Meta-analysis of mortality in patients with high-risk intraductal papillary mucinous neoplasms under observation.

BACKGROUND: Although consensus guidelines suggest that patients with high-risk intraductal papillary mucinous neoplasms (IPMNs) should have surgery, a non-operative strategy is often selected in patients who are poor surgical candidates. The aim was to determine the risk of disease-related death from IPMN in patients with worrisome features or high-risk stigmata who were kept under observation. METHODS: A PubMed literature search was undertaken of articles published from August 1992 to June 2016 (updated October 2017). The methodology was developed from PRISMA and MOOSE checklists. Incidence proportions and rates of overall and IPMN-related deaths were calculated, with subgroup analyses for main-duct/mixed-type and branch-duct IPMNs. Quality of the studies, publication bias and heterogeneity were explored. RESULTS: Six studies reported data on overall mortality and eight described disease-specific mortality for 556 patients during follow-up ranging from 24·9 to 60·0 months. Pooled rates of overall and IPMN-related mortality were 30·9 (95 per cent c.i. 19·6 to 45·1) and 11·6 (6·0 to 21·2) per cent respectively. The pooled incidence rate for overall mortality was substantially higher than that for IPMN-related mortality: 78 (95 per cent c.i. 44 to 111) and 23 (9 to 37) per 1000 patient-years respectively. The pooled incidence rate for disease-specific mortality was considerably lower for branch-duct than for main-duct or mixed-type IPMNs: 5 (0 to 10) and 32 (12 to 52) per 1000 patient-years respectively. CONCLUSION: In patients unfit for surgery, IPMN-related mortality among patients with worrisome features and high-risk stigmata is low, and the risk of death from other causes much higher.

Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas.

BACKGROUND: The objectives of this study are to estimate prevalence and incidence of extrapancreatic malignancies (EPMs) among intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, and to identify risk factors for their occurrence. PATIENTS AND METHODS: We conducted multicentric cohort study in Italy from January 2010 to January 2011 including 390 IPMN cases. EPMs were grouped as previous, synchronous (both prevalent) and metachronous (incident). We calculated the observed/expected (O/E) ratio of prevalent EPMs, and compared the distribution of demographic, medical history and lifestyle habits. RESULTS: Ninety-seven EPMs were diagnosed in 92 patients (23.6%), among them 78 (80.4%) were previous, 14 (14.4%) were synchronous and 5 (5.2%) were metachronous. O/E ratios for prevalent EPMs were significantly increased for colorectal carcinoma (2.26; CI 95% 1.17-3.96), renal cell carcinoma (6.00; CI 95% 2.74-11.39) and thyroid carcinoma (5.56; CI 95% 1.80-12.96). Increased age, heavy cigarette smoking, alcohol consumption and first-degree family history of gastric cancer are significant risk factors for EPMs, while first-degree family history of colorectal carcinoma was borderline. CONCLUSION: We report an increased prevalence of EPMs in Italian patients with IPMN, especially for colorectal carcinoma, renal cell and thyroid cancers. A systematic surveillance of IPMN cases for such cancer types would be advised.

Endoscopic snare papillectomy: a possible radical treatment for a subgroup of T1 ampullary adenocarcinomas.

Pancreaticoduodenectomy is the standard care for invasive ampullary adenocarcinomas. However, endoscopic snare papillectomy (ESP) might play a curative role in very selected patients. We studied a series of 15 patients with T1 ampullary adenocarcinoma who were treated by ESP alone and followed up for a mean of 29.6 ± 21.9 months (range 8 - 81 months). ESP was curative for eight patients (57.1 %). No tumor-related death was observed in patients with a cancer infiltration depth of ≤ 4 mm. According to this preliminary experience, we suggest that this measurable variable threshold should be considered as a possible basis for future large-scale studies.

Fasting glucose and treatment outcome in breast and colorectal cancer patients treated with targeted agents: results from a historic cohort.

BACKGROUND: We investigated pretreatment fasting glucose as a predictor of patients' important outcomes in breast and colorectal cancers undergoing targeted therapies. PATIENTS AND METHODS: In a historic cohort of 202 breast and 218 colorectal cancers treated with targeted agents from 1998 to 2009, we used the Kaplan-Meier method and the log-rank test to estimate survival through tertiles of fasting glucose and the Cox proportional hazards model for multivariate analysis stratified by primary site of cancer and including gender, age and body mass index. RESULTS: The median follow-up was 20 months (1-128). At 60 months, 65% of patients in the lowest tertile of fasting glucose did not experiment disease progression compared with 34% in the highest tertile (P=0.001). Seventy-six percent of females in the lowest tertile showed no progression compared with 49% in the top tertiles (P=0.015). In multivariate analysis, fasting glucose was a significant predictor of time to disease progression only in breast cancer patients in the first tertile compared with the third (P=0.017). CONCLUSIONS: We found evidence of a predictive role of pretreatment fasting glucose in the development of resistance in breast cancer patients treated with targeted agents. Prospective studies are warranted to confirm our findings.

Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases.

BACKGROUND: Surgery for small intestinal neuroendocrine tumours (SI-NETs) is limited by metastatic disease in most patients. However, resection of the primary lesion alone has been advocated in patients with unresectable liver metastases. The present systematic review investigated the value of surgical resection of the primary lesion in patients with unresectable metastatic disease. METHODS: MEDLINE was searched for studies reporting the outcome of patients with SI-NETs and unresectable liver metastases where there was an explicit comparison between resection of the primary lesion alone and no resection. The primary outcome was overall survival. Secondary outcomes were progression-free survival, treatment-related mortality and relief of symptoms. RESULTS: Meta-analysis was not possible, but six studies were analysed qualitatively to highlight useful information. Possible confounders in these studies were the inclusion of patients with other primary tumour sites, unknown primary tumour or non-metastatic disease. Bearing in mind these limitations, there was a clear trend towards longer survival in patients who underwent surgical resection in all studies; their median overall survival ranged from 75 to 139 months compared with 50-88 months in patients who did not have resection. The difference between the two groups was statistically significant in three studies. Data on symptomatic improvement were scarce and did not suggest a clear benefit of surgery. Surgery-related mortality seemed low. CONCLUSION: Available data suggest a possible benefit of resection of the primary lesion in patients with unresectable liver metastases, but the studies have several limitations and the results should therefore be considered with caution.

Practical guidelines for acute pancreatitis.

INTRODUCTION: The following is a summary of the official guidelines of the Italian Association for the Study of the Pancreas regarding the medical, endoscopic and surgical management of acute pancreatitis. STATEMENTS: Clinical features together with elevation of the plasma concentrations of pancreatic enzymes are the cornerstones of diagnosis (recommendation A). Contrast-enhanced computed tomography (CT) provides good evidence for the presence of pancreatitis (recommendation C) and it should be carried out 48-72 h after the onset of symptoms in patients with predicted severe pancreatitis. Severity assessment is essential for the selection of the proper initial treatment in the management of acute pancreatitis (recommendation A) and should be done using the APACHE II score, serum C-reactive protein and CT assessment (recommendation C). The etiology of acute pancreatitis should be able to be determined in at least 80% of cases (recommendation B). An adequate volume of intravenous fluid should be administered promptly to correct the volume deficit and maintain basal fluid requirements (recommendation A); analgesia is crucial for the correct treatment of the disease (recommendation A). Enteral feeding is indicated in severe necrotizing pancreatitis and it is better than total parenteral nutrition (recommendation A). The use of prophylactic broad-spectrum antibiotics reduces infection rates in CT-proven necrotizing pancreatitis (recommendation A). Infected pancreatic necrosis in patients with clinical signs and symptoms of sepsis is an indication for intervention, including surgery and radiological drainage (recommendation B). CONCLUSIONS: The participants agreed to revise the guidelines every 3 years in order to re-evaluate each question on the management of acute pancreatitis patients according to the most recent literature.

Eczema and food allergy in an Italian pediatric cohort: no association with TLR-2 and TLR-4 polymorphisms.

Recent studies have indicated that Toll-like receptor polymorphisms or their impaired signalling, specifically TLR-2 and TLR-4, were correlated with a higher risk for allergy. The purpose of this study is to evaluate the associations of TRL-2 and TRL-4 single nucleotide polymorphisms (SNP) and atopic traits in a cohort of 159 Italian allergic children (102 affected by eczema and 57 by IgE-mediated food allergy) and 147 healthy controls recruited in Rome, Italy. DNA was isolated from the peripheral blood and TLR-2 R753Q/TLR-4 D299G polymorphisms were determined by TaqMan MGB probes using Real-Time PCR technique. In the control group, the TLR-2 polymorphism R753Q had a prevalence of 2.5% while the frequency of the TLR-4 D299G was 12%. None of the 159 allergic patients showed the R753Q SNP. By contrast, 7/57 patients with food allergy (12%) and 6/102 subjects with eczema (6%) carried the TLR-4 mutation. In our cohort, no evidence of correlation between TLR-2 or TLR-4 polymorphism and eczema and food allergy incidence and/or severity was found. Further studies are needed to clarify the possible role of TLR-2 and TLR-4 polymorphism in allergic disease, in Italian children.

