Background Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI. Methods We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes, NCT02497508 ) or nivolumab and ipilimumab (INITIATE, NCT03048474 ) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral blood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis. Results We identified 4.2 million and 12 thousand complementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with 2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p<0.04). Furthermore, a high number of shared TCR clones between pretreatment tissue and in circulation was associated with improved survival (p=0.01). To potentially select antitumor clusters, we filtered for clusters that were (1) not found in healthy controls, (2) recurrent in multiple patients with mesothelioma, and (3) more prevalent in post-treatment than pretreatment samples. The detection of two-specific TCR clusters provided significant survival benefit compared with detection of 1 cluster (HR<0.001, p=0.026) or the detection of no TCR clusters (HR=0.10, p=0.002). These two clusters were not found in bulk tissue RNA-seq data and have not been reported in public CDR3 databases. Conclusions We identified two unique TCR clusters that were associated with survival on treatment with ICI in patients with pleural mesothelioma. These clusters may enable approaches for antigen discovery and inform future targets for design of adoptive T cell therapies.

Immune checkpoint blockade therapy (ICBT) is a first-line treatment option for patients with pleural mesothelioma with the approval of ipilimumab and nivolumab. It has been challenging to identify predictive biomarkers of benefit with ICBT in mesothelioma given its low tumor mutation burden. Since ICBTs enable adaptive anti-tumor immune responses, we investigated T-cell receptor (TCR) associations with survival outcomes from participants of two ICBT clinical trials.

Aggressive, albeit false marketing of electronic nicotine delivery systems (ENDS) or vaping devices as safer alternatives to cigarette smoking, combined with lack of regulations, has led to its mass adoption, especially among youth. A sudden increase in acute lung injuries was noted in 2019 which was linked to ENDS. It was termed by the Centers for Disease Control and Prevention (CDC) as electronic cigarette or vaping product use-associated lung injury (EVALI). Analysis of bronchoalveolar lavage fluid samples linked EVALI to vitamin E acetate (VEA), which is used as a diluting agent for marijuana oils. Patients with EVALI present with a combination of non-specific respiratory, gastrointestinal, and systemic symptoms. Laboratory results may show elevated inflammatory biomarkers. EVALI is a diagnosis of exclusion and must meet the following criteria: i) history of vaping within last 90 days, ii) abnormal chest imaging, iii) negative evaluation for infection, and iv) no other plausible diagnosis. A spectrum of computed tomography (CT) chest findings has been reported in EVALI, ranging from diffuse alveolar damage to organizing pneumonia, characterized by bilateral ground-glass opacities, consolidation, and septal thickening. A similar spectrum is seen on histopathology, characterized by lipid-laden alveolar macrophages, with varying degrees of infiltrative inflammatory cells and fibrin deposition. Early and accurate identification of the EVALI pattern can help optimize patient care. For example, in diffuse alveolar damage (DAD), a lower threshold for ventilation support and corticosteroid may improve outcomes. Here, we review the etiopathogenesis, clinical management, histopathology, and imaging features of EVALI.

Some rhabdomyosarcomas and sarcomatoid carcinomas with heterologous rhabdomyosarcomatous elements resemble high-grade neuroendocrine carcinoma, creating a diagnostic difficulty. The purpose of this study was to characterize the overlap of adult genitourinary rhabdomyosarcomas, excluding those occurring at paratesticular sites, with high-grade neuroendocrine carcinoma and identify features helpful in their separation. Seventeen cases of rhabdomyosarcoma (11 from the urinary bladder and 3 each from kidney and prostate) were compared to 10 cases of high-grade neuroendocrine carcinoma from the urinary bladder. These tumors were analyzed by immunohistochemistry for desmin, MyoD1, myogenin, chromogranin, synaptophysin, CD56, TTF1, and ASCL1, and RNA sequencing was performed on 4 cases of bladder rhabdomyosarcoma (2 rhabdomyosarcomas and 2 sarcomatoid-rhabdomyosarcoma) and 10 cases of bladder high-grade neuroendocrine carcinoma. This was compared to public data from 414 typical urothelial carcinomas from The Cancer Genome Atlas dataset. Morphologic and immunophenotypic overlap with high-grade neuroendocrine carcinoma was seen in half of the bladder tumors, which included 4 rhabdomyosarcomas and 2 sarcomatoid rhabdomyosarcomas. RNA sequencing confirmed expression of neuroendocrine markers in these cases (2 rhabdomyosarcomas and 2 sarcomatoid rhabdomyosarcomas). Differential neuroendocrine differentiation was highlighted by ASCL1 protein expression only in high-grade neuroendocrine carcinoma. Moreover, both a pure alveolar rhabdomyosarcoma and sarcomatoid rhabdomyosarcoma of the urinary bladder demonstrated a fusion involving PPP1R12A. In summary, adult rhabdomyosarcomas of the urinary bladder are molecularly distinct from high-grade neuroendocrine carcinomas based on specific patterns of expression of myogenic and epithelial to mesenchymal transition–related transcription factors as well as the presence of a novel PPP1R12A fusion which is seen in a subset of cases.