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Advances in Diagnosis and Therapy of Neuroendocrine Neoplasms

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 37605

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Prof. Dr. Eva Segelov

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School of Clinical Sciences, Monash University, Melbourne 3168, Australia
Interests: neuroendocrine tumors; gastrointestinal cancer; translational studies; anticancer therapies

Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to neuroendocrine neoplasms (NENs), a category of malignancy that demonstrates wide clinical heterogeneity, posing major challenges in diagnosis and management. There have been significant advances in the field of NEN genomics, pathology, imaging, and treatment over the past five years. NENs are examples of rare tumours (although their incidence and prevalence are rising) where international collaborative efforts have allowed the generation of high-level evidence to guide optimal patient-centred care. This issue presents both reviews and original papers to provide a comprehensive state-of-the-art understanding of this fascinating disease.

Prof. Eva Segelov
Guest Editor

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Keywords

neuroendocrine tumours
functional and non-functional endocrine tumours
somatostatin receptors
genomics
targeted therapy
clinical trials

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Published Papers (9 papers)

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14 pages, 510 KiB

Open AccessArticle

Long-Term Pancreatic Functional Impairment after Surgery for Neuroendocrine Neoplasms

by Valentina Andreasi, Stefano Partelli, Gabriele Capurso, Francesca Muffatti, Gianpaolo Balzano, Stefano Crippa and Massimo Falconi

J. Clin. Med. 2019, 8(10), 1611; https://doi.org/10.3390/jcm8101611 - 3 Oct 2019

Cited by 13 | Viewed by 3768

Abstract

Radical surgery represents the only curative treatment for pancreatic neuroendocrine neoplasms (PanNEN). The aim of this study was to evaluate the postoperative onset of diabetes mellitus (DM) and/or pancreatic exocrine insufficiency (PEI) in surgically treated PanNEN. Consecutive PanNEN patients, without preoperative DM, who underwent partial pancreatic resection, were included. After a median follow-up of 72 months, overall 68/276 patients (24%) developed DM. Patients who developed DM were significantly older (p = 0.002) and they had a higher body mass index (BMI) (p < 0.0001) than those who did not; they were more frequently male (p = 0.017) and with nonfunctioning neoplasms (p = 0.019). BMI > 25 Kg/m² was the only independent predictor of DM (p = 0.001). Overall, 118/276 patients (43%) developed a PEI, which was significantly more frequent after pancreaticoduodenectomy (p < 0.0001) and in patients with T3-T4 tumors (p = 0.001). Pancreaticoduodenectomy was the only independent predictor of PEI (p < 0.0001). Overall, 54 patients (20%) developed disease progression. Patients with and without DM had similar progression free survival (PFS), whereas patients without PEI had better five-year-PFS (p = 0.002), although this association was not confirmed in multivariate analysis. The risk of DM and PEI after surgery for PanNEN is relatively high but it does not affect PFS. BMI and pancreatic head resection are independent predictors of DM and PEI, respectively. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Therapy of Neuroendocrine Neoplasms)

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12 pages, 1240 KiB

Open AccessArticle

Consensus-Derived Quality Performance Indicators for Neuroendocrine Tumour Care

by Braden Woodhouse, Sharon Pattison, Eva Segelov, Simron Singh, Kate Parker, Grace Kong, William Macdonald, David Wyld, Goswin Meyer-Rochow, Nick Pavlakis, Siobhan Conroy, Vallerie Gordon, Jonathan Koea, Nicole Kramer, Michael Michael, Kate Wakelin, Tehmina Asif, Dorothy Lo, Timothy Price, Ben Lawrence and on behalf of the Commonwealth Neuroendocrine Tumour Collaboration (CommNETs) Show full author list Hide full author list

J. Clin. Med. 2019, 8(9), 1455; https://doi.org/10.3390/jcm8091455 - 12 Sep 2019

Cited by 7 | Viewed by 4495

Abstract

Quality performance indicators (QPIs) are used to monitor the delivery of cancer care. Neuroendocrine tumours (NETs) are a family of individually uncommon cancers that derive from neuroendocrine cells or their precursors, and can occur in most organs. There are currently no QPIs available for NETs and their heterogeneity makes QPI development difficult. CommNETs is a collaboration between NET clinicians, researchers and advocates in Canada, Australia and New Zealand. We created QPIs for NETs using a three-step consensus process. First, a multidisciplinary team used the nominal group technique to create candidates (n = 133) which were then curated into appropriateness statements (62 statements, 44 sub-statements). A two-stage modified RAND/UCLA Delphi consensus process was conducted: an online survey rated the statement appropriateness then the top-ranked statements (n = 20) were assessed in a face-to-face meeting. Finally, 10 QPIs met consensus criteria; documentation of primary site, proliferative index, differentiation, tumour board review, use of a structured pathology report, presence of distant metastasis, 5- and 10-year disease-free and overall survival. These NET QPIs will be trialed as a method to monitor and improve care for people with NETs and to facilitate international comparison. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Therapy of Neuroendocrine Neoplasms)

