Diabetes mellitus type 2 is associated with increased tumor expression of programmed death-ligand 1 (PD-L1) in surgically resected non-small cell lung cancer - A matched case-control study

OBJECTIVES: Programmed death-ligand 1 (PD-L1) expression is a biomarker for cancer immunotherapy. Diabetes mellitus type-2 is a comorbid disease associated with adverse outcomes in Non-Small Cell Lung Cancer (NSCLC). We aimed to investigate the differences in PD-L1 expression in diabetics. METHODS: A matched case-control cohort of surgically-resected NSCLC was assembled from an early multicenter study (PMID: 19152440). PD-L1 immunohistochemistry (Clone 22C3) was graded by a tumor positive score (TPS) system (TPS0: no staining; TPS1: \u3c 1%; TPS2: 1-49%; TPS3: \u3e /=50%). Variables showing significance at univariate survival analysis were fit in a Cox regression survival model. RESULTS: Diabetics (n=40) and nondiabetics (n=39) showed no differences in age, gender, cancer stage, and follow-up. NSCLCs were more likely PD-L1 positive in diabetics but with tumor positivity \u3c 50% (TPS0: 7.5 vs. 20.5%, TPS1: 35 vs. 25.6%, TPS2: 45 vs.23.1%, TPS3: 12.5 vs. 30.8%, respectively; P \u3c 0.05). In diabetics, squamous cell carcinomas (SCC) and adenocarcinomas were mainly TPS2 (65% vs. 20%) and TPS1 (50% vs. 26%), respectively. Peritumoral inflammation correlated with TPS (r=0.228), a relationship accentuated in diabetics (r=0.377, P \u3c 0.05) but diminished and non-significant in nondiabetics (r=0.136, P \u3e /=0.05). This association was stronger in SCC (r=0.424). Diabetes was associated with increased tumor recurrence (HR: 3.08; 95%CI: 1.027-9.23). CONCLUSION: Diabetes is associated with an increase in peritumoral inflammation, PD-L1 positivity, and recurrence in NSCLC, more pronounced in SCC, suggesting the possibility of metabolic reprogramming and upregulation of PD-L1 by inducible pathways. reserved

The anatomic substrate of irreversible airway obstruction and barotrauma in a case of hurricane-triggered fatal status asthmaticus during puerperium: Lessons from an autopsy

Non-fully reversible airway obstruction in fatal asthma is often seen in association with profound structural changes of the bronchial wall, termed airway remodeling. Evidence suggests that heavy precipitation events can trigger epidemics of severe asthma. We present a case of fatal asthma in a young woman with no prior near-fatal exacerbations and postulate that the patient's extensive airway remodeling and puerperal state (susceptibility factors), in combination with a massive allergen challenge during a hurricane landfall (triggering factor), played a central role in her death. The autopsy revealed diffuse obstruction of proximal and distal bronchi by mucous plugs together with transmural chronic inflammation, tissue eosinophilia, extensive goblet cell hyperplasia with MUC-5 expression and airway smooth muscle (ASM) thickening. The observed distribution of airway remodeling was heterogeneous with sparing of the lingula, which exhibited hyperinflation and expansion of perivascular spaces indicative of dissecting air. The massive stagnation of mucus and significant inter-airway structural heterogeneity created an anatomical substrate for unequal airflow distribution facilitating the development of barotrauma. Although not considered conventional risk factors for fatal asthma, we believe that in this case, the patient's puerperal state in conjunction with an extreme environmental event dispersing aeroallergens were major contributors to the development of a fatal asthma attack. Our autopsy findings suggest that effective strategies to evacuate stagnated mucus and induce relaxation of thickened ASM are crucial in the management of life-threatening asthma exacerbations. Keywords: Fatal asthma, Airway remodeling, Barotrauma, Thunderstorm, Hurricane, Autops

Reactivation of Epstein–Barr Virus Presenting as Massive Splenomegaly after Initiation of Golimumab Treatment

Epstein–Barr virus infection is most commonly asymptomatic in the acute setting, where the end result of infection is the adoption of a viral latency phenotype. The virus can reactivate later in life leading to the abnormal proliferation of the infected B, T, or NK cells. Hereby, we report a 71-year-old female with seronegative rheumatoid arthritis who presented with massive splenomegaly, pancytopenia, and positivization of antibodies against double-stranded deoxyribonucleic acid (dsDNA) after initiation of the anti-tumor necrosis factor (TNF) golimumab. The diagnosis of EBV-associated lymphoproliferative disorder (LPD) was demonstrated by elevation of the plasmatic EBV viral load. Withdrawal of the anti-TNF and treatment with the anti-CD20 antibody rituximab were able to revert the clinical abnormalities. EBV-associated LPDs are described after initiation of other anti-TNF agents, such as infliximab, but no reports of golimumab-associated EBV LPD are found in the literature. The mechanisms for this occurrence are not clear, but these are known to involve expression of a panel of viral proteins specific to the viral latency phenotypes

