Garlic consumption in relation to colorectal cancer risk and to alterations of blood bacterial DNA.

PURPOSE: Garlic consumption has been inversely associated to intestinal adenoma (IA) and colorectal cancer (CRC) risk, although evidence is not consistent. Gut microbiota has been implied in CRC pathogenesis and is also influenced by garlic consumption. We analyzed whether dietary garlic influence CRC risk and bacterial DNA in blood. METHODS: We conducted a case-control study in Italy involving 100 incident CRC cases, 100 IA and 100 healthy controls matched by center, sex and age. We used a validated food frequency questionnaire to assess dietary habits and garlic consumption. Blood bacterial DNA profile was estimated using qPCR and16S rRNA gene profiling. We derived odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of IA and CRC according to garlic consumption from multiple conditional logistic regression. We used Mann-Whitney and chi-square tests to evaluate taxa differences in abundance and prevalence. RESULTS: The OR of CRC for medium/high versus low/null garlic consumption was 0.27 (95% CI = 0.11-0.66). Differences in garlic consumption were found for selected blood bacterial taxa. Medium/high garlic consumption was associated to an increase of Corynebacteriales order, Nocardiaceae family and Rhodococcus genus, and to a decrease of Family XI and Finegoldia genus. CONCLUSIONS: The study adds data on the protective effect of dietary garlic on CRC risk. Moreover, it supports evidence of a translocation of bacterial material to bloodstream and corroborates the hypothesis of a diet-microbiota axis as a mechanism behind the role of garlic in CRC prevention.

Effects of low-dose aspirin on clinical outcome and disease progression in patients with gastroenteropancreatic neuroendocrine neoplasm.

Objective: The chemopreventive effect of aspirin (ASA) has been observed in the setting of colorectal cancer and other solid neoplasms. Recently, ASA has demonstrated a promising anti-proliferative effect on GEP-NENs in vitro. However, the direct anti-neoplastic impact of ASA on GEP-NEN clinical outcome is yet to be clarified. Materials and methods: All the GEP-NEN patients followed up in three European Centers from January 2005 to September 2016 were retrospectively enrolled. Patients taking ASA in doses of 75-100 mg daily for cardiovascular prevention for at least six months were evaluated. The possible association between ASA and disease grading, staging, primary site, OS and PFS were evaluated. Results: Two hundred fifty one patients were included (117 males, median age 63 years). Of these, 64 patients were prescribed with ASA. No clear impact on OS or PFS was observed in GEP-NEN patients taking ASA compared to those not taking it. ASA intake was related with the patients' older age. At Cox multivariate analysis, stage IV and Ki-67 resulted independent predictors for OS and PFS. In the setting of intestinal NENs, a suggestive, but not statistically significant, protective role of ASA on PFS was observed [HR 0.41 (95% CI: 0.13-1.29)]. Conclusions: Despite ASA showed promising anti-proliferative effects in vitro and a chemopreventive action in NENs has been reported, a clear impact of ASA on survival in NENs has not emerged from the present study. However, in the subgroup of patients with small-intestine NENs, ASA showed a trend toward a protective role.

Relevance of vitamin D deficiency in patients with chronic autoimmune atrophic gastritis: a prospective study.

