Longitudinal Changes in Ki-67 Indices in Small-Intestinal Neuroendocrine Tumours and Their Impact on Survival.

Introduction: The purpose of this study was to evaluate longitudinal changes in Ki-67 indices of SI-NETs and assess the impact of these in overall survival (OS).

Methods: We screened 551 patients with SI-NETs diagnosed from 1993, through 2021, identified using the SI-NET databases from five European referral centres. Only patients with well-differentiated tumours and available baseline tumour samples and follow-up re-biopsies were included.

Prevalence of metastases outside the liver and abdominal lymph nodes on Ga-DOTATOC-PET/CT in patients with small intestinal and pancreatic neuroendocrine tumours.

Metastases outside the liver and abdominal/retroperitoneal lymph nodes are nowadays detected frequently in patients with neuroendocrine tumours (NETs), owing to the high sensitivity of positron emission tomography (PET) with Gallium-68-DOTA-somatostatin analogues (Ga-SSA) and concomitant diagnostic computed tomography (CT). Our aim was to determine the prevalence of extra-abdominal metastases on Ga-DOTATOC-PET/CT in a cohort of patients with small intestinal (Si-NET) and pancreatic NET (Pan-NET), as well as that of pancreatic metastasis in patients with Si-NET. Among 2090 patients examined by Ga-DOTATOC-PET/CT at two tertiary referral centres, a total of 1177 patients with a history of Si- or Pan-NET, were identified.

Modified Histopathological Grading Optimizes Prediction of Survival Outcomes in Small Intestinal Neuroendocrine Tumors.

Context: One of the major prognostic indices in neuroendocrine tumors (NETs) is Ki67 proliferation index.

Objective: To identify optimal grading Ki67 cutoffs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs).

Methods: Multicenter retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at 5 European referral centers with a mean (±SD) follow-up time of 51.

Impact of fine-needle aspiration cytology in thyroidectomy extent and associated surgical morbidity in thyroid cancer.

Purpose: To assess the impact of fine-needle aspiration cytology (FNAC) in the extent of surgery in patients with thyroid cancer (TC) and the associated surgical morbidity in primary and completion setting.

Methods: A Swedish nationwide cohort of patients having surgery for TC (n = 2519) from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal surgery between 2004 and 2013 was obtained. Data was validated through scrutinizing FNAC and histology reports.

Pancreatic metastases in patients with neuroendocrine neoplasms: A multi-centre cohort study.

Pancreatic metastases (PMs) from neuroendocrine neoplasms (NENs) are rare but the increased sensitivity of new diagnostic tools such as Ga-DOTATATE PET/CT has resulted in their increased recognition at initial diagnosis or follow-up. A retrospective analysis of the data of patients from six tertiary referral centres was performed in order to identify the characteristics and the prognostic significance of PMs in patients with NENs. We used a control group of 69 age-, sex- and primary tumour - matched NEN patients from the same cohort with stage IV disease but no PMs.

Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size: a retrospective, Europe-wide, pooled cohort study.

Background: Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy.

Methods: In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010.

Meta-analysis of placebo-arm dropouts in osteoporosis randomized-controlled trials and implications for nocebo-associated discontinuation of anti-osteoporotic drugs in clinical practice.

Unlabelled: Dropout from placebo arms in randomized-controlled trials is a surrogate for nocebo responses, resulting from patients' negative expectations to treatment. Among 16,460 placebo-treated patients in oral anti-osteoporotic drug trials, nocebo dropouts were 8% on average, being higher in older patients. This implies that nocebo may contribute to the osteoporosis treatment gap in clinical practice.

Association of lymph node metastases, grade and extent of mesenteric lymph node dissection in locoregional small intestinal neuroendocrine tumors with recurrence-free survival.

We aimed to assess the prognostic impact of tumor- and patient-related parameters in patients with stage I-III small intestinal neuroendocrine tumors (SI-NETs), who underwent locoregional resective surgery (LRS) with curative intent. We included 229 patients with stage I-III SI-NETs diagnosed from June 15, 1993, through March 8, 2021, identified using the SI-NET databases from five European referral centers. Mean ± SD age at baseline was 62.

Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome.

This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient.

Heterogeneity of Small Intestinal Neuroendocrine Tumors Metastasis: Biologic Patterns of a Series with Virchow's Node Involvement.

Small intestinal neuroendocrine tumors (SI-NETs) may rarely metastasize to the left supraclavicular lymph nodes, also known as Virchow's node metastasis (VM). Data on prevalence, prognostic significance, and clinical course of disease for SI-NET patients with VM is limited. In this retrospective analysis of 230 SI-NET patients treated at two tertiary referral centers, we found nine patients with VM (prevalence 3.

A Critical Appraisal of Contemporary and Novel Biomarkers in Pheochromocytomas and Adrenocortical Tumors.

Pheochromocytomas/Paragangliomas (PPGLs) and adrenocortical tumors are rare neoplasms with significant heterogeneity in their biologic and clinical behavior. Current diagnostic and predictive biomarkers include hormone secretion, as well as histopathological and genetic features. PPGL diagnosis is based on biochemical measurement of catecholamines/metanephrines, while histopathological scoring systems have been proposed to predict the risk of malignancy.

Cardiovascular Toxicities Secondary to Biotherapy and Molecular Targeted Therapies in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.

