ß1. LTBP2 staining in IPF lungs was broadly positive in the fibrotic interstitium, mainly as an extracellular matrix (ECM) protein; however, some of the αSMA-positive myofibroblasts were also stained. Serum LTBP2 concentrations, evaluated using ELISA, in IPF patients were significantly higher than those in healthy volunteers (mean: 21.4 compared with 12.4 ng/ml) and showed a negative correlation with % predicted forced vital capacity (r = -0.369). The Cox hazard model demonstrated that serum LTBP2 could predict the prognosis of IPF patients (hazard ratio for death by respiratory events: 1.040, 95% confidence interval: 1.026-1.054), which was validated using the bootstrap method with 1000-fold replication. LTBP2 is a potential prognostic blood biomarker that may reflect the level of differentiation of lung fibroblasts into myofibroblasts in IPF.

Indacaterol and tiotropium combination therapy in patients with chronic obstructive pulmonary disease.

BACKGROUND: Combination therapy with a long-acting antimuscarinic agent and a long-acting ß2-agonist are recommended in chronic obstructive pulmonary disease (COPD) if control is not adequate with one long-acting bronchodilator alone. We evaluated the effects of indacaterol and tiotropium combination therapy, including the effects of adding indacaterol to tiotropium (indacaterol add-on group) and adding tiotropium to indacaterol (tiotropium add-on group). METHODS: We recruited 79 patients with COPD already treated with tiotropium or indacaterol. We undertook pulmonary function tests, the COPD assessment test (CAT), and the multi-frequency forced oscillation technique (to measure respiratory resistance and reactance) before and after 8 weeks of indacaterol and tiotropium combination therapy. RESULTS: The median age was 72.1 years and the mean forced expiratory volume in 1 s (FEV1) as a proportion of predicted was 57.2 ± 18.3%. After 8 weeks of combination therapy, FEV1 and %predicted FEV1 had increased significantly. There was no change in CAT score. For respiratory impedance, combination therapy improved resistance at 5 Hz (R5) and resistance at 20 Hz (R20) in the whole-breath, inspiratory and expiratory phases, and resonant frequency (Fres) in the inspiratory phase. The indacaterol add-on group (43 patients) and tiotropium add-on group (36 patients) showed improvements in FEV1 and %predicted FEV1 over monotherapy, although the CAT score fell significantly in the indacaterol add-on group (p = 0.005). CONCLUSIONS: Indacaterol and tiotropium combination therapy improved airflow limitation and respiratory resistances. Adding indacaterol to tiotropium, or tiotropium to indacaterol, had similar effects on airflow limitation.

A case of severe thrombocytopenia after the first exposure to rifampicin.

Severe immune thrombocytopenia is a rare side-effect of rifampicin (RFP) and can be life-threatening. Here, we report the case of a 74-year-old male with tuberculous pleurisy who developed severe thrombocytopenia after first exposure to RFP. Platelet count decreased to 1 × 103/µL after 7 days of treatment with RFP, isoniazid, ethambutol, and pyrazinamide. After all the drugs were discontinued, the platelet count recovered. As thrombocytopenia did not occur after re-administration of drugs other than RFP, the patient was diagnosed with RFP-induced thrombocytopenia. Clinicians should be aware that RFP can induce acute and severe thrombocytopenia even without previous exposure to this drug.

Tracheobronchitis and laryngitis associated with Crohn's disease.

We report a 68-year-old woman with tracheobronchitis and laryngitis associated with Crohn's disease (CD), which was discovered during the evaluation of suspected lung cancer. She had no symptoms induced by these upper airway diseases (UADs). Bronchoscopy revealed swelling of the epiglottis with edematous change and a mass like epiglottis fold. There were nodular and edematous changes in the trachea and bilateral main bronchus. Histological findings demonstrated infiltration by numerous lymphocytes and plasma cells. Dexamethasone as the premedication for chemotherapy against lung cancer was efficacious for these extraintestinal manifestations of CD. Our case was rare in that bronchial lesion and UADs appeared concomitantly.

Utility of budgerigar/pigeon/parrot-specific IgG antibody with ImmunoCAP® in bird-related hypersensitivity pneumonitis caused by other bird species and duvet.

BACKGROUND: Bird-related hypersensitivity pneumonitis (BRHP) is an extrinsic allergic alveolitis caused by inhalation of bird antigens. Although the measurement of serum-specific IgG antibodies against budgerigar, pigeon, and parrot with ImmunoCAP® is available in Japan, the utility of the test for patients with causes by bird breeding other than these three species, including contact with wild birds/poultry/bird manure, and use of a duvet is unknown. METHODS: Of the 75 BRHP patients who participated in our previous study, 30 were included. Six cases were caused by bird breeding of species other than pigeon, budgerigar, and parrot, seven were in contact with wild birds/poultry/bird manure, and 17 were using a duvet. Bird-specific IgG antibodies were compared among the patients, 64 controls, and 147 healthy participants. RESULTS: In patients with BRHP caused by bird breeding, budgerigar and parrot-specific IgG levels were significantly higher than in disease controls. Only parrot-specific IgG was significantly higher than in disease controls in patients caused by duvet use. However, among patients with acute episodes (acute and recurrent type of chronic BRHP), IgG antibodies against all three species were significantly higher than those of disease controls caused by bird breeding and the use of a duvet. CONCLUSIONS: Bird-specific IgG antibody with ImmunoCAP® was useful for screening and diagnosing BRHP caused by other bird species and duvets.

