Prognostic Effect of Lymph Node Metastases and Mesenteric Deposits in Neuroendocrine Tumors of the Small Bowel.

Well-differentiated, low-grade neuroendocrine tumors (NETs) are the most frequent tumor types of the small bowel. Despite their generally indolent growth patterns and grade, these tumors tend to metastasize; indeed, at presentation, approximately 50% show nodal metastases and 30% of patients have distant metastases, even though they potentially show long survival. Little is available in the literature concerning the optimal nodal yield in small-bowel resections, and the clinical significance of nodal metastases and lymph node ratio (LNR) at this site is still debated. The aim of this review, through a systematic literature search, is to explore and analyze data regarding nodal status, adequacy of lymphadenectomy, and LNR on the prognosis of small bowel NETs using defined end points (progression-free survival, recurrence-free survival, and overall survival). Some surgical series have demonstrated that extended regional mesenteric lymphadenectomy, together with primary tumor resection, is associated with improved patient survival, and LNR is proving a prognostically important parameter. The new feature of mesenteric tumor deposits (MTDs; neoplastic deposits found in the mesenteric perivisceral adipose tissue that are not LN associated) seems to be a better prognostic predictor in small-bowel NETs compared to nodal metastases, and this feature is explored and critiqued in this review. In particular, increasing number of tumor deposits is correlated with increased risk of disease-specific death, and MTDs seem to correlate with peritoneal carcinomatosis.

From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell?

Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host's metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host's immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.

The management of neuroendocrine tumours: A nutritional viewpoint.

Nutritional status in patients with neuroendocrine tumours (NETs), especially of gastroenteropancreatic origin, can be deeply affected by excessive production of gastrointestinal hormones, peptides, and amines, which can lead to malabsorption, diarrhoea, steatorrhea, and altered gastrointestinal motility. Besides, the surgical and/or medical management of NETs can lead to alteration of gastrointestinal secretory, motor, and absorptive functions, with both dietary and nutritional consequences. Indeed, disease-related malnutrition is a frequently encountered yet both underrecognized and understudied clinical phenomenon in patients with NETs, with substantial prognostic and socioeconomic consequences. Most of these conditions can be alleviated by a tailored nutritional approach, also with the aim of improving the efficacy of cancer treatments. In this setting, skilled nutritionists can play a fundamental role in the multidisciplinary health care team in NETs management and their presence should be recommended. The aim of this review is to provide dietary advices for each specific condition in patients with NETs, underlining the importance of a nutritional approach to treat malnutrition in this setting. Further, we will provide preliminary evidence coming from our data on the assessment of nutritional status in a single cohort of patients with NETs.

Diabetes and pancreatic neuroendocrine tumours: Which interplays, if any?

Pancreatic neuroendocrine tumours (PanNETs) represent an uncommon type of pancreatic neoplasm, whose incidence is increasing worldwide. As per exocrine pancreatic cancer, a relationship seems to exist between PanNETs and glycaemic alterations. Diabetes mellitus (DM) or impaired glucose tolerance often occurs in PanNET patients as a consequence of hormonal hypersecretion by the tumour, specifically affecting glucose metabolism, or due to tumour mass effects. On the other hand, pre-existing DM may represent a risk factor for developing PanNETs and is likely to worsen the prognosis of such patients. Moreover, the surgical and/or pharmacological treatment of the tumour itself may impair glucose tolerance, as well as antidiabetic therapies may impact tumour behaviour and patients outcome. Differently from exocrine pancreatic tumours, few data are available for PanNETs as yet on this issue. In the present review, the bidirectional association between glycaemic disorders and PanNETs has been extensively examined, since the co-existence of both diseases in the same individual represents a further challenge for the clinical management of PanNETs.

The Zollinger-Ellison syndrome: is there a role for somatostatin analogues in the treatment of the gastrinoma?

PURPOSE: Analyze the role of somatostatin analogues (SSAs) in the treatment of sporadic and MEN1-related gastrinomas, trying to define whether recent trials have changed the landscape of gastrinoma therapy. METHODS: We evaluate the rationale of SSA use in the treatment of gastrinomas, summarize the current literature concerning the effect of SSAs on the control of Zollinger-Ellison syndrome (ZES) and gastrinomas tumor progression and discuss their role in the most recent guidelines. RESULTS: The medical treatment of gastrinoma and related ZES is aimed at controlling acid hypersecretion and tumor progression, in inoperable patients. The use of proton pump inhibitors (PPIs) to control the syndrome is a cornerstone in the ZES therapy. SSAs are not usually indicated for antisecretory purpose, because PPIs are considered the treatment of choice, due to their long lasting high efficacy and oral availability. The antiproliferative effect of SSAs has been established by two placebo-controlled trials that have clearly demonstrated a significant increase in progression free survival in patients affected by non-functioning well-differentiated advanced neuroendocrine tumors (NETs). The recent ENETS guidelines recommend the use of SSAs in advanced well differentiated NETs as antiproliferative agents. CONCLUSIONS: The high sstr-expression in gastrinomas make them highly responsive to SSAs and support the use of such drugs to counteract the tumour growth in patients not amenable to surgical cure. Unfortunately, limited data, mainly case reports or small series, support the use of SSAs in advanced gastrinomas, therefore, it is difficult to quantify their ability to control tumour growth and disease progression.

