Neuroendocrine tumours and pregnancy: Real-world data from an European Neuroendocrine Tumour Centre of Excellence.

Neuroendocrine neoplasms (NENs) arise from the diffuse endocrine system and have been considered to be rare. However, the incidence and prevalence of these tumours have increased in recent years, and they are being seen in younger patients including women in the reproductive age group. Due to the paucity of data, diagnostic and therapeutic strategies in managing such tumours during pregnancy can be challenging to both treating physicians and patients.

Exploring the impact of the PNPLA3 I148M variant on primary human hepatic stellate cells using 3D extracellular matrix models.

Background & Aims: The PNPLA3 rs738409 C>G (encoding for I148M) variant is a risk locus for the fibrogenic progression of chronic liver diseases, a process driven by hepatic stellate cells (HSCs). We investigated how the PNPLA3 I148M variant affects HSC biology using transcriptomic data and validated findings in 3D-culture models.

Methods: RNA sequencing was performed on 2D-cultured primary human HSCs and liver biopsies of individuals with obesity, genotyped for the PNPLA3 I148M variant.

Tissue-Specific Human Extracellular Matrix Scaffolds Promote Pancreatic Tumour Progression and Chemotherapy Resistance.

Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed at a late stage and are locally advanced or with concurrent metastases. The aggressive phenotype and relative chemo- and radiotherapeutic resistance of PDAC is thought to be mediated largely by its prominent stroma, which is supported by an extracellular matrix (ECM). Therefore, we investigated the impact of tissue-matched human ECM in driving PDAC and the role of the ECM in promoting chemotherapy resistance.

Insulinoma: a quarter century of dietary control.

Summary: Insulinomas are rare pancreatic neuroendocrine neoplasms (NENs) that are typically sporadic and solitary, with the majority being <2 cm in diameter at diagnosis. The median duration of symptoms before diagnosis is variable; however, this is usually in the region of 12-18 months. We report on an insulinoma diagnosed some 25 years following initial symptoms, having by that stage attained a diameter of 4 cm.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): Prevalence, clinicopathological characteristics and survival outcome in a cohort of 311 patients with well-differentiated lung neuroendocrine tumours.

Introduction: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is considered to be a rare condition associated with lung neuroendocrine tumours (NET), and its natural history is poorly described. We aimed to assess the prevalence and clinicopathologic characteristics of DIPNECH in the lung NET population, and to investigate predictors of time-to-progression (TTP) and overall survival (OS).

Methods: We retrospectively identified patients diagnosed with DIPNECH between April 2005 and December 2020.

Comparison of point-shear wave elastography (ElastPQ) and transient elastography (FibroScan) for liver fibrosis staging in patients with non-alcoholic fatty liver disease.

Background And Aims: ElastPQ is a point shear wave elastography technique used to non-invasively assess liver fibrosis. We compared liver stiffness measurements (LSM) by ElastPQ and fibroscan transient elastography (F-TE) in a cohort of patients with non-alcoholic fatty liver disease (NAFLD). We further evaluated the performance of ElastPQ in a subgroup of patients with available liver histology.

Systematic Evaluation of the Immune Environment of Small Intestinal Neuroendocrine Tumors.

Purpose: The immune tumor microenvironment and the potential therapeutic opportunities for immunotherapy in small intestinal neuroendocrine tumors (siNET) have not been fully defined.

Experimental Design: Herein, we studied 40 patients with primary and synchronous metastatic siNETs, and matched blood and normal tissue obtained during surgery. We interrogated the immune checkpoint landscape using multi-parametric flow cytometry.

Duodenal neuroendocrine neoplasms with unexpectedly aggressive behaviour: Challenging the "watch and wait" approach.

The incidence of duodenal neuroendocrine neoplasms has risen over the past decades as a result of the wide availability of endoscopy and associated expertise. Although it is considered that tumour size greater than 10 mm, higher tumour grade and/or location in relation to the ampulla of Vater represent the main risk factors for local or distant metastases, we describe two cases of well differentiated grade 1 and grade 2 neuroendocrine tumours, which measured < 10 mm at the time of diagnosis but had an aggressive course during follow-up. Furthermore, we also summarise the available therapeutic strategies for the management of small, low grade, non-functioning, non-ampullary duodenal neuroendocrine neoplasms.

