<p>Nonsteroidal anti-inflammatory drugs are among the most commonly used prescription and over-the-counter medications, but they often produce significant gastrointestinal ulceration and bleeding, particularly in elderly patients and patients with certain co-morbidities. Novel anti-inflammatory drugs are seldom tested in animal models that mimic the high-risk human users, leading to an underestimate of the true toxicity of these drugs. In the present study we examined the effects of two novel NSAIDs and two commonly used NSAIDs in models in which mucosal defence was expected to be impaired. Naproxen, celecoxib, ATB-346 (a hydrogen sulfide- and naproxen-releasing compound) and NCX 429 (a nitric oxide- and naproxen-releasing compound) were evaluated in healthy, arthritic, obese, hypertensive rats, and in rats of advanced age (19 months) and rats co-administered low-dose aspirin and/or omeprazole. In all models except hypertension, greater gastric and/or intestinal damage was observed when naproxen was administered in these models than in healthy rats. Celecoxib-induced damage was significantly increased when co-administered with low-dose aspirin and/or omeprazole. In contrast, ATB-346 and NCX 429, when tested at doses that were as effective as naproxen and celecoxib in reducing inflammation and inhibiting cyclooxygenase activity, did not produce significant gastric or intestinal damage in any of the models. These results demonstrate that animal models of human co-morbidities display the same increased susceptibility to NSAID-induced gastrointestinal damage as observed in humans. Moreover, two novel NSAIDs that release mediators of mucosal defence (hydrogen sulfide and nitric oxide) do not induce significant gastrointestinal damage in these models of impaired mucosal defence.</p> / Master of Science (MSc)

<p>Colorectal cancer leads to more than 600,000 deaths worldwide per year. An abundance of research has shown that several non-steroidal anti-inflammatory drugs (NSAIDs) can exert chemotherapeutic and chemo-preventative effects in colorectal cancer patients. It is important to note, that use of many different NSAIDs carries a significant risk for cardiovascular and gastrointestinal (GI) complications. A recently developed group of NSAIDs, which release hydrogen sulfide (H₂S), has been shown to have greatly reduced these side effects as compared to conventional NSAIDs. This is likely attributable to the ability of H₂S to increase the resistance of the GI mucosa to injury, as well as to accelerate repair of injury when it occurs. Moreover, H₂S has been shown to be a vasodilator, and therefore may offset some of the hypertensive effects of NSAIDs.</p> <p>We assessed the chemotherapeutic actions of two of these newly developed NSAIDs. ATB-346 is an H₂S-releasing derivative of naproxen and ATB-352 is an H₂S-releasing derivative of ketoprofen. These drugs were tested in the azoxymethane mouse model and in the APC^Min/+mouse model of Colorectal cancer.</p> <p>In the azoxymethane model of colorectal cancer ATB-346 caused a significant reduction in number aberrant crypt foci (ACF), which are pre-neoplastic lesions used as markers of colorectal cancer. The reduction was superior to naproxen at all doses tested. ATB-352 also caused a significant reduction in the number of ACF, however the reduction was not superior to that produced by ketoprofen. In APC^Min/+mice treated with ATB-346 for 14 days (14.5 mg/kg) we observed a complete inhibition of the formation of colonic polyps/tumours and a 97.5% reduction in total polyp score. Shorter treatment with ATB-346 also produced similar reduction in total polyp score. We found that ATB-346-treated mice had lower levels of b-catenin and cmyc without significant changes in APC or p53 levels. <strong></strong></p> <p>These results demonstrate ATB-346 can exert superior chemo-preventative effects in mice models of colon cancer while leading to no gastric or intestinal damage.</p> / Master of Science (MSc)

