Childhood infectious diseases and risk of non-Hodgkin's lymphoma according to the WHO classification: A reanalysis of the Italian multicenter case-control study.

Since 1960, incidence of non-Hodgkin's lymphoma (NHL) has been increasing in most industrialized countries, but causes of this trend remain unclear. A role of the decreased exposure to infectious agents during childhood has been proposed. Our study evaluates the association between common childhood infectious diseases and the risk of NHL and its major subtypes by a reanalysis of the Italian multicenter case-control study. After exclusion of next-of-kin interviews, 1,193 cases, diagnosed between 1990 and 1993, and 1,708 population-based controls were included in the analyses. OR estimates were obtained by logistic regression, adjusting for gender, age, residence area, education, smoking habit and exposure to radiations, pesticides and aromatic hydrocarbons. Among B-cell lymphomas (n = 1,102) an inverse association was observed for rubella (OR = 0.80, 95% CI: 0.65-0.99), pertussis (OR = 0.74, 95% CI: 0.62-0.88) and any infection (OR = 0.75, 95% CI: 0.61-0.93). A negative trend by number of infections was observed, which was more evident among mature B-cell lymphoma (OR = 0.66 for three infections or more, 95% CI: 0.48-0.90). Our results indicate a potential protective role of common childhood infections in the etiology of B-cell NHL.

The hERG1 Potassium Channel Behaves As Prognostic Factor In Gastric Dysplasia Endoscopic Samples.

PURPOSE: Gastric cancer (GC) is still a relevant health issue worldwide. The identification of prognostic factors for progression of gastric dysplasia (GD), the main pre-cancerous lesion of the intestinal-type GC, is hence mandatory. PATIENTS AND METHODS: A cohort of 83 GD endoscopic samples belonging to Italian subjects was collected. hERG1 expression was evaluated by immunohistochemistry and scored 0-3, depending on the percentage of stained cells. Expression data were analysed in conjunction with clinico-pathological and survival data. RESULTS: hERG1 turned out to be expressed in 67.47% (56 out of 83) of the GD samples. hERG1 expression was higher in high-grade GD compared to low-grade GD (29 out of 39, 74.36% vs 27 out of 44, 61.36%), although the statistical significance was not reached (P=0.246). No association emerged between hERG1 expression and clinical features of the patients (age, gender, localization, H. pylori infection, gastritis and intestinal metaplasia). In a subset of cases for which sequential samples of gastric lesions (from GD to Early Gastric Cancer and Advanced Gastric Cancer) were available, hERG1 expression was maintained in all the steps of gastric carcinogenesis from GD onwards. A general trend to increased expression in advanced lesions was observed. hERG1 score had a statistically significant impact on both Progression-Free Survival (P=0.018) and Overall Survival (P=0.031). In particular, patients displaying a high hERG1 score have a shorter survival. CONCLUSION: hERG1 is aberrantly expressed in human GD samples and has an impact on both PFS and OS, hence representing a novel prognostic marker for progression of GD towards GC of the intestinal histotype. Once properly validated, hERG1 detection could be included in the clinical practice, during endoscopic surveillance protocols, for the management of GD at higher risk of progression, as already proposed for Barrett's oesophagus.

MICAL2 is expressed in cancer associated neo-angiogenic capillary endothelia and it is required for endothelial cell viability, motility and VEGF response.

The capacity of inducing angiogenesis is a recognized hallmark of cancer cells. The cancer microenvironment, characterized by hypoxia and inflammatory signals, promotes proliferation, migration and activation of quiescent endothelial cells (EC) from surrounding vascular network. Current anti-angiogenic drugs present side effects, temporary efficacy, and issues of primary resistance, thereby calling for the identification of new therapeutic targets. MICALs are a unique family of redox enzymes that destabilize F-actin in cytoskeletal dynamics. MICAL2 mediates Semaphorin3A-NRP2 response to VEGFR1 in rat ECs. MICAL2 also enters the p130Cas interactome in response to VEGF in HUVEC. Previously, we showed that MICAL2 is overexpressed in metastatic cancer. A small-molecule inhibitor of MICAL2 exists (CCG-1423). Here we report that 1) MICAL2 is expressed in neo-angiogenic ECs in human solid tumors (kidney and breast carcinoma, glioblastoma and cardiac myxoma, n = 67, were analyzed with immunohistochemistry) and in animal models of ischemia/inflammation neo-angiogenesis, but not in normal capillary bed; 2) MICAL2 protein pharmacological inhibition (CCG-1423) or gene KD reduce EC viability and functional performance; 3) MICAL2 KD disables ECs response to VEGF in vitro. Whole-genome gene expression profiling reveals MICAL2 involvement in angiogenesis and vascular development pathways. Based on these results, we propose that MICAL2 expression in ECs participates to inflammation-induced neo-angiogenesis and that MICAL2 inhibition should be tested in cancer- and noncancer-associated neo-angiogenesis, where chronic inflammation represents a relevant pathophysiological mechanism.

