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Introduction: In the last decade, GEP-NET nomenclature has been twice reviewed. The 2000 WHO classification had poor prognostic power in well-differentiated (WD) neoplasms which led to the introduction of two new important parameters: grade and stage, by ENETS; the former became part of the new 2010 WHO classification. Aim(s): Considering the recent introduction of grade and stage, their external validation has been called for in the literature. Since these are important tools in the management of patients, our aim was to reclassify retrospectively with grade and stage our series and correlate with follow-up. Materials and methods: From the histopathology archive at our center, 170 GEPNETs (1993-2011) were identified. Until now, 50 patients have been reclassified. Mean age at diagnosis was 56 years, F:M ratio was 1:1.2 and mean follow-up was 56 months (2-196). Results: Correlating differentiation with overall survival (OS), WD NETs had a strikingly better outcome with respect to poorly differentiated ones. However, only grade identified a subgroup of patients with WD lesions with less favorable clinical behavior (OS at 5 yrs: G1 - 96% v. G2 - 50%). Stage was also useful though not statistically significant in our small series. Conclusion: Our series confirms the importance of grade and stage in prognostic stratification. Retrospective classification of patients who may not have been previously graded or staged may influence the choice of therapeutic options in the future. [ABSTRACT FROM AUTHOR]

Introduction: MCC is a rare cutaneous neuroendocrine neoplasm with aggressive behavior, a high recurrence rate and, generally, poor prognosis. Aim(s): To report histological and clinical features of a series of 12 patients with nodal MCC in the lack of evidence of a primary. Materials and methods: The cases were collected from a multicentric database: mean age at diagnosis was 67 yrs; F:M ratio was 1:1.4; mean follow-up was 54 months. Involved nodal sites were: inguinal (9) and axillar (3). All cases had typical MCC immunoprofile: neuroendocrine (CgA, NSE) and epithelial (CK 20 dot-like) marker positivity. Complete and extensive clinical, dermatologic, radiologic and endoscopic work-up was performed. M1 patients underwent surgery; in one case, chemotherapy, in another case biotherapy and in one further case, radiotherapy was administered. Results: All cases were in stage III of disease, according to UICC. All patients were alive without recurrence at the time of the study. The overall median survival was 52 months. The 4-yr survival was 100%. Conclusion: In patients with nodal metastases of MCC in the absence of a primary lesion, survival seems to be more similar to stage I rather than stage III, since 4-yr survival is reported about 60% for stage III disease in MCC. Regression of a small skin primary with nodal metastases or alternatively a primary nodal MCC might be hypothesized. In conclusion, the unknown primary nodal metastatic skin MCC seems to be associated with a more favorable prognosis. [ABSTRACT FROM AUTHOR]

Background: The role of vitamin D (25(OH)D) in the pathogenesis and outcome of several conditions, including autoimmune diseases, diabetes and cancers is largely described in the literature. The aims of this study were to evaluate the prevalence of 25(OH)D deficit in a cohort of patients with neuroendocrine neoplasms (NENs) in comparison to a matched healthy control group and to analyze the possible role of 25(OH)D as a prognostic factor for NENs in terms of biological aggressiveness, tumor progression and survival. Methods: From 2009 to 2023, 172 patients with NENs (99 females; median age, 63 years) were included in the study. Serum 25(OH)D levels were defined as deficient if ≤20 ng/mL. The possible associations between 25(OH)D levels and disease grading, staging, ki67%, overall survival (OS), and progression-free survival (PFS) were considered. Results: NEN patients had significantly lower 25(OH)D levels compared to controls (p < 0.001) regardless of the primary origin. Patients with 25(OH)D < 20 ng/mL had a significantly higher ki67 index (p = 0.02) compared to the ones with 25(OH)D levels above 20 ng/mL. Patients with disease progression were found to have a significantly lower 25(OH)D at baseline (p = 0.02), whereas PFS and OS were not significantly influenced by 25(OH)D. Conclusions: Vitamin D deficiency is highly prevalent among NENs and is associated with higher ki67 and disease progression. Our study highlights the importance of monitoring 25(OH)D levels in patients with NENs, as its deficiency appeared to be linked to the worst biological tumor aggressiveness. [ABSTRACT FROM AUTHOR]

