Impact of immune-related adverse events on survival outcomes in extensive-stage small cell lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors have recently become the standard of care in the first-line treatment of extensive-stage small cell lung cancer. Although immune-related adverse events have been reported to influence prognosis in non-small cell lung cancer patients, few studies have investigated the prognostic value of immune-related adverse events in small cell lung cancer patients. In this study, we evaluated the prognosis of patients who developed immune-related adverse events after first-line treatment with immune checkpoint inhibitor-based chemotherapy for extensive-stage small cell lung cancer. METHODS: We enrolled 90 patients with extensive-stage small cell lung cancer who received immune checkpoint inhibitor-based chemotherapy as first-line treatment from September 2019 to December 2022 in six hospitals in Japan. The patients were categorized into groups with and without immune-related adverse events. RESULTS: There were 23 patients with and 67 without immune-related adverse events. Seventeen patients had grade 1-2 immune-related adverse events, and nine (including overlapping cases) had grade ≥3. The most frequent immune-related adverse event was a skin rash. The median survival time was 22 months in patients with immune-related adverse events and 9.3 months in patients without immune-related adverse events. The hazard ratio was 0.40 (95% confidence interval: 0.19-0.83, p = 0.013). CONCLUSIONS: The results of this study show that immune-related adverse events are associated with improved survival outcomes in patients with extensive-stage small cell lung cancer.

Role of microbiota-derived corisin in coagulation activation during SARS-CoV-2 infection.

BACKGROUND: Coagulopathy is a major cause of morbidity and mortality in COVID-19 patients. Hypercoagulability in COVID-19 results in deep vein thrombosis, thromboembolic complications, and diffuse intravascular coagulation. Microbiome dysbiosis influences the clinical course of COVID-19. However, the role of dysbiosis in COVID-19-associated coagulopathy is not fully understood. OBJECTIVES: The present study tested the hypothesis that the microbiota-derived proapoptotic corisin is involved in the coagulation system activation during SARS-CoV-2 infection. METHODS: This cross-sectional study included 47 consecutive patients who consulted for symptoms of COVID-19. A mouse acute lung injury model was used to recapitulate the clinical findings. A549 alveolar epithelial, THP-1, and human umbilical vein endothelial cells were used to evaluate procoagulant and anticoagulant activity of corisin. RESULTS: COVID-19 patients showed significantly high circulating levels of corisin, thrombin-antithrombin complex, D-dimer, tumor necrosis factor-α, and monocyte-chemoattractant protein-1 with reduced levels of free protein S compared with healthy subjects. The levels of thrombin-antithrombin complex, D-dimer, and corisin were significantly correlated. A monoclonal anticorisin-neutralizing antibody significantly inhibited the inflammatory response and coagulation system activation in a SARS-CoV-2 spike protein-associated acute lung injury mouse model, and the levels of corisin and thrombin-antithrombin complex were significantly correlated. In an in vitro experiment, corisin increased the tissue factor activity and decreased the anticoagulant activity of thrombomodulin in epithelial, endothelial, and monocytic cells. CONCLUSION: The microbiota-derived corisin is significantly increased and correlated with activation of the coagulation system during SARS-CoV-2 infection, and corisin may directly increase the procoagulant activity in epithelial, endothelial, and monocytic cells.

Elevated plasma and bile levels of corisin, a microbiota-derived proapoptotic peptide, in patients with severe acute cholangitis.