BACKGROUND: Chronic autoimmune atrophic gastritis (CAAG) is an autoimmune disease characterized by hypo/achlorhydria. A role of CAAG in the pathogenesis of nutritional deficiencies has been reported, therefore we hypothesized a possible association between CAAG and 25-OH-Vitamin D [25(OH)D] deficiency. Aim of the present study is to evaluate the prevalence of 25(OH)D deficiency in CAAG patients. METHODS: 87 CAAG patients (71 females; mean age 63.5 ± 12.8 years) followed at our Centre from January 2012 to July 2015 were consecutively evaluated. 25(OH)D, vitamin B12, parathormone, and calcium were measured in all the CAAG patients. The results were compared with a control group of 1232 healthy subjects. RESULTS: In the CAAG group the mean 25(OH)D levels were significantly lower than in the control group (18.8 vs. 27.0 ng/ml, p < 0.0001). 25(OH)D levels < 20 ng/ml was observed in 57 patients, while levels < 12.5 ng/ml in 27 patients. A significant correlation between vitamin B12 values at diagnosis and 25(OH)D levels was observed (rs = 0.25, p = 0.01). Interestingly, the CAAG patients with moderate/severe gastric atrophy had lower 25(OH)D values as compared to those with mild atrophy (11.8 vs. 20 ng/ml; p = 0.0047). Moreover, the 25(OH)D levels were significantly lower in CAAG patients with gastric carcinoid as compared to those without gastric carcinoid (11.8 vs. 19.8 ng/ml; p = 0,0041). CONCLUSION: Data from the present study showed a significant reduction of 25(OH)D levels in CAAG patients and a possible impairment of vitamin D absorption in CAAG may be postulated. Any implication to the genesis of gastric carcinoids remains to be elucidated.

Impact of Vitamin D on the Clinical Outcome of Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: Report on a Series from a Single Institute.

BACKGROUND/AIMS: Vitamin D deficiency is hypothesized to represent a risk factor in several neoplasms. The aim of this study was to determine whether serum 25-hydroxyvitamin D (25-OHvitD) deficiency represents a risk factor for neuroendocrine neoplasms (NENs) and can be associated with overall survival (OS) and progression-free survival (PFS). METHODS: From 2010 to 2015, 138 patients with gastro- entero-pancreatic NENs (61 females; median age, 63 years) were included in the study. Serum 25-OHvitD levels, which were measured at baseline, were defined as deficient if ≤20 ng/mL. In such cases, 25-OHvitD supplementation was administered to the patients. The possible associations between 25-OHvitD levels and disease grading, staging, overall OS, and PFS were considered. Furthermore, the possible association between 25-OHvitD supplementation and PFS or OS was evaluated by Cox proportional hazards regression. RESULTS: Median 25-OHvitD levels were 12.9 ng/mL (range 2-32); in detail, 94 patients (68%) had ≤20 ng/mL, with 46 cases (33%) having ≤10 ng/mL. An inverse correlation was observed between 25-OHvitD levels and OS (p = 0.03, rs = -0.18) and PFS (p = 0.01, rs = -0.22). At Cox proportional hazards regression, mortality was not related to 25-OHvitD levels; however, there was an association between 25-OHvitD supplementation and OS (p < 0.002). CONCLUSIONS: Vitamin D deficiency is highly prevalent among NEN patients. 25-OHvitD supplementation potentially plays an important role in the correction of 25-OHvitD values, and has an influence on the clinical outcome. However, further studies are needed to confirm this observation.

Gastric neuroendocrine neoplasms and proton pump inhibitors: fact or coincidence?

OBJECTIVE: Reporting on three cases of gastric neuroendocrine tumors (g-NETs) in patients taking long-term proton pump inhibitors (PPIs). These tumors are not classifiable considering current criteria. g-NETs are currently grouped as: types 1 and 2, related to hypergastrinemia due to chronic atrophic gastritis and Zollinger-Ellison syndrome respectively, and type 3, normogastrinemic and more aggressive. Although the g-NETs onset in patients taking PPIs is biologically plausible, only a few cases have been reported so far. MATERIALS AND METHODS: From January 2005 to July 2014, 31 g-NETs were referred to our Unit: 24 (77%), one (3%) and three (10%) resulted types 1, 2 and 3, respectively. Three cases (10%) did not meet the current classification criteria. RESULTS: The three patients were administered long-term PPIs for gastro-esophageal reflux disease. Patient 1: a 78-year-old man, with a 4-mm well-differentiated g-NET (Ki-67<1%) and marked hypergastrinemia. Patient 2: a 58-year-old man affected by a 6-mm well-differentiated (Ki-67 = 4%) g-NET, with normal gastrin levels. Patients 3: a 67-year-old woman with an 18-mm well-differentiated g-NET (Ki-67 <2%), with mild hypergastrinemia. In the three patients, histology and pertinent blood tests excluded chronic atrophic gastritis, Helicobacter pylori infection or Zollinger-Ellison syndrome. The first two patients underwent endoscopic polypectomy; in the third case total gastrectomy was performed. Further clinical, endoscopic and imaging follow-up did not show any g-NET recurrence. CONCLUSIONS: The present data point to the existence and epidemiological relevance of g-NETs associated with PPIs intake. These neoplasms are not included in the current classification, thus their treatment and follow-up have not been established.