Le microbiote gastro-intestinal joue un rôle important dans le maintien de la santé de l’hôte. Il est composé de nombreux micro-organismes tels que des bactéries, des virus, des champignons et des archées. Cependant, la majorité de ces cellules microbiennes sont des cellules bactériennes et, pour cette raison, de nombreuses études se concentrent sur l’exploration des communautés bactériennes en particulier dans le tube gastro-digestif. Un déséquilibre de cette microbiote, appelé dysbiose, a été observé dans plusieurs pathologies telles que la diarrhée, la pneumonie, après l'administration d'antibiotiques ou une modification du régime alimentaire. L’objectif de cette étude était de caractériser la dynamique du microbiote fécal des veaux entrant dans une unité d’élevage. Cinquante veaux Holstein âgés de 8 à 14 jours et arrivant dans une unité de veaux ont été inscrits à cette étude. Des échantillons fécaux ont été collectés à l'arrivée et les jours 4, 10 et 24 après l'arrivée. Les scores fécaux, le poids des veaux et l’administration d’antibiotiques ont été enregistrés au cours de l’étude. Le séquençage a été réalisé à l'aide de la plateforme Illumina MiSeq et les données analysées à l'aide du logiciel Mothur. Contrairement aux attentes, la richesse et la diversité étaient plus élevées lorsque la proportion d'animaux diarrhéiques était plus élevée (p < 0,001) et, comme prévu, la composition et la structure du microbiote changeaient au fil des jours de collecte (p > 0,001), mais les changements n'étaient pas associés à présence ou non de diarrhée et de traitement antibiotique comme prévu, ils sont associés aux jours de prélèvement. La proportion de diarrhée (nombre de veaux diarrhéiques par jour) était numériquement plus élevée les jours 4, 10 et 24 après l'arrivée. Comme prévu, les abondances relatives de bactéries associées à la santé (par example : Bifidobacterium, Lactobacillus et Faecalibacterium) ont diminué chez les veaux diarrhéiques. Bien que l'analyse de la diarrhée et de l'utilisation d'antibiotiques ne fît pas partie des objectifs de cette étude, il y avait une tendance (p=0,09) dans le poids des animaux ayant eu la diarrhée et ayant reçu des antibiotiques. Le poids final des veaux malades ayant reçu des antibiotiques avant l'abattage étaient inférieurs par rapport au poids final des animaux qui n'étaient pas malades et n'avaient pas reçu d'antibiotiques (p=0,072). La principale limite de cette étude est le manque d'information sur l'origine des veaux avant leur arrivée à l'unité d'élevage. Cette étude contribue à une meilleure compréhension des changements microbiens liés au stress auquel sont confrontés les veaux de boucherie et pourrait servir de base à d’autres études visant à proposer des méthodes alternatives de manipulation du microbiote pour prévenir les maladies et rétablir la santé des veaux. / The gastrointestinal microbiota plays an important role in maintaining the health of the host. It is composed of many microorganisms such as bacteria, viruses, fungi, and archaea. However, the majority of these microbial cells are bacterial cells, and for that reason, many studies focus on exploring especially bacterial communities in the GIT. Imbalance of the GIT microbiota, termed dysbiosis, has been observed in several conditions such as diarrhea, pneumonia, after antibiotic administration, or diet modification. The objective of this study was to characterize the dynamics of the fecal microbiota of veal calves entering a rearing unit. Fifty Holstein calves ranging from 8-14 days of life and arriving in a veal unit were enrolled in this study. Fecal samples were collected on arrival and on days 4 ,10 and 24 after arrival. Fecal scores, calves’ weight and antibiotic administration were recorded during the study. Sequencing was performed using the Illumina MiSeq platform and data analysed using the software Mothur. Contrary to expectations, richness and diversity were higher when the proportion of diarrheic animals were higher (p<0.001), and as expected, the microbiota composition and structure changed among days of collection (p>0.001), but the changes were not associated to presence or absence of diarrhea and antibiotic treatment as expected, they are associated to the sampling days. Diarrhea proportion (number of diarrheic calves per day) were numerically higher on days 4, 10 and 24 after arrival (As expected, the relative abundances of bacteria associated to health (i.e., Bifidobacterium, Lactobacillus and Faecalibacterium) were decreased in the diarrheic calves. Although analyzing diarrhea and antibiotic usage was not one of the objectives of this study, there was a tendence (p=0.09) in the weigh of the animals that had diarrhea and received antibiotics. The final weight of the sick calves that received antibiotics before slaughter were lower when compared to the final weigh of the animals that were not sick and did not received antibiotics (p=0.072). The main limitation of this study is the lack of information about calves’ origin before arrival at the rearing unit. This study contributes to the better understanding of the microbial changes related to the stress faced by veal calves and might be the basis for further studies to propose alternative methods of microbiota manipulation to prevent disease and restore health in calves.