Refined risk stratification for gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) has the potential to improve comparisons of study populations across clinical trials and facilitate drug development. Tumor growth rate (TGR) is a radiological metric with demonstrated prognostic value in well differentiated grade 1 and 2 (G1–2) GEP‐NETs, but little is known about TGR in G3 NETs. In this retrospective study of 48 patients with advanced G1–3 GEP‐NET, we calculated baseline TGR (TGR0) from radiological images of metastases acquired prior to first‐line therapy and evaluated its association with disease characteristics and outcomes. The median pretreatment Ki67 proliferation index for G1–3 tumors combined was 5% (range = 0.1%–52%) and median TGR0 was 4.8%/month (m) (range = 0%–45.9%/m). TGR0 correlated with pretreatment Ki67 across G1–3 pooled and within G3 GEP‐NET. Patients with higher TGR0 (>11.7%/m) tumors, which were primarily G3 pancreatic NETs, exhibited decreased time to first therapy (median, 2.2 vs. 5.3 months; p =.03) and shorter overall survival (median, 4.1 years vs. not reached; p =.003). Independent of therapies given, higher TGR0 GEP‐NETs experienced a greater incidence of Ki67 increase (100 vs. 50%; p =.02) and greater magnitude of Ki67 change (median, 14.0 vs. 0.1%; p =.04) upon serial biopsy. Importantly, TGR0, but not grade, predicted for future Ki67 increase in this series. Given the heterogeneity of well differentiated GEP‐NETs, future clinical trials may benefit from stratification for TGR0, particularly in G1–2 tumors, in which TGR0 does not correlate with Ki67. TGR0 has the potential to noninvasively identify patients with previously undiagnosed grade progression and those in whom more or less frequent monitoring may be appropriate. Additional research is needed to determine the prognostic and predictive value of TGR0 in larger and more homogeneously treated cohorts, and to ascertain if post‐treatment TGR has value in previously treated patients starting a new line of therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-functional pancreatic neuroendocrine tumors (NF-PanNETs) are a highly heterogeneous group of tumors with an increasing incidence. This study aimed to summarize the surgical and therapeutic activities of NF-PanNETs and to perform survival analyses at Fudan University Shanghai Cancer Center (FUSCC) over the past 15 years. We screened 1001 patients with neuroendocrine neoplasms treated at FUSCC, and 509 patients with NF-PanNETs from 2006 to 2020 were included. Time trend analyses revealed an increasing number of diagnosed and resected NF-PanNETs. Among three randomly divided periods, a significant decrease in the tumor size and a substantial increase in minimally invasive techniques were observed. In the subgroup of non-metastatic and resected NF-PanNETs, tumor size, positive lymph node, adjuvant treatment, and tumor grade were independent prognostic factors for recurrence-free survival. Microvascular invasion and tumor grade were independent prognostic factors for overall survival (OS). Notably, a malignant transformation from NET into neuroendocrine carcinoma was observed. Background: This study aimed to summarize the surgical and therapeutic activities of non-functional pancreatic neuroendocrine tumors (NF-PanNETs) and perform survival analyses of a 15-year single-institutional cohort of NF-PanNETs. Methods: In total, 1001 patients with neuroendocrine neoplasms treated at Fudan University Shanghai Cancer Center were screened for inclusion, and 509 patients with NF-PanNETs from 2006 to 2020 were included. For time trend analyses, the 15-year study period was randomly divided into three periods. Survival analyses used the Kaplan–Meier method and Cox regression models. Results: The total number of resected NF-PanNETs increased over the 15-year study period, from 5 resections in 2006 to 94 resections in 2020. A significant decrease in the tumor size was observed, from a mean of 4.0 cm to 3.3 cm, and to 3.0 cm in the most recent period (p = 0.006). Minimally invasive techniques gradually increased from 3.5% to 12.9%, and finally to 46.4% in the most recent period (p < 0.001). In non-metastatic and resected tumors, the tumor size (p < 0.001), positive lymph node (p < 0.001), adjuvant treatment (p = 0.048), and tumor grade (p < 0.001) were independent prognostic factors for recurrence-free survival (RFS). The microvascular invasion (p = 0.024) and tumor grade (p = 0.013) were independent prognostic factors for overall survival (OS). A malignant transformation from NET into neuroendocrine carcinoma was observed. Conclusions: An increasing number of NF-PanNETs resection and minimally invasive surgery was shown. In non-metastatic and resected tumors NF-PanNETs, tumor size, positive lymph node, adjuvant treatment, and tumor grade were independent predictors of RFS. Microvascular invasion and tumor grade were independent prognostic factors for OS. [ABSTRACT FROM AUTHOR]

