Search

Simple Summary: Metformin is one of the most widely used drugs in the world, since its first use in the second part of the 1950s in France (Aron, 1957) and in the United Kingdom (Rona, 1958), and is on the World Health Organization's List of Essential Medicines. Traditionally, metformin is used in diabetes mellitus, mainly in overweight and obese subjects, but also in other conditions of impaired glucose metabolism, such as insulin resistance. In recent years, in vitro and in vivo data on this molecule as an antiproliferative modulator have suggested a series of clinical trials in several tumors that—at the moment—have not confirmed the expected positive results. The aim of this paper is to offer a double vision of this molecule, with a very light side about the metabolic aspects and a darker side concerning its antineoplastic activity, focusing on molecular and subcellular pathways involved in both fields and discussing the contrast between preliminary cellular data and real clinical outcomes in different neoplasms. The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua, which means door. How many new doors will this old drug be able to open? [ABSTRACT FROM AUTHOR]

Type I gastric neuroendocrine neoplasms (gNENs) are associated with atrophic gastritis and have a high recurrence rate, which means frequent endoscopies are required. The objective of this study was to identify factors predicting the local recurrence of type I gNENs. The clinical course and the pathological and biochemical data of patients with type I gNENs treated at Bnai Zion Medical Center between 2006 and 2022 were analyzed retrospectively. Twenty-seven type I gNENs were evaluated. The follow-up period was 41 months (range: 11–288 months). Recurrence of the tumor occurred in 13/27 (48%) patients after 35 months (median (M), interquartile range (IQR): 21–67.5). Serum gastrin levels were significantly higher in patients with recurrent disease versus patients with non-recurrent disease (788 vs. 394 ng/L; p = 0.047), while the Ki-67 index was significantly lower in patients with recurrent disease versus patients with non-recurrent disease (1% vs. 3.5%; p = 0.035). Tumor size, mitotic count, and serum chromogranin A levels did not correlate with recurrence. The present study emphasizes the role of gastrin in the pathogenesis of gNEN recurrence and highlights the debate regarding the ability of the Ki-67 index to predict the clinical course of this disease. [ABSTRACT FROM AUTHOR]

Autoimmune metaplastic atrophic gastritis (AMAG) is associated with an increased risk of gastric neoplasms. This study aimed to systematically analyze the incidence rate of gastric cancer (GC), low-grade dysplasia (LGD) and type-1 gastric neuroendocrine tumor (gNETs) development in AMAG adults. Studies on AMAG patients reporting the incidence of gastric neoplasms was identified through a systematic search in PUBMED and EMBASE. Study quality was assessed using the Joanna Briggs Institute quality assessment tool. Incidence rates of GC, LGD and type-1 gNETs were examined by meta-analysis. Thirteen studies met eligibility criteria. Incidence rate of gastric cancer calculated from the pooled data was 0.14% per person-year in both single-center studies and national registration studies. Meta-analysis showed a relative risk of 11.05 (95% CI: 6.39–19.11) for gastric cancer development in AMAG patients. The calculated pooled gastric LGD and type-1 gNETs incidence rates were 0.52% and 0.83% per person-year, respectively. As for experience from our center, we presented three distinctive cases of gastric neoplasm arising from the background of AMAG. This study underscores the potential for malignant transformation of precancerous lesions and reiterates the importance of careful esophagogastroduodenoscopy screening. [ABSTRACT FROM AUTHOR]

Male genitourinary neuroendocrine neoplasms (GU-NENs) are rare, without any definite imaging characteristics. The WHO classified neuroendocrine neoplasms in the 2016 classification of the tumors of the urinary tract and genital organs along with other GU tumors; however, no pathologic grading system is available as published for gastroenteropancreatic neuroendocrine neoplasms. Often a multimodality approach using cross-sectional imaging techniques, such as molecular imaging and histopathology are implemented to arrive at the diagnosis. This article provides a review of the pathology and imaging features of the male GU-NENs. [ABSTRACT FROM AUTHOR]

Acromegaly is a systemic disease caused by excessive inappropriate secretion of GH and IGF-I levels, resulting in many systemic complications, including cardiovascular, respiratory, metabolic diseases, and a possible increased risk of some neoplasias. Although many studies on acromegaly and cancer remain uncertain, most data indicate that colorectal cancer (CRC) incidence is increased in this population. The exact mechanism involved in the role of GH-IGF-I axis in CRC has not been fully explained, yet it is associated with local and circulating effects of GH and IGF-I on the colon, promoting angiogenesis, cell proliferation, risk of mutation, inhibition of tumor-suppressor genes and apoptosis, thus facilitating a tumor microenvironment. Nevertheless, population-based studies present controversial findings on CRC incidence and mortality. All worldwide guidelines and expert consensuses agree with the need for colonoscopic screening and surveillance in acromegaly, although there is no consensus regarding the best period to do this. This review aims to analyze the existing data on CRC and acromegaly, exploring its pathophysiology, epidemiological studies and their limitations, colonic polyp characteristics, overall cancer and CRC incidences and mortality, risk factors for colon cancer pathophysiology, and recommendation guideline aspects. [ABSTRACT FROM AUTHOR]

