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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.

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.

ObjectiveWe aimed to investigate the relation of blood bacterial DNA load and profiling with intestinal adenoma (IA) and colorectal cancer (CRC) patients.DesignWe performed 16S rRNA gene analysis of blood from 100 incident histologically confirmed CRC cases, 100 IA and 100 healthy subjects, matched to cases by centre, sex and age. Bacterial load was analysed using multiple conditional logistic regression. Differences in terms of abundance of bacteria between groups were estimated through analysis based on negative binomial distribution normalization. Random Forest was applied to predict the group assignment.ResultsWe found an overrepresentation of blood 16S rRNA gene copies in colon cancer as compared to tumor-free controls (IA and healthy subjects). The odds ratio of colon cancer for the highest versus the lowest three quintiles of gene copies was 2.62. (95% confidence interval=1.22-5.65). No difference was found for rectal cancer and IA. For high 16S rRNA, community diversity was higher in colon cancers than controls. CRC cases had an enrichment of Peptostreptococcaceae and Acetobacteriaceae and a reduced abundance of Bacteroidaceae, Lachnospiraceae, and Ruminococcaceae. Identified variables predicted CRC from control and IA patients with an accuracy of 0.70.ConclusionColon cancer patients had a higher DNA bacterial load and a different bacterial profiling as compared to healthy subjects, IA and rectal cancers, indicating a higher passage of bacteria from gastrointestinal tract to bloodstream. Further studies are needed to confirm this result and exploit it to conceive new non-invasive techniques for an early diagnosis of CRC.

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.

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.

Background and AimsA 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.MethodsFrom 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.ResultsEight 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 ConclusionsSeroprevalence 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.

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.

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

Simple Summary In colorectal cancer patients, epithelial barrier dysfunction can lead to increased intestinal permeability, and gut microbiome was found to vary compared to healthy subjects. We conducted a study to investigate whether bacterial translocation from gastrointestinal tract to bloodstream is associated to intestinal adenoma and/or colorectal cancer. In particular, an epidemiological and metagenomic approach was used to evaluate the relation of the bacterial DNA load and the bacterial taxonomic groups—assessed by 16S rRNA profiling—in blood with the risks of intestinal adenoma and colorectal cancer. These findings can confirm the presence of bacterial DNA in blood in healthy adults and serve as a basis to evaluate new non-invasive techniques for an early CRC diagnosis through the analyses of bacterial DNA circulating in peripheral blood. Abstract 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.

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.

// Sara Massironi 1 , Roberta Elisa Rossi 1, 2 , Alessandra Zilli 1, 2 , Giovanni Casazza 3 , Clorinda Ciafardini 1 , Dario Conte 1, 2 1 Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 2 Postgraduate School of Gastroenterology, Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy 3 Department of Biomedical and Clinical Sciences “L. Sacco”, University of Milan, Milan, Italy Correspondence to: Sara Massironi, email: sara.massironi@policlinico.mi.it Keywords: pancreatic neuroendocrine neoplasms, neuroendocrine tumors, pNEN, non-functional pancreatic neuroendocrine tumors Received: December 22, 2015 Accepted: February 11, 2016 Published: March 3, 2016 ABSTRACT Background: Whether all the small (o≤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 o ≤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

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.

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. 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. 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. 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). 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.

Background: Circulating chromogranin A (CgA) levels, a marker for neuroendocrine tumors including carcinoids, have recently been found elevated in some patients with inflammatory bowel disease (IBD), although their significance is unclear. Therefore, we aimed to evaluate CgA levels and their possible relationship with clinical and biochemical disease activity indexes in 119 IBD patients. Methods: The study groups comprised 75 patients with ulcerative colitis, 44 with Crohn's disease, in both active and quiescent phases, and 85 controls. Results: Mean CgA levels were significantly higher in IBD patients than in controls (20.4 ± 14.0 [SD] versus 11.3 ± 4.3 U/L, P < 0.001), without any statistical significant difference among the IBD subgroups. However, CgA levels were above the normal range (20 U/L) in 25/45 patients with active IBD (55%; 95% confidence interval [CI]: 40%–70%) and in 18/74 patients with remission IBD (24%; 95% CI: 15%–36%) (P < 0.001, Fisher's test). Among biochemical parameters, CgA correlated with serum TNF-α levels (rs = 0.398, P < 0.001). Conclusions: High CgA levels can occur in IBD. The disease activity and TNF-α levels seem to influence the CgA pattern, which could reflect the neuroendocrine system activation in response to inflammation. From a clinical point of view, the possibility of high CgA levels in IBD should be taken into consideration when a carcinoid is suspected in such patients, since this event seems to be more frequent than previously considered. Indeed, revision of our 83 patients with gastrointestinal carcinoids, studied between 1997 and 2006, showed that 4 patients had IBD, with a prevalence of 4.8%, which is markedly higher than that of the general population. (Inflamm Bowel Dis 2008)