Simple Summary: Esophageal neuroendocrine neoplasms (E-NENs) are a rare malignancy in esophageal carcinoma; their clinical and oncologic characteristics are poorly reported. Additionally, the effect of surgery on E-NENs remains unclear and controversial. In this study, we retrospectively analyzed the clinicopathological characteristics, prognosis, and immune cell infiltration in E-NENs and compared them with those of esophageal squamous cell carcinoma (ESCC) to determine whether surgery has the same therapeutic efficacy for E-NENs as for ESCC based on a cohort who received surgical treatment. According to our results, first, the target population for surgery may be limited to stage I E-NENs patients. Secondly, E-NENs and especially pure NENs were correlated with the cold tumor phenotype because of the less infiltration of immune cells compared with ESCC. The findings suggest that strategies for immune activation should be developed and applied when immunotherapy is considered for E-NENs in the future. Background: Esophageal neuroendocrine neoplasms (E-NENs) are a rare and poorly reported subtype of esophageal carcinoma. We analyzed the differences in clinicopathological features, prognosis, and tumor-infiltrating lymphocytes (TILs) between E-NENs and esophageal squamous cell carcinoma (ESCC). Methods: A total of 3620 patients who underwent esophagectomy were enrolled retrospectively. The study cohort was divided into two groups (E-NENs and ESCC) through propensity-score matching, and the prognosis and TILs were compared between the two groups. The TILs were assessed using tumor specimens (including six cases of ESCC, six cases of neuroendocrine carcinomas [NECs], and six cases of mixed neuroendocrine–non-neuroendocrine neoplasms [MiNENs]). Results: E-NENs accounted for 3.0% (107/3620) of cases, among which there were just 3 neuroendocrine tumor cases, 51 NEC cases, and 53 MiNENs cases. After matching, esophageal neuroendocrine carcinomas (E-NECs) showed both poorer 5-year overall survival (OS; 35.4% vs. 54.8%, p = 0.0019) and recurrence-free survival (RFS; 29.3% vs. 48.9%, p < 0.001) compared with ESCC. However, the differences were not prominent in the subgroup with stage I. No significant survival benefit was observed for E-NECs with multimodal therapy. Multivariate analysis demonstrated that E-NECs are an independent risk factor for OS and RFS. In the exploratory analysis, E-NECs were associated with less infiltration of immune cells compared with ESCC. Conclusion: E-NECs are significantly associated with a poorer prognosis than ESCC except for early-stage disease. The fewer TILs within the tumor microenvironment of E-NECs compared with ESCC results in weaker anti-tumor immunity and may lead to a poorer prognosis. [ABSTRACT FROM AUTHOR]

The introduction of Ki67 immunohistochemistry in the work-up of neuroendocrine neoplasms (NENs) has opened a new approach for their diagnosis and prognostic evaluation. Since the first demonstration of the prognostic role of Ki67 proliferative index in pancreatic NENs in 1996, several studies have been performed to explore its prognostic, diagnostic, and predictive role in other neuroendocrine and endocrine neoplasms. A large amount of information is now available and published results globally indicate that Ki67 proliferative index is useful to this scope, although some differences exist in relation to tumor site and type. In gut and pancreatic NENs, the Ki67 proliferative index has a well-documented and accepted diagnostic and prognostic role and its evaluation is mandatory in their diagnostic work-up. In the lung, the Ki67 index is recommended for the diagnosis of NENs on biopsy specimens, but its diagnostic role in surgical specimens still remains to be officially accepted, although its prognostic role is now well documented. In other organs, such as the pituitary, parathyroid, thyroid (follicular cell-derived neoplasms), and adrenal medulla, the Ki67 index does not play a diagnostic role and its prognostic value still remains a controversial issue. In medullary thyroid carcinoma, the Ki67 labelling index is used to define the tumor grade together with other morphological parameters, while in the adrenal cortical carcinoma, it is useful to select patients to treated with mitotane therapy. In the present review, the most important information on the diagnostic, prognostic, and predictive role of Ki67 proliferative index is presented discussing the current knowledge. In addition, technical issues related to the evaluation of Ki67 proliferative index and the future perspectives of the application of Ki67 immunostaining in endocrine and neuroendocrine neoplasms is discussed. [ABSTRACT FROM AUTHOR]