Background: Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) of the pancreas are extremely rare. Their pathogenesis and molecular landscape are largely unknown. Here, we report a case of mixed pancreatic intraductal papillary mucinous neoplasm (IPMN) and well-differentiated neuroendocrine tumor (NET) and identify its genetic alterations by next-generation sequencing (NGS). Case presentation: A fifty-year-old male was admitted into the hospital for evaluation of a pancreatic lesion detected during a routine examination. Abdominal ultrasound indicated a hypoechoic mass of 2.6 cm at the head of the pancreas. Malignancy was suspected and partial pancreatectomy was performed. Thorough histopathological examination revealed a mixed IPMN-NET. In some areas, the two components were relatively separated, whereas in other areas IPMN and NET grew in a composite pattern: The papillae were lined with epithelial cells of IPMN, and there were clusters of NET nests in the stroma of papillary axis. NGS revealed shared somatic mutations (KRAS, PCK1, MLL3) in both components. The patient has been uneventful 21 months after the surgery. Conclusions: Our case provides evidence of a common origin for mixed IPMN-NET with composite growth features. Our result and literature review indicate that KRAS mutation might be a driver event underlying the occurrence of MiNEN. We also recommend the inclusion of mixed non-invasive exocrine neoplasms and neuroendocrine neoplasms into MiNEN. [ABSTRACT FROM AUTHOR]

Background and Purpose: Dopamine agonists targeting D2 receptor have been used for decades in treating pituitary adenomas. There has been little clear evidence implicating the canonical G protein signalling as the mechanism by which D2 receptor suppresses the growth of pituitary tumours. We hypothesize that β-arrestin2-dependent signalling is the molecular mechanism dictating D2 receptor inhibitory effects on pituitary tumour growth.Experimental Approach: The involvement of G protein and β-arrestin2 in bromocriptine-mediated growth suppression in rat MMQ and GH3 tumour cells was assessed. The anti-growth effect of a β-arrestin2-biased agonist, UNC9994, was tested in cultured cells, tumour-bearing nude mice and primary cultured human pituitary adenomas. The effect of G protein signalling on tumour growth was also analysed by using a G protein-biased agonist, MLS1547, and a Gβγ inhibitor, gallein, in vitro.Key Results: β-arrestin2 signalling but not G protein pathways mediated the suppressive effect of bromocriptine on pituitary tumour growth. UNC9994 inhibited pituitary tumour cell growth in vitro and in vivo. The suppressive function of UNC9994 was obtained by inducing intracellular reactive oxygen species generation through downregulating mitochondrial complex I subunit NDUFA1. The effects of Gαi/o signalling and Gβγ signalling via D2 receptor on pituitary tumour growth were cell-type-dependent.Conclusion and Implications: Given the very low expression of Gαi/o proteins in pituitary tumours and the complexity of the responses of pituitary tumours to G protein signalling pathways, our study reveals D2 receptor β-arrestin2-biased ligand may be a more promising choice to treat pituitary tumours with improved therapeutic selectivity. [ABSTRACT FROM AUTHOR]

Background. A higher Ki-67 labeling index is associated with a poorer prognosis in gastroenteropancreatic neuroendocrine neoplasms. It has also been proposed that the Ki-67 labeling index may increase during disease progression from the primary site to metastatic sites. Although biopsy specimens are used to measure the Ki-67 labeling index, heterogeneity in lesions is thought to affect the assessment of the Ki-67 labeling index. To overcome tumor heterogeneity, we evaluated the variability in the Ki-67 labeling index between primary lesions and hepatic metastases by analyzing only surgically resected specimens. Methods. We conducted a single-center retrospective study to analyze the variability in the Ki-67 labeling index and the change in tumor grade between the primary site and metastatic hepatic sites in 19 patients diagnosed with gastroenteropancreatic neuroendocrine neoplasms at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 1998 to 2018. Both the primary site and metastatic hepatic sites were surgically resected. Results. Among the 19 patients with gastroenteropancreatic neuroendocrine neoplasms, 12 patients (63%) showed higher levels of the Ki-67 labeling index at metastatic hepatic sites than at the primary site. The median Ki-67 labeling index levels for the primary lesion and metastatic hepatic lesions were 5% and 10%, respectively. The Ki-67 labeling index levels were significantly elevated in the metastatic hepatic lesions compared to the primary lesion (P =.002). Conclusions. This study addressed the heterogeneity of the Ki-67 labeling index by analyzing only surgically resected specimens. We observed a statistically significant increase in the Ki-67 labeling index in hepatic metastases compared to the primary lesion. [ABSTRACT FROM AUTHOR]