Clinically amyopathic dermatomyositis with interstitial lung disease double-positive for anti-MDA5 and anti-PL12 antibodies.

Anti-melanoma differentiation-associated gene 5 (MDA5) and anti-aminoacyl-tRNA synthetase (ARS) antibodies are two major myositis-specific autoantibodies with distinct clinical features. However, the clinical course remains unclear in patients with clinically amyopathic dermatomyositis (CADM)-interstitial lung disease (ILD) who have co-existing anti-MDA5 and anti-ARS antibodies. Here, we describe the case of a 32-year-old woman with CADM-ILD who had anti-MDA5 and anti-PL12 antibodies. Her serum ferritin level was within the normal range. However, chest computed tomography revealed bilateral lower-lobe consolidation and ground-glass opacities. Treatment with prednisolone and immunosuppressants was successful in improving the skin lesion and ILD, but relapse occurred on reducing the dose of prednisolone. These clinical features match those of anti-ARS antibody-positive dermatomyositis-ILD. Because these two conditions show significantly different clinical features and require different intensities of treatment, clinicians should carefully follow-up these patients throughout the course of the disease.

BNT162b2 coronavirus disease-2019 vaccination accelerated rheumatoid arthritis disease activity in chronic eosinophilic pneumonia: A case report.

RATIONALE: The relationship between rheumatoid arthritis (RA) and eosinophilic inflammation is unclear. According to recent studies, it has been suggested that T helper 2 cell responses play a role in the inhibition of RA. It is unclear how the immunological response after coronavirus disease-2019 (COVID-19) vaccination affects T cell immune reactions. PATIENT CONCERNS AND DIAGNOSES: Here, we report the case of an 88-year-old woman diagnosed with RA and chronic eosinophilic pneumonia (CEP). She was diagnosed with CEP about 20 years ago, and, through steroid treatment, she improved and had no relapse for 16 years. At the time of diagnosis of CEP, the rheumatoid factor (RF) was increased; however, there were no joint symptoms. After receiving the COVID-19 vaccine, joint and respiratory symptoms gradually worsened. Laboratory examinations showed increased RF, anti-cyclin citrullinated peptide antibody, and peripheral absolute eosinophil count. Musculoskeletal ultrasonography showed synovitis. INTERVENTION AND OUTCOME: Methylprednisolone pulse therapy improved respiratory and joint symptoms immediately; RA and CEP stabilized with no relapses. LESSONS: Eosinophilic and rheumatoid reactions following COVID-19 vaccination were an-reported adverse events. Eosinophilic inflammation might be reflected on an anti-inflammatory reaction in initial phase of RA.

[A case of pulmonary alveolar proteinosis presenting with miniscule ground-glass opacity in the apex of the left lung].

A 66-year-old man was found to have a very small ground-glass opacity in the apex of the left lung. Because the ground-glass opacity had slightly enlarged after 2 years, video-assisted thoracic surgery (VATS) biopsy was performed. The histological findings showed the alveolar spaces to be filled with PAS-positive granular materials, so pulmonary alveolar proteinosis was diagnosed. Although his bronchoalveolar lavage fluid (BALF) did not have a milky appearance, his serum and BALF GM-CSF autoantibody and serum KL-6 levels were elevated. Asymptomatic pulmonary alveolar proteinosis may appear as very small ground-grass opacities.

Multicentric Castleman disease with infiltration of eosinophils to the lung.

A 41-year-old man presented with multiple superficial lymph nodes (LNs) swollen with elevated levels of serum immunoglobulin (Ig)G4 and C-reactive protein. Histological findings of his left inguinal LN revealed lymphoplasmacytic infiltration with numerous IgG4-positive plasma cells; IgG4+/IgG+ plasma cell ratio >40%. Chest computed tomography (CT) showed poorly defined centrilobular nodules, interlobular septal thickening, consolidations, and mediastinal LNs swelling. Bronchoalveolar lavage fluid (BALF) showed elevated eosinophils. A surgical lung biopsy showed focal dense eosinophil infiltration, in addition to lymphoplasmacytic infiltration, but few IgG4+ plasma cells. The diagnosis of multicentric Castleman disease (MCD) was made because of serum interleukin-6elevation. Treatment with prednisolone and tocilizumab improved his symptoms and lung lesions. This case shows that overlapping clinical and pathological features of MCD and IgG4-related disease may present in a single patient, showing the difficulty in distinguishing between these two diseases.