Background: Large Cell Neuroendocrine Carcinoma (LCNEC) is a rare subtype of lung cancer with poor clinical outcomes. Data on recurrence-free survival (RFS) in early and locally advanced pure LCNEC after complete resection (R0) are lacking. This study aims to evaluate clinical outcomes in this subgroup of patients and to identify potential prognostic markers. Methods: Retrospective multicenter study including patients with pure LCNEC stage I-III and R0 resection. Clinicopathological characteristics, RFS, and disease-specific survival (DSS) were evaluated. Univariate and multivariate analyses were performed. Results: 39 patients (M:F = 26:13), with a median age of 64 years (44–83), were included. Lobectomy (69.2%), bilobectomy (5.1%), pneumonectomy (18%), and wedge resection (7.7%) were performed mostly associated with lymphadenectomy. Adjuvant therapy included platinum-based chemotherapy and/or radiotherapy in 58.9% of cases. After a median follow-up of 44 (4–169) months, the median RFS was 39 months with 1-, 2- and 5-year RFS rates of 60.0%, 54.6%, and 44.9%, respectively. Median DSS was 72 months with a 1-, 2- and 5-year rate of 86.8, 75.9, and 57.4%, respectively. At multivariate analysis, age (cut-off 65 years old) and pN status were independent prognostic factors for both RFS (HR = 4.19, 95%CI = 1.46–12.07, p = 0.008 and HR = 13.56, 95%CI 2.45–74.89, p = 0.003, respectively) and DSS (HR = 9.30, 95%CI 2.23–38.83, p = 0.002 and HR = 11.88, 95%CI 2.28–61.84, p = 0.003, respectively). Conclusion: After R0 resection of LCNEC, half of the patients recurred mostly within the first two years of follow-up. Age and lymph node metastasis could help to stratify patients for adjuvant therapy. [ABSTRACT FROM AUTHOR]

Objective: The aims of the present study were to investigate gender differences in the clinicopathological features, distant metastasis and prognosis of pancreatic neuroendocrine neoplasms (pNENs) in a Chinese population, and to identify any important gaps in the classification and management of pNENs relative to gender. Methods: Retrospective collection of the clinicopathological data of 193 patients with pathologically confirmed pNENs were analyzed and follow up was extended to observe the prognosis of the disease. Differences between genders in basic characteristics, clinical symptoms, comorbidities, and tumor parameters were analyzed. Results: There was no significant difference in females and males, however, moderately higher for females (52.8% vs. 47.2%), with the largest subgroup being 40~60 years of age (54.9%). Age at onset (P=0.002) and age at diagnosis (P=0.005) were both younger in females compared to males. Males lived more in urban areas and females lived more in rural areas (P=0.047). The proportion of smokers and alcohol drinkers was significantly higher in males than in females (P < 0.001). Non-functional pNENs were more frequent in males and functional pNENs in females (P=0.032). In women, functional status of the tumor was significantly associated with metastatic outcome (P=0.007) and functional tumors proved to be a protective factor compared to non-functional tumors (OR=0.090,95% CI: 0.011~ 0.752). There were no gender differences in tumor size, location, grade, stage or prognosis. Conclusions: Gender differences in some clinicopathological features, and distant metastasis in patients with pNENs were identified, which suggested certain management details that justified emphasis based on gender. [ABSTRACT FROM AUTHOR]

A positive fluorine‐18 labelled 2‐deoxy‐2‐fluoroglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has been associated with more aggressive disease and less differentiated neuroendocrine neoplasms (NEN). Although a high maximum standardized uptake value (SUVmax) predicts poor outcome in NEN, volumetric parameters from [18F]FDG PET have not been evaluated for prognostication in a pure high‐grade gastroenteropancreatic (GEP) NEN cohort. In this retrospective observational study, we evaluated the volumetric PET parameters total metabolic tumour volume (tMTV) and total total lesion glycolysis (tTLG) for independent prognostication of overall survival (OS). High‐grade GEP NEN patients with [18F]FDG PET/CT examination and biopsy within 90 days were included. Total MTV and tTLG were calculated using an adaptive thresholding software. Patients were dichotomised into low and high metabolic groups based on median tMTV and tTLG. OS was compared using Kaplan–Meier estimator and log‐rank test. Uni and multivariable Cox regression was used to estimate effect sizes and adjust for tumour differentiation and SUVmax. Sixty‐six patients (median age 64 years) were included with 14 NET G3 and 52 NEC cases after histological re‐evaluation. Median tMTV was 208 cm3 and median tTLG 1899 g. Median OS in the low versus high tMTV‐group was 21.2 versus 5.7 months (HR 2.53, p = 0.0007) and 22.8 versus 5.7 months (HR 2.42, p = 0.0012) in the tTLG‐group. Adjusted for tumour differentiation and SUVmax, tMTV and tTLG still predicted for poor OS, and both tMTV and tTLG were stronger prognostic parameters than SUVmax. Both regression models showed a strong association between volumetric parameters and OS for both neuroendocrine tumours (NET) G3 and neuroendocrine carcinomas (NEC). OS for the tTLG low metabolic NEC was much higher than for the tTLG high metabolic NET G3 (18.3 vs. 5.7 months). High‐grade GEP NEN patients with high tMTV or tTLG had a worse OS regardless of tumour differentiation (NET G3 or NEC). Volumetric PET parameters were stronger prognostic parameters than SUVmax. [ABSTRACT FROM AUTHOR]