Familial aggregation of gastric cancer with microsatellite instability.

BACKGROUND: Microsatellite instability (MSI) is currently a new molecular subtype of gastric cancer (GC). About 90% of GC cases appear sporadically. MSI seems to be responsible for both sporadic and familial GC. The aim of this study was to analyze the frequency of MSI in GC with familial history of GC. METHODS: The MSI analysis was conducted using five quasi-monomorphic mononucleotide repeats: BAT-26, BAT-25, NR-24, NR-21 and NR-27. From our database, we analyzed 457 patients in terms of cancer history across family members, particularly focusing on GC. RESULTS: MSI status in patients without familial history of GC was present in 22.1% of the cases, whereas in the patients with familial history of GC it was present in 28% of the cases (p = 0.220). For 1st or 2nd degree family members with GC, MSI was observed in 27.6% and in 30.8%, respectively (p = 0.812). MSI was observed in hereditary gastric cancer (HGC) in 33.3% and in familial gastric cancer (FGC) in 30%. No difference in survival rates was observed between the analyzed groups. CONCLUSIONS: In our publication, we could not find any link between familial background and the MSI status in GC patients. More detailed molecular and genetic analysis of subgroups of these patients is required.

PIK3CA mutation in gastric cancer and the role of microsatellite instability status in mutations of exons 9 and 20 of the PIK3CA gene.

BACKGROUND: A better understanding of molecular gastric cancer (GC) entities may help in tailored treatments of that neoplasm. The PIK3CA mutation is one of the most important in many cancers. OBJECTIVES: We performed a comparison of clinical and pathological data of the PIK3CA mutation in GC patients. MATERIAL AND METHODS: The analysis was done on 472 patients operated on in 1 center. Polymerase chain reaction (PCR) was used for the screening of PIK3CA (exon 9 and 20). For microsatellite instability (MSI) we used 5 quasi-monomorphic mononucleotide repeats - BAT-26, BAT-25, NR-24, NR-21, and NR-27. The clinical and pathological data was analyzed. RESULTS: PIK3CA mutation was observed in 10 out of 472 GC patients (2.1%). Nine out of 10 were MSI (9 of 111 MSI patients - 8.1%). Half of the 10 patients had mutations in exon 9 and the other half in exon 20. A majority of patients with the PIK3CA mutation had MSI (p < 0.001). The 5-year survival of MSI patients with the PIK3CA mutation was 40% and without the mutation, 70.4% (p = 0.309). For patients with the mutation in exon 9, the 5-year survival was 0%, and for those with the mutation in exon 20, 80% (p = 0.031). The Cox proportional hazards regression analysis did not show that PIK3CA is statistically correlated with a worse overall survival. CONCLUSIONS: PIK3CA mutation in GC is a rare finding. It is strongly associated with the MSI molecular subgroup, presenting a worse outcome than other MSI patients. A completely different outcome is associated with the mutation in exon 9 compared to the mutation in exon 20, with the latter being more favorable.

Gastric Cancer Maximum Tumour Diameter Reduction Rate at CT Examination as a Radiological Index for Predicting Histopathological Regression after Neoadjuvant Treatment: A Multicentre GIRCG Study.

