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Introduction: Transjugular intrahepatic porto-systemic shunt (TIPS) is an accepted indication for treating refractory ascites. Different models have been proposed for the prediction of survival after TIPS; aim of present study was to evaluate the factors associated with mortality after TIPS for refractory ascites. Methods: Seventy-three consecutive patients undergoing a TIPS for refractory ascites in our centre between 2003 and 2008, were prospectively recorded in a database ad were the subject of the study. Mean follow-up was 17±2 months. Forty patients were awaiting liver transplantation (LT) and 12 (16.4%) underwent LT during follow-up. Results: Mean MELD at the moment of TIPS was 15.7±5.3. Overall mortality was 23.3% (n=17) with a mean survival after TIPS of 17±14 months. MELD score (B=0.161, p=0.042), AST (B= 0.020, p=0.090) and pre-TIPS HVPG (B=0.016, p=0.093) were independent predictors of overall mortality. On multivariate analysis MELD (B=0.419, p=0.018) and pre-TIPS HVPG (B=0.223, p=0.060) independently predicted 1 year survival. Patients were stratified into categories of death risk, using ROC curves for the variables MELD and HVPG. Patients with MELD<10 had a low probability of death after TIPS (n=6, 16% mortality); patients with HVPG <16 mmHg (n=6) had no mortality. Maximum risk of death was found in patients with MELD score 19 (n=16, 31% mortality) and in those with HVPG 25 mmHg (n=27, 26% mortality). Conclusions: TIPS increases overall survival in patients with refractory ascites. Liver function (assessed by MELD), necroinflammation (AST) and portal hypertension (HVPG) are independent predictors of survival; patients with MELD>19 and HVPG>25 mmHg are at highest risk of death after TIPS

IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. Recent evidence suggests that the IL-33/ST2 axis plays a critical role in several autoimmune and inflammatory disorders; however, its role in inflammatory bowel disease (IBD) has not been clearly defined. We characterized IL-33 and ST2 expression and modulation following conventional anti-TNF therapy in Crohn’s disease and ulcerative colitis (UC) patients, and investigated the role of IL-33 in SAMP1/YitFc (SAMP) mice, a mixed Th1/Th2 model of IBD. Our results showed a specific increase of mucosal IL-33 in active UC, localized primarily to intestinal epithelial cells (IEC) and colonic inflammatory infiltrates. Importantly, increased expression of full-length IL-33, representing the most bioactive form, was detected in UC epithelium, while elevated levels of cleaved IL-33 were present in IBD serum. ST2 isoforms were differentially modulated in UC epithelium and sST2, a soluble decoy receptor with anti-inflammatory properties, was also elevated in IBD serum. Infliximab (anti-TNF) treatment of UC decreased circulating IL-33 and increased sST2, while stimulation of HT-29 IEC confirmed IL-33 and sST2 regulation by TNF. Similarly, IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6 and IL-17 from mucosal immune cells in SAMP mice. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis, is modulated by anti-TNF therapy, and may represent a specific biomarker for active UC.

Scopo dello studio: Stabilire se cambiamenti della perfusione di una lesione target di epatocarcinoma (HCC), valutati quantitativamente mediante ecografia con contrasto (CE-US) alla settimana 2 e 4 di terapia con sorafenib, possono predire la progressione di malattia alla settimana 8, valutata con la tomografia computerizzata o la risonanza magnetica con mezzo di contrasto (TC-RM) usando i criteri RECIST/RECIST modificati (response evaluation criteria in solid tumors). Pazienti e metodi: Il comitato etico ha approvato lo studio ed i pazienti hanno fornito un consenso informato scritto prima dell’arruolamento. Lo studio è stato effettuato su un campione di soggetti con epatocarcinoma avanzato o non suscettibile di trattamento curativo, in monoterapia con sorafenib. La valutazione della risposta tumorale è stata effettuata con TC o RM a 2 mesi usando i criteri RECIST/RECIST modificati. La CE-US è stata effettuata entro 1 settimana prima dell’inizio del trattamento con sorafenib e durante la terapia alla settimana 2, 4, 8, 16 e 32. I parametri quantitativi funzionali sono stati ottenuti impiegando un software dedicato. I cambiamenti dei valori dei parametri suddetti tra il tempo zero ed i