Liposarcoma in the Inguinal Canal: Challenges in Preoperative Diagnosis and Importance of Routine Pathological Examination of “Hernia Sacs”

Liposarcoma is the most common histologic subtype of soft tissue sarcoma in the retroperitoneum. The distinction of primary cord liposarcomas, which arise in and are confined to the inguinal canal, from inguinoscrotal extension of a retroperitoneal tumor is mandatory. Both can be found incidentally in inguinal hernia sac specimens. Preoperative diagnosis is essential for adequate surgery with clear margins. We present a clinicopathological correlation of two men with slowly growing right para-testicular masses diagnosed as inguinal hernias. Pathological examination revealed well-differentiated lipoma-like liposarcoma and well-differentiated liposarcoma mixed type (lipoma-like and sclerosing types), respectively. The first tumor was considered a primary cord liposarcoma with no recurrence on follow-up. The second tumor showed an unusual growth pattern of discontinuous nodules that gave the false impression of complete resection. This growth pattern may explain why inguinal liposarcomas have a high recurrence rate despite apparently negative surgical margins. A follow-up CT scan exposed a fatty tumor in the retroperitoneum of the second patient. Careful interpretation of imaging studies in patients with fatty inguinal masses is mandatory to rule out a retroperitoneal or intraperitoneal component. Although the two cases herein discussed represent less than 0.1% of the total inguinal hernia sacs examined over the past five years in our pathology department, we recommend routine examination of all “mass-containing” hernia sacs as missing the diagnosis of liposarcoma can lead to substantial morbidity and mortality

Pathobiology of airway smooth muscle remodeling

El mecanismo primario de asma y EBPOC involucra una excesiva contracción de las vías aéreas (VA), cuya severidad se encuentra en relación a inflamación crónica. Evidencia reciente sugiere que las células de músculo liso de las vías aéreas (MLVA) poseen elevada plasticidad celular que puede contribuir en inflamación, resultando en su engrosamiento mediante hiperplasia y/o hipertrofia. La interacción MLVA-microambiente tisular es la base para hiperreactividad y remodelado tisular, con contribuciones importantes de virus y mediadores químicos, especialmente acetilcolina. Esta revisión abarca la fisiopatología del remodelado del MLVA en relación a fenotipos graves de enfermedades inflamatorias bronquiales. Un análisis in silico de hibridación entre secuencias de ARN humano y virales fue realizado, obteniendo datos para apoyar una hipótesis de ‘hit and run’. Como una propuesta de integración, se resumen los últimos hallazgos moleculares con una perspectiva que ayude al establecimiento de fundamentos para investigaciones futuras y la comprensión de las vías de señalización que regulan la biología del MLVA.   Abstract The primary mechanism of morbidity and mortality in asthma and COPD is excessive airway narrowing, which severity is based on chronic inflammation. New evidence suggests airway smooth muscle (ASM) cells show extraordinary cellular plasticity that may contribute to airway inflammation, ensuing ASM thickening by either hyperplasia and/or hypertrophy. Tissue microenvironment-ASM interaction is a complex crosstalk that supports hyperresponsiveness and tissue remodeling, with major contributions of viruses and chemical mediators, especially acetylcholine. This review addresses the ASM pathology in relation with severe phenotypes of airway inflammatory diseases. An in silico analysis of hybridization between human and viral RNA strands was performed, obtaining data to support a ‘hit and run’ hypothesis. As an integrative proposal, we summarized the last molecular findings in this field with a perspective that helps to set the stage for future research toward understanding the signaling pathways regulating ASM biology

M2 Muscarinic acetylcholine receptor modulates rat airway smooth muscle cell proliferation