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10 pages, 730 KiB

Open AccessArticle

Safety and Activity of Metronomic Temozolomide in Second-Line Treatment of Advanced Neuroendocrine Neoplasms

by Salvatore Tafuto, Claudia von Arx, Monica Capozzi, Fabiana Tatangelo, Manuela Mura, Roberta Modica, Maria Luisa Barretta, Antonella Di Sarno, Maria Lina Tornesello, Annamaria Colao and Alessandro Ottaiano

J. Clin. Med. 2019, 8(8), 1224; https://doi.org/10.3390/jcm8081224 - 15 Aug 2019

Cited by 12 | Viewed by 2944

Abstract

Background. Platinum-based chemotherapy is the mainstay of front-line treatment of patients affected by pluri-metastatic intermediate/high grade NeuroEndocrine Neoplasms (NENs). However, there are no standard second-line treatments at disease progression. Previous clinical experiences have evidenced that temozolomide (TMZ), an oral analog of dacarbazine, is active against NENs at standard doses of 150 to 200 mg/mq per day on days 1 to 5 of a 28-day cycle, even if a significant treatment-related toxicity is reported. Methods. Metastatic NENs patients were treated at the ENETS (European NeuroEndocrine Tumor Society) center of excellence of Naples (Italy), from 2014 to 2017 with a second-line alternative metronomic schedule of TMZ, 75 mg/m² per os “one week on/one week off”. Toxicity was graded with NCI-CTC criteria v4.0; objective responses with RECIST v1.1 and performance status (PS) according to ECOG. Results. Twenty-six consecutive patients were treated. Median age was 65.5 years. The predominant primary organs were pancreas and lung. Grading was G2 in 11 patients, G3 in 15. More than half of patients had a PS 2 (15 vs. 11 with PS 1). The median time-on-temozolomide therapy was 12.2 months (95% CI: 11.4–19.6). No G3/G4 toxicities were registered. Complete response was obtained in 1 patient, partial response in 4, stable disease in 19 (disease control rate: 92.3%), and progressive disease in 2. The median overall survival from TMZ start was 28.3 months. PS improved in 73% of patients. Conclusions. Metronomic TMZ is a suitable treatment for G2 and G3 NENs particularly in PS 2 patients. Prospective and larger trials are needed to confirm these results. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Therapy of Neuroendocrine Neoplasms)

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8 pages, 325 KiB

Open AccessArticle

Multidisciplinary Management of Neuroendocrine Neoplasia: A Real-World Experience from a Referral Center

by Ludovica Magi, Federica Mazzuca, Maria Rinzivillo, Giulia Arrivi, Emanuela Pilozzi, Daniela Prosperi, Elsa Iannicelli, Paolo Mercantini, Michele Rossi, Patrizia Pizzichini, Andrea Laghi, Alberto Signore, Paolo Marchetti, Bruno Annibale and Francesco Panzuto

J. Clin. Med. 2019, 8(6), 910; https://doi.org/10.3390/jcm8060910 - 25 Jun 2019

Cited by 35 | Viewed by 3578

Abstract

Purpose: Multidisciplinary approach is widely advised for an effective care of patients with neuroendocrine neoplasia (NEN). Since data on efficacy of multidisciplinary management of NENs patients in referral centers are scanty, this study aimed at analyzing the modality of presentation and clinical outcome of patients with NENs managed by a dedicated multidisciplinary team. Methods. In this prospective observational study, we included all consecutive new patients visiting the Sant’Andrea Hospital in Rome (ENETS—Center of Excellence) between January 2014 and June 2018. Results. A total of 195 patients were evaluated. The most frequent sites were pancreas (38.5%), small bowel (22%), and lung (9.7%). Median Ki67 was 3%. After the first visit at the center, additional radiological and/or nuclear medicine procedures were requested in 163 patients (83.6%), whereas histological data revision was advised in 84 patients (43.1%) (revision of histological slides: 27.7%, new bioptic sampling: 15.4%). After that, disease imaging staging and grading was modified in 30.7% and 17.9% of patients, respectively. Overall, a change in therapeutic management was proposed in 98 patients (50.3%). Conclusions. Multidisciplinary approach in a dedicated team may lead to change of disease imaging staging and grading in a significant proportion of patients. Enhancing referral routes to dedicated-NEN center should be promoted, since it may improve patients’ clinical outcome. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Therapy of Neuroendocrine Neoplasms)