punti temporali successivi sono stati confrontati con la risposta tumorale basata sui criteri RECIST/RECIST modificati. Risultati: La riduzione dei valori dei parametri relativi alla perfusione tumorale, in particolare di WiAUC e PE (parametri correlati con il volume ematico), al T2/T4 (settimana 2, 4), predice la risposta tumorale a 2 mesi, valutata secondo i criteri RECIST e RECIST modificati, risultata indicativa di malattia stabile (responders). Conclusione: L’ecografia con contrasto può essere impiegata per quantificare i cambiamenti della vascolarizzazione tumorale già alla settimana 2, 4 dopo la somministrazione di sorafenib nei pazienti con HCC. Questi precoci cambiamenti della perfusione tumorale possono essere predittivi della risposta tumorale a 2 mesi e possono avere un potenziale nella valutazione precoce dell'efficacia della terapia antiangiogenica nell’epatocarcinoma. / Aim of the study: To assess whether perfusion changes in one target hepatocellular carcinoma (HCC) lesion, assessed quantitatively by contrast-enhanced ultrasonography (CE-US) at week 2 and 4 of sorafenib therapy, can predict progression of disease at week 8 assessed by contrast enhanced-multidetector computed tomography or magnetic resonance imaging (CE-MDCT or MRI) using RECIST/modified RECIST criteria (response evaluation criteria in solid tumors). Patients and methods: The institutional review board approved the study and all patients provided written informed consent before their enrollment. The study was performed on a sample of subjects with advanced HCC or that was not amenable to curative treatment, in single-agent sorafenib therapy. Tumor response was based on CE-CT or CE-MRI at 2 months using RECIST/modified RECIST criteria. Contrast-enhanced US was performed within 1 week before sorafenib treatment start and during therapy at week 2, 4, 8, 16 and 32. Functional quantitative parameters were assessed using a dedicated software. The changes in dynamic US functional parameters between time 0 and the later time points were compared with tumor response based on RECIST/modified RECIST criteria. Results: The decrease in tumor perfusion parameter values, in particular WiAUC and PE (related to the blood volume), at week 2, 4, predicts the tumor response at 2 months, assessed using RECIST and modified RECIST criteria, that was indicative of stable disease (responders). Conclusion: Dynamic US can be used to quantify changes in tumor vascularity as early as week 2, 4 after sorafenib administration in patients with HCC. These early changes in tumor perfusion may be predictive of tumor response at 2 months and they may have potential in the early evaluation of the effectiveness of antiangiogenic therapy in HCC.

Introduzione: le Coliti Microscopiche, altrimenti note come Colite Collagena e Colite Linfocitica, sono disordini infiammatori cronici del colon che causano diarrea e colpiscono più frequentemente donne in età avanzata e soggetti in terapia farmacologica. Negli ultimi anni la loro incidenza sembra aumentata in diversi paesi occidentali ma la prevalenza in Italia è ancora incerta. Scopo: il presente studio prospettico e multicentrico è stato disegnato per valutare la prevalenza delle CM in pazienti sottoposti a colonscopia per diarrea cronica non ematica. Pazienti e metodi: dal Maggio 2010 al Settembre 2010 sono stati arruolati consecutivamente tutti i soggetti adulti afferenti in due strutture dell’area metropolitana milanese per eseguire una pancolonscopia. Nei soggetti con diarrea cronica non ematica sono state eseguite biopsie multiple nel colon ascendente, sigma e retto nonché in presenza di lesioni macroscopiche. Risultati: delle 8008 colonscopie esaminate 265 sono state eseguite per diarrea cronica; tra queste, 8 presentavano informazioni incomplete, 52 riscontri endoscopici consistenti con altri disordini intestinali (i.e. IBD, tumori, diverticoliti). 