Background: Although some factors that predict the prognosis in pancreatic neuroendocrine tumor (pNET) have been confirmed, the predictive value of lymph node metastasis (LNM) in the prognosis of pNETs remains conflicting and it is not clear whether regional lymphadenectomy should be performed in all grades of tumors.Methods: We included pNET patients undergoing surgery in Shanghai pancreatic cancer institute (SHPCI). The risk factors for survival were investigated by the Kaplan-Meier method and Cox regression model. We evaluated the predictors of LNM using Logistic regression.Results: For 206 patients in the SHPCI series, LNM was an independent prognostic factor for entire cohort suggested by multivariate Cox regression analysis. LNM (P = 0.002) predicted poorer overall survival (OS) in grade 2/3 cohort, but there is no significant association between LNM and OS in grade 1 cohort. Grade (P < 0.001) and size (P = 0.049) predicted LNM in entire cohort. Grade (P = 0.002) predicted LNM while regardless of size in grade 2/3 cohort.Conclusions: Based on our own retrospective data obtained from a single center series, LNM seems to be associated with poorer outcome for patients with grade 2/3 and/or grade 1 > 4 cm tumors. On the other way, LNM was seems to be not associated with prognosis in patients with grade 1 tumors less than 4 cm. Moreover, tumor grade and tumor size seem to act as independent predictors of LNM. Thus, regional lymphadenectomy should be performed in grade 2/3 patients but was not mandatory in grade 1 tumors < 4 cm. It is reasonable to perform functional sparing surgery for grade 1 patients or propose a clinical-radiological monitoring. [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]

Given the increasing incidence of neuroendocrine neoplasms (NENs) over the past few decades, a more comprehensive knowledge of their pathophysiological bases and the identification of innovative NEN biomarkers represents an urgent unmet need. There is still little advance in the early diagnosis and management of these tumors, due to the lack of sensible and specific markers with prognostic value and ability to early detect the response to treatment. Chronic systemic inflammation is a predisposing factor for multiple cancer hallmarks, as cancer proliferation, progression and immune-evading. Therefore, the relevance of inflammatory biomarkers has been identified as critical in several types of tumours, including NENs. A bidirectional relationship between chronic inflammation and development of NENs has been reported. Neuroendocrine cells can be over-stimulated by chronic inflammation, leading to hyperplasia and neoplastic transformation. As the modulation of inflammatory response represents a therapeutic target, inflammatory markers could represent a promising new key tool to be applied in the diagnosis, the prediction of response to treatment and also as prognostic biomarkers in NENs field. The present review provides an overview of the pre-clinical and clinical data relating the potentially usefulness of circulating inflammatory markers: neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), cytokines and tissue inflammatory markers (PD-1/PD-L1), in the management of NENs. (1) NLR and PLR have both demonstrated to be promising and simple to acquire biomarkers in patients with advanced cancer, including NEN. To date, in the context of NENs, the prognostic role of NLR and PLR has been confirmed in 15 and 4 studies, respectively. However, the threshold value, both for NLR and PLR, still remains not defined. (2) Cytokines seem to play a central role in NENs tumorigenesis. In particular, IL-8 levels seems to be a good predictive marker of response to anti-angiogenic treatments. (3) PD-1 and PD-L1 expression on tumour cells and on TILs, have demonstrated to be promising predictive and prognostic biomarkers in NENs. Unfortunately, these two markers have not been validated so far and further studies are needed to establish their indications and utility. [ABSTRACT FROM AUTHOR]

Survival prognostic markers are extremely needed to better define therapeutic strategies in patients with bronchial carcinoids (BC). We aim to verify the applicability of the NEP-Score in a homogeneous BC cohort and identify a derivative prognostic marker, the NEP-Score at diagnosis (NEP-D) that does not consider new metastases during follow-up. Sixty-four patients (38 females, and 26 males, mean age at diagnosis 58.9 ± 1.7 years) with BC were retrospectively evaluated. NEP-Score was calculated at the end of follow-up (NEP-T). A derivative score, the NEP-Score at diagnosis (NEP-D) that does not consider new metastases during follow-up, was then assessed. Patients were subdivided according to their living status at the end of follow-up. A NEP-Score threshold was investigated to predict survival. Mean NEP-T and mean NEP-D were significantly lower in live patients at end of follow-up. A NEP-T cut-off >138 significantly predicts survival. Atypical BC relapsed more frequently than Typical BC. Male gender and previous malignancy were negative prognostic factors for survival. We confirmed NEP-Score applicability in BC and NEP-D utility, being the latter a simple, quick, and cheap prognostic score that can help clinicians in decision making. The identified NEP-D threshold can predict NEN aggressiveness and may be used to define the best personalized therapeutic strategy. In this context, a validation study is needed. [ABSTRACT FROM AUTHOR]