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11 pages, 503 KiB

Open AccessArticle

Carcinoid Heart Disease and Decreased Overall Survival among Patients with Neuroendocrine Tumors: A Retrospective Multicenter Latin American Cohort Study

by Deise Uema, Carolina Alves, Marcella Mesquita, Jose Eduardo Nuñez, Timo Siepmann, Martin Angel, Juliana F. M. Rego, Rui Weschenfelder, Duilio R. Rocha Filho, Frederico P. Costa, Milton Barros, Juan M. O’Connor, Ben M. Illigens and Rachel P. Riechelmann

J. Clin. Med. 2019, 8(3), 405; https://doi.org/10.3390/jcm8030405 - 23 Mar 2019

Cited by 13 | Viewed by 4322

Abstract

The background to this study was that factors associated with carcinoid heart disease (CHD) and its impacts on overall survival (OS) are scantly investigated in patients (pts) with neuroendocrine tumors (NETs). In terms of materials and methods, a retrospective multicenter cohort study was conducted of factors associated with CHD in advanced NET pts with carcinoid syndrome (CS) and/or elevated urinary 5-hidroxyindole acetic acid (u5HIAA). CHD was defined as at least moderate right valve alterations. The results were the following: Among the 139 subjects included, the majority had a midgut NET (54.2%), 81.3% had CS, and 93% received somatostatin analogues. In a median follow-up of 39 months, 48 (34.5%) pts developed CHD, with a higher frequency in pts treated in public (77.2%) versus private settings (22.9%). In a multivariate logistic regression, unknown primary or colorectal NETs (Odds Ratio (OR) 4.35; p = 0.002), at least 50% liver involvement (OR 3.45; p = 0.005), and being treated in public settings (OR 4.76; p = 0.001) were associated with CHD. In a Cox multivariate regression, bone metastases (Hazard Ratio {HR} 2.8; p = 0.031), CHD (HR 2.63; p = 0.038), and a resection of the primary tumor (HR 0.33; p = 0.026) influenced the risk of death. The conclusions were the following: The incidence of CHD was higher in pts with a high hepatic tumor burden and in those treated in a public system. Delayed diagnosis and limited access to effective therapies negatively affected the lives of NET patients. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Therapy of Neuroendocrine Neoplasms)

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13 pages, 1200 KiB

Open AccessArticle

Treatment of Liver Metastases from Midgut Neuroendocrine Tumours: A Systematic Review and Meta-Analysis

by Enes Kaçmaz, Charlotte M. Heidsma, Marc G. H. Besselink, Koen M. A. Dreijerink, Heinz-Josef Klümpen, Elisabeth J. M. Nieveen van Dijkum and Anton F. Engelsman

J. Clin. Med. 2019, 8(3), 403; https://doi.org/10.3390/jcm8030403 - 22 Mar 2019

Cited by 25 | Viewed by 4120

Abstract

Strong evidence comparing different treatment options for liver metastases (LM) arising from gastroenteropancreatic neuroendocrine tumours (GEP-NET) is lacking. The aim of this study was to determine which intervention for LMs from GEP-NETs shows the longest overall survival (OS). A systematic search was performed in MEDLINE, Embase and the Cochrane Library in February 2018. Studies reporting on patients with LMs of any grade of sporadic GEP-NET comparing two intervention groups were included for analysis. Meta-analyses were performed where possible. Eleven studies, with a total of 1108, patients were included; 662 patients had LM from pancreatic NETs (pNET), 164 patients from small-bowel NETs (SB-NET) and 282 patients of unknown origin. Improved 5-year OS was observed for surgery vs. chemotherapy (OR 0.05 95% CI [0.01, 0.21] p < 0.0001), for surgery vs. embolization (OR 0.18 95% CI [0.05, 0.61] p = 0.006) and for LM resection vs. no LM resection (OR 0.15 95% CI [0.05, 0.42] p = 0.0003). This is the largest meta-analysis performed comparing different interventions for LMs from GEP-NETs. Despite the high risk of bias and heterogeneity of data, surgical resection for all tumour grades results in the longest overall survival. Chemotherapy and embolization should be considered as an alternative in case surgery is not feasible. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Therapy of Neuroendocrine Neoplasms)

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Review

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23 pages, 733 KiB

Open AccessReview

Mixed Neuroendocrine Non-Neuroendocrine Neoplasms: A Systematic Review of a Controversial and Underestimated Diagnosis

by Melissa Frizziero, Bipasha Chakrabarty, Bence Nagy, Angela Lamarca, Richard A. Hubner, Juan W. Valle and Mairéad G. McNamara

