Concordance of ASCL1, NEUROD1 and POU2F3 transcription factor-based subtype assignment in paired tumour samples from small cell lung carcinoma.

Aims: Small cell lung carcinoma (SCLC) can be classified into transcription factor-based subtypes (ASCL1, NeuroD1, POU2F3). While in-vitro studies suggest intratumoral heterogeneity in the expression of these markers, how SCLC subtypes vary over time and among locations in patients remains unclear.

Methods And Results: We searched a consecutive series of patients at our institution in 2006-22 for those with greater than one available formalin-fixed paraffin-embedded SCLC sample in multiple sites and/or time-points.

Lymphocyte-activation gene 3 in non-small-cell lung carcinomas: correlations with clinicopathologic features and prognostic significance.

Lymphocyte-activation gene 3 (LAG-3) modulates the tumor microenvironment through immunosuppressive effects. Its associations with clinicopathologic parameters and prognostic significance in non-small-cell lung carcinomas remain unclear. We examined LAG-3 expression in 368 resected non-small-cell lung carcinomas (including 218 adenocarcinomas and 150 squamous-cell carcinomas) using tissue microarrays, with normalization to CD8 T-cell count (LAG-3/CD8 index), and correlated LAG-3, CD8, and LAG-3/CD8 index with clinicopathologic features, molecular status, and survival.

Nuclear IL-33/SMAD signaling axis promotes cancer development in chronic inflammation.

Interleukin (IL)-33 cytokine plays a critical role in allergic diseases and cancer. IL-33 also has a nuclear localization signal. However, the nuclear function of IL-33 and its impact on cancer is unknown.

Accuracy and Reproducibility of Intraoperative Assessment on Tumor Spread Through Air Spaces in Stage 1 Lung Adenocarcinomas.

Introduction: Tumor spread through air spaces (STAS) is associated with worse prognosis in early-stage lung adenocarcinomas, particularly in sublobar resection. Intraoperative consultation for STAS has been advocated to guide surgical management. However, data on accuracy and reproducibility of intraoperative assessment of STAS remain limited.

Programmed Death Ligand 1 and Immune Cell Infiltrates in Solitary Fibrous Tumors of the Pleura.

Background: Approximately 10% to 15% of patients with solitary fibrous tumors of the pleura (SFTP) have recurrence after resection. Many are not candidates for reresection and lack effective treatments. We explored the expression of programmed death ligand 1 (PD-L1) as a biomarker for candidacy for treatment with immune checkpoint inhibitors.

Thoracic nuclear protein in testis (NUT) carcinoma: expanded pathological spectrum with expression of thyroid transcription factor-1 and neuroendocrine markers.

Aims: Nuclear protein in testis (NUT) carcinoma, an aggressive tumour driven by NUTM1 rearrangements, often involves the lung/mediastinum and shows squamous differentiation. We encountered an index patient with a thoracic NUT carcinoma diagnosed by molecular testing, showing extensive pleural involvement and diffuse thyroid transcription factor-1 (TTF-1) expression, initially suggestive of lung adenocarcinoma with pseudomesotheliomatous growth. We thus gathered an institutional series of thoracic NUT carcinomas to examine their pathological spectrum.

Small cell transformation of fusion-positive lung cancer resistant to ROS1 inhibition.

Histologic transformation from non-small cell to small cell lung cancer has been reported as a resistance mechanism to targeted therapy in -mutant and fusion-positive lung cancers. Whether small cell transformation occurs in other oncogene-driven lung cancers remains unknown. Here we analyzed the genomic landscape of two pre-mortem and 11 post-mortem metastatic tumors collected from an advanced, fusion-positive lung cancer patient, who had received sequential ROS1 inhibitors.

Immune checkpoint inhibitor-associated celiac disease.