Introduction: Little is known about how pancreatic neuroendocrine tumors (PanNETs) evolve over time and if changes toward a more aggressive biology correlate with prognosis. The purpose of this study was to characterize changes in PanNET differentiation and proliferation over time and to correlate findings to overall survival (OS). Patients and Methods: In this retrospective cohort study, we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were reevaluated with regard to tumor histopathology and Ki-67 index. Results: Forty-six patients with 106 tumor samples (56 available for pathology reevaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1–38%), grade 1 n = 8, grade 2 n = 36, and grade 3 n = 2. The median change in Ki-67 index (absolute value; follow-up – baseline) was +14% (range –11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (n = 24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (hazard ratio 3.89, 95% CI 1.91–7.94, p < 0.001). Conclusions: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET. [ABSTRACT FROM AUTHOR]

Background: Here we describe the treatments and prognosis for metachronous metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs) after initial R0 surgical resection at a large center in China.Methods: The clinicopathological data and survival outcomes for 108 patients (median age, 54.0 years) with metachronous hepatic metastatic GEP-NETs disease who were initially treated using R0 surgical resection between August 2003 and July 2014 were analyzed using one-way comparisons, survival analysis, and a predictive nomogram.Results: Fifty-five (50.9%) patients had pancreatic NETs and 92 (85.2%) had G2 primary tumors. For treatment of the hepatic metastases, 48 (44.4%) patients received liver-directed local treatment (metastasectomy, radiofrequency ablation, transcatheter arterial chemoembolization, etc.), 15 (13.9%) received systemic treatment (interferon, somatostatin analogs, etc.), and 45 (41.7%) received both treatments. Multivariable analyses revealed that OS was associated with hepatic tumor number (P < 0.001), treatment modality (P = 0.045), and elevated Ki-67 index between the metastatic and primary lesions (P = 0.027). The predictive nomogram C-index was 0.63.Conclusions: A higher Ki-67 index in metastases compared to primary tumor was an independent factor for poor prognosis. Local treatment was associated with prolonged survival of hepatic metastatic GEP-NET patients. Optimal treatment strategies based on clinicopathological characteristics should be developed. [ABSTRACT FROM AUTHOR]

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Background: Gastric neuroendocrine neoplasms (NENs) are very heterogeneous, ranging from mostly indolent, atrophic gastritis-associated, type I neuroendocrine tumors (NETs), through highly malignant, poorly differentiated neuroendocrine carcinomas (pdNECs), to sporadic type III NETs with intermediate prognosis, and various rare tumor types. Histologic differentiation, proliferative grade, size, level of gastric wall invasion, and local or distant metastases are used as prognostic markers. However, their value remains to be tailored to specific gastric NENs. Methods: Series of type I NETs (n = 123 cases), type III NETs (n = 34 cases), and pdNECs (n = 43 cases) were retrospectively collected from four pathology centers specializing in endocrine pathology. All cases were characterized clinically and histopathologically. During follow-up (median 93 months) data were recorded to assess disease-specific patient survival. Results: Type I NETs, type III NETs, and pdNECs differed markedly in terms of tumor size, grade, invasive and metastatic power, as well as patient outcome. Size was used to stratify type I NETs into subgroups with significantly different invasive and metastatic behavior. All 70 type I NETs < 0.5 cm (micro-NETs) were uneventful. Ki67-based grading proved efficient for the prognostic stratification of type III NETs; however, grade 2 (G2) was not associated with tumor behavior in type I NETs. Although G3 NETs (2 type I and 9 type III) had a very poor prognosis, it was found that patient survival was longer with type III G3 NETs compared to pdNECs. Conclusions: Given the marked, tumor type-related behavior differences, evaluation of gastric NEN prognostic parameters should be tailored to the type of neoplastic disease. [ABSTRACT FROM AUTHOR]

