Study Design and Rationale for Marble Study: A Phase II Trial of Atezolizumab (MPDL3280A) Plus Carboplatin and Paclitaxel in Patients With Advanced or Recurrent Thymic Carcinoma (JTD2101).

BACKGROUND: Thymic carcinoma (TC) is a rare thymic epithelial tumor, and advanced or recurrent TC has limited prognosis. Treatment for chemotherapy-naïve, advanced, or recurrent TC remains unchanged with the combination of carboplatin and paclitaxel; therefore, a new treatment strategy is warranted. Immune checkpoint blockades inhibiting the programmed cell death-1 (PD-1) pathway (PD-1 and its ligand, PD-L1) have shown potential as a monotherapy for TC, although the efficacy of monotherapy was moderate for previously treated TC. We hypothesized that the combination of an anti-PD-L1 antibody, atezolizumab, with carboplatin and paclitaxel, would be effective in inducing immunogenic cell death in patients with advanced or recurrent TC. METHODS: We initiated a multicenter, single-arm, open-label phase II study of atezolizumab combined with carboplatin and paclitaxel for metastatic or recurrent TC. Eligible patients will receive atezolizumab plus carboplatin and paclitaxel every 3 weeks for up to 6 cycles, followed by atezolizumab every 3 weeks for up to 2 years until progression or unacceptable toxicity. A total of 47 patients will be enrolled in this study, with a 24-month enrollment period and 12-month follow-up. The primary endpoint is the objective response rate (ORR), based on an independent central review. The secondary endpoints are the investigator-assessed ORR, disease control rate, progression-free survival, duration of response, overall survival, and safety. RESULTS: This study aims to establish the safety and efficacy of atezolizumab combined with carboplatin and paclitaxel in patients with advanced or recurrent TC. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT), jRCT2031220144. Registered on June 18, 2022, https://jrct.niph.go.jp/en-latest-detail/jRCT2031220144.

CALML5 is a novel diagnostic marker for differentiating thymic squamous cell carcinoma from type B3 thymoma.

BACKGROUND: Thymic squamous cell carcinoma and type B3 thymoma are primary neoplasms of the anterior mediastinum that are sometimes difficult to differentiate from one another histologically. However, only a few immunohistochemical markers are available for the differential diagnosis. The purpose of this study was to discover a novel marker for differentiating between thymic squamous cell carcinoma and type B3 thymoma. METHODS: We used histological samples of thymic carcinomas (n = 26) and type B3 thymomas (n = 38) which were resected between 1986 and 2017. To search for candidates of differential markers, gene expression levels were evaluated in samples using promoter analysis by cap analysis of gene expression (CAGE) sequencing. RESULTS: Promoter level expression of CALML5 genes was significantly higher in thymic carcinomas than in type B3 thymomas. We further validated the results of the CAGE analysis in all 26 thymic carcinomas and 38 type B3 thymomas by immunohistochemistry (IHC). CALML5 was strongly expressed in the cytoplasm in 19 of 26 cases with thymic carcinoma, whereas positivity at the protein level was shown in two of 38 type B3 thymomas. Thus, the sensitivity (73.1%) and specificity (94.7%) of CALML5 as markers for immunohistochemical diagnosis of thymic carcinoma were extremely high. CONCLUSION: We identified CALML5 as a potential marker for differentiating thymic squamous cell carcinoma from type B3 thymoma. It is assumed that future clinical use of CALML5 may improve the diagnostic accuracy of differentiating between these two diseases.

Late relapse of ulcerative colitis presenting as tracheobronchitis: a case report.

BACKGROUND: Lung involvement in inflammatory bowel diseases usually follows colitis. However, the time to lung involvement onset varies depending on the case, and pulmonary lesions are usually not parallel to exacerbations of the colitis. CASE PRESENTATION: A 67-year-old Asian woman with a 38-year history of ulcerative colitis presented to our hospital with a complaint of prolonged dry cough for 2 months. The colitis had remained quiescent for > 35 years with low-dose salazosulfapyridine treatment. Chest computed tomography indicated circumferential thickening of the tracheal wall, while bronchoscopy examination revealed widespread erythematous edema and diffuse narrowing of the bronchial lumen. Biopsy of the bronchial mucosa showed submucosal lymphocytic infiltration. She was diagnosed with ulcerative-colitis-related tracheobronchitis and successfully treated with corticosteroids. CONCLUSIONS: Tracheobronchitis, in our case, occurred despite the longest remission period previously reported. Careful follow-up is necessary for the early recognition and treatment of pulmonary disease in patients with ulcerative colitis, regardless of the disease duration and long-term remission of colitis.

A Case of Tuberculosis-related Cerebral Venous Sinus Thrombosis and Pulmonary Thromboembolism Successfully Treated with Edoxaban.

A 22-year-old woman was admitted to the hospital with complaints of headache and vomiting. Radiological examinations revealed cerebral sinus venous thromboses, pulmonary thromboembolism, and cavities in the left upper lung. Pulmonary tuberculosis was diagnosed based on sputum and gastric aspirate culture. Heparin followed by warfarin was administered. Anti-tuberculosis agents including rifampicin were also initiated. Since the effect of warfarin did not reach the therapeutic level because of interaction with rifampicin, edoxaban was administered and thromboses were ameliorated. This report illustrates rare thrombotic complications in a TB-induced hypercoagulable state and the potential benefits and safety of edoxaban in combination with rifampicin.