AIM: To investigate the role of maximum tumour diameter (D-max) reduction rate at CT examination in predicting histopathological tumour regression grade (TRG according to the Becker grade), after neoadjuvant chemotherapy (NAC), in patients with resectable advanced gastric cancer (AGC). MATERIALS AND METHODS: Eighty-six patients (53 M, mean age 62.1 years) with resectable AGC (≥T3 or N+), treated with NAC and radical surgery, were enrolled from 5 centres of the Italian Research Group for Gastric Cancer (GIRCG). Staging and restaging CT and histological results were retrospectively reviewed. CT examinations were contrast enhanced, and the stomach was previously distended. The D-max was measured using 2D software and compared with Becker TRG. Statistical data were obtained using "R" software. RESULTS: The interobserver agreement was good/very good. Becker TRG was predicted by CT with a sensitivity and specificity, respectively, of 97.3% and 90.9% for Becker 1 (D-max reduction rate > 65.1%), 76.4% and 80% for Becker 3 (D-max reduction rate < 29.9%), and 70.8% and 83.9% for Becker 2. Correlation between radiological and histological D-max measurements was strongly confirmed by the correlation index (c.i.= 0.829). CONCLUSIONS: D-max reduction rate in AGC patients may be helpful as a simple and reproducible radiological index in predicting TRG after NAC.

An aggressive early gastric cancer: Kodama's PenA type.

BACKGROUND: To investigate the role of Kodama PenA subtype in influencing survival in patients with early gastric cancer (EGC). METHODS: All patients surgically treated for EGC at 7 Italian centers (Forlì, Varese, Siena, Verona, Milan, Rome and Perugia) belonging to the Italian Research Group for Gastric Cancer (GIRCG) from January 1982 and December 2009 were included. RESULTS: PenA patients were 230 (21.5%) while other types were 839 (78.5%). Nodal metastases were more common in PenA (30.7%) than non-PenA (10.4%) EGCs. Among preoperative variables, only age (OR 1.02; 95% CI 1.00-1.03, p = 0.009) and macrotype III (OR 1.95; 95% CI 1.39-2.75, p = 0.0001) were significantly associated with Pen A type. Survival analysis performed on N0 patients demonstrated that only size >2 cm (HR 1.85; 95% CI 1.12-3.05, p = 0.017) and age (HR 1.06; 95% CI 1.03-1.08, p < 0.0001) were independent poor prognostic factor. Among N+ patients age (HR 1.04; 95% CI 1.00-1.07, p = 0.048), number of positive lymph nodes (HR 1.13; 95% CI 1.05-1.20, p = 0.0002) and PenA (HR 4.23; 95% CI 1.70-10.55, p = 0.002) were significantly correlated with poor prognosis at multivariate analysis. CONCLUSIONS: Kodama PenA subtype was the most powerful independent prognostic factor in patients with nodal metastases. Its status should always be investigated in EGCs patients.

Early Gastric Cancer: Clinical Behavior and Treatment Options. Results of an Italian Multicenter Study on Behalf of the Italian Gastric Cancer Research Group (GIRCG).

BACKGROUND: Early gastric cancer (EGC) generally has a good prognosis. However, the current definition of EGC includes various subgroups of patients with different pathological characteristics and different prognoses, some of whom have aggressive disease with a biological behavior similar to that of advanced carcinoma. MATERIALS AND METHODS: We retrospectively evaluated 1,074 patients with EGC who had undergone surgery between 1982 and 2009. The cumulative incidence function of cancer-specific mortality and competing mortality were estimated using the Fine and Gray method. RESULTS: The median follow-up period was 193 months (range 1-324). Five hundred and sixty-two (52.3%) patients died, 96 (8.9%) from EGC. The 5-, 10-, and 15-year cumulative incidence rates for mortality of all causes were 20.5% (95% confidence interval [CI] 18.0-22.9), 37.1% (95% CI 34.7-40.7), and 52.6% (95% CI 49.1-56.0), respectively; for cancer-specific mortality, 6.0% (95% CI 4.5-7.6), 9.9% (95% CI 7.9-11.9), and 11.1% (95% CI 8.8-13.3), respectively; and for mortality of other causes, 14.4% (95% CI 12.1-16.6), 27.2% (95% CI 24.2-30.2), and 41.5% (95% CI 38.1-43.3), respectively. A significant increase in the risk of cancer-specific mortality was observed for lesions >2 cm (adjusted hazard ratio [HR] = 1.44, 95% CI 1.07-1.94), Pen A-type disease (adjusted HR = 1.73, 95% CI 1.15-2.61), and node-positive cancers (adjusted HR = 2.28, 95% CI 1.61-3.21). CONCLUSION: Patients with EGC with tumors >2 cm, Pen A-type disease according to Kodama, or lymph node metastases show a poorer prognosis and an increased risk of cancer-specific mortality. IMPLICATIONS FOR PRACTICE: Early gastric cancer generally has a good prognosis, and some patients can be treated radically by endoscopic resection. However, the current definition of early gastric cancer includes subgroups of patients with an aggressive disease. In particular, patients with lymph node metastases and Pen A-type tumors according to Kodama's classification need a more invasive treatment, such as subtotal or total gastrectomy with an extended D2 lymphadenectomy, plus eventual adjuvant chemotherapy.