The human liver microenvironment shapes the homing and function of CD4 T-cell populations.

Objective: Tissue-resident memory T cells (T) are vital immune sentinels that provide protective immunity. While hepatic CD8 T have been well described, little is known about the location, phenotype and function of CD4 T.

Design: We used multiparametric flow cytometry, histological assessment and novel human tissue coculture systems to interrogate the ex vivo phenotype, function and generation of the intrahepatic CD4 T-cell compartment.

Collagen proportionate area predicts long-term mortality in patients with alcoholic hepatitis.

Background And Aims: There are several short-term prognostic scores for alcoholic hepatitis (AH) that combine demographical and biochemical parameters. The extent of liver fibrosis may also be relevant to the prognosis of AH with potential added value. We evaluated collagen proportionate area (CPA) as a predictor of short and long-term mortality in AH.

Biopsy for advanced hepatocellular carcinoma: results of a multicentre UK audit.

Background: Advanced hepatocellular carcinoma (HCC) is commonly diagnosed using non-invasive radiological criteria (NIRC) defined by the European Association for the Study of the Liver or the American Association for the Study of Liver Diseases. In 2017, The National Institute for Clinical Excellence mandated histological confirmation of disease to authorise the use of sorafenib in the UK.

Methods: This was a prospective multicentre audit in which patients suitable for sorafenib were identified at multidisciplinary meetings.

Middle ear neuroendocrine tumours: Insight into their pathogenesis, diagnosis and management.

Recent advances in the diagnosis of neuroendocrine tumours (NETs) have led to the identification of NETs in unusual locations. NETs originating in the middle ear have been reported in a number of case reports with differing terminologies, where they were variously referred to as middle ear adenomas or middle ear carcinoids. In this report, we describe two cases of middle ear NETs with locally advanced disease and with distant metastases, respectively.

The Lipopolysaccharide-Sensing Caspase(s)-4/11 Are Activated in Cirrhosis and Are Causally Associated With Progression to Multi-Organ Injury.

Background And Aims: The development of multi-organ injury in cirrhosis is associated with increased intestinal permeability, translocation of gut-derived bacterial products [e.g., lipopolysaccharide (LPS)] into the circulation, and increased non-apoptotic hepatocyte cell death.

Whole-genome sequencing of single circulating tumor cells from neuroendocrine neoplasms.

Single-cell profiling of circulating tumor cells (CTCs) as part of a minimally invasive liquid biopsy presents an opportunity to characterize and monitor tumor heterogeneity and evolution in individual patients. In this study, we aimed to compare single-cell copy number variation (CNV) data with tissue and define the degree of intra- and inter-patient genomic heterogeneity. We performed next-generation sequencing (NGS) whole-genome CNV analysis of 125 single CTCs derived from seven patients with neuroendocrine neoplasms (NEN) alongside matched white blood cells (WBC), formalin-fixed paraffin-embedded (FFPE), and fresh frozen (FF) samples.

Collagen and elastic fibres in acute and chronic liver injury.

The histological distinction between acute and chronic liver injury is a challenging aspect of liver histopathology. It is traditionally based on the interpretation of morphological changes to the extracellular matrix (ECM) at sites of hepatocyte loss using histochemical stains. Our aim was to investigate whether immunohistochemistry and multiplexing for collagen type (I & III) and elastic fibres and a modified Victoria blue method could be helpful.

Collagen proportionate area correlates with histological stage and predicts clinical events in primary sclerosing cholangitis.

Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease in need of accurate biomarkers for stratification and as surrogates for clinical endpoints in trials. Quantitative liver fibrosis assessment by collagen proportionate area (CPA) measurement has been demonstrated to correlate with clinical outcomes in chronic hepatitis C, alcohol-related and non-alcoholic fatty liver disease. We aimed to investigate the ability of CPA to quantify liver fibrosis and predict clinical events in PSC.

High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Improved Prognostic Stratification With the New World Health Organization 2019 Classification: A Validation Study From a Single-Institution Retrospective Analysis.

Objectives: There is a pressing need to develop clinical management pathways for grade 3 (G3) gastroenteropancreatic neuroendocrine neoplasms (GEP NEN).

Methods: We performed a retrospective study on patients with metastatic G3 GEP NEN. The relationship between baseline characteristics and progression-free survival and overall survival was analyzed using the Kaplan-Meier method.