Metformin reduces pleural fibroelastosis by inhibition of extracellular matrix production induced by CD90-positive myofibroblasts.

Metformin, an AMP-activated protein kinase activator used to treat diabetes mellitus, has recently attracted attention as a promising anti-fibrotic agent. However, its anti-fibrotic effects on pleural fibroelastosis remain unknown. We induced mouse pleural fibroelastosis by intra-pleural coadministration of bleomycin and carbon and evaluated its validity as a preclinical model for human pleural fibrosis. We assessed the expression of the myofibroblast surface marker CD90 in the fibrotic pleura and the effects of metformin in vivo and in vitro. Finally, we evaluated the effects of metformin on human pleural mesothelial cells stimulated by transforming growth factor ß1 (TGFß1). The fibrotic pleura in mice had collagen and elastin fiber deposition similar to that seen in human fibrotic pleura. Moreover, CD90-positive myofibroblasts were detected in and successfully isolated from the fibrotic pleura. Metformin significantly suppressed the deposition of collagen and elastic fibers in the fibrotic pleura and decreased the expression of extracellular matrix (ECM)-related genes, including Col1a1, Col3a1, Fn1, and Eln, in pleural CD90-positive myofibroblasts. In human pleural mesothelial cells, metformin decreased TGFß1-induced upregulation of ECM-related genes and SNAI1. Overall, metformin suppresses pleural fibroelastosis by inhibition of ECM production by pleural myofibroblasts, suggesting that this drug has therapeutic potential against human pleural fibrosis, including pleuroparenchymal fibroelastosis.

Pneumocystis jirovecii Pneumonia in a Patient with Breast Cancer Receiving Neoadjuvant Dose-dense Chemotherapy.

We herein report a 38-year-old woman with breast cancer who developed Pneumocystis jirovecii pneumonia (PCP) during neoadjuvant dose-dense chemotherapy combined with dexamethasone as antiemetic therapy. Chest computed tomography showed bilateral ground-glass opacities and consolidation. The serum ß-D-glucan levels were elevated, and P. jirovecii DNA was detected from the bronchoalveolar lavage fluid by polymerase chain reaction. Her clinical findings improved with trimethoprim/sulfamethoxazole and adjunctive steroid therapy. Clinicians must be mindful of the manifestations of PCP in non-human immunodeficiency virus (HIV)-infected immunocompromised patients and include the possibility of PCP in the differential diagnosis when confronted with breast cancer on dose-dense chemotherapy showing diffuse lung disease.

[Two cases of pneumonitis caused by Seishinrenshiin, Chinese herbal medicine].

We report two cases of pneumonitis caused by Seishinrenshiin. A 54-year-old woman and a 80-year-old man had taken Seishinrenshiin for cystitis and benign prostatic hypertrophy. Their chest radiograph showed diffuse ground-glass shadows in the whole lung fields and chest CT showed diffuse ground-glass-opacities predominantly in the lower lung fields of both lungs. Biochemical tests revealed mild liver dysfunction and inflammatory reactions. Their abnormal chest shadows disappeared after discontinuation of Seishinrenshiin. We should be aware that Seishinrenshiin, as well as other Chinese herbal medicine, could be cause of drug-induced pneumonitis.

[Thyroid involvement of sarcoidosis].

A 54-year-old woman was found to have abnormal shadows on her chest radiograph taken on an annual medical examination. The chest radiograph showed multiple nodules in the bilateral middle and lower lung fields accompanied with bilateral hilar lymphadenopathy. A computed tomography of the neck and chest revealed nodules in her right middle lobe and bilateral lower lobes with an enlarged thyroid. A metastatic malignant disease involving both thyroid and lungs was suspected, therefore thyroid and lung biopsies were performed. The histological examination of the thyroid and the lung specimens revealed non-caseating epithelioid cell granulomas which were compatible with sarcoidosis. Although the thyroid involvement of sarcoidosis is rare, it should be included in the differential diagnosis with patients with thyroid swelling.

A case of a primary hepatic so-called adenosarcoma with heterotopic ossification: possibly of biliary adenofibroma origin.

We present an autopsy case of a "so-called adenosarcoma with ossification of the liver" in a 63-year-old man. Macroscopically, the well-circumscribed tumor with portal vein invasion was observed in the right lobe of the liver. The cut surface of the tumor had a solid and microcystic appearance. Microscopically, the tumor was characterized by a benign epithelial component and a malignant mesenchymal component. We believe the presence of biliary adenofibroma-like areas and the von Meyenburg complexes suggests that the tumor is possibly associated with a biliary adenofibroma. In addition, the present tumor was unique in that it showed scattered heterotopic ossification. Immunohistochemical study showed that the mesenchymal atypical spindle cells had characteristics of undifferentiated mesenchymal cells. This is the first report of a primary hepatic so-called adenosarcoma.