Updates in classification of gastro‐entero‐pancreatic neuroendocrine neoplasms better reflect the biological characteristics of these tumours. In the present study, we analysed the characteristics of neuroendocrine tumours that could aid in a more precise stratification of risk groups. In addition, we have highlighted the importance of grade (re)assessment based on investigation of secondary tumour lesions. Two hundred and sixty‐four cases of neuroendocrine tumours of gastro‐entero‐pancreatic origin from three centres were included in the study. Tumour morphology, mitotic count and Ki67 labelling index were evaluated in specimens of primary tumours, lymph node metastases and distant metastases. These variables were correlated with overall survival (OS) and relapse‐free survival (RFS). Tumour stage, number of affected lymph nodes, presence of tumour deposits and synchronous/metachronous metastases were tested as possible prognostic features. Mitotic count, Ki‐67 labelling index, primary tumour site, tumour stage, presence of tumour deposits and two or more affected lymph nodes were significant predictors of OS and RFS. At the same time, mitotic count and Ki‐67 labelling index can be addressed as continuous variables determining prognosis. We observed a very high correlation between the measures of proliferative activity in primary and secondary tumour foci. The presence of isolated tumour deposits was identified as an important determinant of both RFS and OS for pancreatic (hazard ratio [HR] = 7.61, 95% confidence interval [CI] = 3.96‐14.6, P < 0.0001 for RFS; HR = 3.28, 95% CI = 1.56‐6.87, P = 0.0017 for OS) and ileal/jejunal neuroendocrine tumours (HR = 1.98, 95% CI = 1.25‐3.13, P = 0.0036 for RFS and HR 2.59, 95% CI = 1.27‐5.26, P = 0.009 for OS). The present study identifies the presence of mesenterial tumour deposits as an important prognostic factor for gastro‐entero‐pancreatic neuroendocrine tumours, provides evidence that proliferative parameters need to be treated as continuous variables and further supports the importance of grade determination in all available tumour foci. The study represents an analysis of well‐known and novel prognostic features of neuroendocrine neoplasms from different gastro‐entero‐pancreatic sites in a relatively large pool of cases. [ABSTRACT FROM AUTHOR]

During the 5th NIKE (Neuroendocrine tumors Innovation in Knowledge and Education) meeting, held in Naples, Italy, in May 2019, discussions centered on the understanding of pathology reports of gastroenetropancreactic neuroendocrine neoplasms. In particular, the main problem concerned the difficulty that clinicians experience in extrapolating relevant information from neuroendocrine tumor pathology reports. During the meeting, participants were asked to identify and rate issues which they have encountered, for which the input of an expert pathologist would have been appreciated. This article is a collection of the most rated questions and relative answers, focusing on three main topics: 1) morphology and classification; 2) Ki67 and grading; 3) immunohistochemistry. Patient management should be based on multidisciplinary decisions, taking into account clinical and pathology-related features with clear comprehension between all health care professionals. Indeed, pathologists require clinical details and laboratory findings when relevant, while clinicians require concise and standardized reports. In keeping with this last statement, the minimum requirements in pathology datasets are provided in this paper and should be a baseline for all neuroendocrine tumor professionals. [ABSTRACT FROM AUTHOR]

Recent studies have shown that G protein‐coupled receptors (GPCRs), the largest signal‐conveying receptor family, are targets for mutations occurring frequently in different cancer types. GPCR alterations associated with cancer development represent significant challenges for the discovery and the advancement of targeted therapeutics. Among the different molecules that can activate GPCRs, we focused on two molecules that exert their biological actions regulating many typical features of tumorigenesis such as cellular proliferation, survival, and invasion: somatostatin and melatonin. The modulation of signaling pathways, that involves these two molecules, opens an interesting scenario for cancer therapy, with the opportunity to act at different molecular levels. Therefore, the aim of this review is the analysis of the biological activity and the therapeutic potential of somatostatin and melatonin, displaying a high affinity for GPCRs, that interfere with cancer development and maintenance. [ABSTRACT FROM AUTHOR]

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare, heterogeneous group of tumors that originate from the endocrine system of the gastrointestinal tract and pancreas. GEP-NENs are subdivided according to their differentiation into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Since GEP-NENs represent rare diseases, only limited data from large prospective, randomized clinical trials are available, and recommendations for treatment of GEP-NEN are in part based on data from retrospective analyses or case series. In this context, tractable disease models that reflect the situation in humans and that allow to recapitulate the different clinical aspects and disease stages of GEP-NET or GEP-NEC are urgently needed. In this review, we highlight available data on mouse models for GEP-NEN. We discuss how these models reflect tumor biology of human disease and whether these models could serve as a tool for understanding the pathogenesis of GEP-NEN and for disease modeling and pharmacosensitivity assays, facilitating prediction of treatment response in patients. In addition, open issues applicable for future developments will be discussed. [ABSTRACT FROM AUTHOR]

