COMPREHENSIVE ANALYSIS OF NEUROD1, ASCL1, POU2F3 AND YAP1 EXPRESSION SIGNATURES REVEAL UNIQUE LCNEC SUBGROUPS WITH POTENTIAL THERAPEUTIC IMPLICATIONS.

Large-cell neuroendocrine carcinoma (LCNEC) can be genomically subtyped into small cell lung cancer (SCLC)- and non-SCLC (NSCLC)-like. NEUROD1, ASCL1, POU2F3, and YAP1 (NAPY) subtypes have been reported for SCLC. We immunohistochemically evaluated NAPY in LCNEC alongside relevant protein expression data.

Clinical insight on the pathway of SLFN11 as emergent biomarker in SCLC.

Schlafen 11 (SLFN11) is a gene encoding for a protein involved in the irreversible arrest of cell replication under DNA-damaging stress. SLFN11 is expressed differently across various cancers. When overexpressed, SLFN11 inhibits tumor replication and growth by early recruitment to stressed replication forks, making tumors more sensitive to a range of anti-cancer treatments, including topoisomerase I-II inhibitors, DNA alkylating agents, platinum salts, anti-metabolites, anti-tumor antibiotics, poly ADP-ribose polymerase (PARP) inhibitors and immunotherapies.

Deep Learning-Based Retinoblastoma Protein Subtyping of Pulmonary Large-Cell Neuroendocrine Carcinoma on Small Hematoxylin and Eosin-Stained Specimens.

Molecular subtyping of pulmonary large-cell neuroendocrine carcinoma (LCNEC) based on retinoblastoma protein (pRb) expression may influence systemic treatment decisions. Current histomorphologic assessments of hematoxylin and eosin-stained tissue samples cannot reliably differentiate LCNEC molecular subtypes. This study explores the potential of deep learning (DL) to identify histologic patterns that distinguish these subtypes, by developing a custom convolutional neural network to predict the binary expression of pRb in small LCNEC tissue samples.

Basic science and translational implications of current knowledge on neuroendocrine tumors.

Neuroendocrine tumors (NETs) are a diverse group of malignancies that can occur in various organs, with a notable prevalence in the lungs and gastrointestinal tract, which are the focus of this Review. Although NETs are rare in individual organs, their incidence has increased over recent decades, highlighting the urgent need for current classification systems to evolve by incorporating recent advances in the understanding of NET biology. Several omics studies have revealed molecular subtypes, which, when integrated into existing classification frameworks, may provide more clinically relevant insights for patients with NETs.

OTP, CD44, and Ki-67: A Prognostic Marker Panel for Relapse-Free Survival in Patients with Surgically Resected Pulmonary Carcinoid.

Although most patients with pulmonary carcinoid (PC) can be cured by surgery, relapse may occur until 15 years after resection in up to 10% of patients. This is unpredictable at the outset, necessitating extensive follow-up (FU). We sought to determine whether an immunohistochemical marker panel (OTP, CD44, and Ki-67) could better indicate relapse-free survival (RFS) and increase uniformity among pathologists regarding carcinoid classification.

Identification of Defined Molecular Subgroups on the Basis of Immunohistochemical Analyses and Potential Therapeutic Vulnerabilities of Pulmonary Carcinoids.

Introduction: Multi-omic studies have identified three molecular separated pulmonary carcinoid (PC) subgroups (A1, A2, B) with distinctive mRNA expression profiles (e.g., orthopedia homeobox protein [OTP], achaete-scute homolog [ASCL1], and hepatocyte nuclear factor 1 homeobox A [HNF1A]).

[Intoxication due to apricot pits].

Background: Apricot seeds are recommended online for their alleged cancer-fighting and energy-boosting properties. However, they contain high levels of cyanogenic glycosides. Ingesting just a few apricot pits (1-3) can result in severe symptoms and fatalities have been reported after consuming more than 20 pits.

Disease relapse in relation to lymph node sampling in lung carcinoid patients.

The predictive value of the extent of peri-operative lymph node (LN) sampling in relation to disease relapse in patients with pulmonary carcinoid (PC) is unknown. Furthermore, post-surgery follow-up recommendations rely on institutional retrospective studies with short follow-ups. We aimed to address these shortcomings by examining the relation between LN sampling and relapse in a population-based cohort with long-term follow-up.

Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites.

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites.

Development and verification of new monoclonal orthopedia homeobox (OTP) specific antibodies for pulmonary carcinoid diagnostics.

Background: Orthopedia homeobox (OTP) has shown to be a useful prognostic marker to predict outcome in pulmonary carcinoids, which is also supported by the World Health Organization. However, the discontinuation of the initially used polyclonal antibody and absence of a reliable routinely applicable monoclonal OTP antibody hampers implementation in routine diagnostics. Here, new monoclonal antibodies directed against OTP were developed and verified on formalin-fixed paraffin-embedded tissue of pulmonary neuroendocrine tumors (NETs) for clinical diagnostics.

In-depth molecular analysis of combined and co-primary pulmonary large cell neuroendocrine carcinoma and adenocarcinoma.

Up to 14% of large cell neuroendocrine carcinomas (LCNECs) are diagnosed in continuity with nonsmall cell lung carcinoma. In addition to these combined lesions, 1% to 7% of lung tumors present as co-primary tumors with multiple synchronous lesions. We evaluated molecular and clinicopathological characteristics of combined and co-primary LCNEC-adenocarcinoma (ADC) tumors.

Preoperative Biopsy Diagnosis in Pulmonary Carcinoids, a Shot in the Dark.

Introduction: The preferred treatment for pulmonary carcinoids (PCs) is lobectomy, and parenchyma-sparing approaches might be considered for typical carcinoids (TCs). Treatment decisions are based on a preoperative biopsy diagnosis. Following the WHO criteria (2015), definitive diagnosis is only feasible postoperatively, thereby hampering preoperative treatment decisions.

Unique Metastatic Patterns in Neuroendocrine Neoplasms of Different Primary Origin.

Introduction: Neuroendocrine neoplasms (NEN) can originate in different organs, for example, the gastroenteral tract (GE), pancreas (Pan), or lungs (L). Our aim was to examine metastatic patterns for patients with NEN of various primary origins with a special focus on brain metastases to indicate utility for screening.

Methods: All NEN patients except for small cell lung cancer registered in the Netherlands Cancer Registry from 2008 to 2018 were selected.

Orthopedia Homeobox (OTP) in Pulmonary Neuroendocrine Tumors: The Diagnostic Value and Possible Molecular Interactions.

Generally, patients with stage I-IIIa (TNM) pulmonary carcinoid disease have a favourable prognosis after curative resection. Yet, distant recurrence of disease after curative surgery occurs in approximately 1-6% of patients with typical carcinoid and 14-29% in patients with atypical carcinoid disease, respectively. Known predictors of distant recurrence of disease are atypical carcinoid, lymphatic involvement, and incomplete resection status.

Is the sum of positive neuroendocrine immunohistochemical stains useful for diagnosis of large cell neuroendocrine carcinoma (LCNEC) on biopsy specimens?

Aims: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is underdiagnosed on biopsy specimens. We evaluated if routine neuroendocrine immunohistochemical (IHC) stains are helpful in the diagnosis of LCNEC on biopsy specimens.

Methods And Results: Using the Dutch pathology registry (PALGA), surgically resected LCNEC with matching pre-operative biopsy specimens were identified and haematoxylin and IHC slides (CD56, chromogranin-A, synaptophysin) requested.

New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management.

Carcinoids and large cell neuroendocrine carcinomas (LCNECs) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes.

Molecular Subtypes of Pulmonary Large-cell Neuroendocrine Carcinoma Predict Chemotherapy Treatment Outcome.

Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the mutated (mostly comutated with ) and the wild-type groups. We assessed whether these subtypes have a predictive value on chemotherapy outcome. Clinical data and tumor specimens were retrospectively obtained from the Netherlands Cancer Registry and Pathology Registry.

Chemotherapy for pulmonary large cell neuroendocrine carcinomas: does the regimen matter?

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is rare. Chemotherapy for metastatic LCNEC ranges from small cell lung carcinoma (SCLC) regimens to nonsmall cell lung carcinoma (NSCLC) chemotherapy regimens. We analysed outcomes of chemotherapy treatments for LCNEC.