A broad spectrum of novel targeted therapies with prime antitumor activity and/or ample control of hormonal symptoms together with an overall acceptable safety profile have emerged for patients with metastatic neuroendocrine neoplasms (NENs). In this systematic review and quantitative meta-analysis, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov databases were searched to assess and compare the safety profile of NEN treatments with special focus on the cardiovascular adverse effects of biotherapy and molecular targeted therapies (MTTs).

Clinical Utility of F-FDG PET in Neuroendocrine Tumors Prior to Peptide Receptor Radionuclide Therapy: A Systematic Review and Meta-Analysis.

The role of F-FDG PET in patients with variable grades of neuroendocrine tumors (NETs) prior to peptide receptor radionuclide therapy (PRRT) has not been adequately elucidated. We aimed to evaluate the impact of F-FDG PET status on disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in neuroendocrine tumor (NET) patients receiving PRRT. We searched the MEDLINE, Embase, Cochrane Library, and Web of Science databases up to July 2020 and used the Newcastle-Ottawa scale (NOS) criteria to assess quality/risk of bias.

Changing biological behaviour of NETs during the evolution of the disease: progress on progression.

Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead to an occasion of increase in grading, but generally does not appear to be correlated with histologically confirmed dedifferentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner.

Currently available treatment options for neuroendocrine liver metastases.

Neuroendocrine neoplasms (NEN) are frequently characterized by a high propensity for metastasis to the liver, which appears to be a dominant site of distant-stage disease, affecting quality of life and overall survival. Liver surgery with the intention to cure is the treatment of choice for resectable neuroendocrine liver metastases (NELM), aiming to potentially prolong survival and ameliorate hormonal symptoms refractory to medical control. Surgical resection is indicated for patients with NELM from well-differentiated NEN, while its feasibility and complexity are largely dictated by the degree of liver involvement.

The Role of Serum 5-HIAA as a Predictor of Progression and an Alternative to 24-h Urine 5-HIAA in Well-Differentiated Neuroendocrine Neoplasms.

Our aim was to investigate the clinical utility of serum 5HIAA for disease surveillance and diagnostic purposes in a cohort of patients with well-differentiated neuroendocrine neoplasms (WD-NENs). Forty-eight patients with WD-NENs and concurrent serum and urinary 5HIAA testing, as well as CT/MRI imaging, were included. Analysis of matching-pairs did not reveal any association between RECIST 1.

Association of a Palliative Surgical Approach to Stage IV Pancreatic Neuroendocrine Neoplasms with Survival: A Systematic Review and Meta-Analysis.

The role of primary tumor resection in patients with pancreatic neuroendocrine neoplasms (PanNENs) and unresectable distant metastases remains controversial. We aimed to evaluate the effect of palliative primary tumor resection (PPTR) on overall survival (OS) in this setting. We searched the MEDLINE, Embase, Cochrane Library, Web of Science and SCOPUS databases up to January 2020 and used the Newcastle-Ottawa scale (NOS) criteria to assess quality/risk of bias.

The effect of prophylactic surgery in survival and HRQoL in appendiceal NEN.

Background/aims: Long-term outcomes are understudied in patients with well-differentiated appendiceal neuroendocrine neoplasms (WD-ANENs). We aimed to evaluate the validity of currently applied criteria for completion prophylactic right hemicolectomy (pRHC) and determine its association with patient outcomes, including health-related quality of life (HRQoL).

Methods: Eligible patients from five European referral centers were divided between those who underwent appendectomy alone and those who underwent completion pRHC.

Pathogenesis and Clinical Management of Mesenteric Fibrosis in Small Intestinal Neuroendocine Neoplasms: A Systematic Review.

Mesenteric fibrosis (MF) constitutes an underrecognized sequela in patients with small intestinal neuroendocrine neoplasms (SI-NENs), often complicating the disease clinical course. The aim of the present systematic review, carried out by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, is to provide an update in evolving aspects of MF pathogenesis and its clinical management in SI-NENs. Complex and dynamic interactions are present in the microenvironment of tumor deposits in the mesentery.

Increased autophagy/mitophagy levels in primary tumours of patients with pancreatic neuroendocrine neoplasms.

Background/aims: We assessed the levels of autophagy and mitophagy, that are linked to cancer development and drug resistance, in well differentiated pancreatic neuroendocrine neoplasms (PanNENs) and correlated them with clinico-pathological parameters.

Methods: Fluorescent immunostaining for the autophagy markers LC3Β and p62/or LAMP1 was performed on 22 PanNENs and 11 controls of normal pancreatic tissues and validated through Western blotting. Autophagy quantitative scoring was generated for LC3B-positive puncta and analysed in relation to clinico-pathological parameters.

Endocrinological Toxicity Secondary to Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs).

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasingly recognized, characterized by prolonged survival even with metastatic disease. Their medical treatment is complex involving various specialties, necessitating awareness of treatment-related adverse effects (AEs). As GEP-NENs express somatostatin receptors (SSTRs), long-acting somatostatin analogs (SSAs) that are used for secretory syndrome and tumor control may lead to altered glucose metabolism.

Anti-Tumor Activity and Safety of Multikinase Inhibitors in Advanced and/or Metastatic Thyroid Cancer: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Many trials have demonstrated prime antitumor activity of novel, small molecule multikinase inhibitors (MKIs) in advanced and/or metastatic thyroid cancer (TC). In this work, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, and clinicaltrials.gov databases were searched.