Background and Objective: Patient-reported outcome measures can provide clinicians with valuable information to improve doctor-patient communication and inform clinical decision-making. The aim of this study was to evaluate the physician-perceived utility of the QLQ-GINET21 in routine clinical practice in patients with gastrointestinal neuroendocrine tumours (GI-NETs). Secondary aims were to explore the patient, clinician, and/or centre-related variables potentially associated with perceived clinical utility.Methods: Non-interventional, cross-sectional, multicentre study conducted at 34 hospitals in Spain and Portugal (NCT02853422). Patients diagnosed with GI-NETs completed two health-related quality of life (HRQoL) questionnaires (QLQ-C30, QLQ-GINET21) during a single routine visit. Physicians completed a 14-item ad hoc survey to rate the clinical utility of QLQ-GINET21 on three dimensions: 1)therapeutic and clinical decision-making, 2)doctor-patient communication, 3)questionnaire characteristics.Results: A total of 199 patients at 34 centres were enrolled by 36 participating clinicians. The highest rated dimension on the QLQ-GINET21 was questionnaire characteristics (86.9% of responses indicating "high utility"), followed by doctor-patient communication (74.4%), and therapeutic and clinical decision-making (65.8%). One physician-related variable (GI-NET patient volume > 30 patients/year) was associated with high clinical utility and two variables (older age/less experience treating GI-NETs) with low clinical utility.Conclusions: Clinician-perceived clinical utility of QLQ-GINET21 is high. Clinicians valued the instruments' capacity to provide a better understanding of patient perspectives and to identify the factors that had the largest influence on patient HRQoL. [ABSTRACT FROM AUTHOR]

Although there is evidence of a significant rise of neuroendocrine neoplasms (NENs) incidence, current treatments are largely insufficient due to somewhat poor knowledge of these tumours. Despite showing differentiated features, NENs exhibit therapeutic resistance to most common treatments, similar to other cancers in many instances. Molecular mechanisms responsible for this resistance phenomenon are badly understood. We aimed at identifying signalling partners responsible of acquired resistance to treatments in order to develop novel therapeutic strategies. We engineered QGP-1 cells resistant to current leading treatments, the chemotherapeutic agent oxaliplatin and the mTor inhibitor everolimus. Cells were chronically exposed to the drugs and assessed for acquired resistance by viability assay. We used microarray-based kinomics to obtain highthroughput kinase activity profiles from drug sensitive vs resistant cells and identified 'hit' kinases hyperactivated in drug-resistant cells, including kinases from FGFR family, cyclin-dependant kinases and PKCs in oxaliplatin-resistant (R-Ox) QGP-1 cells. We then validated these 'hit' kinases and observed that ERK signalling is specifically enhanced in QGP-1 R-Ox cells. Finally, we assessed drug-resistant cells sensitivity to pharmacological inhibition of 'hit' kinases or their signalling partners. We found that FGFR inhibition markedly decreased ERK signalling and cell viability in QGP-1 R-Ox cells. These results suggest that the FGFR/ERK axis is hyperactivated in response to oxaliplatin-based chemotherapeutic strategy. Thus, this sensitive approach, based on the study of kinome activity, allows identifying potential candidates involved in drug resistance in NENs and may be used to broadly investigate markers of NENs therapeutic response. [ABSTRACT FROM AUTHOR]

Objective: Diabetes mellitus (DM) is probably a risk factor for pancreatic neuroendocrine neoplasms (PNENs). However, the prevalence of DM in PNEN patients remains inconclusive. In the present study we observed the prevalence of DM and possible risk factors in PNEN patients. Methods: After excluding those with insulinoma, a total of 197 patients with PNENs were included. The demographic data, pathological characteristics, and data of blood biochemical tests were recorded. DM was considered if there was evidence of a fasting plasma glucose level of ≥7.0 mmol/L or a 2-h plasma glucose level of ≥11.1 mmol/L, or a history of DM at the time of PNEN diagnosis. Impaired fasting glucose was considered if fasting plasma glucose level was between 6.1 and 7.0 mmol/L. Results: The prevalence of DM, new-onset DM, and impaired fasting glucose were 17.26, 9.14, and 7.1%, respectively. The prevalence of DM was 26.0% in patients ≥60 years old (19/73) and 12.1% in patients <60 years old. Multivariable logistic regression analysis demonstrated that age, tumor size, and nerve invasion were independent risk factors for DM and impaired fasting glucose + DM (p < 0.05). Age, organs and nerve invasion were independent risk factors for impaired fasting glucose. Low high-density lipoprotein (HDL) was also a risk factor for incident of DM (OR = 0.15, 95%CI: 0.03–0.66). G2/G3 was an independent risk factor for DM in women. Conclusion: Our data shows that the prevalence of DM is 17.26% in patients with PNENs and is 26.0% in patients ≥60 years of age after excluding insulinoma. Age, nerve invasion, tumor size, and HDL are risk factors for DM in PNEN patients. [ABSTRACT FROM AUTHOR]