205 colonscopie sono risultate sostanzialmente negative, 175 dotate di adeguato campionamento microscopico (M:F=70:105; età mediana 61 anni). L’analisi istologica ha permesso di documentare 38 nuovi casi di CM (M:F=14:24; età mediana 67.5 anni): 27 CC (M:F=10:17; età mediana 69 anni) e 11 CL (M:F=4:7; età mediana 66 anni). In altri 25 casi sono state osservate alterazioni microscopiche prive dei sufficienti requisiti per la diagnosi di CM. Conclusioni: nel presente studio l’analisi microscopica del colon ha identificato la presenza di CM nel 21,7% dei soggetti con diarrea cronica non ematica ed indagine pancolonscopica negativa. Lo studio microscopico del colon è pertanto un passo diagnostico fondamentale per il corretto inquadramento diagnostico delle diarree croniche, specialmente dopo i 60 anni di età. Ampi studi prospettici e multicentrici dovranno chiarire ruolo e peso dei fattori di rischio associati a questi disordini. / Background and aim: Microscopic colitis (MC) encompasses Lymphocytic (LC) and Collagenous colitis (CC) and is a chronic, inflammatory condition of the colon causing watery diarrhea. MC is more prevalent in elderly women and in patients taking multiple drugs. The overall incidence of MC appears to have increased in recent years and to be relatively common in subjects with chronic diarrhea; however, the prevalence of this condition in Italy is still unclear. We designed a prospective multicenter study in order to evaluate the prevalence of MC in subjects undergoing colonoscopy for chronic non-bloody diarrhea. Methods: from May 2010 to September 2012, we prospectively enrolled subjects undergoing colonscopy in the metropolitan area of Milan for chronic non-bloody diarrhea. Biopsies were obtained from any macroscopic finding detected in the course of the endoscopic and from ascending, sigmoid colon and rectum. Results: a total of 8008 colonoscopies were performed; of these, 265 were done for non-bloody diarrhea; 8 were not complete, 52 detected relevant endoscopic findings consistent with a specific diagnosis (i.e. IBD, neoplasm, diverticulitis). Colonoscopy was grossly normal in 205 subjects; microscopic analysis was available in 175 cases (M:F=70:105; median age 61 yrs). Histopathologic evaluation revealed MC in 38 patients (M:F=14:24; median age 67.5 yrs): 27 CC (M:F=10:17; mean age 69 yrs), and 11 LC (M:F=4:7; mean age 66 yrs). In 25 subjects we observed non-diagnostic changes, such as a mild increase in intraepithelial lymphocytes or a slight thickening of sub-epithelial collagen. Conclusions: in this study endoscopic biopsies allowed the diagnosis of MC in 21.7% of patients complaining non-bloody diarrhea with a normal colonoscopy. Indeed, the identification of MC is pivotal for the adequate management of chronic diarrhea, especially in elderly people. Larger multicenter prospective studies are warranted to define the real impact of this clinical entity in our country.

IL-33/ST2 axis is known to promote Th2 immune responses and has been linked to several autoimmune and inflammatory disorders, including inflammatory bowel disease (IBD), and recent evidences show that it can regulate eosinophils (EOS) infiltration and function. Based also on the well documented relationship between EOS and IBD, we assessed the role of IL-33-mediated eosinophilia and ileal inflammation in SAMP1/YitFc (SAMP) murine model of Th1/Th2 chronic enteritis, and we found that IL-33 is related to inflammation progression and EOS infiltration as well as IL-5 and eotaxins increase. Administering IL-33 to SAMP and AKR mice augmented eosinophilia, eotaxins mRNA expression and Th2 molecules production, whereas blockade of ST2 and/or typical EOS molecules, such as IL-5 and CCR3, resulted in a marked decrease of inflammation, EOS infiltration, IL-5 and eotaxins mRNA expression and Th2 cytokines production. Human data supported mice’s showing an increased colocalization of IL-33 and EOS in the colon mucosa of UC patients, as well as an augmented IL-5 and eotaxins mRNA expression, when compared to non-UC. Lastly we analyzed SAMP raised in germ free (GF) condition to see the microbiota effect on IL-33 expression and Th2 responses leading to chronic intestinal inflammation. We found a remarkable decrease in ileal IL-33 and Th2 cytokines mRNA expression as well as EOS infiltration in GF versus normal SAMP with comparable inflammatory scores. Moreover, EOS depletion in normal SAMP didn’t affect IL-33 mRNA expression. These data demonstrate a pathogenic role of IL-33-mediated eosinophilia in chronic intestinal inflammation, and that blockade of IL-33 and/or downstream EOS activation may represent a novel therapeutic modality to treat patients with IBD. Also they highlight the gut microbiota role in IL-33 production, and the following EOS infiltration in the intestinal mucosa, confirming that the microbiota is essential in mounting potent Th2 response leading to chronic ileitis in SAMP.