Stromal cell‑derived factor‑1 (SDF‑1) predicts poor clinical outcomes of certain types of cancer. Furthermore, vascular endothelial growth factor (VEGF) promotes the growth and metastasis of solid tumors. The aim of the present study was to examine the expression of SDF‑1 and VEGF in patients with synovial sarcoma and to determine their expression is correlated with unfavorable outcomes. Levels of SDF‑1 and VEGF proteins were evaluated in 54 patients with synovial sarcoma using immunohistochemical and immunofluorescence staining. Potential associations between the expression of SDF‑1 and VEGF and various clinical parameters were analyzed using Pearson's χ2 test and the Spearman‑rho test. Additionally, univariate and multivariate Cox regression analyses were used to identify potential prognostic factors, and the Kaplan‑Meier method was used to analyze the overall survival rates of patients. Low SDF‑1 and VEGF expression was detected in 20.4% (11/54) and 22.2% (12/54) of patients with synovial sarcoma; moderate expression was detected in 35.2% (19/54) and 37.0% (20/54) of patients and high expression was detected in 44.4% (24 of 54) and 40.7% (22 of 54) of patients, respectively. Levels of SDF‑1 and VEGF proteins were significantly associated with histological grade (P<0.05), metastasis (P<0.05) and American Joint Committee on Cancer staging (P<0.05). In addition, levels of SDF‑1 and VEGF expression were positively correlated with each other (P<0.001). Univariate analysis also indicated that VEGF expression was associated with shorter overall survival rates in (P<0.05), whereas multivariate analysis demonstrated that SDF‑1 expression was associated with shorter patient survival rates (P<0.05). Finally, both SDF‑1 and VEGF expression were associated with various characteristics of synovial sarcoma. Therefore, SDF‑1 expression may be a potential independent prognostic indicator in patients with synovial sarcomas. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the prognosis and progression of spinal and bulbar muscular atrophy (SBMA), a rare X-linked motor neuron disorder caused by trinucleotide repeat expansion in the AR (androgen receptor) gene, after long-term androgen suppression with leuprorelin acetate treatment.Methods: In the present natural history-controlled study, 36 patients with SBMA treated with leuprorelin acetate for up to 84 months (leuprorelin acetate-treated group; LT group) and 29 patients with SBMA with no specific treatment (non-treated group; NT group) were analysed. Disease progression was evaluated by longitudinal quantitative assessment of motor functioning using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the modified Norris score. In addition, we selected two major clinical endpoint events, namely the occurrence of pneumonia requiring hospitalisation and death, to evaluate disease prognosis following long-term leuprorelin acetate treatment.Results: In our analysis of the longitudinal disease progression using the random slope model, we observed a significant difference in the ALSFRS-R total score, the Limb Norris Score, and the Norris Bulbar Score (p=0.005, 0.026 and 0.020, respectively), with the LT group exhibiting a slower per-12-months decline compared with the NT group. As for the event analysis, the prognosis of the LT group was better in comparison to the NT group as for the event-free survival period (p=0.021).Conclusion: Long-term treatment with leuprorelin acetate appears to delay the functional decline and suppress the incidence of pneumonia and death in subjects with SBMA. [ABSTRACT FROM AUTHOR]

Purpose: Abnormal expression of succinate dehydrogenase, (SDH), in particular of the B subunit (SDHB), is implicated in the pathogenesis of neuroendocrine tumors. This study evaluates the distribution of SDHB in WHO grading G1 and G2 intestinal, well-differentiated neuroendocrine tumors and corresponding lymph node or liver metastases. Methods: We collected ileal well-differentiated neuroendocrine tumors specimens from consecutive patients with prior primary resection and distant synchronous or metachronous liver metastases. We obtained 195 specimens from primary tumors ( n = 106) and metastases ( n = 89). The expression (E) of SDHB and the immunostaining intensity (I) were evaluated semiquantitatively and combined into a single score. SDHB score was evaluated in primitive tumor and metastatic specimens. Results: SDHB was found in all tumor cells. Mean SDHB expression was 72.7 % ± 17.1 % in primitive specimens and 27.9 % ± 24.6 % in metastatic specimens ( p < 0.0001). SDH intensity was higher in primitive specimens ( p < 0.0001). SDHB score was 9-12 in 96 specimens of the primitive group and 2 metastatic specimens ( p < 0.0001). None of the analyzed parameters was predictive of overall survival in the primitive subset. In the metastatic subset, loss of SDHB expression, intensity, and score were prognostic factors for survival. Lower expression and intensity of SDHB in metastatic lesions were associated with longer overall survival. When combining SDHB score and Ki-67 % in the metastatic subset, a lower SDHB score was associated with prolonged overall survival, independently from Ki-67 %. Conclusions: SDHB score was different in primitive and metastatic specimens. The combination of SDHB score and Ki-67 % was a stronger predictor of overall survival than Ki-67 % alone. This stratification might help predict survival. [ABSTRACT FROM AUTHOR]