Chromogranin A in diagnosing and monitoring patients with gastroenteropancreatic neuroendocrine neoplasms: a large series from a single institution.

BACKGROUND/AIMS: Plasma chromogranin A (CgA) is the most widely used biochemical biomarker in the diagnostic workup and follow-up of gastroenteropancreatic neuroendo- crine neoplasms (GEP-NENs). Herein, we assessed the clinical utility of CgA in diagnosing and monitoring a large series of GEP-NENs. PATIENTS AND METHODS: A total of 181 GEP-NEN patients (87 males, 94 females) with pancreatic (n = 81) and gastrointestinal neoplasms (n = 100) were included; 99 patients had grade (G)1 NENs (Ki-67 ≤2%), 57 G2 NENs (Ki-67 3-20%) and 25 G3 NENs (Ki-67 >20%); 81 patients had tumor-node-metastasis (TNM) stage I, 14 stage II, 17 stage III and 69 stage IV cancer. For every patient, CgA values were assessed at diagnosis and during follow-up. RESULTS: At diagnosis, the CgA values were above the upper reference limit in 148 patients (82%); the median CgA levels were significantly higher in functioning than in nonfunctioning tumors (295 vs. 43 U/l; p = 0.0001) as well as significantly higher in patients with metastases than in those without metastases (324.5 vs. 42 U/l; p = 0.0001). In logistic regression analysis, baseline CgA levels were significantly associated with Ki-67 index (p < 0.0001) and TNM stage (p < 0.0001) independently of the age and sex of the patient and the primary site of the tumor. The overall 5- and 10-year survival rates were 74 and 64.5%, respectively. A low Ki-67 index, the type of treatment and an early CgA decrease after treatment were positively correlated with the survival rate. After radical surgery, 15/95 patients relapsed, and an increase in CgA values anticipated the clinical and objective disease recurrence after a period of 9-12 months. CONCLUSIONS: In GEP-NENs, plasma CgA has a significant prognostic relevance.

Superficial oesophageal mucosal innervation may contribute to severity of symptoms in oesophageal motility disorders.

BACKGROUND: Mechanisms underlying perception of dysphagia and chest pain have not been completely elucidated, although oesophageal mucosal afferent nerves might play an important role. AIMS: To evaluate the relationship between oesophageal mucosal afferent nerves and the severity of dysphagia and chest pain in oesophageal motility disorders. METHODS: We prospectively recruited patients with oesophageal motility disorders having dysphagia and/or chest pain from whom oesophageal biopsies were obtained. High-resolution manometry classified patients into disorders of oesophagogastric junction (OGJ) outflow and disorders of peristalsis. Symptom severity was assessed using validated questionnaires including Brief Oesophageal Dysphagia Questionnaire (BEDQ). Immunohistochemistry was performed on oesophageal biopsies to evaluate the location of calcitonin gene-related peptide (CGRP)-immunoreactive mucosal afferent nerves. Findings were compared to existing data from 10 asymptomatic healthy volunteers. RESULTS: Of 79 patients, 61 patients had disorders of OGJ outflow and 18 had disorders of peristalsis. CGRP-immunoreactive mucosal nerves were more superficially located in the mucosa of patients with oesophageal motility disorders compared to healthy volunteers. Within disorders of OGJ outflow, the location of CGRP-immunoreactive nerves negatively correlated with BEDQ score both in the proximal (ρ = -0.567, p < 0.001) and distal oesophagus (ρ = -0.396, p = 0.003). In the proximal oesophagus, strong chest pain was associated with more superficially located mucosal nerves than weak chest pain (p = 0.04). Multivariate analysis showed superficial nerves in the proximal oesophagus was independently associated with severe dysphagia in disorders of OGJ outflow (p = 0.008). CONCLUSIONS: Superficial location of mucosal nerves in the proximal oesophagus might contribute to symptoms, especially severe dysphagia, in disorders of OGJ outflow.