The Role of Microsatellite Instability in Positive Margin Gastric Cancer Patients.

PURPOSE: A positive resection margin (RM+) is acknowledged as a poor prognostic factor after gastrectomy. Microsatellite instability (MSI-H) gastric cancer has been identified as a subgroup of gastric cancer that may be associated with an improved prognosis. The aim of the study was an analysis of MSI status on patients with margin involvement after gastrectomy and examination of the association between MSI, margin status, and survival outcomes. METHODS: From a large prospectively annotated surgical database we collected clinicopathological and survival data on patients who had undergone a potentially curative resection for gastric cancer. MSI status was assessed using a standard 5-marker quasi-monomorphic mononucleotide repeat panel. Patients who were R+ and either microsatellite stable (MSS) or MSI-H were identified and clinicopathological characteristics and disease specific survival was compared. RESULTS: Three hundred and eighty-six patients were identified; 102 (26.4%) cancers were MSI-H. The proportion of R+ resections was not significantly different in MSS and MSI-H groups. For MSS patients 3-, 5-, and 10-year disease-specific survival rates were 9.1%, 0%, and 0%, respectively; for patients with MSI-H R+ tumors these were 38.5%, 30.8%, and 15.4%, respectively. In Cox analysis MSI-H, female gender, and T ≥3 were significantly associated with survival. CONCLUSIONS: Patients with MSI-H gastric cancer may have long-term survival despite R+ margin status. The molecular division of gastric cancer may be an important step in identifying possible tailored surgical treatments corresponding to clinical and pathological factors.

Prognostic Value of Perineural Invasion in Resected Gastric Cancer Patients According to Lauren Histotype.

The purpose of this study is to investigate perineural invasion (PNI) as a prognostic factor in gastric cancer patients. 455 patients submitted to extended (D2 or more) lymphadenectomy (median number of 39 retrieved lymph nodes, range: 15-140) between 1995 and 2012 were retrospectively studied. Patients were categorized in two groups according to the PNI status, and PNI positivity was assessed in presence of cancer cells in the perinerium or the neural fascicles using hematoxylin and eosin staining. Median follow-up for surviving patients was 80.3 months. Survival analysis was performed by univariate and multivariate analysis, using a Cox proportional hazards model. 162 patients (33.9%) had positive PNI; this was strongly associated with advanced stages of disease, residual tumor, lymphovascular invasion, Lauren diffuse-mixed histotype and tumor size. Five-year cancer-related survival was 65,7% and 20,6% in PNI negative vs. positive groups, respectively (p < 0.001). The prognostic impact of PNI at univariate analysis was particularly evident in patients submitted to R0 surgery, early as well as advanced stage, advanced nodal stage and T status. At multivariate analysis, PNI did not result statistically significant in the overall series, but emerged as an independent prognostic factor in the group of patients with Lauren intestinal histotype (p = 0.005, hazard ratio: 1.99, 95% confidence interval 1.24-3.19). PNI is related to advanced stage and poor long-term survival in gastric cancer, and may serve as an adjunctive prognostic factor in the intestinal histotype.

Recurrence in node-negative advanced gastric cancer: Novel findings from an in-depth pathological analysis of prognostic factors from a multicentric series.