Introduction: Recent advances in diagnostic modalities and therapeutic agents have raised the importance of prognostic factors in predicting overall survival, as well as predictive factors for surgical outcomes, in tailoring therapeutic strategies of patients with pancreatic neuroendocrine neoplasms (panNENs).Areas covered: Numerous recent studies of panNEN patients report the prognostic values of a number of clinically related factors (clinical, laboratory, imaging, treatment-related factors), pathological factors (histological, classification, grading) and molecular factors on long-term survival. In addition, an increasing number of studies showed the usefulness of various factors, specifically biomarkers and molecular makers, in predicting recurrence and mortality related to surgical treatment. Recent findings (from the last 3 years) in each of these areas, as well as recent controversies, are reviewed.Expert commentary: The clinical importance of prognostic and predictive factors for panNENs is markedly increased for both overall outcome and post resection, as a result of recent advances in all aspects of the diagnosis, management and treatment of panNENs. Despite the proven prognostic utility of routinely used tumor grading/classification and staging systems, further studies are required to establish these novel prognostic factors to support their routine clinical use. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are a relatively rare group of heterogeneous tumours originating from neuroendocrine cells found throughout the body. Pancreatic NENs (PanNENs) are the second most common pancreatic malignancy accounting for 1-3% of all neoplasms developing in the pancreas. Despite having a low background mutation rate, driver mutations in MEN1, DAXX/ATRX and mTOR pathway genes (PTEN, TSC1/2) are implicated in disease development and progression. Their increased incidence coupled with advances in sequencing technologies has reignited the interest in PanNEN research and has accelerated the acquisition of molecular data. Studies utilising such technological advances have further enriched our knowledge of PanNENs' biology through novel findings, including higher-than-expected presence of germline mutations in 17% of sporadic tumours of no familial background, identification of novel mutational signatures and complex chromosomal rearrangements and a dysregulated epigenetic machinery. Integrated genomic studies have progressed the field by identifying the synergistic action between different molecular mechanisms, while holding the promise for deciphering disease heterogeneity. Although our understanding is far from being complete, these novel findings have provided the optimism of shaping the future of PanNEN research, ultimately leading to an era of precision medicine for NETs. He re, we recapitulate the existing knowledge on pancreatic neuroendocrine tumours (PanNETs) and discuss how recent, novel findings have furthered our understanding of these complex tumours. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are traditionally considered as a single group of rare malignancies that originate from the highly spread neuroendocrine system. The clinical management is complex due to the high heterogeneity of these neoplasms in terms of clinical aggressiveness and response to the therapy. Indeed, a multidisciplinary approach is required to reach a personalization of the therapy, including cancer rehabilitation. In this review, we discuss the possibility to adopt a precision medicine (PM) approach in the management of NENs. To this purpose, we summarize current knowledge and future perspectives about biomarkers and preclinical in vitro and in vivo platforms, potentially useful to inform clinicians about the prognosis and for tailoring therapy in patients with NENs. This approach may represent a breakthrough in the therapy and tertiary prevention of these tumors. [ABSTRACT FROM AUTHOR]

The molecular events leading to gastroenteropancreatic neuroendocrine tumor (GEPNET) formation are largely unknown. Over the past decades, systemic chemotherapies have been replaced by therapies directed at particular molecular targets such as the somatostatin receptors, mTOR complexes or proangiogenic molecules. These approaches have demonstrated some success in subtypes of this heterogeneous tumor group, but responses are still widely varied. This review highlights the clinical trials ongoing for neuroendocrine tumors (NETs) and includes emerging immunotherapy, which holds great promise for NETs based on successes in other tumor types. Current avenues of preclinical research, including Notch and PI3K/AKT, will lead to additional targeted therapies based on genome-wide studies that have cast a wide net in the search for driver mutations. Future preclinical and clinical investigations are required to identify those mutations predictive of therapeutic response or disease progression. Results of current clinical trials outlined here will better inform patient management with respect to agent selection, timing, duration and combination therapy in the treatment of NETs. [ABSTRACT FROM AUTHOR]

The use of patient-derived primary cell cultures in cancer preclinical assays has increased in recent years. The management of resected tumor tissue remains complex and a number of parameters must be respected to obtain complete sample digestion and optimal vitality yield. We provide an overview of the benefits of correct primary cell culture management using different preclinical methodologies, and describe the pros and cons of this model with respect to other kinds of samples. One important advantage is that the heterogeneity of the cell populations composing a primary culture partially reproduces the tumor microenvironment and crosstalk between malignant and healthy cells, neither of which is possible with cell lines. Moreover, the use of patient-derived specimens in innovative preclinical technologies, such as 3D systems or bioreactors, represents an important opportunity to improve the translational value of the results obtained. In vivo models could further our understanding of the crosstalk between tumor and other tissues as they enable us to observe the systemic and biological interactions of a complete organism. Although engineered mice are the most common model used in this setting, the zebrafish (Danio rerio) species has recently been recognized as an innovative experimental system. In fact, the transparent body and incomplete immune system of zebrafish embryos are especially useful for evaluating patient-derived tumor tissue interactions in healthy hosts. In conclusion, ex vivo systems represent an important tool for cancer research, but samples require correct manipulation to maximize their translational value. [ABSTRACT FROM AUTHOR]