Flavonoid Intake in Relation to Colorectal Cancer Risk and Blood Bacterial DNA.

Flavonoids have been inversely associated to colorectal cancer (CRC) and are plausible intermediaries for the relation among gut microbiome, intestinal permeability and CRC. We analyzed the relation of flavonoid intake with CRC and blood bacterial DNA. We conducted a case-control study in Italy involving 100 incident CRC cases and 200 controls. A valid and reproducible food-frequency questionnaire was used to assess dietary habits and to estimate six flavonoid subclass intakes. We applied qPCR and 16S rRNA gene profiling to assess blood bacterial DNA. We used multiple logistic regression to derive odds ratios (ORs) of CRC and Mann-Whitney and chi--square tests to evaluate abundance and prevalence of operational taxonomic units (OTUs) according to flavonoid intakes. Inverse associations with CRC were found for anthocyanidins (OR for the highest versus the lowest tertile = 0.24, 95% confidence interval, CI = 0.11-0.52) and flavanones (OR = 0.18, 95% CI = 0.08-0.42). We found different abundance and prevalence according to anthocyanidin and flavanone intake for OTUs referring to Oligoflexales order, Diplorickettsiaceae family, Staphylococcus, Brevundimonas, Pelomonas and Escherischia-Shigella genera, and Flavobacterium and Legionella species. The study provides evidence to a protective effect of dietary anthocyanidins and flavanones on CRC and suggests an influence of flavonoids on blood bacterial DNA, possibly through intestinal permeability changes.

Thrombotic risk in gastroenteropancreatic neuroendocrine tumor patients: a single-center experience.

BACKGROUND: Only scanty specific studies are available on venous thromboembolism (VTE) in neuroendocrine neoplasms (NEN). We retrospectively assessed the incidence of VTE in gastroenteropancreatic (GEP) NEN patients. METHODS: Between 2000 and 2016, GEP-NEN patients were retrospectively evaluated for VTE. Major thrombotic events included deep venous thrombosis (DVT) and pulmonary embolism (PE). 160 patients were included. The primary tumor site was: the gut in 99, pancreas in 54, and unknown in 7. A total of 93 patients had grade (G) 1 tumor, 36 G2, 4 G3; G was not available in 27 patients. TNM stage was I in 76 patients, II in 17, III in 23, and IV in 44. RESULTS: Twelve patients developed VTE: 9 had DVT and 3 PE. The primary site of the tumor was located in the pancreas in 9 patients, in the gut in 2, and it was unknown in one patient. Two patients had a functioning tumor. Grading was G1 in 3 patients, G2 in 6, G3 in 2 cases, and not available in one. The TNM stage was IV in 5 patients, III in 2, II in 3, and I in 2. Two patients died during the study period, one of whom died from PE. CONCLUSION: GEP-NEN patients harbor a considerable risk of VTE, particularly high for pancreatic NEN patients, for patients with moderate-poorly differentiated neoplasms, and at an advanced tumor stage.

Surface plasmon resonance unveils important pitfalls of enzyme-linked immunoassay for the detection of anti-infliximab antibodies in patients' sera.

Measurements of serum concentrations of therapeutic antibodies and anti-drug antibodies (ADA) can support clinical decisions for the management of non-responders, optimizing the therapy. In the present study we compared the results obtained by classical ELISA and a recently proposed surface plasmon resonance (SPR)-based immunoassay, in 76 patients receiving infliximab for inflammatory bowel diseases. The two methods indicated very similar serum concentrations of the drug, but there were striking differences as regards ADA. All the sera showing ADA by ELISA (14) also showed ADA by SPR, but the absolute amounts were different, being 7-490 times higher with SPR, with no correlation. Eight patients showed ADA only with SPR, and these ADA had significantly faster dissociation rate constants than those detectable by both SPR and ELISA. The underestimation, or the lack of detection, of ADA by ELISA is likely to reflect the long incubation steps which favor dissociation of the patient's low-affinity ADA, while the commercial, high-affinity anti-infliximab antibodies used for the calibration curve do not dissociate. This problem is less important with SPR, which monitors binding in real time. The possibility offered by SPR to detect ADA in patients otherwise considered ADA-negative by ELISA could have important implications for clinicians.