AIM: To analyze the clinicopathological characteristics of patients with both node-negative gastric carcinoma and diagnosis of recurrence during follow-up. METHODS: We enrolled 41 patients treated with curative gastrectomy for pT2-4aN0 gastric carcinoma between 1992 and 2010, who developed recurrence (Group 1). We retrospectively selected this group from the prospectively collected database of 4 centers belonging to the Italian Research Group for Gastric Cancer, and compared them with 437 pT2-4aN0 patients without recurrence (Group 2). We analyzed lymphatic embolization, microvascular infiltration, perineural infiltration, and immunohistochemical determination of p53, Ki67, and HER2 in Group 1 and in a subgroup of Group 2 (Group 2bis) of 41 cases matched with Group 1 according to demographic and pathological characteristics. RESULTS: T4a stage and diffuse histotype were associated with recurrence in the group of pN0 patients. In-depth pathological analysis of two homogenous groups of pN0 patients, with and without recurrence during long-term follow-up (groups 1 and 2bis), revealed two striking patterns: lymphatic embolization and perineural infiltration (two parameters that pathologists can easily report), and p53 and Ki67, represent significant factors for recurrence. CONCLUSION: The reported pathological features should be considered predictive factors for recurrence and could be useful to stratify node-negative gastric cancer patients for adjuvant treatment and tailored follow-up.

High-mobility group box protein 1 expression in inflammatory diseases of the middle ear.

High-mobility group box 1 (HMGB1) is a nuclear non-histone protein, playing a critical role as a mediator between innate and acquired immunity; when released extracellularly, it coordinates the cellular stress response (under necrosis, bacterial lipopolysaccharide stimulation) and acts as an inflammatory marker and cytokine. The aim of the study was to demonstrate whether HMGB1 is over-expressed in chronic middle-ear pathologies and whether the entity of expression and the localization are correlated with the degree of the inflammatory reaction, thus suggesting that HMGB1 may play a crucial role in chronic inflammatory disorders of the middle ear, as already demonstrated in other airway diseases. We analyzed 30 samples of middle-ear mucosa in patients affected by chronic suppurative otitis media with ear drum perforation with/without cholesteatoma and otosclerosis as control. The distribution of HMGB1 was evaluated as nuclear, cytoplasmic, and/or extracellular staining. The inflammatory cells observed in the biopsies were mostly lymphocytes and plasmacells. A statistically significant difference in inflammation score between otosclerosis and chronic otitis samples ( P < 0.01; Anova test) and between otosclerosis and cholesteatoma samples ( P < 0.05; Anova test) was observed; the HMGB1 positivity was in accordance with the density of the inflammatory infiltrate. HMGB1 is over-expressed in chronic middle-ear pathologies and may play a role in the progression of the inflammatory process from recurrent acute otitis media to chronic suppurative otitis media.

Single Center Experience on Anatomy-and Histopathology-Based Gastric Cancer Molecular Classification.

We analyzed the clinical utility of molecular classification based on anatomical and histological background. The study was conducted on 457 patients treated for gastric cancer with additional information about microsatellite instability status. We divided the patients in three groups of molecular classification based on anatomical and histological background: proximal non-diffused, diffused, and distal non-diffused groups. These groups varied in terms of clinical and pathological factors as well as survival rates. The molecular classification based on anatomical and histological data seems to be a useful tool in a simple classification of gastric cancer.

The Italian Research Group for Gastric Cancer (GIRCG) guidelines for gastric cancer staging and treatment: 2015.

This article reports the guidelines for gastric cancer staging and treatment developed by the GIRCG, and contains comprehensive indications for clinical management, including radiological, endoscopic, surgical, pathological, and oncological paths.

hERG1 behaves as biomarker of progression to adenocarcinoma in Barrett's esophagus and can be exploited for a novel endoscopic surveillance.