Background: Gastric neuroendocrine neoplasms (G-NENs) are uncommon, and data on their management is limited. We here investigated the clinicopathological characteristics, surgical and survival outcomes in G-NENs among Chinese. Moreover, we will discuss their prognostic value.Methods: From existing databases of the West China Hospital, we retrospectively identified 135 consecutive patients who were surgically treated and pathologically diagnosed as G-NENs from January 2009 to August 2015.Results: This entire cohort comprised 98 males and 37 females, with a median age of 60 years. Twenty-five patients underwent endoscopic resection, while 110 patients underwent open/laparoscopic surgery. Thirty-nine patients had neuroendocrine tumor G1 (NET G1), seven patients had neuroendocrine tumor G2 (NET G2), 69 patients had neuroendocrine carcinoma G3 (NEC G3) and 20 patients had mixed adenoneuroendocrine carcinoma (MANEC). The median survival was not achieved for both NET G1 and NET G2 versus 19 months (range 3-48) for NEC G3 and 10.5 months (range 3-45) for MANEC. The 3-year survival rates for stage I, II, III, and IV were 91.1 %, 78.6 %, 51.1 % and 11.8 %, respectively (P < 0.001). As for the prognostic analysis, both surgical margin and the newly updated World Health Organization (WHO) classification were independent predictors of overall survival (OS).Conclusions: G-NENs are a kind of rare tumors, and patients with NET G3 and MANEC have unfavorable prognosis even surgically treated. Moreover, surgical margin and the new 2010 WHO criteria are closely associated with OS for G-NENs. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumors (PanNETs) are rare tumors; however, their incidence greatly increases with age, and they occur more frequently among the elderly. They represent 5% of all pancreatic tumors, and despite the fact that low-grade tumors often have an indolent evolution, they portend a poor prognosis in an advanced stages and undifferentiated tumors. Additionally, functional pancreatic neuroendocrine tumors greatly impact quality of life due to the various clinical syndromes that result from abnormal hormonal secretion. With limited therapeutic and diagnostic options, patient stratification and selection of optimal therapeutic strategies should be the main focus. Modest improvements in the management of pancreatic neuroendocrine tumors have been achieved in the last years. Therefore, it is imperative to find new biomarkers and therapeutic strategies to improve patient survival and quality of life, limiting the disease burden. MicroRNAs (miRNAs) are small endogenous molecules that modulate the expression of thousands of genes and control numerous critical processes involved in tumor development and progression. New data also suggest the implication of miRNAs in treatment resistance and their potential as prognostic or diagnostic biomarkers and therapeutic targets. In this review, we discusses the current and new challenges in the management of PanNETs, including genetic and epigenetic approaches. Furthermore, we summarize the available data on miRNAs as potential prognostic, predictive, or diagnostic biomarkers and discuss their function as future therapeutic targets. [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]

Background: The Ki-67 index in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) may change throughout the disease course. However, the definitive effect of Ki-67 variability on GEP-NENs remains unknown. The aims of this study were to evaluate changes in Ki-67 levels throughout the disease course and investigate the role of Ki-67 index variability in GEP-NENs. Methods: Specimens with multiple pathologies were evaluated from 30 patients who were selected from 514 patients with GEP-NENs, being treated at Wuhan Union Hospital from July 2009 to February 2018. The Ki-67 index was evaluated among multiple specimens over the disease course. Univariable and multivariable Cox proportional hazards regression analyses were performed to assess the prognostic significance of various clinical and histopathologic features. Results: Among the 514 patients with GEP-NENs, metastases were seen in 182 (35.41%). Among the 30 patients from whom specimens with multiple pathologies were obtained, 24 were both primary and metastatic specimens and six were specimens collected over the course of the disease. Changes in Ki-67 levels were detected in 53.3% of the patients, of whom 40% had up-regulated Ki-67 levels, and 13.3% had down-regulated Ki-67 levels. Kaplan–Meier survival analysis showed that the group with Ki-67 variability had a shorter overall survival ( p = 0.0297). The Cox regression analysis indicated that Ki-67 variability ( p = 0.038) was the only independent prognostic factor for overall survival. Conclusions: Our data suggest that patients with GEP-NENs and Ki-67 variability had a poorer prognosis. The re-assessment of Ki-67 at sites of metastasis or during the disease course might play a role in predicting the prognosis of patients with GEP-NENs. This finding could have implications for how GEP-NENs are monitored and treated. [ABSTRACT FROM AUTHOR]