Inhibition of TLR7 and TLR9 Reduces Human Cholangiocarcinoma Cell Proliferation and Tumor Development.

Background: Toll-like receptors (TLRs) are key players in innate immunity and modulation of TLR signaling has been demonstrated to profoundly affect proliferation and growth in different types of cancer. However, the role of TLRs in human intrahepatic cholangiocarcinoma (ICC) pathogenesis remains largely unexplored.

Aims: We set out to determine if TLRs play any role in ICCs which could potentially make them useful treatment targets.

Transcriptomic Profiling of Tumor-Stromal Cell Paracrine Crosstalk Identifies Involvement of the Integrin Signaling Pathway in the Pathogenesis of Mesenteric Fibrosis in Human Small Intestinal Neuroendocrine Neoplasms.

Aim: Analysis of the pathophysiology of mesenteric fibrosis (MF) in small intestinal neuroendocrine tumors (SI-NETs) in an paracrine model and in human SI-NET tissue samples.

Methods: An indirect co-culture model of SI-NET cells KRJ-I and P-STS with stromal cells HEK293 was designed to evaluate the paracrine effects on cell metabolic activity, gene expression by RT2 PCR Profilers to analyse cancer and fibrosis related genes, and RNA sequencing. The integrin signaling pathway, a specific Ingenuity enriched pathway, was further explored in a cohort of human SI-NET tissues by performing protein analysis and immunohistochemistry.

AICAR and compound C negatively modulate HCC-induced primary human hepatic stellate cell activation in vitro.

Tumor stroma and microenvironment have been shown to affect hepatocellular carcinoma (HCC) growth, with activated hepatic stellate cells (HSC) as a major contributor in this process. Recent evidence suggests that the energy sensor adenosine monophosphate-activated kinase (AMPK) may mediate a series of essential processes during carcinogenesis and HCC progression. Here, we investigated the effect of different HCC cell lines with known or mutations on primary human HSC activation, proliferation, and AMPK activation.

Elastic fibres in alcoholic liver disease.

The literature on the contribution of elastic fibre deposition to alcohol-related liver disease (ARLD) is limited. We studied: (1) 180 liver biopsies from ARLD patients; (2) 20 ARLD explant livers; (3) 213 liver biopsies with non-ARLD injury. Elastic fibres were assessed in terms of their distribution around hepatocytes [pericellular elastosis (PCE)] and within bridging fibrous septa (septal elastosis) and scored using a semiquantitative system.

Collagen proportionate area predicts clinical outcomes in patients with alcohol-related liver disease.

Background: No prognostic tools are established for alcohol-related liver disease (ALD). Collagen proportionate area (CPA) measurement is a technique that quantifies fibrous tissue in liver biopsies using digital image analysis.

Aim: To assess the predictive value of CPA on hepatic decompensation and liver-related mortality in ALD METHODS: In a multicentre cohort study, we included 386 patients with biopsy-verified ALD and with long-term follow-up.

Understanding the Treatment Algorithm of Patients with Metastatic Pancreatic Neuroendocrine Neoplasms: A Single-Institution Retrospective Analysis Comparing Outcomes of Chemotherapy, Molecular Targeted Therapy, and Peptide Receptor Radionuclide Therapy in 255 Patients.

Background: The number of therapeutic options for patients with pancreatic neuroendocrine neoplasms (PNEN) has increased, but the optimal therapeutic algorithm has not been defined due to lack of randomised trials comparing different modalities.

Methods: We performed a retrospective study in patients with metastatic PNEN treated with ≥1 line of systemic therapy. The relationship between baseline characteristics, treatment type, and time to treatment failure (TTF), time to progression (TTP), and overall survival (OS) was analysed using the Kaplan-Meier method.

Should immunohistochemical expression of mismatch repair (MMR) proteins and microsatellite instability (MSI) analysis be routinely performed for poorly differentiated colorectal neuroendocrine carcinomas?

Summary: Colorectal poorly differentiated neuroendocrine carcinomas (NECs) are typically associated with poor outcomes. The mechanisms of their aggressiveness are still being investigated. Microsatellite instability (MSI) has recently been found in colorectal NECs showing aberrant methylation of the MLH1 gene and is associated with improved prognosis.