Seroprevalence of SARS-CoV2 in IBD Patients Treated with Biologic Therapy.

BACKGROUND AND AIMS: A similar course of COVID-19 in patients with inflammatory bowel diseases [IBD] and in the general population has been reported. However, disease prevalence in IBD patients is presently unknown. In this prospective observational study, we aimed at determining SARS-CoV2 infection prevalence in IBD patients treated with biologic therapy. METHODS: From IBD patients under biologic therapy and recruited from three different locations in Italy and Germany, 354 sera were evaluated for antibody presence by RBD ELISA. Control groups were: i] age-matched healthy subjects tested in the same time period in Milan, Italy; ii] healthy subjects collected in the pre-COVID era; iii] IBD patients under biologic therapy collected in the pre-COVID era. RESULTS: Eight out of 354 patients tested positive for the anti-RBD-SARS-CoV2 IgG antibody [prevalence 2.3%]. The percentage of IgG-positive patients among those recruited from Milan was significantly higher than among those recruited from other locations [prevalence 5.4% vs 0.4%, p <0.005]. IgG-positive patients reported a significantly higher incidence of fever, anosmia, and ageusia, and were more likely to have entered into close contact with COVID-19-positive subjects before the study enrolment. CONCLUSIONS: Seroprevalence of SARS-CoV2 in IBD patients treated with biologic therapy reflects values measured in the local general population. Specific symptoms and contact history with SARS-CoV2-infected individuals strongly increase the likelihood of SARS-CoV2 seropositivity.

Blood Bacterial DNA Load and Profiling Differ in Colorectal Cancer Patients Compared to Tumor-Free Controls.

Inflammation and immunity are linked to intestinal adenoma (IA) and colorectal cancer (CRC) development. The gut microbiota is associated with CRC risk. Epithelial barrier dysfunction can occur, possibly leading to increased intestinal permeability in CRC patients. We conducted a case-control study including 100 incident histologically confirmed CRC cases, and 100 IA and 100 healthy subjects, matched to cases by center, sex and age. We performed 16S rRNA gene analysis of blood and applied conditional logistic regression. Further analyses were based on negative binomial distribution normalization and Random Forest algorithm. We found an overrepresentation of blood 16S rRNA gene copies in colon cancer as compared to tumor-free controls. For high levels of gene copies, community diversity was higher in colon cancer cases than controls. Bacterial taxa and operational taxonomic unit abundances were different between groups and were able to predict CRC with an accuracy of 0.70. Our data support the hypothesis of a higher passage of bacteria from gastrointestinal tract to bloodstream in colon cancer. This result can be applied on non-invasive diagnostic tests for colon cancer control.

Plasma chromogranin A response to octreotide test: prognostic value for clinical outcome in endocrine digestive tumors.