Airways chronic inflammatory conditions in asthma and COPD are characterized by tissue remodeling, being smooth muscle hyperplasia, the most important feature. Non-neuronal and neuronal Acetylcholine acting on muscarinic receptors (MAChRs) has been postulated as determinant of tissue remodeling in asthma and COPD by promoting proliferation and phenotypic changes of airway smooth muscle cells (ASMC). The objective was to evaluate proliferative responses to muscarinic agonist as carbamylcholine (Cch) and to identify the MAchR subtype involved. ASMC were isolated from tracheal fragments of Sprague–Dawley rats by enzymatic digestion. Proliferation assays were performed by MTS-PMS method. Viability was confirmed by trypan blue exclusion method. Mitogens as, epidermal growth factor (EGF), Tumor necrosis factor-alpha (TNF-α) and fetal bovine serum (FBS) increased ASMC proliferation (p < 0.05, n = 5). Cch alone increased ASMC proliferation at 24 and 48 hrs. However, combination of Cch with other mitogens exhibited a dual effect, synergistic proliferation effect in the presence of EGF (5 ng/mL) and 5% FBS and inhibiting the proliferation induced by 10% FBS, EGF (10 ng/mL) and TNF-α (10 ng/mL). To determine the MAChR subtype involved in these biological responses, a titration curve of selective muscarinic antagonists were performed. The Cch stimulatory and inhibitory effects on ASCM proliferation was blocked by AF-DX-116 (M2AChR selective antagonist), in greater proportion than 4-DAMP (M3AChR selective antagonist), suggesting that the modulation of muscarinic agonist-induced proliferation is M2AChR mediated responses. Thus, M2AChR can activate multiple signal transduction systems and mediate both effects on ASMC proliferation depending on the plethora and variable airway microenvironments existing in asthma and COPD. Keywords: Airway smooth muscle, Muscarinic receptors, Carbamylcholine, ASMC inhibitio

Abstract 3931: BRD4, BRD3, NSD3, and ZNF532 fusions in histologies beyond NUT carcinomas: Investigation of a large pan-cancer cohort

Abstract Background: NUT rearrangements drive NUT carcinomas (NCs), which are rare, poorly differentiated tumors with a survival from diagnosis of ~6-7 months. Common NUT fusion partners (NCFPs) include BRD4, BRD3, NSD3, and ZNF532, which are associated with epigenetic changes leading to tumor growth. Recent clinical trials have aimed to address NCs, but little is known about fusions involving NCFPs in other histologies. We characterized NCFPs in a large, pan-cancer cohort. Methods: The MSK-IMPACT (DNA sequencing; n=71,423) and MSK-Fusion (RNA sequencing; n=10,897) clinical cohorts were mined to identify patients (pts) with all forms of structural variants (SVs) involving NCFPs, detected between April, 2015 and June, 2022. The targeted NGS panels included BRD4 and NSD3 only; detection of BRD3 and ZNF532 SVs was possible for fusions with a partner present on either panel. SVs were manually reviewed to identify in-frame fusions with oncogenic potential if critical domains present in NC fusions were conserved. Pts were followed through July 2022 and manual chart review enabled assessment of treatment history and clinical outcomes. Results: SVs involving NCFP genes were detected in 182 (BRD4=110, NSD3=61, BRD3=8 and ZNF532=3) pts (0.002%). Putative NCFP fusions not involving any of the NUT gene family members comprised a total of 20 fusions with likely oncogenic potential including 11 with BRD4 (55%), 5 with NSD3 (25%), 3 with ZNF532 (15%), and 1 with BRD3 (5%). BRD4::NOTCH3 and ZNF532::MALT1 were the most enriched fusions, present in 3 samples each. The most common histologies were breast (3 ductal; 1 lobular), lung (2 squamous cell carcinoma, 1 adenocarcinoma and 1 mixed histology), and colon and esophageal adenocarcinoma (2 samples each). Median age at diagnosis was 62. 11 (55%) pts were female and 9 (45%) were male. 13 (65%) pts ultimately were diagnosed with stage IV disease and had a median overall survival from stage IV diagnosis of 2.5 years (95% CI: 1.41, NR). DNA sequencing in 19/20 tumors revealed a mean tumor mutational burden (TMB) of 5.0 mut/Mb including 15 with low TMB (10). No tumor showed microsatellite instability (MSI-high). TP53 mutations were the most common co-alteration, found in 11 (58%) cases. 18/20 pts received systemic therapy; 18 (90%) received cytotoxic chemotherapy and/or mAb therapy, including 13 (65%) who received a platinum. 8 pts (40%) received immunotherapy (IO), and 4 (20%) received small molecule inhibitors. No pts received BET inhibitors. Among pts who received IO, median time to treatment discontinuation was 64 days (95% CI: 20, NR). Conclusion: Tumor sequencing from a large cohort reveals potential oncogenic fusions involving BRD4, BRD3, NSD3, and ZNF532 across multiple histologies. Further biological characterization of their oncogenicity and potential targetability is warranted. Citation Format: Ian R. Nykaza, Christopher A. Febres-Aldana, Sabrina T. Lin, Ryma Benayed, Kerry Mullaney, Emiliano Cocco, Alexia Iasonos, Marc Ladanyi, Alexander E. Drilon, Yonina R. Murciano-Goroff. BRD4, BRD3, NSD3, and ZNF532 fusions in histologies beyond NUT carcinomas: Investigation of a large pan-cancer cohort. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3931