Biomarkers have been the mainstay in the diagnosis and follow-up of patients with neuroendocrine tumors (NETs) over the last few decades. In the beginning, secretory products from a variety of subtypes of NETs were regarded as biomarkers to follow during diagnosis and treatment: serotonin for small intestinal (SI) NETs, and gastrin and insulin for pancreatic NETs. However, it became evident that a large number of NETs were so-called nonfunctioning tumors without secreting substances that caused hormone-related symptoms. Therefore, it was necessary to develop so-called "general tumor markers." The most important ones so far have been chromogranin A and neuron-specific enolase (NSE). Chromogranin A is the most important general biomarker for most NETs with a sensitivity and specificity somewhere between 60 and 90%. NSE has been a relevant biomarker for patients with high-grade tumors, particularly lung and gastrointestinal tract tumors. Serotonin and the breakdown product urinary 5-hydroxyindoleacetic acid (U-5-HIAA) is still an important marker for diagnosing and follow-up of SI NETs. Recently, 5-HIAA in plasma has been analyzed by high- performance liquid chromatography and fluorometric detection and has shown good agreement with U-5-HIAA analysis. In the future, we will see new tests including circulating tumor cells, circulating DNA and mRNA. Recently, a NET test has been developed analyzing gene transcripts in circulating blood. Preliminary data indicate high sensitivity and specificity for NETs. However, its precise role has to be validated in prospective randomized controlled trials which are ongoing right now. [ABSTRACT FROM AUTHOR]

Introduction: Somatostatin and dopamine receptors are both G-protein-coupled receptors. Somatostatin receptor (SSTR) expression in neuroendocrine tumours has been well characterised, and there is evidence of dopamine receptor expression in neuroendocrine tumours. In this study, we examined expression of D2R, SSTR-2 and SSTR-5 using immunohistochemistry in patients with neuroendocrine tumours. Methods: Consecutive samples of formalin-fixed paraffin-embedded tumour tissue were available from 56 patients with a histologically confirmed diagnosis of neuroendocrine tumour (NET). The study population was divided into low-grade (n = 29), intermediate-grade (n = 18) and high-grade NET (n = 9). Immunohistochemical evaluation was performed for the expression of SSTR-2a, SSTR-5 and D2 receptors (D2R). Results: Both SSTR-2 and SSTR-5 were expressed in 100% of low-grade, 94.4% of intermediate-grade and 66.7% of high-grade NET. D2R was expressed in 93.1% of low-grade, 77.8% of intermediate-grade and 44.4% of high-grade tumours. Co-expression of all 3 receptors was present in 93.1% of low-grade tumours. There was an inverse correlation of SSTR-2 (r = –0.380, p < 0.005) and SSTR-5 (r = –0.472, p < 0.0001) with tumour grade. D2R was positively correlated with SSTR-2 (r = 0.269, p = 0.041) and SSTR-5 (r = 0.267, p = 0.045). Also, D2R expression was inversely correlated with grade of tumour (r = 0.395, p = 0.006). Octreoscan correlated with SSTR-2, SSTR-5 and D2R expression. Conclusion: D2R is expressed in the majority of low and intermediate grade tumours. It is co-expressed with SSTR-2 and SSTR-5 in the majority of cases. The advent of new chimeric molecules that bind both somatostatin and dopamine receptors may provide a new therapeutic option in the management of neuroendocrine patients. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms which arise from neuroendocrine cells that are distributed widely throughout the body. Although heterogenous, many of them share their ability to overexpress somatostatin receptors (SSTR) on their cell surface. Due to this, SSTR and somatostatin have been a large subject of interest in the discovery of potential biomarkers and treatment options for the disease. The aim of this review is to describe the molecular characteristics of somatostatin and somatostatin receptors and its application in diagnosis and therapy on patients with NENs as well as the use in the near future of somatostatin antagonists. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumors with different types of physiology and prognosis. Therefore, prognostic information, including morphological differentiation, grade, tumor stage and primary location, are invaluable and contribute to the formulation of treatment decisions. Biomarkers that are currently used, including chromogranin A (CgA), serotonin and neuron-specific enolase, are singular parameters that cannot be used to accurately predict variables associated with tumor growth, including proliferation, metabolic rate and metastatic potential. In addition, site-specific biomarkers, such as insulin and gastrin, cannot be applied to all types of NENs. The clinical application of broad-spectrum markers, as it is the case for CgA, remains controversial despite being widely used. Due to limitations of the currently available mono-analyte biomarkers, recent studies were conducted to explore novel parameters for NEN diagnosis, prognosis, therapy stratification and evaluation of treatment response. Identification of prognostic factors for predicting NEN outcome is a critical requirement for the planning of adequate clinical management. Advances in 'liquid' biopsies and genomic analysis techniques, including microRNA, circulating tumor DNA or circulating tumor cells and sophisticated biomathematical analysis techniques, such as NETest or molecular image-based biomarkers, are currently under investigation as potentially novel tools for the management of NENs in the future. Despite these recent findings yielding promising observations, further research is necessary. The present review therefore summarizes the existing knowledge and recent advancements in the exploration of biochemical markers for NENs, with focus on gastroenteropancreatic-neuroendocrine tumors. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are relatively rare and complex tumors that can be sporadic or hereditary, as in the context of multiple endocrine neoplasia type 1 (MEN1) where patients display a 70% lifelong risk of developing a pancreatic NENs (pNENs). To date, specific personalized treatment for pNENs in patients with MEN1 are lacking. The aim of this study was to systematically analyze the efficacy and safety of somatostatin analogue (SSA) treatment in patients affected by MEN1-related pNENs. We performed a systematic review of the literature, searching for peer-reviewed articles on SSA (octreotide or lanreotide) treatment in MEN1 associated with pNENs. We selected 20 studies with a pooled population of 105 MEN1 patients with pNENs. Females were 58.5%, median age was 44 years (18–73). TNM stage at diagnosis was stage I–II in 84.8% and stage IV in 15.2%. The overall response rate (SD+PR+CR) was achieved in 88.3% of cases, with stable disease in 75.6% and objective response in 12.7% of patients. The safety profile was favorable with both SSA agents. SSAs appear to be an effective and safe treatment option for MEN1-related pNEN, either at localized or advanced stages. [ABSTRACT FROM AUTHOR]