Clinical Significance of Tumor Markers for Advanced Thymic Carcinoma: A Retrospective Analysis from the NEJ023 Study.

The optimal tumor marker for predicting the prognosis of advanced thymic carcinoma (ATC) remains unclear. We conducted a multi-institutional retrospective study of patients with ATC. A total of 286 patients were treated with chemotherapy. Clinicopathological information, including serum tumor markers, was evaluated to determine the overall survival (OS) and progression-free survival (PFS). The carcinoembryonic antigen, cytokeratin-19 fragment, squamous cell carcinoma (SCC) antigen, progastrin-releasing peptide, neuron-specific enolase (NSE), and alpha-fetoprotein levels were evaluated. In the Kaplan-Meier analysis, the OS was significantly shorter in the patients with elevated NSE levels than in those with normal NSE levels (median, 20.3 vs. 36.8 months; log-rank test p = 0.029; hazard ratio (HR), 1.55; 95% confidence interval (CI), 1.05-2.31 (Cox proportional hazard model)); a similar tendency regarding the PFS was observed (median, 6.4 vs. 11.0 months; log-rank test p = 0.001; HR, 2.04; 95% CI, 1.31-3.18). No significant differences in the OS and PFS were observed among the other tumor markers. In both univariate and multivariate analyses of the patients with SCC only, the NSE level was associated with the OS and PFS. Thus, the NSE level may be a prognostic tumor marker for thymic carcinoma, regardless of histology.

Novel use for an EGFR mutation-specific antibody in discriminating lung adenocarcinoma from reactive pneumocyte hyperplasia.

AIMS: Pulmonary ground-glass nodules (GGNs) are frequently observed. Histopathologically, their presentation can indicate a wide range of disorders from an inflammatory process to malignancy. An accurate diagnosis based on GGNs can sometimes be challenging on small-sized biopsies. Mutations in the EGFR gene are detected in pulmonary adenocarcinomas (ADCs). Immunohistochemical analysis using antibodies that detect specific EGFR mutations has been shown to correlate with mutational status as determined by molecular methods. We hypothesized that these antibodies could be used to discriminate between ADCs and benign pneumocyte hyperplasias. METHODS AND RESULTS: Surgically resected, pre-invasive to invasive lung ADC (n = 32) and reactive pneumocyte hyperplasia (n = 40) tissue samples were probed with antibodies against EGFR mutations, p53, Mouse double minute 2 and 14-3-3 sigma. Of the 32 lung ADC specimens analysed, 12 (38%) were positive using the EGFR mutation-specific antibodies, while no immunoreactivity was observed in reactive pneumocyte hyperplasia specimens. Analyses of receiver operating characteristic curves showed that the highest area under the curve values were associated with the use of EGFR mutation-specific antibodies. In addition, a high concordance rate was observed between surgically resected and corresponding biopsy materials using these antibodies. CONCLUSIONS: EGFR mutation-specific antibodies can be used to discriminate between lung ADC and benign pneumocyte hyperplasia, even in small-sized biopsies.

Epidermal growth factor receptor tyrosine kinase inhibitors beyond progressive disease: a retrospective analysis for Japanese patients with activating EGFR mutations.

INTRODUCTION: It is not determined whether the continuous use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is reasonable for patients with activating EGFR mutations, who have progressed with the drug. METHODS: We retrospectively analyzed the data from 2002 to 2010 of consecutive patients who had advanced non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations and showed radiological disease progression after EGFR-TKI treatment as the first-line or second-line setting. We classified them into two groups: continuous EGFR-TKI and switching to chemotherapy, and compared the clinical outcomes. Multivariate analysis for survival was performed including age, sex, Eastern Cooperative Oncology Group performance status (0-1/ 2-4), brain metastasis, EGFR mutations (deletions in exon 19 versus L858R), continuous EGFR-TKI (yes/no), and initiation of EGFR-TKI (first versus second). RESULTS: A total of 551 NSCLC patients were screened for EGFR mutations in the period, and 186 patients had activating EGFR mutations. To explore the potential use of EGFR-TKI beyond progressive disease (PD), 64 patients were selected and analyzed. There were 13 men and 51 women, and median age was 65.5 years (range, 42-86). Among them, 31 patients had deletions in exon 19, and 33 had point mutation of L858R in exon 21. Thirty-nine patients were continuing EGFR-TKI beyond PD; 25 patients were switched to cytotoxic chemotherapy alone. The median overall survival was 32.2 months in the patients continuing EGFR-TKI, and 23.0 months in the patients switching to chemotherapy, presenting a significant difference between the two groups (p = 0.005). Cox analysis showed that continuous EGFR-TKI after PD (hazards ratio 0.42, 95% confidence interval: 0.21-0.83, p = 0.013) was associated with improved survival. CONCLUSION: Continuous use of EGFR-TKI beyond PD may prolong overall survival compared with switching to cytotoxic chemotherapy in patients with activating EGFR mutations. A prospective study will be needed to confirm our results.

[Bronchofiberscopic treatment for malignant tracheobronchial tumor].

We evaluated bronchofiberscopic treatment for 38 cases with malignant tracheobronchial tumor. We performed bronchofiberscopic ethanol injection therapy in 13 cases, endoscopic diode laser treatment in 19 cases and airway stent insertion in 9 cases. Each treatment was comparatively easy and improved symptoms such as dyspnea effectively.