OBJECTIVES: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) expressing somatostatin receptors may be treated with somatostatin analogs (SSAs). Selection criteria are a positive Octreoscan or a >50% hormone level decrease after octreotide subcutaneous (s.c.) injection (octreotide test) (OT). Plasma chromogranin A (CgA) is the best general GEP-NET marker, but data on CgA response to OT are scanty. Thus, we evaluated whether plasma CgA response to OT could predict the clinical response to SSAs. METHODS: At diagnosis, 38 GEP-NET patients received octreotide 200 microg s.c., with plasma CgA determination at 0, 3, and 6 h. Long-term SSA treatment was then given by monitoring symptomatic, biochemical, and objective responses, and survival. RESULTS: Basal plasma CgA levels were significantly higher in patients with functioning than non-functioning tumors (median (range): 220 (18-2,230) vs. 46 (25-8,610) U/l, P=0.03) and in those with than without metastases (171 (18-8,610) vs. 43 (28-220) U/l, P=0.04). CgA levels significantly correlated with WHO classification, clinical TNM staging, and Ki-67 proliferative index. After OT, CgA levels decreased from 146 (18-8,610) to 61 (10-8,535) U/l (basal and nadir values), P<0.001. In patients responsive to OT, a successful objective response occurred in 21/31 patients (68%). Successful symptomatic response occurred in 13/18 patients (72%), biochemical response in 25/31 (81%), and objective response in 21/31 (68%). In the remaining seven unresponsive cases, with CgA decrement <30%, disease progressed to death in six (86%). Median survival from enrollment was 48 months (6-138) in responsive and 6 (6-30) in unresponsive patients (P=0.0005). CONCLUSIONS: In GEP-NETs, plasma CgA is a reliable marker, and a >30% decrease after OT has a relevant prognostic meaning allowing the identification of the subgroup of patients most likely to be responsive to chronic SSAs.

Deficiency of micronutrients in patients affected by chronic atrophic autoimmune gastritis: A single-institution observational study.

BACKGROUND: Chronic atrophic autoimmune gastritis (CAAG) leads to vitamin B12 deficiency, but other micronutrient deficiencies are largely understudied. AIMS: To investigate the prevalence of micronutrient deficiencies in CAAG patients and their potential relationship with the grading of gastric atrophy or entero-chromaffin-like cells hyperplasia or body mass index (BMI). METHODS: From 2005 to 2016 a number of CAAG patients underwent regular follow-up with annual blood testing and upper gastrointestinal tract endoscopy every years. RESULTS: Out of the 122 CAAG patients checked (100 F; median age 65 years), 76 presented nutritional deficiencies, single in 24 and multiple in 52 cases: a deficiency of B12 and iron showed in 42 patients, 25-OH vitamin D lacked in 76 and folic acid in 6 cases. 25-OH vitamin D levels directly correlated with B12 levels and were significantly lower in patients with macronodular than in those with linear or micronodular hyperplasia. No significant correlation was observed between B12, folic acid or ferritin levels and BMI, blood gastrin levels, the grading of gastric atrophy or ECL cells hyperplasia. CONCLUSIONS: 25-OH vitamin D deficiency was the main one in CAAG patients: its correlation with B12 deficiency may indicate underlying shared pathogenic mechanisms, although further studies are needed to confirm this hypothesis.

Chromogranin A in the Follow-up of Gastroenteropancreatic Neuroendocrine Neoplasms: Is It Really Game Over? A Systematic Review and Meta-analysis.

OBJECTIVES: Little is known about chromogranin A (CgA) during follow-up of gastroenteropancreatic neuroendocrine neoplasms. We hypothesized that serial CgA monitoring might be useful for the assessment of tumor progression, and we performed a systematic review of the literature and meta-analysis. METHODS: A bibliographical search was performed in PubMed using "chromogranin A" and "neuroendocrine tumors" and "follow-up" and "biomarker" to identify all pertinent articles published in the last 10 years. RESULTS: Eight studies were included in current meta-analysis. Chromogranin A as a follow-up marker shows sensitivity between 46% and 100% and specificity between 68% and 90%. The meta-analysis results showed an overall accuracy of 84% (95% confidence interval [CI], 81-86.6), a cumulative sensitivity of 74.6% (95% CI, 61.9-85.4), and a cumulative specificity of 84.7% (95% CI, 81.3-87.7). These data indicate that circulating CgA has a better overall accuracy in the follow-up setting; it can be used to rule the diagnosis of recurrence/progression in, rather than to rule it out. CONCLUSIONS: Chromogranin A is more reliable when used to monitor disease progression and response to treatment and for the early detection of recurrence after treatment rather than in the diagnostic setting. It is more sensible to use this marker in those cases where the initial values were impaired.

A wait-and-watch approach to small pancreatic neuroendocrine tumors: prognosis and survival.