J. Clin. Med. 2020, 9(1), 273; https://doi.org/10.3390/jcm9010273 - 19 Jan 2020

Cited by 86 | Viewed by 6241

Abstract

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) represent a rare diagnosis of the gastro-entero-pancreatic tract. Evidence from the current literature regarding their epidemiology, biology, and management is of variable quality and conflicting. Based on available data, the MiNEN has an aggressive biological behaviour, mostly driven by its (often high-grade) neuroendocrine component, and a dismal prognosis. In most cases, the non-neuroendocrine component is of adenocarcinoma histology. Due to limitations in diagnostic methods and poor awareness within the scientific community, the incidence of MiNENs may be underestimated. In the absence of data from clinical trials, MiNENs are commonly treated according to the standard of care for pure neuroendocrine carcinomas or adenocarcinomas from the same sites of origin, based on the assumption of a biological similarity to their pure counterparts. However, little is known about the molecular aberrations of MiNENs, and their pathogenesis remains controversial; molecular/genetic studies conducted so far point towards a common monoclonal origin of the two components. In addition, mutations in tumour-associated genes, including TP53, BRAF, and KRAS, and microsatellite instability have emerged as potential drivers of MiNENs. This systematic review (91 full manuscripts or abstracts in English language) summarises the current reported literature on clinical, pathological, survival, and molecular/genetic data on MiNENs. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Therapy of Neuroendocrine Neoplasms)

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16 pages, 334 KiB

Open AccessReview

Follow-Up Recommendations after Curative Resection of Well-Differentiated Neuroendocrine Tumours: Review of Current Evidence and Clinical Practice

by Angela Lamarca, Hamish Clouston, Jorge Barriuso, Mairéad G McNamara, Melissa Frizziero, Was Mansoor, Richard A Hubner, Prakash Manoharan, Sarah O’Dwyer and Juan W Valle

J. Clin. Med. 2019, 8(10), 1630; https://doi.org/10.3390/jcm8101630 - 5 Oct 2019

Cited by 16 | Viewed by 2962

Abstract

The incidence of neuroendocrine neoplasms (NENs) is increasing, especially for patients with early stages and grade 1 tumours. Current evidence also shows increased prevalence, probably reflecting earlier stage diagnosis and improvement of treatment options. Definition of adequate postsurgical follow-up for NENs is a current challenge. There are limited guidelines, and heterogeneity in adherence to those available is notable. Unfortunately, the population of patients at greatest risk of recurrence has not been defined clearly. Some studies support that for patients with pancreatic neuroendocrine tumours (PanNETs), factors such as primary tumour (T), stage, grade (Ki-67), tumour size, and lymph node metastases (N) are of relevance. For bronchial neuroendocrine tumours (LungNETs) and small intestinal neuroendocrine tumours (siNETs), similar factors have been identified. This review summarises the evidence supporting the rationale behind follow-up after curative resection in well-differentiated PanNETs, siNETs, and LungNETS. Published evidence informing relapse rate, disease-free survival, and relapse patterns are discussed, together with an overview of current guidelines informing postsurgical investigations and duration of follow-up. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Therapy of Neuroendocrine Neoplasms)

21 pages, 1235 KiB

Open AccessReview

Updates on the Role of Molecular Alterations and NOTCH Signalling in the Development of Neuroendocrine Neoplasms

by Claudia von Arx, Monica Capozzi, Elena López-Jiménez, Alessandro Ottaiano, Fabiana Tatangelo, Annabella Di Mauro, Guglielmo Nasti, Maria Lina Tornesello and Salvatore Tafuto

J. Clin. Med. 2019, 8(9), 1277; https://doi.org/10.3390/jcm8091277 - 22 Aug 2019

Cited by 20 | Viewed by 4051

Abstract

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of rare malignancies, mainly originating from hormone-secreting cells, which are widespread in human tissues. The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout the multiple endocrine neoplasia type 1 (MEN-1) gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development. Other molecular mechanisms, such as the NOTCH signalling pathway, have shown to play an important role in the pathogenesis of NENs. NOTCH receptors are expressed on neuroendocrine cells and generally act as tumour suppressor proteins, but in some contexts can function as oncogenes. The biological heterogeneity of NENs suggests that to fully understand the role and the potential therapeutic implications of gene mutations and NOTCH signalling in NENs, a comprehensive analysis of genetic alterations, NOTCH expression patterns and their potential role across all NEN subtypes is required. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Therapy of Neuroendocrine Neoplasms)

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