Background: Chronic inflammatory enteropathy (CIE) in dogs is often associated with cobalamin deficiency. Hypocobalaminemia is also a risk factor for negative clinical outcomes in dogs with CIE and affected dogs may not respond to treatment unless receiving supplemental cobalamin. It has been proposed that the uptake of cobalamin from the intestinal lumen is compromised as a result of receptor deficiency in dogs with CIE, but the expression of the cobalamin receptor in dogs with chronic intestinal inflammation has not been studied. In addition to cobalamin deficiency, increased serum cobalamin concentrations could also be linked to relevant health conditions if not resulting from cobalamin supplementation. Cobalamin is essential for many cell functions, and both under- and oversupply may be associated with severe disease. Objectives: The study aimed to quantify protein and mRNA abundances of components involved in intestinal cobalamin uptake (i.e., amnionless [AMN], cubilin [CUBN], and the basolateral efflux transporter multi-drug resistance protein 1 [MRP1]) in ileal biopsies from dogs diagnosed with CIE compared to healthy dogs. These receptor levels were also evaluated in relation to the patient clinical, clinicopathologic, and histologic variables. Further, the study aimed to retrospectively determine the prevalence of hypercobalaminemia compared to hypocobalaminemia and its potential association with pathologies in a large group of dogs and cats. Material and Methods: The intestinal expression of the cobalamin receptor subunits AMN and CUBN, as well as MRP1, was evaluated in dogs with CIE (n=22) compared to healthy control dogs (n=9 for protein and n=11 for mRNA analysis). Epithelial CUBN and AMN levels were quantified by confocal laser scanning microscopy using immunofluorescent stainings in endoscopic ileal biopsies from dogs with (i) CIE and normocobalaminemia, (ii) CIE and suboptimal serum cobalamin status, (iii) CIE and severe hypocobalaminemia, and (iv) healthy controls. Expression of CUBN and MRP1 was also quantified by RT-qPCR. Receptor expression levels were analyzed for correlation with clinical patient data using non-parametric two- or multiple-group comparison or likelihood ratio tests and calculating correlation coefficients, applying a Bonferroni correction (significance at P<0.05) if indicated. For the second part of the study, medical records of all dogs and cats that presented at the Small Animal Clinic of the Leipzig University between 2007 and 2019 and had the serum cobalamin concentration measured were reviewed (1,227 cobalamin measurements). Patients receiving prior cobalamin supplementation or with incomplete medical record data were excluded from further analysis. The proportion of animals with hypercobalaminemia (serum cobalamin concentration >908 ng/L in dogs and >1,334 ng/L in cats) was calculated, and the association of hypercobalaminemia with individual patient characteristics and pathologic findings was evaluated. Results: Ileal mucosal protein levels of AMN and CUBN, as well as mRNA levels of CUBN and MRP1, were significantly increased in dogs with CIE, particularly those dogs with hypocobalaminemia, compared to healthy controls (all P=0.05). Ileal cobalamin receptor expression was positively correlated with age, clinical disease activity index (CCECAI) score, and lacteal dilation in the ileum, inversely correlated with serum folate concentrations but was not associated with serum cobalamin concentrations. Of the 654 dogs included in the second part of the study, 3% (n=21) were hypercobalaminemic, and 48% of these dogs had chronic gastrointestinal signs. Two of the 21 hypercobalaminemic dogs (10%) were diagnosed with hypoadrenocorticism, and adrenal insufficiency was significantly associated with hypercobalaminemia (P=0.031). Of the 315 cats included in the final analysis, 11% (n=34) were hypercobalaminemic. Of these cats, 65% (n=22) were diagnosed with chronic enteropathy, 24% (n=8) with acute or chronic pancreatitis, and 18% (n=6) with cholangiohepatopathy. Conclusions: Contrary to the previously proposed pathogenetic mechanism, cobalamin receptor downregulation does not appear to be the primary cause of hypocobalaminemia in canine CIE. Especially in dogs of older age, with severe clinical signs and/or more pronounced microscopic intestinal lesions, intestinal upregulation of the cobalamin receptor may be a mechanism to compensate for CIE-associated hypocobalaminemia. These findings also support an oral supplementation strategy in canine hypocobalaminemic patients with CIE. Hypercobalaminemia occurs infrequently in cats and less often in dogs. Increased serum cobalamin concentrations in patients without prior supplementation should not be ignored as they may indicate severe inflammatory, immunemediated, or neoplastic diseases.