BACKGROUND: Whether all the small (ø≤20mm) non-functional pancreatic neuroendocrine neoplasms (pNENs) should be routinely resected is unclear. AIM: To assess the overall survival (OS) and progression-free survival (PFS) of patients with small pNENs, followed-up with different management options. MATERIAL AND METHODS: Between 2007-2014, 51 patients were newly diagnosed with pNEN. 15 patients with pNENs ø ≤20 mm underwent an intensive follow-up at 3-month intervals during the first year and then every 6 months (FU pNEN group). They were all at TNM stage I, except for one patient at stage IIA. 21 patients underwent surgical resection (SR pNEN group): 2 patients were at TNM stage I, 9 IIA, one IIIB, 9 IV. 15 patients received systemic therapy (ST pNEN group) due to advanced disease or contraindications to surgery: 5 were at stage IIA, 2 IIB, 8 IV. RESULTS: The median follow-up for the entire cohort was 50 months. Survival was similar in the FU and SR pNEN groups, but significantly worst in the ST pNEN patients (log-rank test P <0.05). The 4-year survival rate was 100% in the FU pNEN group, 90.5% among the SR pNEN patients, 61% for the ST pNEN ones (p <0.0001). The disease remained stable in all but one patient in the FU pNEN group, whereas six patients in the SR group and five in the ST group showed disease progression. CONCLUSIONS: The "wait-and-watch" approach to early-stage small pNENs appears to be safe although further studies are needed to confirm these results in larger cohorts of patients.

Intermittent treatment of recurrent type-1 gastric carcinoids with somatostatin analogues in patients with chronic autoimmune atrophic gastritis.

BACKGROUND: Optimal management and treatment of type-1 gastric carcinoids is under debate. AIMS: This prospective study evaluates the outcome of patients with recurrent type-1 gastric carcinoids treated with somatostatin analogues. METHODS: From 2000 to 2013, among a population of 107 chronic atrophic gastritis patients, 25 (20% males, median age 62 years) developed type-1 gastric carcinoids and underwent regular clinical and endoscopic follow-up (median 77 months, range 6-165) after the initial treatment. Those patients showing recurrent disease were treated with somatostatin analogues until carcinoid disappearance. RESULTS: 12/25 patients (33% males, median age 65 years) showed recurrent gastric carcinoids and were treated with somatostatin analogues for a median duration of 12 months. Median gastrin and chromogranin A levels, which were 802 pg/mL and 33 U/L, respectively, decreased to 299 pg/mL (p=0.002) and 15.6 U/L (p=0.001) at the end of the treatment. Gastric carcinoids disappeared after a median length of treatment of 12 months. After a median time of 19.5 months from somatostatin analogues discontinuation, 4/12 patients (25% males, median age 56 years) showed a further recurrence. A new cycle of treatment was performed successfully. CONCLUSIONS: This study confirms that type-1 gastric carcinoids are a recurring disease and somatostatin analogues, administered on 12-month cycles, represent an effective treatment.

Chronic autoimmune atrophic gastritis associated with primary hyperparathyroidism: a transversal prospective study.

DESIGN: The coexistence of chronic autoimmune atrophic gastritis (CAAG) and primary hyperparathyroidism (PHPT) has been described previously, even if its extent and underlying mechanisms remain poorly understood. We therefore prospectively evaluated this association in two series of patients, one with CAAG and the other with sporadic PHPT. METHODS: From January 2005 to March 2012, 107 histologically confirmed CAAG patients and 149 PHPT patients were consecutively enrolled. Routine laboratory assays included serum calcium, parathyroid hormone (PTH), plasma gastrin and chromogranin A (CgA). In CAAG patients with high PTH levels, ionized calcium and 25(OH)-vitamin D were evaluated. All CAAG and hypergastrinemic PHPT patients received an upper gastrointestinal endoscopy. Exclusion criteria were familial PHPT, MEN1 syndrome, treatment with proton pump inhibitor drugs, Helicobacter pylori infection and renal failure. RESULTS: Of the 107 CAAG patients, nine (8.4%) had PHPT and 13 (12.1%) had secondary hyperparathyroidism stemming from vitamin D deficiency. Among the 149 PHPT patients, 11 (7.4%) had CAAG. Gastrin and CgA levels were similar in the CAAG patients with vs those without hyperparathyroidism (either primary or secondary), and calcium and PTH levels were similar in the PHPT patients with vs those without CAAG. CONCLUSIONS: This study confirms a non-casual association between PHPT and CAAG. The prevalence of PHPT in CAAG patients is threefold that of the general population (8.4 vs 1-3%), and the prevalence of CAAG in PHPT patients is fourfold that of the general population (7.4 vs 2%). The mechanisms underlying this association remain unknown, but a potential role for autoimmunity is suggested.