Barrett's esophagus (BE) is the only well-known precursor lesion of esophageal adenocarcinoma (EA). The exact estimates of the annual progression rate from BE to EA vary from 0.07% to 3.6%. The identification of BE patients at higher risk to progress to EA is hence mandatory, although difficult to accomplish. In search of novel BE biomarkers we analyzed the efficacy of hERG1 potassium channels in predicting BE progression to EA. Once tested by immunohistochemistry (IHC) on bioptic samples, hERG1 was expressed in BE, and its expression levels increased during progression from BE to esophageal dysplasia (ED) and EA. hERG1 was also over-expressed in the metaplastic cells arising in BE lesions obtained in different BE mouse models, induced either surgically or chemically. Furthermore, transgenic mice which over express hERG1 in the whole gastrointestinal tract, developed BE lesions after an esophago-jejunal anastomosis more frequently, compared to controls. A case-control study was performed on 104 bioptic samples from newly diagnosed BE patients further followed up for at least 10 years. It emerged a statistically significant association between hERG1 expression status and risk of progression to EA. Finally, a novel fluorophore- conjugated recombinant single chain variable fragment antibody (scFv-hERG1-Alexa488) was tested on freshly collected live BE biopsies: it could recognize hERG1 positive samples, perfectly matching IHC data.Overall, hERG1 can be considered a novel BE biomarker to be exploited for a novel endoscopic surveillance protocol, either in biopsies or through endoscopy, to identify those BE patients with higher risk to progress to EA.

High-risk and low-risk gastric cancer areas in Italy and its association with microsatellite instability.

PURPOSE: The different pathological characteristics and prognoses between gastric cancer patients coming from high-risk (group A) and low-risk (group B) areas of Italy were analyzed. We investigated a suspected difference in microsatellite instability (MSI) between these two groups. METHODS: MSI analyses of 452 gastric cancer patients were performed using five quasimonomorphic mononucleotide repeats NR-21, NR-24, NR-27, BAT-25, and BAT-26. MSI analysis was done by PCR usage. An allelic profile of these five mononucleotides was detected on an automated DNA sequencer ABI PRISM 3100 Genetic Analyser. Data were analyzed according to high-risk and low-risk gastric cancer areas. RESULTS: MSI was observed in 23.9 % of all gastric cancer patients studied. Patients from group A showed a higher rate of MSI (28.4 %) than from group B (13.5 %) (p < 0.001). We analyzed this association together with tumor location and Lauren classification: A nonsignificant differences were seen when analyzing cardia and non-cardia tumors (p = 0.854) but significant for Lauren histotype (p = 0.028). There was no statistical difference in survival between high-risk and low-risk areas (p = 0.437), with a nonsignificant trend for better survival in the high-risk group, especially when measured over a longer period of time. Analyzing MSI or MSS in these groups, the survival curves were almost the same. CONCLUSIONS: A higher frequency of MSI in patients coming from high-risk areas may help explain geographical differences in gastric cancer. The trend of better survival in high-risk areas may be due to a higher rate of MSI gastric cancer patients.

Reperfusion in non-occlusive mesenteric ischaemia (NOMI): effectiveness of CT in an emergency setting.

OBJECTIVE: To investigate the CT features of reperfusion (presence/absence) in non-occlusive mesenteric ischaemia (NOMI) and their prognostic value in an emergency setting. METHODS: A revision was undertaken of imaging from 20 patients (16 males/4 females) with a dismissal summary of NOMI. All patients had previously undergone a minimum of one multidetector CT examination, and consequently underwent surgery (n = 8), autopsy (n = 2), angiography (n = 1) or endoscopy (n = 9). An evaluation of the CT scans was conducted to determine vessels, mesentery, bowel and peritoneal cavity features. The superior mesenteric artery (SMA) average diameter of NOMI cases were compared with 30 controlled cases. Kappa, Kolmogorov-Smirnov (K-S) and Fisher's exact tests were used for statistical analysis. RESULTS: A mean SMA diameter significantly smaller than that of the controlled cases was found for patients with NOMI (K-S test: D = 0.75, p = 3.7 × 10-08). Fisher's exact tests showed a strong connection between the presence of reperfusion and mesenteric fat stranding (p = 0.026), bowel wall thickening (p = 3.2 × 10-05) and a high attenuation of the bowel wall on unenhanced CT images (p = 2.8 × 10-04). A reduction in mortality was significantly linked to the combination of normal mesenteric vessels and wall thickening (p = 0.034). CONCLUSION: Analysis of not only vessels findings but also mesentery and bowel CT features will support the identification of NOMI with or without a reperfusion event in an emergency setting. A strong correlation between some CT features and lower mortality exists. ADVANCES IN KNOWLEDGE: CT features of NOMI with or without reperfusion are demonstrated. Correctly assessing the presence of reperfusion in NOMI, may allow better management of these conditions in the emergency setting.