Inflammatory Bowel Diseases (IBD) are intestinal chronic relapsing diseases which ethiopathogenesis remains uncertain. Several group have attempted to study the role of factors involved such as genetic susceptibility, environmental factors such as smoke, diet, sex, immunological factors as well as the microbioma. None of the treatments available satisfy several criteria at the same time such as safety, long-term remission, histopatological healing, and specificity. We used two different approaches for the development of new therapeutic treatment for Inflammatory Bowel Disease. The first is focused on the understanding of the potential role of functional food and nutraceuticals nutrients in the treatment of IBD. To do so, we investigated the role of Curcuma longa in the treatment of chemical induced colitis in mice model. Since Curcma Longa has been investigated for its antinflammatory role related to the TNFα pathway as well investigators have reported few cases of patients with ulcerative colites treated with this herbs, we harbored the hypothesis of a role of Curcuma Longa in the treatment f IBD as well as we decided to assess its role in intestinal motility. The second part is based on an immunological approach to develop new drugs to induce suppression in Crohn’s disease or to induce mucosa immunity such as in colonrectal tumor. The main idea behind this approach is that we could manipulate relevant cell-cell interactions using synthetic peptides. We demonstrated the role of the unique interaction between molecules expressed on intestinal epithelial cells such as CD1d and CEACAM5 and on CD8+ T cells. In normal condition this interaction has a role for the expansion of the suppressor CD8+ T cells. Here, we characterized this interaction, we defined which are the epitope involved in the binding and we attempted to develop synthetic peptides from the N domain of CEACAM5 in order to manipulate it.

Introdução: O câncer do esôfago tem média a alta incidência na região sul do Brasil e em regiões vizinhas no Uruguai e Argentina. Os tipos histológicos mais freqüentes são o carcinoma epidermóide e o adenocarcinoma numa proporção de 4:1. Essa proporção, também presente nos Estados Unidos da América e na Europa até a década de 1960 tem mudado dramaticamente nos últimos 30 anos pela crescente incidência do adenocarcinoma. Esse fato tem sido associado à epidemia de obesidade e doença do refluxo gastresofágico naquelas áreas geográficas. Um aumento do adenocarcinoma do esôfago é desconhecido no Brasil. Objetivos: Determinar a prevalência do adenocarcinoma do esôfago durante 10 anos em hospital universitário, referência do sistema único de saúde no sul do Brasil, e compará-la aos dados do período imediatamente anterior na mesma instituição. Métodos: Prontuários consecutivos de pacientes submetidos à endoscopia digestiva alta entre 1997 e 2006, relatando “ câncer esofágico “ ou “ suspeita para câncer esofágico” foram revisados e os laudos histopatológicos das biópsias endoscópicas revistos. Todos os laudos descrevendo neoplasia foram incluídos e classificados nas categorias “adenocarcinoma”, “carcinoma epidermóide” ou “outras neoplasias”. Os resultados foram comparados aos dados observados em período anterior (1987-1996) pelo teste qui-quadrado. Resultados: Houve confirmação de neoplasia em 509 pacientes na presente série histórica. Adenocarcinoma foi identificado em 90 (17,7%), carcinoma epidermóide em 390 (76,6%) e “outras neoplasias” em 29 (5,7%) com uma distribuição anual estável. A prevalência de adenocarcinoma (17,7%) foi mais elevada na presente série quando comparada à série anterior (15,2%), mas não houve diferença estatisticamente significativa entre as duas séries (p= 0, 229). Conclusões: A prevalência do adenocarcinoma aumentou quando comparada com o período anterior, mas os resultados não atingiram significância estatística. Esses dados podem representar um aumento do adenocarcinoma do esôfago, mas estudos populacionais, com maior amostragem, são recomendados. / Introduction: Esophageal cancer has a medium to high incidence in the geographic areas of southern Brazil and neighboring Uruguay and Argentina. The main histological types are squamous cell carcinoma and adenocarcinoma in a proportion of 4:1. This proportion, also reported in the United States of America and Europe in the 1960s has been dramatically changing over the past 30 years due to adenocarcinoma growing incidence, most likely associated to obesity epidemics and gastroesophageal reflux disease. Such a growing incidence in Brazil is unknown. Objectives: Determine adenocarcinoma prevalence during a consecutive 10 years period in a single university hospital referral center in southern Brazil and compare it to data from a similar past study in the same hospital. Methods: Consecutive records from patients that underwent upper digestive endoscopy between 1997 and 2006 reporting “esophageal cancer” or “suspicious for esophageal cancer” were surveyed and histopathology reports from endoscopic biopsies reviewed. All reports describing neoplasia were included and classified either as “adenocarcinoma”, “squamous cell carcinoma” or “other neoplasia” and results compared to the data observed in the period 1987-1996 using a qui-square test. Results: Neoplasia were confirmed in 509 patients in the presents series. Adenocarcinoma was found in 90 (17,7%) squamous cell carcinoma in 390 (76,6%) and “other neoplasias” in 29 (5,7%) with a stable yearly distribution. Adenocarcinoma prevalence (17,7%) was higher in the present series when compared to the previous one (15,2%) but there was no statistical difference (p= 0, 229). Conclusions: In this series from a single institution in southern Brazil adenocarcinoma prevalence increased when comparing to a previous series, but results did not reach statistical significance. This may represent a trend towards an increasing frequency of adenocarcinoma of the esophagus, but populational studies with larger sample are recommended.