Upper and lower gastrointestinal causes of iron deficiency anemia in elderly compared with adult outpatients.

AIM: In the elderly, prevalence of bleeding- and/or iron malabsorption-related gastrointestinal (GI) causes of iron deficiency anemia (IDA) has not been addressed yet. The aim of this study was to assess the occurrence of malabsorptive diseases and bleeding lesions of the upper and lower GI tract in early (65-74 year-old) and late (over 75 year-old) elderly group compared with adult (50-64 year-old) outpatients. METHODS: The study enrolled 136 consecutive adult (N.=31), early (N.=48) and late elderly (N.=57) IDA outpatients who were referred to the Gastroenterology Department for IDA evaluation and underwent gastroscopy/histology and colonoscopy. RESULTS: Bleeding lesions were significantly less frequent in adult patients than in elderly patients (29% vs. 49.5%, P=0.0252). The most common bleeding lesions were large hiatal hernia (14.7%) and colon cancer (12.5%). Iron malabsorption diseases (Hp-related pangastritis, atrophic body gastritis and celiac disease) were more frequent in the adult group than in the early elderly group (80.6% vs. 56.2%, P=0.0367). In elderly patients, the observed prevalence of bleeding and iron malabsorption IDA causes was similar, whereas in adult patients iron malabsoptive diseases were more frequently detected (P<0.0001). The occurrence of concomitant IDA causes was not different among the three age-groups. CONCLUSION: In the early and late elderly, almost half of GI IDA causes are related to bleeding lesions which are more frequently observed respect to the adult patients. Iron malabsorption diseases affect almost 60% of early and late elderly groups. As for adult patients, an accurate upper and lower endoscopical/histological evaluation diagnoses IDA causes in the vast majority of the elderly outpatients.

Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours.

BACKGROUND: Non-functioning pancreatic endocrine tumours (NF-PETs) are an aggressive gastroenteropancreatic neoplasm. The present study assessed survival, value of World Health Organisation (WHO) classification and prognostic utility of clinicopathological parameters at diagnosis. PATIENTS AND METHODS: From 1990 to 2004, 180 patients with NF-PETs were entered in a prospective database, and predictors of prognosis were tested in uni- and multivariate models. RESULTS: There were 25 (14%) benign lesions, 38 (21%) neoplasms of uncertain behaviour, 100 well-differentiated carcinomas (56%) and 17 poorly differentiated carcinomas (9%). Radical resection was possible in 93 cases (51.6%). Overall 5-, 10- and 15-year survival rates were 67%, 49.3% and 32.8%, respectively, and were significantly higher in radically resected patients (93%, 80.8% and 65.2%, respectively; P < 0.00001). By multivariate analysis, poor differentiation [hazard ratio (HR) 7.3; P = 0.0001], nodal metastases (HR 3.05; P = 0.02), liver metastases (HR 3.29; P = 0.003), K(i)-67 >5% (HR 2.5; P = 0.012) and weight loss (HR 3.06; P = 0.001) were significantly associated with mortality. CONCLUSION: This study confirms the good long-term survival of patients with NF-PETs and the prognostic value of WHO classification, liver metastases, poor differentiation, Ki-67, nodal metastases and weight loss. These latter two parameters have a prognostic value similar to that of liver metastases and Ki-67.

Management of neuroendocrine tumors: a meeting of experts from Latin America.

A panel of experts from Latin America convened in Brazil, in May of 2007, for consensus recommendations regarding the management of neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas. The recently introduced World Health Organization classification of NETs represents a step forward, but the former classification of carcinoids into foregut, midgut and hindgut is still likely to be useful in the near future. Macroscopic description of the tumor should be followed by light microscopic examination and immunohistochemical staining, whereas other techniques might not be widely available in Latin America. Surgery remains the mainstay of treatment for patients with potentially curable tumors, and adequate selection is paramount in order to optimize treatment results. Regarding systemic therapy, patients with well-differentiated tumors or islet-cell carcinomas may be categorized as having indolent disease, while patients with poorly differentiated, anaplastic, and small-cell carcinomas, or with atypical carcinoids, may be approached initially as having aggressive disease. Somatostatin analogues play a cytostatic role in indolent tumors, and chemotherapy may play a role against other, more aggressive NETs. Obviously, there is an urgent need for novel therapies that are effective against NETs.