Hepatocellular carcinoma (HCC) is the relevant cause of death in patients with compensated cirrhosis. Alpha-fetoprotein (AFP) is used for screening HCC, with limited success.We evaluated plasma chromogranin A (CgA) as a marker of HCC.CgA plasma levels and AFP serum levels were prospectively measured in 30 patients with HCC, 14 with cirrhosis, 79 with chronic hepatitis and 65 controls.CgA was measured with an enzyme-linked immunosorbent assay (DAKO A/S Glostrup, Denmark). AFP was measured by electrochemiluminoimmunoassay (Elecsys, Roche S.p.A., Italy).CgA levels were significantly higher in the three groups of patients than in controls and in patients with HCC they were significantly higher than in chronic hepatitis patients [median 44.5 (interquartile range 21-145.9)U/L vs. 15.3 (10.9-29.25)U/L, p0.001]. AFP values were above the upper reference limit in 75% of patients with HCC, 50% of cirrhotic patients and 11% of chronic hepatitis patients (p0.005). CgA values significantly correlated with AFP levels (r(s)=0.42, p0.0001). The overall diagnostic accuracy of CgA was 75% (CI 66-82), with a sensitivity of 70% (CI 50.6-85.2) and a specificity of 67% (CI 55.9-76.3).Despite the evidence of higher CgA levels in patients with HCC, this test has low-diagnostic accuracy. Its pathophysiological meaning remains unknown, even if it could suggest an endocrine phenotype of HCC.

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.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.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-671%) 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-672%), 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.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.

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.

Gastro-Entero-Pancreatic (GEP) NETs originate from both pancreatic islet cells or gastroenteric tissue (from diffuse neuroendocrine cells distributed throughout the gut) and are rare neoplasms, representing about 2% of all the gastrointestinal tumors. Due to their rarity, they are difficult to diagnose and the begnning of the diagnostic process is often based on the measurement of circulating markers, before planning expensive and invasive diagnostic tests (2, 3). A critical point is that the frequent late diagnosis of NETs is due to failure to identify symptoms or to establish the biochemical diagnosis; in fact 60-80% of NETs are metastatic at diagnosis. A prompt identification by the use of specific biomarkers is therefore useful to recognize these tumors (1).

Gastric carcinoids are rare tumors of the stomach. Gastric carcinoid type 1 is associated with chronic atrophic gastritis, and because of a low metastatic potential, is the most benign type. Death from metastatic disease has been reported in only three patients in a review including 724 cases. The present report refers to a 60-year-old man who was affected by type 2 diabetes mellitus and pernicious anemia and died from metastatic gastric carcinoid type 1. In 1998, a well-differentiated 1.2 cm gastric neuroendocrine tumor, immunoreactive for chromogranin A, with a Ki-67 index less than 2% and with infiltration to the submucosal layer was diagnosed and enucleated. In 2002, a new well-differentiated gastric endocrine tumor 6 mm in size with a Ki-67 of approximately 2% was detected, and endoscopic ultrasound confirmed it to be limited to the submucosal layer. The patient refused antrectomy and started long-acting somatostatin analog (lanreotide) in 2005 when the Ki-67 index was 7%, but he stopped the treatment after 4 months. In 2007, despite previous endoscopic stability, endoscopic ultrasound showed an infiltrating gastric lesion of 7 cm. At surgery, the disease appeared to be extended to the liver and to the peritoneum (well-differentiated endocrine carcinoma, Ki-67 40%) with both hepatic and massive peritoneal metastases. A regimen of somatostatin analog was soon restarted; however, the disease continued to spread, and the patient died 6 months later. Overall, despite their generally benign course, type 1 gastric carcinoids may have malignant potential, a finding that should be considered when planning the medical workup of these patients.