BACKGROUND: Acute cholangitis is a severe, life-threatening infection of the biliary system that requires early diagnosis and treatment. The Tokyo Guidelines recommend a combination of clinical, laboratory, and imaging findings for diagnosis and severity assessment, but there are still challenges in identifying severe cases that need immediate intervention. The microbiota and its derived products have been implicated in the pathogenesis of acute cholangitis. Corisin is a microbiome-derived peptide that induces cell apoptosis, acute tissue injury, and inflammation. This study aimed to evaluate the potential of plasma and bile corisin as a biomarker of acute cholangitis. METHODS: Forty patients with acute cholangitis associated with choledocholithiasis or malignant disease were enrolled. Nine patients without acute cholangitis were used as controls. Corisin was measured by enzyme immunoassays in plasma and bile samples. Patients were classified into severe and non-severe groups. The associations of plasma and bile corisin with the clinical grade of acute cholangitis and other parameters were analyzed by univariate and multivariate regression analysis. RESULTS: Plasma and bile corisin levels were significantly higher in patients with acute cholangitis than in controls. Patients with severe acute cholangitis had significantly higher plasma and bile corisin levels than those with non-severe form of the disease. Bile corisin level was significantly correlated with markers of inflammation, coagulation, fibrinolysis, and renal function. Univariate analysis revealed a significant association of bile corisin but a weak association of plasma corisin with the clinical grade of acute cholangitis. In contrast, multivariate analysis showed a significant relationship between plasma corisin level and the disease clinical grade. The receiver operating characteristic curve analysis showed low sensitivity but high specificity for plasma and bile corisin to detect the severity of acute cholangitis. The plasma and bile corisin sensitivity was increased when serum C-reactive protein level was included in the receiver operating characteristic curve analysis. CONCLUSIONS: Overall, these findings suggest that plasma and bile corisin levels may be useful biomarkers for diagnosing and monitoring acute cholangitis and that corisin may play a role in the pathophysiology of the disease by modulating inflammatory, coagulation and renal pathways.

Close-to-lesion transbronchial biopsy: a novel technique to improve suitability of specimens for genetic testing in patients with peripheral pulmonary lesions.

Bronchoscopy with radial-probe endobronchial ultrasound, a guide sheath, and electromagnetic navigation can improve the diagnostic yield of peripheral lung nodules. However, the suitability of specimens for genetic analysis remains unsatisfactory. We hypothesized that a transbronchial biopsy performed after closely approaching the bronchoscope tip to the lesion might provide more suitable specimens for genetic analysis. We enrolled 155 patients with peripheral pulmonary lesions who underwent bronchoscopy with a thin or ultrathin bronchoscope. Bronchoscopy was performed using virtual bronchoscopic navigation and radial-probe endobronchial ultrasound with a guide sheath. The bronchoscope tip was placed closer to the lesion during bronchoscopy to collect larger specimens with higher malignant cell content. The patients who underwent a close-to-lesion biopsy had higher rates of overall diagnostic yield, histopathological diagnostic yield, and specimen quality for genetic testing than those who did not. The significant determinants of the specimen's suitability were the close-to-lesion approach, within-the-lesion image, the use of standard 1.9-mm-forceps, and the number of cancer-cell-positive specimens. The significant predictors of the specimen's suitability for genetic analysis were close-to-lesion biopsy and the number of malignant cell-positive tissue samples. This study demonstrates that the close-to-lesion transbronchial biopsy significantly improves the suitability of bronchoscopic specimens for genetic analysis.

Prognostic Value of CXCL12 in Non-Small Cell Lung Cancer Patients Undergoing Tumor Resection.

Adjuvant chemotherapy is commonly indicated in lung cancer patients undergoing surgical therapy because tumor recurrence is frequent. A biomarker that can predict tumor recurrence in the postoperative period is currently unavailable. CXCR4 receptor and its ligand CXCL12 play important roles in metastasis. This study investigated the value of tumor CXCL12 expression to predict prognosis and indicate adjuvant chemotherapy in non-small cell lung cancer patients. This study enrolled 82 non-small cell lung cancer patients. The expression of CXCL12 was evaluated by immunohistochemistry. The degree of CXCL12 expression was assessed using the Allred score system. Among all subjects, the progression-free survival and overall survival were significantly prolonged in cancer patients with low tumor expression of CXCL12 compared to patients with high tumor expression. Multivariate analysis showed that the increased level of CXCL12 is a significant predictor of progression-free survival and overall survival in NSCLC patients. Among subjects with high tumor CXCL12 expression, progression-free survival and overall survival were significantly improved in patients treated with adjuvant chemotherapy compared to untreated patients. These results suggest the potential value of tumor CXCL12 expression as a marker to predict prognosis and to indicate adjuvant chemotherapy after surgical tumor resection in non-small cell lung cancer patients.

Amelioration of Pulmonary Fibrosis by Matrix Metalloproteinase-2 Overexpression.