Meta-analysis: the use of non-steroidal anti-inflammatory drugs and pancreatic cancer risk for different exposure categories.

BACKGROUND: A better understanding of predictors of risk for pancreatic ductal adenocarcinoma (PDAC) could inform preventive efforts against this lethal cancer. While aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDS) might protect against several gastrointestinal cancers, their role in the development of PDAC remains unclear. AIM: To conduct a systematic review and meta-analysis on the relation between ASA/NSAIDs exposure and the risk of PDAC. Methods We searched Pubmed, Embase, Scopus, Cochrane database of systematic reviews and reference lists of identified papers and included observational (cohort or case-control) studies and randomized controlled trials examining exposure to ASA and/or NSAIDs and the incidence or mortality of PDAC. We defined three categories (low, intermediate, high), based on exposure duration and dose. RESULTS: Eight studies fulfilled our inclusion criteria (four cohort, three case controls, and one randomized controlled trial studies) enrolling 6301 patients between 1971-2004; all but one study took place in the US. The pooled OR were 0.99 (0.83-1.19), 1.11 (0.84-1.47) and 1.09 (0.67-1.75) in the low, intermediate and high exposure groups respectively, with considerable heterogeneity (I(2) ranging 60-86%). Sensitivity analysis by ASA use only, study design or sex did not reveal additional important information. CONCLUSIONS: This study did not show an association between ASA/NSAIDs and PDAC. The large baseline exposure in controls in North-America may have obscured an association. There is need for additional studies, especially in Europe, to clarify this issue.

Rhabdomyolysis due to severe hypokaliemia in a Crohn's disease patient after budesonide treatment.

Patients with Crohn's disease may experience several non-digestive complications, including muscle disorders. Rabdomyolysis has rarely been reported in patients with inflammatory bowel disease, however a number of factors may cause muscular damage in this setting. We report the case of a young woman with Crohn's disease who developed a severe, symptomatic skeletal muscle damage associated with severe hypokaliemia. Reversal of the potassium levels to normal ranges led to clinical resolution. The possible causes that might have lead to hypokalemia development and subsequent rhabdomyolysis are discussed with special emphasis for the potential causative role of medical treatment, especially budesonide for which similar side effects have been previously reported. Physicians should be aware that hypokalemia is possible in the setting of Crohn's disease and muscle damage can present as a complication.

Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets.

The intrinsic nature of tumour behaviour (stable vs progressive) and the presence of liver metastases are key factors in determining the outcome of patients with a pancreatic endocrine tumour (PET). Previous expression profile analyses of PETs were limited to non-homogeneous groups or to primary lesions only. The aim of this study was to investigate the gene expression profiles of a more uniform series of sporadic, non-functioning (NF) PETs with progressive disease and, for the first time, their liver metastases, on the Affymetrix human genome U133A and B GeneChip set. Thirteen NF PET samples (eight primaries and five liver metastases) from ten patients with progressive, metastatic disease, three cell lines (BON, QGP and CM) and four purified islet samples were analysed. The same samples were employed for confirmation of candidate gene expression by means of quantitative RT-PCR, while a further 37 PET and 15 carcinoid samples were analysed by immunohistochemistry. Analysis of genes differentially expressed between islets and primaries and metastases revealed 667 up- and 223 down-regulated genes, most of which have not previously been observed in PETs, and whose gene ontology molecular function has been detailed. Overexpression of bridging integrator 1 (BIN1) and protein Z dependent protease inhibitor (SERPINA10) which may represent useful biomarkers, and of lymphocyte specific protein tyrosine kinase (LCK) and bone marrow stromal cell antigen (BST2) which could be used as therapeutic targets, has been validated. When primary tumours were compared with metastatic lesions, no significantly differentially expressed genes were found, in accord with cluster analysis which revealed a striking similarity between primary and metastatic lesions, with the cell lines clustering separately. We have provided a comprehensive list of differentially expressed genes in a uniform set of aggressive NF PETs. A number of dysregulated genes deserve further in-depth study as potentially promising candidates for new diagnostic and treatment strategies. The analysis of liver metastases revealed a previously unknown high level of similarity with the primary lesions.

Corpus-predominant gastritis as a risk factor for false-negative 13C-urea breath test results.

BACKGROUND: Urea breath test sensitivity seems affected by increased intragastric acidity during therapy with antisecretory drugs. Intragastric pH is increased in patients with corpus gastritis with/without atrophy. AIM: To test the hypothesis that urea breath test results may also be affected by this gastritis phenotype. METHODS: 123 untreated patients underwent gastroscopy plus biopsies and intragastric pH measurement. The study included 82 endoscopically proven Helicobacter pylori-positive patients who were offered urea breath test with an acidic meal. Histological findings, urea breath test results and intragastric pH were compared in 66 of the subjects. RESULTS: 21 of 66 (31.8%) patients had a false-negative urea breath test. In these patients corpus-predominant gastritis (85.7% vs. 37.7%; P = 0.0004) and fundic atrophy (66.6% vs. 17.7%; P = 0.0001) were more frequent than in patients with true-positive urea breath test. Intragastric pH was higher in false-negative patients (mean 6.3 vs. 4.4; P = 0.001). In a multivariate analysis, the only risk factor for a false-negative urea breath test was the presence of corpus-predominant gastritis (OR = 5.6; 95% CI: 1.1-27). There was a negative correlation between the intragastric pH and the delta over baseline values (r = -0.378; P = 0.0023). CONCLUSIONS: Our results support the hypothesis that the pattern of gastritis can affect the sensitivity of urea breath test, and suggest that patients with corpus-predominant gastritis have a high risk of false-negative urea breath test results.

Unawareness of gastrointestinal symptomatology in adult coeliac patients with unexplained iron-deficiency anaemia presentation.

BACKGROUND: Most adults with coeliac disease have a subclinical form of the disease and iron-deficiency anaemia may be the sole presenting symptom. AIM: To evaluate demographic, clinical and biochemical characteristics of adult coeliac disease patients presenting with iron-deficiency anaemia. PATIENTS: A total of 108 iron-deficiency anaemia patients in whom coeliac disease has been diagnosed were studied. As a control group 108 non-coeliac iron-deficiency anaemia patients, comparable for sex and age, were studied. RESULTS: Of the 108 coeliac disease patients, 95 (88%) were female (mean age 34 years, range 19-72) and 13 (12%) were male (mean age 33 years, range 15-65). The median duration of iron-deficiency anaemia before diagnosis was 66 months in coeliac disease patients and 14 months in the iron-deficiency anaemia control group (P = 0.0001). The occurrence of at least one gastrointestinal symptom, not spontaneously reported, was observed in 92 (85%) patients with coeliac disease and in 67 (62%) patients in the control group (P = 0.001). The concomitant presence of diarrhoea, abdominal pain and abdominal bloating was detected in 14% patients with coeliac disease with respect to 3% in the control group (P = 0.005). CONCLUSIONS: The vast majority of coeliac disease patients with iron-deficiency anaemia presentation were unaware of the gastrointestinal symptoms and this relationship is useful for diet compliance.

Vasoactive intestinal peptide receptor subtypes and signalling pathways involved in relaxation of human stomach.

Vasoactive intestinal peptide (VIP) relaxes smooth muscle by interacting with receptors coupled to cAMP- or cGMP-signalling pathways. Their relative contribution to human gastric relaxation is unknown. This study aimed at investigating, in terms of biological activity, receptor expression and related signalling pathways, the action of VIP separately on the human fundus and the antrum. VIP caused greater relaxation of smooth muscle cells (SMC) and strips of the antrum presenting on the former a higher efficacy and potency (ED(50): 0.53 +/- 0.17 nmol L(-1)) than on the fundus (ED(50): 3.4 +/- 1.4 nmol L(-1)). On both fundus and antrum strips, its effect was tetrodotoxin insentitive. Reverse transcriptase-polymerase chain reaction analysis showed the sole expression of VPAC2 and natriuretic peptide clearance receptors, with VPAC2 being more abundant in the antrum. Functional regional differences in receptor-related signalling pathways were found. Activation of the cAMP-pathway by forskolin or its inhibition by adenylate cyclase (2'5'-dideoxyadenosine) or kinase (Rp-cAMPs) inhibitors had more pronounced effects on antrum SMC. Activation of the cGMP-pathway by sodium nitroprusside or its inhibition by guanylate cyclase (LY83583) or kinase (KT5823) inhibitors had more effects on fundus SMC, on which a higher expression of endothelial nitric oxide synthase was found. In conclusion, regional differences in VIP action on human stomach are related to distinct myogenic properties of SMC of the antrum and the fundus.