Bisphenol A in polycystic ovary syndrome and its association with liver-spleen axis.

CONTEXT: Bisphenol A, one of the highest-volume chemicals currently available, is known to act as endocrine disruptor and alters several metabolic functions, including inflammatory pathways. Elevated serum levels of bisphenol A have been found in women with polycystic ovary syndrome (PCOS) and a role of low-grade chronic inflammation has been recently reported in the pathogenesis of this syndrome. Increased spleen volume, a reliable and stable index of chronic inflammation, was strictly associated with the severity of hepatic steatosis (HS) in obese subjects, determining the so-called liver-spleen axis. OBJECTIVE: To evaluate the contribution of increased serum bisphenol A levels to low-grade chronic inflammation, HS and hyperandrogenism in women with PCOS. DESIGN, SETTING AND PARTICIPANTS: Forty lean and overweight/obese premenopausal women with PCOS and 20 healthy age-matched women were consecutively enrolled in a cross-sectional study from 2009 to 2011 at the Federico II University Hospital in Naples. MEASUREMENTS: Bisphenol A, homoeostasis model assessment of insulin resistance (HoMA-IR), laboratory liver tests, testosterone, sex hormone-binding globulin, free androgen index (FAI), C-reactive protein, interleukin-6, and the ultrasound quantification of HS and spleen longitudinal diameter. RESULTS: Independently of body weight, higher bisphenol A levels in PCOS women were associated with higher grades of insulin resistance, HS, FAI and inflammation, spleen size showing the best correlation. At multivariate analysis, spleen size and FAI were the best predictors of bisphenol A (ß coefficients 0.379, P = 0.007 and 0.343, P = 0.014, respectively). CONCLUSIONS: In premenopausal women with PCOS, we evidenced an association of serum bisphenol A levels with HS and markers of low-grade inflammation, in particular with spleen size, unravelling the presence of the liver-spleen axis in this syndrome.

Liver-spleen axis, insulin-like growth factor-(IGF)-I axis and fat mass in overweight/obese females.

BACKGROUND: Fat mass (FM) in overweight/obese subjects has a primary role in determining low-grade chronic inflammation and, in turn, insulin resistance (IR) and ectopic lipid storage within the liver. Obesity, aging, and FM influence the growth hormone/insulin-like growth factor (IGF)-I axis, and chronic inflammation might reduce IGF-I signaling. Altered IGF-I axis is frequently observed in patients with Hepatic steatosis (HS). We tested the hypothesis that FM, or spleen volume and C-reactive protein (CRP)--all indexes of chronic inflammation--could affect the IGF-I axis status in overweight/obese, independently of HS. METHODS: The study population included 48 overweight/obese women (age 41 ± 13 years; BMI: 35.8 ± 5.8 kg/m2; range: 25.3-53.7), who underwent assessment of fasting plasma glucose and insulin, homeostasis model assessment of insulin resistance (HOMA), cholesterol and triglycerides, HDL-cholesterol, transaminases, high-sensitive CRP, uric acid, IGF-I, IGF binding protein (BP)-1, IGFBP-3, and IGF-I/IGFBP-3 ratio. Standard deviation score of IGF-I according to age (zSDS) were also calculated. FM was determined by bioelectrical impedance analysis. HS severity grading (score 0-4 according liver hyperechogenicity) and spleen longitudinal diameter (SLD) were evaluated by ultrasound. RESULTS: Metabolic syndrome (MS) and HS were present in 33% and 85% of subjects, respectively. MS prevalence was 43% in subjects with increased SLD. IGF-I values, but not IGF-I zSDS, and IGF-I/IGFBP-3 ratio were significantly lower, while FM%, FPI, HOMA, ALT, CRP, were significantly higher in patients with severe HS than in those with mild HS. IGF-I zSDS (r = -0.42, r = -0.54, respectively; p < 0.05), and IGFBP-1 (r = -0.38, r = -0.42, respectively; p < 0.05) correlated negatively with HS severity and FM%. IGF-I/IGFBP-3 ratio correlated negatively with CRP, HS severity, and SLD (r = -0.30, r = -0.33, r = -0.43, respectively; p < 0.05). At multivariate analysis the best determinants of IGF-I were FM% (ß = -0.49; p = 0.001) and IGFBP-1 (ß = -0.32; p = 0.05), while SLD was in the IGF-I/IGFBP-3 ratio (ß = -0.43; p = 0.004). CONCLUSIONS: The present study suggests that lower IGF-I status in our study population is associated with higher FM, SLD, CRP and more severe HS.