Strong Prognostic Value of Microsatellite Instability in Intestinal Type Non-cardia Gastric Cancer.

BACKGROUND: The clinical role of microsatellite instability (MSI) in gastric cancer (GC) is controversial. A large series of patients submitted to respective surgery for primary GC with a long follow-up time was evaluated. METHODS: 472 patients with prospectively collected frozen samples of normal mucosa and tumor tissue stored in a biological tissue bank were included. Microsatellite analysis was evaluated using 5 quasi monomorphic mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21, and NR-27). The presence of MSI in 2 or more loci was classified as MSI-H, whereas all other cases were included in the microsatellite-stable (MSS) group. RESULTS: MSI-H phenotype was found in 111 of 472 patients (23.5%). MSI-H status was related significantly with older age, female gender, non-cardia location, WHO histotype, non-cardia Lauren intestinal type, and less advanced stages. Cancer-related 5-year survival was significantly higher in MSI-H versus MSS group (67.6% vs. 35%, p < 0.001). Stratified analysis revealed a significant impact of MSI on prognosis in non-cardia tumors of intestinal type or tubular/poorly differentiated histology, particularly in stages II and III; multivariate Cox regression analysis confirmed MSS status as a strong predictor of poor prognosis (hazard ratio 2.65, 95% CI 1.56-4.51, p < 0.001) in non-cardia intestinal type. No prognostic value of MSI in the diffuse-mixed type and signet-ring cell/mucinous histotypes was observed. CONCLUSIONS: MSI was confirmed as a significant predictor of long term outcome in a large series of GC with a long follow-up time, but the prognostic value is limited to selected histotypes of non-cardia tumors.

MICAL2 is a novel human cancer gene controlling mesenchymal to epithelial transition involved in cancer growth and invasion.

The MICAL (Molecules Interacting with CasL) proteins catalyze actin oxidation-reduction reactions destabilizing F-actin in cytoskeletal dynamics. Here we show for the first time that MICAL2 mRNA is significantly over-expressed in aggressive, poorly differentiated/undifferentiated, primary human epithelial cancers (gastric and renal). Immunohistochemistry showed MICAL2-positive cells on the cancer invasive front and in metastasizing cancer cells inside emboli, but not at sites of metastasis, suggesting MICAL2 expression was 'on' in a subpopulation of primary cancer cells seemingly detaching from the tissue of origin, enter emboli and travel to distant sites, and was turned 'off' upon homing at metastatic sites. In vitro, MICAL2 knock-down resulted in mesenchymal to epithelial transition, reduction of viability, and loss of motility and invasion properties of human cancer cells. Moreover, expression of MICAL2 cDNA in MICAL2-depleted cells induced epithelial to mesenchymal transition. Altogether our data indicate that MICAL2 over-expression is associated with cancer progression and metastatic disease. MICAL2 might be an important regulator of epithelial to mesenchymal transition and therefore a promising target for anti-metastatic therapy.

Assessment of a Test for the Screening and Diagnosis of Celiac Disease.

BACKGROUND: Celiac disease (CD) is an immune-mediated intolerance to dietary gluten, affecting genetically predisposed individuals. ELISA-based serological tests help to decide if further duodenal biopsy is necessary, for this the diagnostic kits have to be accurate, specific, and sensible. In this study, we investigate the performance of an ELISA that uses the purified cross-linked complex of tissue transglutaminase and gliadin, referred as the "neoepitope" (AESKULISA® tTG New Generation), as antigen. METHODS: We evaluated 41 newly diagnosed celiac patients, 18 celiac patients on gluten-free diet, and 169 controls, comprising healthy subjects, patients affected by other autoimmune diseases, and patients affected by several non-autoimmune diseases. RESULTS AND CONCLUSION: The assay has an excellent performance. Due to its high level of diagnostic accuracy, this assay constitutes a new approach for the screening of celiac patients not only for the diagnosis of CD, but also for monitoring patients on gluten-free diet and their compliance. Moreover, cases of neoepitope-positive subjects who were tested negative with "classical" serological markers could have a predictive value for this pathology. This aspect will require further studies of elaboration.