Simple Summary: Autophagy is a complex cell process that allow the cell to survive in unfavorable conditions, e.g., in the lack of nutritional elements coming from the environment. Here we focused on the role played by autophagy in the crosstalk between the microenvironment surrounding the tumor and cancer cells. This environment is in fact known as pivotal in determining the growth or the inhibition of a tumor. Cancer progression and response to therapy significantly differ between women and men and the microenvironment, in particular sex hormones and microRNAs, appears a critical factor. Four representative types of cancer, i.e., colon cancer, melanoma, lymphoma, and lung cancer showing sex/gender specificities have been described herein. We underscore that the use of a "gender tailored" approach could provide a better comprehension of the cellular and molecular mechanisms of cancer growth control contributing to the development of novel therapeutic approaches towards an increasingly personalized medicine. The interplay between cancer cells and the tumor microenvironment (TME) has a fundamental role in tumor progression and response to therapy. The plethora of components constituting the TME, such as stroma, fibroblasts, endothelial and immune cells, as well as macromolecules, e.g., hormones and cytokines, and epigenetic factors, such as microRNAs, can modulate the survival or death of cancer cells. Actually, the TME can stimulate the genetically regulated programs that the cell puts in place under stress: apoptosis or, of interest here, autophagy. However, the implication of autophagy in tumor growth appears still undefined. Autophagy mainly represents a cyto-protective mechanism that allows cell survival but, in certain circumstances, also leads to the blocking of cell cycle progression, possibly leading to cell death. Since significant sex/gender differences in the incidence, progression and response to cancer therapy have been widely described in the literature, in this review, we analyzed the roles played by key components of the TME, e.g., estrogen and microRNAs, on autophagy regulation from a sex/gender-based perspective. We focused our attention on four paradigmatic and different forms of cancers—colon cancer, melanoma, lymphoma, and lung cancer—concluding that sex-specific differences may exert a significant impact on TME/cancer interaction and, thus, tumor growth. [ABSTRACT FROM AUTHOR]

The carcinoid syndrome (CS) and hyperinsulinemic hypoglycemia (HH) represent two of the most common clinical syndromes associated with neuroendocrine neoplasms (NENs). The former is mainly related to the serotonin secretion by a small bowel NEN, whereas the latter depends on an insulin hypersecretion by a pancreatic insulinoma. Both syndromes/conditions can affect prognosis and quality of life of patients with NENs. They are often diagnosed late when patients become strongly symptomatic. Therefore, their early detection and management are a critical step in the clinical management of NEN patients. A dedicated and experienced multidisciplinary team with appropriate therapeutic strategies is needed and should be encouraged to optimize clinical outcomes. This review aims to critically analyze clinical features, evidence and treatment options of CS and HH and therefore to improve their management. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are a widely heterogeneous family of neoplasms arising from neuroendocrine cells, which are interspersed throughout the body. Despite NENs are relatively rare, their incidence and prevalence are constantly increasing probably due to the improvement in earlier diagnosis and patients' management. When surgery is not curative, particularly for patients with metastatic disease, several medical options are available. Somatostatin analogues (SSA) are the first-line medical therapy for well-differentiated NENs. Interestingly, the heterodimerization of somatostatin receptors (SSTs) with dopamine receptors (DRs) has been discovered in NENs. This phenomenon results in hybrid receptors with enhanced functional activity. On these bases, chimeric molecules embracing somatostatin and dopamine features have been recently developed. The aim of this review is to provide a comprehensive overview of the available preclinical and clinical data regarding chimeric somatostatin-dopamine agonists as a new class of "magic bullet" in the therapy of NENs. [ABSTRACT FROM AUTHOR]