Validity of bioelectrical impedance analysis to estimate body composition changes after bariatric surgery in premenopausal morbidly women.

In obese patients, subtle variations of the hydration of soft tissues can propagate errors in bioelectrical impedance analysis (BIA) measures of body composition. Bioelectrical impedance vector analysis (BIVA) is a useful method to evaluate tissue hydration. Laparoscopic adjustable gastric banding (LAGB) is a purely restrictive bariatric surgical procedure resulting in lower fat-free mass (FFM) loss than other malabsorptive or mixed intervention. The aim of this study was to evaluate the 6- and 12-month changes in body composition in a homogeneous group of premenopausal morbidly obese women treated by LAGB by comparing the results of conventional BIA and BIVA with dual-energy X-ray absorptiometry (DXA) method. Forty-five consecutive morbidly obese patients (mean age, 35.3 +/- 9.1 years; body mass index, 34.5-48.7 kg/m(2)) were prospectively evaluated at the Endocrinology Unit of the Department of Molecular and Clinical Endocrinology and Oncology. The LAGB device (Lap-Band System; Inamed Health, Santa Barbara, CA, USA) was inserted laparoscopically. Soft tissue hydration was evaluated by BIVA; fat mass (FM) and FFM were evaluated by BIA (BIA 101 RJL, Akern Bioresearch, Firenze, Italy) and by DXA (Hologic QDR 4500A S/N 45622; Hologic Inc., Bedford, MA, USA). Pre- and postoperative BIVA vectors indicated a normal hydration in all patients. Postoperatively, the excess of body weight loss was mainly due to a decrease in FM. The regression analysis of BIA and DXA methods at baseline and at the 6- and 12-month follow-up for FM r (2) values were 0.98, 0.94, and 0.99, respectively (p < 0.001); FM% r (2) values were 0.91, 0.89, and 0.98, respectively (p < 0.001); and FFM r (2) values were 0.87, 0.82, 0.99, respectively (p < 0.001). BIA and DXA measurements of body composition exhibit a high relative agreement in the study group of normo-hydrated obese subjects. BIA tends to overestimate FFM, but this effect is reduced along with the weight loss during the follow-up. Under the stable hydration, the BIA method may be useful as an alternative to DXA in a selected clinical setting when repeated comparisons of body composition are required.

Hepatic steatosis in overweight/obese females: new screening method for those at risk.

AIM: To identify which parameters could help to distinguish the "metabolically benign obesity", which is not accompanied by insulin resistance (IR) and early atherosclerosis. METHODS: Eighty two of 124 overweight/obese females formed the study population, which was divided into two groups (52 and 30 subjects, respectively) with and without IR according to a HO meostatic Metabolic Assessment (HOMA) cut-off of 2, and were studied in a cross-sectional manner. The main outcome measures were waist circumference, serum uric acid, high-density lipoprotein-cholesterol and triglycerides, alanine aminotransferase, blood pressure and the two imaging parameters, hepatic steatosis and longitudinal diameter of the spleen, which were measured in relation to the presence/absence of IR. RESULTS: A variable grade of visceral obesity was observed in all subjects with the exception of three. Obesity of a severe grade was represented more in the group of IR individuals (P = 0.01). Hepatic steatosis, revealed at ultrasound, was more pronounced in IR than in non-IR subjects (P = 0.005). The two groups also demonstrated a clear difference in longitudinal spleen diameter and blood pressure, with raised and significant values in the IR group. Metabolic syndrome was frequent in the IR group, and was not modified when adjusted for menopause (P = 0.001). At linear regression, the beta values of waist circumference and body mass index predicting HOMA were 0.295, P = 0.007 and 0.41, P = 0.0001, respectively. Measures of spleen longitudinal diameter were well predicted by body mass index (BMI) values, beta = 0.35, P = 0.01, and by HOMA, beta = 0.41, P = 0.0001. Blood pressure was predicted by HOMA values, beta = 0.39, P = 0.0001). HOMA and hepatic steatosis were highly associated (rho = 0.34, P = 0.002). Interestingly, IR patients were almost twice as likely to have hepatic steatosis as non-IR patients. Among the MS criteria, blood pressure was very accurate in identifying the presence of IR (AUROC for systolic blood pressure 0.66, cut-off 125 mm of Hg, sensibility 64%, specificity 75%; AUROC for diastolic blood pressure 0.70, cut-off 85 mm of Hg, sensibility 54.5%, specificity 75%). CONCLUSION: As health care costs are skyrocketing, reliable and mainly inexpensive tools are advisable to better define subjects who really need to lose weight.