Objectives At presentation, gastroenteropancreatic neuroendocrine tumours (GEP NETs) frequently show prognostically negative hepatic involvement. The aim of this study was to characterise hepatic metastases of GEP NETs as revealed by contrast-enhanced ultrasonography (CEUS), which allows the fine definition of the microvascular system, and to correlate these findings to the biological behaviour of the tumour. Methods Eighteen out of 62 GEP NET patients examined between January 2007 and September 2008 had histologically proven hepatic metastases from primary ileal (#6), gastric (#1) or rectal (#1) carcinoids, pancreatic tumours (#7), or primary duodenal (#2) or occult gastrinomas (#1), and all underwent low mechanical index real-time CEUS with SonoVue® injection. Results Strong early enhancement in the arterial phase was observed in 15 cases (83%), and a rapid wash-out in the portal venous phase in 14 (78%). In the late venous phase, the lesions were hypoechoic in 12 cases (67%), isoechoic in five (28%), and hyperechoic in one (0.05%). The time of arterial enhancement correlated with the Ki-67 proliferative index (rs = 0.516; p = 0.028). Conclusions Most of the neuroendocrine liver metastases showed increased arterial enhancement at CEUS, a behaviour that is similar to that of hepatocellular carcinomas and the opposite of that of other metastases. CEUS can be a useful diagnostic means of characterising such metastases.

RISK STRATIFICATION USING OCTREOTIDE TEST FOR PATIENTS WITH GASTRO-ENTERO-PANCREATIC NEUROENDOCRINE TUMORS: RESULTS OF PROSPECTIVE VALIDATION OF THE TEST S. Massironi 1, M.P. Spampatti 2 , R.E. Rossi∗ ,2, D. Conte2, C. Ciafardini 2 , M. Peracchi 2 1Fondazione Irccs Ca’ Granda Ospedale Maggiore Policlinico Milano, Milano, Italy; 2Dipartimento di Scienze Mediche, Universita degli Studi di Milano, Milan, Milano, Italy

Gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs) are rare neoplasms, although their prevalence has increased substantially over the past three decades. Moreover, there has been an increased clinical recognition and characterization of these neoplasms. They show extremely variable biological behavior and clinical course. Most NETs have endocrine function and secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome; however, many are clinically silent until late presentation with mass effects. Investigation and management should be individualized for each patient, taking into account the likely natural history of the tumor and general health of the patient. Management strategies include surgery for cure or palliation, and a variety of other cytoreductive techniques, and medical treatment including chemotherapy, and biotherapy to control symptoms due to hormone release and tumor growth, with somatostatin analogues (SSAs) and alpha-interferon. New biological agents and somatostatin-tagged radionuclides are under investigation. Advances in the therapy and development of centers of excellence which coordinate multicenter studies, are needed to improve diagnosis, treatment and therefore survival of patients with GEP NETs.

Previous experiments reported desensitization to SS action in rat anterior pituitary cells and cell lines. The aim of the study was to verify whether the lack of desensitization to SS analogs (SSa) observed in acromegalic patients was also present in subjects with normal hypothalamic-pituitary function. The effect of chronic treatment with octreotide long-acting release (o-LAR, 10-30 mg/28 days) on IGF-I levels was then evaluated in 23 patients with gastroenteropancreatic (GEP) endocrine tumors (8 gastrinomas, 6 carcinoids, and 9 functioning pancreatic tumors). Serum IGF-I, clinical symptoms, plasma chromogranin-A (CgA) and markers of hepatic synthesis were evaluated before and after a short-term period in all the patients (median 4.5 months), after a medium-term period in 12 (median 18 months) and after a long-term follow-up period in 9 of them (median 48 months). Mean IGF-I levels decreased from 17.3+/-7.0 to 12.8+/-6.2 nmol/l in the short-term (p0.005) being reduced from baseline concentrations in 87% and under the normal range for age in 35% of patients. Afterwards, they always remained stable both in the medium- and long-term periods, still being low in 3/12 and 2/9 patients, respectively. No alterations in biochemical markers of liver function were found either before or during therapy. No correlation between IGF-I levels, CgA concentrations and/or clinical definitive outcome was observed. In conclusion, the study demonstrated that: a) similarly to that observed in acromegalic patients, chronic o-LAR treatment did not induce desensitization of pituitary SS receptors (SSR) in humans with intact hypothalamic-pituitary axis, and b) in patients with GEP endocrine tumors, GH/IGF-I inhibition did not contribute to SSa efficacy.