Background: Chromogranin A (CgA), synaptophysin (Syn) and the Ki-67 index play significant roles in diagnosis or the evaluation of the proliferative activity of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, little is known about whether these biological markers change during tumor metastasis and whether such changes have effect on prognosis. Methods: We analyzed 35 specimens of both primary and metastatic tumor from 779 patients who had been diagnosed as GEP-NENs at Wuhan Union Hospital from August 2011 to October 2019. The heterogeneity of CgA, Syn and Ki-67 index was evaluated by immunohistochemical analysis. Results: Among these 779 patients, the three most common sites of NENs in the digestive tract were the pancreas, rectum and stomach. Metastases were found in 311 (39.9%) patients. Among the 35 patients with both primary and metastatic pathological specimens, differences in the Ki-67 level were detected in 54.3% of the patients, while 37.1% showed a difference in CgA and only 11.4% showed a difference in Syn. Importantly, due to the difference in the Ki-67 index between primary and metastatic lesions, the WHO grade was changed in 8.6% of the patients. In addition, a Kaplan–Meier survival analysis showed that patients with Ki-67 index variation had a shorter overall survival (p = 0.0346), while neither Syn variation nor CgA variation was related to patient survival (p = 0.7194, p = 0.4829). Conclusions: Our data indicate that primary and metastatic sites of GEP-NENs may exhibit pathological heterogeneity. Ki-67 index variation is closely related to the poor prognosis of patients with tumor metastasis, but neither Syn variation nor CgA variation is related to patient prognosis. Therefore, clinicopathologic evaluation of the primary tumor and metastatic sites could be helpful for predicting the prognosis. [ABSTRACT FROM AUTHOR]

Endogenous somatostatin shows anti-secretory effects in both physiological and pathological settings, as well as inhibitory activity on cell growth. Since somatostatin is not suitable for clinical practice, researchers developed synthetic somatostatin receptor ligands (SRLs) to overcome this limitation. Currently, SRLs represent pivotal tools in the treatment algorithm of neuroendocrine tumors (NETs). Octreotide and lanreotide are the first-generation SRLs developed and show a preferential binding affinity to somatostatin receptor (SST) subtype 2, while pasireotide, which is a second-generation SRL, has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). A number of studies demonstrated that first-generation and second-generation SRLs show distinct functional properties, besides the mere receptor affinity. Therefore, the aim of the present review is to critically review the current evidence on the biological effects of SRLs in pituitary adenomas and neuroendocrine tumors, by mainly focusing on the differences between first-generation and second-generation ligands. [ABSTRACT FROM AUTHOR]

Introduction: Y90-DOTATATE and Y90-DOTATOC are established treatments for patients with advanced neuroendocrine tumours. Outcomes associated with improved survival following therapy are still unclear. Aim(s): To determine clinical, biochemical and radiological response rates to Y90 therapy and their possible association with improved survival. Materials and methods: A retrospective case note analysis was conducted on 60 patients who had received Y90. Clinical response was assessed subjectively. Biochemical and radiological response were assessed using WHO and RECIST criteria, respectively. Survival curves were constructed for responders (stable/regression) v. non-responders (progression). Results: Sixty patients received a total of 146 treatments of Y90 DOTATOC/DOTATATE (median 3, range 1-3). During a median follow-up of 21 (range 1-91) months, 25 (41.6%) patients died with a median survival time of 51 months se+/- 5.2 (range 40-61 months). Eighty-three percent were clinical responders (46.5% improved and 35.5% stable), 76% were radiological responders (24% improved and 52% stable) and 69% were biochemical responders (23% improved and 46% stable). A clinical and radiological response (stable disease or regression post therapy) was associated with improved survival (51 months se+/-5.2 v. 10 +/-5.5; p=0.001 and 56 v. 18+/- 2.8; p=0.001, respectively) compared with no response. Conclusion: A significant survival benefit in clinical and radiological responders has important implications in selecting patients for re-treatment with targeted therapy. [ABSTRACT FROM AUTHOR]

Introduction: A recent study of a small series of patients with appendiceal neuroendocrine tumors (ANETs) fulfilling various criteria for right hemicolectomy (RHC) revealed that approximately 25% may harbor identifiable extra-appendiceal disease. The residual disease might not have been detected using the latest European Neuroendocrine Tumors Society (ENETS) revised pathological criteria. Aim(s): To evaluate the pathological criteria for RHC in an extended series of patients with ANETs. Materials and methods: The medical files of 27 consecutive patients who underwent RHC for ANETs were retrospectively assessed. Results: In 8/27 patients with tumor diameter less than 1 cm, the indications for RHC included: tumor presence in surgical margins (3), extensive mesoappendiceal invasion (EMI) (5), vascular invasion (VI) (2), Ki-67 ≥2% (3); residual disease was present in one patient. In 12/27 patients with tumor diameter of 1-2 cm, RHC followed tumor presence in surgical margins (1), EMI (10), VI (2), Ki-67 ≥2% (2); residual disease was present in two patients. In 7/27 patients with tumor diameter ≥2 cm, tumor was present in surgical margins in three patients, in seven patients there was EMI, in five patients VI was demonstrated, and Ki-67 ≥2% was found in five patients; residual disease was present in two patients. Conclusion: In the subgroup of patients with a primary tumor size between 1-2 cm (the "gray zone"), the risk of residual disease is high. Using the latest criteria for RHC, residual disease may be missed in 7% of ANETs patients. [ABSTRACT FROM AUTHOR]