Reduction of CD68+ macrophages and decreased IL-17 expression in intestinal mucosa of patients with inflammatory bowel disease strongly correlate with endoscopic response and mucosal healing following infliximab therapy.

BACKGROUND: Antibodies against tumor necrosis factor represent an effective therapy for patients with inflammatory bowel disease. Despite their successful results, the exact mechanism by which infliximab suppresses intestinal inflammation is still a matter of debate. In this study, we used a translational approach to identify the key mechanisms associated with resolution of mucosal inflammation induced by infliximab. METHODS: A total of 16 patients with active inflammatory bowel disease (9 with Crohn's disease and 7 with ulcerative colitis) and 16 controls were enrolled in the study. Patients received infliximab infusions at 0, 2, and 6 weeks. At enrollment and at week 6, patients underwent flexible sigmoidoscopy, and biopsies were taken from the sigmoid colon. RNA was extracted, and mucosal expression of 96 immune-related genes was evaluated by qRT-PCR and confirmed by immunofluorescence microscopy on tissue. Correlation between infliximab-induced gene expression modulation and endoscopic response to therapy was calculated. Lamina propria mononuclear cell apoptosis induced by infliximab was evaluated on tissue sections by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. RESULTS: We found that infliximab-induced downregulation of macrophage and Th17 pathway genes was significantly associated with both endoscopic response to the therapy and achievement of mucosal healing. Importantly, the observed reduction of lamina propria CD68 macrophages was associated with an increased rate of macrophage apoptosis. CONCLUSIONS: The 2 mechanisms associated with infliximab-induced resolution of intestinal inflammation are the reduction of lamina propria infiltrating CD68 macrophages and the downregulation of interleukin 17A. Moreover, the data suggest that infliximab-induced macrophage apoptosis may represent a key mechanism for the therapeutic success of anti-tumor necrosis factor antibodies.

Treatment of liver metastases in patients with digestive neuroendocrine tumors.

BACKGROUND: Liver metastases are a strong prognostic indicator in patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). Therapeutic options for metastatic NETs are expanding and not mutually exclusive. AIMS: This paper reviews the literature relating to multidisciplinary approach towards GEP-NET metastases, to highlight advances in knowledge regarding these tumors, and to understand the interdisciplinary management of individual patients. METHODS: A PubMed search was performed for English-language publications from 1995 through 2012. Reference lists from studies selected were manually searched to identify further relevant reports. Manuscripts comparing different therapeutic options and advances for GEP-NET-related liver metastases were selected. RESULTS: There is considerable controversy regarding the optimal management of GEP-NET metastases. Although radical surgery still remains the gold standard, a variety of other therapeutic options are available for metastatic GEP-NETs, including loco-regional chemotherapy/radiotherapy, radioembolization, systemic peptide receptor radionuclide therapy, biotherapy, and chemotherapy. In selected patients, liver transplantation should also be considered. Systemic somatostatin analogues and/or interferon show anti-proliferative effects, representing an appropriate first-line treatment for most patients. In advanced metastatic NETs, recent options include targeted therapies (i.e., everolimus and sunitinib). CONCLUSIONS: It is evident that multidisciplinary care and multimodality treatments remain the cornerstone of management of NET patients. Since NETs often show a more indolent behavior compared to other malignancies, physicians should aim to preserve a satisfactory quality of life for the patient by personalizing the therapeutic approach according to the tumor's features and prognostic factors.