Orientadora: Lorete Maria da Silva Kotze / Tese (doutorado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Clínica Cirúrgica / Resumo: O objetivo do presente estudo foi determinar índice pHmétrico em crianças brasileiras, mediante o desenvolvimento de modelos estatísticos de regressão multivariados. Para tanto foram estudados 60 pacientes, divididos em dois grupos de 30 crianças. O primeiro, constituído de pacientes recrutados entre portadores de doenças da região inguino-escrotal, sem história pregressa da DRGE, analisados prospectivamente, submetidos à monitorização do pH esofágico por 24 horas e considerados normais pelo índice de DeMeester. O segundo grupo constituído por pacientes portadores da DRGE, analisados retrospectivamente, após pHmetria de 24 horas e considerados anormais pelo mesmo índice. A idade média no grupo assintomático foi de 46,4 meses; a maioria do sexo masculino (53,3%), peso médio de 16,6 Kg. A idade média no grupo sintomático foi de 43,7 meses, a maioria do sexo masculino (76,7%), peso médio de 14,9 Kg. Ambos os grupos foram igualmente divididos em faixas etárias de 03 - 12 meses, 1 2 - 4 8 meses e acima de 48 meses. Nas monitorizações pHmétricas foram avaliados os parâmetros: número total de refluxos ácidos, número de refluxos ácidos longos, refluxo ácido mais longo e percentagem de tempo passado sob pH<4 em pé, deitado e total, índice de DeMeester, além do sexo, peso e idade. Estes dados foram analisados estatisticamente mediante os testes não paramétricos Mann-Witney, qui-quadrado, com correlação de Yates, exato de Fisher e análise de variância para a seleção das variáveis a serem incluídas nos modelos de regressão múltipla. Estas variáveis foram incluídas em equações, que constituíram modelos entre os pacientes assintomáticos e do somatório dos dois grupos que passaram a ser chamados de total geral, criando-se, assim, seis diferentes índices, com taxas de correlação entre as variáveis e probabilidades de significância diferentes. O índice que apresentou maior correlação (91,2%) entre as variáveis e maior probabilidade de significância (p<0,00001) foi o modelo completo do total geral dos pacientes. Com esse "novo índice", o corte de normalidade (média +/-2 desvios padrões) para os pacientes assintomáticos foi de 11,4. Encontrou-se, um "novo índice" com variação em relação ao corte de normalidade do índice de DeMeester de 29,3%, concluindo-se que para a realidade da população pediátrica brasileira estudada este " novo índice " estabelecido oferece aproximadamente 30% mais de possibilidade diagnostica na Doença do Refluxo Gastroesofágico. x / Abstract: The objective of this study was to determine pHmetric index in Brazilian children through development of models of multivariate regression. Sixty patients were divided in 2 groups with 30 children each. The first group contained normal volunteer patients with inguino-escrotal pathologies, without previous history of gastroesophageal reflux, prospectively analysed, submitted to 24 h oesophageal pH measure, considered normals by DeMeester score. The second group consisted in patients with GERD, prospectively analysed, after 24h-pHmeasure, considered abnormal by DeMeester score. Mean age in normal group was 46.4 month, most patients were male (53.3%), mean weight was 16,6 Kg. Mean age in abnormal group was 43,7 month, most were male (76,7%), mean weight were 14,9 Kg. Both groups were equally divided into age groups: 03-12 months, 12-48 months e more than 48 months. On pH measure, the following parameters were evaluated: total number of acid reflux, number of long acid reflux, longest acid reflux and percentage of time with pH < 4 supine, ortosthatic and total, DeMeester score, and sex, weight and age. These data were analysed statistically with non-parametric tests Mann-Whiney, chisquare with Yates correction, Fisher's exact test, and the variables to be included in models of multiple regression. These variables were included in equations, which constituted models between normal patients and somatory of the 2 groups to be called total general group, creating six different indexes with taxes of correlation between variables and probabilities of different significance. The index that mostly presented greatest correlation (91,2%) between variants and probability of significance (p<0,00001) was complete model of total-general patients. With this index, the cohort of normality (average +/- 2 standards deviations) for normal group was 11,4. With this new index, a variation of 29,3% in relation and variance analysis with DeMeester index was found. In conclusion, it is possible to make a pHmetric score for the brazilian pediatric population, with the application of the multivariate models.