Idiopathic pulmonary fibrosis is a progressive and fatal disease with a poor prognosis. Matrix metalloproteinase-2 is involved in the pathogenesis of organ fibrosis. The role of matrix metalloproteinase-2 in lung fibrosis is unclear. This study evaluated whether overexpression of matrix metalloproteinase-2 affects the development of pulmonary fibrosis. Lung fibrosis was induced by bleomycin in wild-type mice and transgenic mice overexpressing human matrix metalloproteinase-2. Mice expressing human matrix metalloproteinase-2 showed significantly decreased infiltration of inflammatory cells and inflammatory and fibrotic cytokines in the lungs compared to wild-type mice after induction of lung injury and fibrosis with bleomycin. The computed tomography score, Ashcroft score of fibrosis, and lung collagen deposition were significantly reduced in human matrix metalloproteinase transgenic mice compared to wild-type mice. The expression of anti-apoptotic genes was significantly increased, while caspase-3 activity was significantly reduced in the lungs of matrix metalloproteinase-2 transgenic mice compared to wild-type mice. Active matrix metalloproteinase-2 significantly decreased bleomycin-induced apoptosis in alveolar epithelial cells. Matrix metalloproteinase-2 appears to protect against pulmonary fibrosis by inhibiting apoptosis of lung epithelial cells.

Inhibition of a Microbiota-Derived Peptide Ameliorates Established Acute Lung Injury.

Acute lung injury (ALI) is a clinical syndrome characterized by a diffuse lung inflammation that commonly evolves into acute respiratory distress syndrome and respiratory failure. The lung microbiota is involved in the pathogenesis of ALI. Corisin, a proapoptotic peptide derived from the lung microbiota, plays a role in ALI and acute exacerbation of pulmonary fibrosis. Preventive therapeutic intervention with a monoclonal anticorisin antibody inhibits ALI in mice. However, whether inhibition of corisin with the antibody ameliorates established ALI is unknown. Here, the therapeutic effectiveness of the anticorisin antibody in already established ALI in mice was assessed. Lipopolysaccharide was used to induce ALI in mice. After causing ALI, the mice were treated with a neutralizing anticorisin antibody. Mice treated with the antibody showed significant improvement in lung radiological and histopathologic findings, decreased lung infiltration of inflammatory cells, reduced markers of lung tissue damage, and inflammatory cytokines in bronchoalveolar lavage fluid compared with untreated mice. In addition, the mice treated with anticorisin antibody showed significantly increased expression of antiapoptotic proteins with decreased caspase-3 activation in the lungs compared with control mice treated with an irrelevant antibody. In conclusion, these observations suggest that the inhibition of corisin is a novel and promising approach for treating established ALI.

Next-generation sequencing clarified why first-line treatment with osimertinib was ineffective in an autopsied case of EGFR-mutated lung squamous cell carcinoma.

Epidermal growth factor receptor (EGFR)-mutated squamous cell carcinoma (SCC) is less common than adenocarcinoma. The third-generation EGFR-tyrosine kinase inhibitor, osimertinib, is effective in EGFR-mutated lung adenocarcinoma, but its efficacy in EGFR-mutated lung SCC is unclear. The patient was an 83-year-old male. He was diagnosed with SCC of the lung, and molecular analysis revealed that the tumor was positive for EGFR exon19 deletion. He was treated with osimertinib 80 mg/day. No adverse events were observed, but after 18 days of therapy, he complained of dyspnea, and a computed tomography scan showed enlarged lung cancer. The case was categorized as a progressive disease. The patient died 3 weeks later. The autopsy findings confirmed the diagnosis of lung SCC, with morphology and immunohistochemical staining identical to the tumor obtained by bronchoscopy. Next-generation sequencing showed the presence of TP53 R158L, CDK6, and KRAS amplifications. The current case report shows that next-generation sequencing can explain why osimertinib is ineffective in EGFR-mutated SCC.

Transforming Growth Factorß1 Overexpression Is Associated with Insulin Resistance and Rapidly Progressive Kidney Fibrosis under Diabetic Conditions.