Background: Rare cases of immune checkpoint inhibitor (ICI)-associated celiac disease (ICI-CeD) have been reported, suggesting that disruption of tolerance mechanisms by ICIs can unmask celiac disease (CeD). This study aims to characterize the clinicopathological and immunophenotypic features of ICI-CeD in comparison to ICI-associated duodenitis (ICI-Duo) and usual CeD.

Methods: A medical and pathological records search between 2015 and 2019 identified eight cases of ICI-CeD, confirmed by tTG-IgA.

SWI/SNF protein and claudin-4 expression in anaplastic carcinomas arising in mucinous tumours of the ovary and retroperitoneum.

Aims: Anaplastic carcinoma arising in a mucinous tumour of the ovary and rarely in the retroperitoneum is an uncommon neoplasm with three morphological patterns; rhabdoid, sarcomatoid and pleomorphic. We investigated expression of switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex components and claudin-4 expression.

Methods And Results: Twenty-two ovarian and three retroperitoneal mucinous tumours were investigated using antibodies against SMARCB1, SMARCA4, SMARCA2, ARID1A and claudin-4.

Clinicopathologic Characteristics of BRG1-Deficient NSCLC.

Introduction: Ten percent of NSCLCs harbor mutations in SMARCA4, the gene encoding the SWItch/Sucrose Non-Fermentable ATPase BRG1. In preclinical models, BRG1 inactivation increases tumor aggressiveness but enhances sensitivity to drugs that target oxidative phosphorylation and inhibit SMARCA2, EZH2, CDK4, or CDK6. To facilitate translation of preclinical findings into clinical studies exploiting these therapeutic vulnerabilities, we assessed the clinical features of patients with tumors harboring BRG1-inactivating mutations.

Microscopic size measurements in post-neoadjuvant therapy resections of pancreatic ductal adenocarcinoma (PDAC) predict patient outcomes.

Aims: Pancreatic ductal adenocarcinomas (PDACs) are increasingly being treated with neoadjuvant therapy. However, the American Joint Committee on Cancer (AJCC) 8th edition T staging based on tumour size does not reflect treatment effect, which often results in multiple, small foci of residual tumour in a background of mass-forming fibrosis. Thus, we evaluated the performance of AJCC 8th edition T staging in predicting patient outcomes by the use of a microscopic tumour size measurement method.

Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive malignancy in which inhibitors of PARP have modest single-agent activity. We performed a phase I/II trial of combination olaparib tablets and temozolomide (OT) in patients with previously treated SCLC. We established a recommended phase II dose of olaparib 200 mg orally twice daily with temozolomide 75 mg/m daily, both on days 1 to 7 of a 21-day cycle, and expanded to a total of 50 patients.

Loss of expression of MLH1 in non-dysplastic crypts is a harbinger of neoplastic progression in sessile serrated adenomas/polyps.

Aims: Dysplasia in colonic sessile serrated adenomas (SSAs)/sessile serrated polyps often shows loss of MLH1 expression as determined with immunohistochemistry, but the significance of loss of MLH1 expression in non-dysplastic crypts in these polyps is less well studied. The purpose of this study was to evaluate the prevalence of loss of MLH1 expression in non-dysplastic crypts in SSAs, and to evaluate its significance with regard to progression of these polyps.

Methods And Results: Four hundred SSAs, including 158 SSAs without dysplasia, 219 SSAs with dysplasia (SSAD), and 23 SSAs with invasive adenocarcinoma (SSAC), were evaluated immunohistochemically for loss of MLH1 expression in both non-dysplastic and dysplastic portions of the polyps.

Differential expression of PD-L1 and IDO1 in association with the immune microenvironment in resected lung adenocarcinomas.

Like programmed cell death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase 1 (IDO1) is known to exert immunosuppressive effects and be variably expressed in human lung cancer. However, IDO1 expression has not been well studied in lung adenocarcinoma. PD-L1 and IDO1 expression was evaluated in 261 resected lung adenocarcinomas using tissue microarrays and H-scores (cutoff: 5).

Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts.

Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs.

Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival.

Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice.