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Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.

Background: Despite major advances in the management of metastatic colorectal cancer (mCRC) with liver-only involvement, relapse rates are high and reliable prognostic markers are needed. Methods: To assess the prognostic impact of BRAF and RAS mutations in a large series of liver-resected patients, medical records of 3024 mCRC patients were reviewed. Eligible cases undergoing potentially curative liver resection were selected. BRAF and RAS mutational status was tested on primary and/or metastases by means of pyrosequencing and mass spectrometry genotyping assay. Primary endpoint was relapse-free survival (RFS). Results: In the final study population ( N =309) BRAF mutant, RAS mutant and all wild-type (wt) patients were 12(4%), 160(52%) and 137(44%), respectively. Median RFS was 5.7, 11.0 and 14.4 months respectively and differed significantly (Log-rank, P =0.043). At multivariate analyses, BRAF mutant had a higher risk of relapse in comparison to all wt (multivariate hazard ratio (HR)=2.31; 95% CI, 1.09–4.87; P =0.029) and to RAS mutant (multivariate HR=2.06; 95% CI, 1.02–4.14; P =0.044). Similar results were obtained in terms of overall survival. Compared with all wt patients, RAS mutant showed a higher risk of death (HR=1.47; 95% CI, 1.05–2.07; P =0.025), but such effect was lost at multivariate analyses. Conclusions: BRAF mutation is associated with an extremely poor median RFS after liver resection and with higher probability of relapse and death. Knowledge of BRAF mutational status may optimise clinical decision making in mCRC patients potentially candidate to hepatic surgery. RAS status as useful marker in this setting might require further studies.

Background Cutaneous malignant melanoma (CMM) ranks among the ten most frequent malignancies, clinicopathological staging being of key importance to predict prognosis. Artificial intelligence (AI) has been recently applied to develop prognostically reliable staging systems for CMM. This study aims to provide a useful machine learning based tool to predict the overall CMM short-term survival. Methods CMM records as collected at the Veneto Cancer Registry (RTV) and at the Veneto regional health service were considered. A univariate Cox regression validated the strength and direction of each independent variable with overall mortality. A range of machine learning models (Logistic Regression classifier, Support-Vector Machine, Random Forest, Gradient Boosting, and k-Nearest Neighbors) and a Deep Neural Network were then trained to predict the 3-years mortality probability. Five-fold cross-validation and Grid Search were performed to test the best data preprocessing procedures, features selection, and to optimize models hyperparameters. A final evaluation was carried out on a separate test set in terms of balanced accuracy, precision, recall and F1 score. The best model was deployed as online tool. Results The univariate analysis confirmed the significant prognostic value of TNM staging. Adjunctive clinicopathological variables not included in the AJCC 8th melanoma staging system, i.e., sex, tumor site, histotype, growth phase, and age, were significantly linked to overall survival. Among the models, the Neural Network and the Random Forest models featured the best prognostic performance, achieving a balanced accuracy of 91% and 88%, respectively. According to the Gini importance score, age, T and M stages, mitotic count, and ulceration appeared to be the variables with the greatest impact on survival prediction. Conclusions Using data from patients with CMM, we developed an AI algorithm with high staging reliability, on top of which a web tool was implemented ( unipd.link/melanomaprediction ). Being essentially based on routinely recorded clinicopathological variables, it can already be implemented with minimal effort and further tested in the current clinical practice, an essential phase for validating the model’s accuracy beyond the original research context.

Background: The cancer risk associated with gastric non-invasive neoplasia (formerly dysplasia) is debated. This prospective long term follow up study investigates the clinicopathological behaviour of non-invasive gastric neoplasia (and related lesions), focusing on the cancer risk associated with each different histological phenotype. Patients and methods: A total of 118 consecutive cases (nine indefinite for non- invasive neoplasia; 90 low grade non-invasive neoplasia; 16 high grade non- invasive neoplasia; and three suspicious for invasive adenocarcinoma) with a histological follow up of more than 12 months (average 52 months; range 12–206) were prospectively followed up with a standardised protocol. Patients in whom gastric cancer was detected within 12 months from the initial diagnosis of non-invasive neoplasia were excluded, assuming that invasive carcinoma had been missed at the initial endoscopy procedure. Results: Non-invasive neoplasia was no longer detectable in 57/118 cases (48%), was unchanged in 32 (30%), and evolved into gastric cancer in 20 patients (17%). Evolution to invasive adenocarcinoma was documented in both low and high grade non-invasive neoplastic lesions (8/90 low grade; 11/16 high grade) and correlated with histological severity (low versus high grade) at baseline (p<0.001). Seventy five per cent of cancers occurring during the long term follow up were stage I. Conclusions: The risk of invasive gastric cancer increases with the histological grade of the non-invasive neoplasia. Following up non-invasive gastric neoplasia increases the likelihood of gastric cancer being detected in its early stages.

Background: AMP-activated protein kinase (AMPK) has a central role in cellular energy sensing and is activated in preclinical tumour models following anti-vascular endothelial growth factor (VEGF) therapy. The possible predictive or prognostic role of AMPK status in cancer patients treated with anti-VEGF drugs has not been investigated so far. Methods: Expression of components of the AMPK pathway including phosphorylated AMPK (pAMPK), phosphorylated acetyl-Coa carboxylase (pACC) and liver kinase B1 (LKB1) was investigated by immunohistochemistry in 48 colorectal cancers treated with FOLFIRI plus bevacizumab. Correlation between pAMPK and pACC and associations between the AMPK pathway scores and clinico-pathological characteristics were assessed. Overall survival (OS) was estimated through Kaplan–Meier method, whereas hazard ratios were computed to identify prognostic factors. Results: Fourteen patients (29.2%) were included in the pAMPK-negative group (score ⩽5), whereas 34 patients (70.8%) were included in the pAMPK-positive group (score >5). The Spearman's coefficient for the correlation between pAMPK and pACC scores in primary tumour samples was 0.514 ( P =0.0002). Low pAMPK levels were associated with worse OS ( P -value 0.0002) but not with PFS, whereas low pACC levels were associated both with worse OS and PFS ( P -value 0.0007 and 0.01, respectively). Conclusions: Our findings suggest that high tissue AMPK activation is a prognostic biomarker in this cohort of metastatic colorectal cancer patients.

Background: Recently, we developed an apoptotic assay for expanding the monitoring capabilities of the circulating tumour cells (CTC) test during therapy. An automated platform for computing CTCs was integrated with a mAb (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 in early apoptosis; we showed that live CTCs were associated with progression, consistent with enhanced cell migration and invasion. The test was first applied here to mRCC. Methods: Live/apoptotic CTCs changes were measured in mRCC patients receiving first-line Sunitinib and compared with circulating endothelial cell (CEC) levels. Results: The presence of EpCAM-positive, live CTCs predicts progression in individual mRCC patient, being associated with distant metastasis under first-line Sunitinib. Synchronous detection of CTCs and CEC levels discloses for the first time an association between their dynamic changes and outcome: a rapid increase of the CEC number as early as the first cycle of therapy is associated with CTC decrease in non-progressed patients, whereas a delayed response of CECs is related to higher CTC values in the progressed group indicating treatment failure. Conclusion: We demonstrated that a delayed response to antiangiogenic treatment indicated by persistent detection of CECs correlates with persistent live CTCs and more aggressive disease.

Background:Squamous cell carcinoma antigen (SCCA) is a serine protease inhibitor that can be overexpressed in hepatocellular carcinoma (HCC) at both molecular and protein level, but no data are available on its expression in pre-malignant stages.Aim:To assess SCCA expression by immunohistochemistry in HCC and its nodular precursors in cirrhotic livers.Methods:55 nodules from 42 explanted livers were evaluated: 7 large regenerative nodules (LRNs), 7 low-grade dysplastic nodules (LG-DNs), 10 high-grade DNs (HG-DNs), and 31 HCC. SCCA expression was semiquantitatively scored on a four-tiered scale.Results:SCCA hepatocyte immunostaining was always restricted to the cytoplasm, mainly exhibiting a granular pattern. Stain intensity varied, ranging from weak to very strong. Within the nodules, positive cells were unevenly distributed, either scattered or in irregular clusters. The prevalence of SCCA expression was 29% in LRNs, 100% in DNs and 93% in HCC. A significant difference emerged in both prevalence and score for LRNs versus LG-DNs (p<0.039), HG-DNs (p = 0.001), and HCC (p = 0.000). A barely significant difference (p = 0.49) was observed between LG-DNs and HG-DNs, while no difference in SCCA expression was detected between HG-DNs and HCC. Cirrhotic tissue adjacent to the nodules was positive in 96% of cases, with a significant difference in the score (p = 0.000) between hepatocytes adjacent to HCC and those surrounding LRNs.Discussion:This study provides the first evidence that aberrant SCCA expression is an early event in liver cell carcinomatous transformation.

BackgroundAlthough in vivo studies have demonstrated that periodontitis aggravates experimental arthritis, there are no animal models that mimic the co-occurrence of these diseases.ObjectivesTo investigate the arthritogenic effect of lipopolysaccharide (LPS) in a mouse model of periodontal disease.MethodsPeriodontitis was induced in CD1 mice by injection of 0.01 or 0.05 µg of LPS in 5 µl of PBS every 48 hour into the vestibular gingiva of the second molar on the left maxilla. Untreated mice or injected with LPS at the tail were used as controls. Mice (n=10 per condition) were monitored daily and arthritis was estimated by conventional visual scoring method (scale 0–5) and recording the paw swelling with a calliper. 2 weeks after the 9th injection mice were sacrificed to collect blood, maxilla and paw samples. The left maxilla was analysed by microCT and the alveolar bone loss was assessed measuring the distance between the cementum-enamel junction (CEJ) and the alveolar bone crest (ABC) of each molar. Ultrasound (US) was performed to measure the ankle joint space. Periodontal and paw tissues were processed for histological analysis. Inflammation, vascular proliferation and bone resorption were scored (0–3) in maxilla. Inflammation, pannus formation, cartilage and bone destruction were scored (0–5) in ankle joints. CXCL1, IL-1β, IL-6 and TNF serum levels were determined by ELISA.ResultsAnkle swelling and inflammation were noted after the 5th periodontal injection of 0.05 µg of LPS, picked at day 18 and continued for the next 15 days with paw swelling and score higher than those of untreated mice (at the sacrifice p<0.001). 0.01 µg of LPS did not induce paw changes. Therefore, the subsequent assessments were conducted only in mice injected with 0.05 µg of LPS. The CEJ-ABC distance was greater in the inoculated (0.29±0.08 mm) than in the control (0.17±0.05 mm) mice (p<0.001). Histological analysis showed that LPS induced a mild vascular proliferation (score 0.8±0.42) in periodontal tissue and a substantial alveolar bone resorption (score 1.8±0.42), but not inflammation. US revealed the presence of effusion and a 1.5-fold higher joint space in the ankle of mice with periodontitis than in controls (p<0.05). Leukocyte infiltration (score 2.36±1.56) and synovial proliferation (score 2.09±1.54) were observed after histology in ankle joints of mice injected orally. The same sections had slight cartilage (score 1.32±1.21) and bone destruction (score 0.68±0.72). Animals that received LPS tail injection did not show any clinical and histological signs of arthritis. CXCL1 and TNF were higher in arthritic mice (CXCL1:2226.87±264.38 pg/ml; TNF:24.55±7.0 pg/ml), than in controls (CXCL1:445.97±92.09 pg/ml; TNF:3.22±1.04 pg/ml). Although there was no statistical difference, IL-1β and IL-6 were highest in LPS-mice (IL-1β:79.49±11.99 pg/ml; IL-6:196.02±40.62 pg/ml).ConclusionsThis study shows that experimental arthritis and periodontal disease can co-occur after LPS oral injection in mice. Our model may be useful to improve the understanding of the mechanisms underlying the link between periodontitis and arthritis.Disclosure of InterestNone declared

Autoimmune gastritis is a chronic progressive inflammatory condition that results in the replacement of the parietal cell mass by atrophic and metaplastic mucosa. This Review summarizes the epidemiology, pathogenesis and pathological aspects of autoimmune atrophic gastritis. The authors also provide practical advice for the diagnosis and management of patients with this disease. Autoimmune gastritis is a chronic progressive inflammatory condition that results in the replacement of the parietal cell mass by atrophic and metaplastic mucosa. A complex interaction of autoantibodies against the parietal cell proton pump and sensitized T cells progressively destroy the parietal cells, inducing hypochlorhydria and then achlorhydria, while autoantibodies against the intrinsic factor impair the absorption of vitamin B 12 . The resulting cobalamin deficiency manifests with megaloblastic anaemia and neurological and systemic signs and symptoms collectively known as pernicious anaemia. Previously believed to be predominantly a disease of elderly women of Northern European ancestry, autoimmune gastritis has now been recognized in all populations and ethnic groups, but because of the complexity of the diagnosis no reliable prevalence data are available. For similar reasons, as well as the frequent and often unknown overlap with Helicobacter pylori infection, the risk of gastric cancer has not been adequately assessed in these patients. This Review summarizes the epidemiology, pathogenesis and pathological aspects of autoimmune metaplastic atrophic gastritis. We also provide practical advice for the diagnosis and management of patients with this disease. Key Points Atrophic gastritis can be associated with long-standing Helicobacter pylori infection (multifocal atrophic gastritis) and with an autoimmune process that progressively destroys the oxyntic mucosa (autoimmune atrophic gastritis) Both types of atrophic gastritis are underdiagnosed, in part because of inadequate biopsy sampling Autoimmune atrophic gastritis progresses from a mild chronic inflammation of the gastric corpus to an advanced stage associated with a severe form of vitamin B 12 deficiency anaemia known as pernicious anaemia Traditionally, autoimmune atrophic gastritis has been viewed as a disease affecting predominantly elderly women of Northern European descent, but growing evidence suggests that there might be no racial specificity The diagnosis of autoimmune gastritis rests on the demonstration of its characteristic histopathological features and the demonstration of autoantibodies against intrinsic factor and parietal cells Management of the early stages of autoimmune atrophic gastritis is focused on the prevention of vitamin B 12 , folate and iron deficiencies

Aims: To determine any associations between the Helicobacter pylori genes babA2, oipA, cagA and the s and m alleles of vacA. In addition, to verify whether these genes work synergistically or independently in causing gastritis, peptic ulcer, and intestinal metaplasia. Methods: One hundred and sixty seven H pylori positive patients were studied (52 antral gastritis, 41 diffuse gastritis, 41 peptic ulcer, and 33 duodenitis). Helicobacter pylori virulence genes were amplified by means of the polymerase chain reaction. Results: Significant associations were found between babA2 and the other H pylori genes studied. When considered singly, all the genes were associated with disease diagnosis, inflammation, and intestinal metaplasia. Four H pylori groups were defined. Group A: cagA−, s2m2, babA2−; group B: cagA+, s1m1, babA2+; group C: cagA+, s1m2, babA2+; group D: cagA+, s1m2, babA2−. Group A infecting strains were associated with less severe endoscopic and inflammatory conditions, whereas group B strains were associated with the worst endoscopic and inflammatory findings. Intestinal metaplasia was a rare finding in group A infected patients (< 10%), whereas it was frequent in those infected with group B strains (48%). Conclusions: The H pylori genes cagA, oipA “on”, s1 and m1 vacA, and babA2 are associated with each other, possibly as a result of shared selective pressure. When coexpressed by the same H pylori strain, cagA, s1 and m1 vacA, and babA2 work synergistically in worsening inflammation. Infections caused by strains coexpressing cagA, s1m1 vacA, and babA2 are those at higher risk for intestinal metaplasia.