Diabetes mellitus is a global health problem. Diabetic nephropathy is a common complication of diabetes mellitus and the leading cause of end-stage renal disease. The clinical course, response to therapy, and prognosis of nephropathy are worse in diabetic than in non-diabetic patients. The role of transforming growth factorß1 in kidney fibrosis is undebatable. This study assessed whether the overexpression of transforming growth factorß1 is associated with insulin resistance and the rapid progression of transforming growth factorß1-mediated nephropathy under diabetic conditions. Diabetes mellitus was induced with streptozotocin in wild-type mice and transgenic mice with the kidney-specific overexpression of human transforming growth factorß1. Mice treated with saline were the controls. Glucose tolerance and kidney fibrosis were evaluated. The blood glucose levels, the values of the homeostasis model assessment for insulin resistance, and the area of kidney fibrosis were significantly increased, and the renal function was significantly impaired in the diabetic transforming growth factorß1 transgenic mice compared to the non-diabetic transgenic mice, diabetic wild-type mice, and non-diabetic mice. Transforming growth factorß1 impaired the regulatory effect of insulin on glucose in the hepatocyte and skeletal muscle cell lines. This study shows that transforming growth factorß1 overexpression is associated with insulin resistance and rapidly progressive kidney fibrosis under diabetic conditions in mice.

Tenascin C in radiation-induced lung damage: Pathological expression and serum level elevation.

Radiation-induced lung damage (RILD) is a critical problem in lung cancer radiotherapy, and it is difficult to predict its severity. Although no biomarkers for RILD have been established, tenascin C (TNC) is an extracellular matrix glycoprotein involved in the remodeling of damaged tissues and has been implicated in inflammation and fibrosis. We report the unique case of a 36-year-old man with adenocarcinoma of the lung, Union for International Cancer Control stage IIIB, who was treated with radiotherapy before lung surgery. The surgical specimen showed histopathological expression of TNC in the region where radiation pneumonitis was observed radiographically. Serum TNC levels were elevated after radiotherapy. In this case, TNC is suggested to be implicated in RILD and may be a potential candidate as a biomarker for the onset and severity of the condition.

Efficacy and Safety of Amrubicin in Small Cell Carcinoma Previously Treated with Immune Checkpoint Inhibitors and Chemotherapy.

Adding an immune checkpoint inhibitor to chemotherapy to treat extensive-stage small cell lung cancer is effective. However, there are no reports of an effective second-line treatment in patients previously treated with chemotherapy and immune checkpoint inhibitors as a first-line treatment. Here, we assessed the efficacy and safety of amrubicin as a second-line treatment for extensive-stage small cell lung cancer after chemotherapy and immune checkpoint inhibitor combination therapy. The study enrolled 150 patients with extensive-stage small cell lung cancer. The efficacy and the incidence of adverse events were compared between patients previously treated with immune checkpoint inhibitors and patients without previous immune checkpoint inhibitor treatment. One hundred and twenty-three patients were eligible. There was no difference in objective response rate, time-to-treatment failure, progression-free survival, and overall survival between both groups. The incidence of adverse events was similar in both treatment groups. Pretreatment with immune checkpoint inhibitors was not associated with an increase in amrubicin-related adverse events. This study shows that the efficacy of amrubicin in extensive-stage small cell lung cancer remains unchanged irrespective of previous treatment with immune checkpoint inhibitors. Amrubicin-related adverse events did not increase in patients previously treated with immune checkpoint inhibitors.

Good Response of Advanced Thymic Carcinoma with Low PD-L1 Expression to Chemotherapy plus Pembrolizumab as First-Line Therapy and to Pembrolizumab as Maintenance Therapy: A Case Report.

Thymic carcinoma is a rare malignant tumor with a poor prognosis. No standard treatment is currently available. The present case was a 64-year-old male smoker with no symptoms referred to our hospital because of abnormal chest radiological findings. The CT study showed a tumor between the anterior mediastinum and the right lung upper lobe, multiple nodular shadows along the right pleura, and pleural effusion. A CT-guided needle biopsy revealed squamous cell carcinoma. However, the differential diagnosis between thymic carcinoma and primary lung cancer was difficult. Treatment with carboplatin, nanoparticle albumin-bound paclitaxel, and pembrolizumab was initiated. The CT scan showed tumor shrinkage and good clinical response after four treatment cycles. Therapy was switched to maintenance therapy with pembrolizumab alone. Imaging studies showed further tumor shrinkage after twelve cycles of maintenance therapy with pembrolizumab. Sixteen cycles of maintenance therapy were continued without performance status deterioration. An abnormal radiological finding was detected after a twelve-month exacerbation-free period. The diagnosis was thymic carcinoma. Treatment with lenvatinib was initiated, and tumor-size reduction was observed. This is the first report of a case showing a successful maintenance therapy with pembrolizumab after effective first-line therapy with a combination of carboplatin-based chemotherapy plus pembrolizumab in advanced thymic carcinoma.