Zytotoxische Chemotherapien, die zur Behandlung gastrointestinaler Karzinome eingesetzt werden, sind mit unerwünschten Wirkungen und insbesondere mit Hämatotoxizität verbunden. Diese können Behandlungsverzögerungen zur Folge haben, welche die Wirksamkeit der Tumortherapie und damit die Überlebenschancen verschlechtern. Chemotherapie-bedingte Nebenwirkungen sind variabel und das individuelle Risiko ist auf Grundlage klinischer Merkmale eines Patienten schwer vorherzusagen. Aus diesem Grund werden hierfür biomathematische Modelle der Hämatopoese unter Chemotherapie als modellbasierter Ansatz der Präzisionsmedizin vorgeschlagen. Bisher wurde die Leistung dieser Modelle nur in geringem Umfang für Therapien solider Tumore untersucht. In die vorliegende prospektive klinische multizentrische Beobachtungsstudie wurden 28 Patienten mit lokal fortgeschrittenem Adenokarzinom des Magens (n= 9, 32.1%), Ösophagus, ösophago-gastralen Übergangs (Typ I-III nach Siewert) (n=14, 50.0%) und Pankreaskarzinom (n=5, 17.9%) eingeschlossen, bei denen eine neoadjuvante oder adjuvante Chemotherapie mit dem FLO(T)- (5-Fluorouracil, Folinsäure, Oxaliplatin, Docetaxel) (n=23, 82.1%) oder FOLFIRINOX- (5-Fluorouracil, Folinsäure, Oxaliplatin und Irinotecan) Schema (n=5, 17.9%) geplant war. Während der Therapiezyklen wurden engmaschige Blutbildkontrollen durchgeführt. Darüber hinaus wurden die aufgetretenen Nebenwirkungen zu jedem Zyklus gemäß CTCAE v5.0 dokumentiert. Es wurde ein mechanistisches biomathematisches integriertes Modell der Hämatopoese, der Chemotherapie sowie der Wirkung hämatopoetischer Wachstumsfaktoren verwendet, um die individuelle, Chemotherapie-bedingte Hämatotoxizität eines Patienten vorherzusagen. Bei 21 Studienpatienten (75%) trat eine höhergradige hämatologische Toxizität (Grad 3 oder 4 nach CTCAE) auf, wobei es sich am häufigsten um eine Neutropenie handelte (n= 19, 67.9%). Für die Zyklen zwei, drei und sechs konnten die Neutropenie-Grade mit durchschnittlich weniger als einem Toxizitätsgrad Abweichung prognostiziert werden, die Leukopenie-Grade hingegen bis einschließlich Zyklus 6, die Thrombopenie-Grade sogar bis Zyklus 8. Somit unterschied sich die Vorhersagegenauigkeit für die verschiedenen hämatologischen Zelllinien. Die Übereinstimmung der Prognosen für die frühen Therapiezyklen (Zyklus 2 und 3) war für alle betrachteten Blutzelllinien und Therapie-Schemata ausgezeichnet. Bei den Prognosen für die späteren Therapiezyklen traten erwartungsgemäß größere Abweichungen zwischen den vorhergesagten und den klinisch beobachteten Toxizitätsgraden auf. Die Anwendung dieses biomathematischen Modells zur Vorhersage der individuellen hämatologischen Toxizität von Patienten mit gastrointestinalem Karzinom, die mit einem FLO(T)- oder FOLFIRINOX-Schema behandelt werden, führt selbst bei dieser heterogenen Population zu zuverlässigen Ergebnissen. Die Vorhersageleistung dieses Modells erwies sich für Kurzzeitprognosen als ausgezeichnet und für Langzeitprognosen als annehmbar. Der klinische Nutzen dieses präzisionsmedizinischen Ansatzes sollte in einer größeren prospektiven Kohorte weiter untersucht und validiert werden.

Gastrointestinale Tumorpatienten leiden bei ihrer Akutaufnahme im Krankenhaus und in der sich anschließenden Chemotherapie unter somatischen, psychischen und sozialen Belastungen, die sie psychoonkologisch behandlungsbedürftig erscheinen lassen. Bei 60 % dieser Patienten wurde ein solcher Behandlungsbedarf festgestellt. Das Anliegen der Arbeit war es, neben der Ermittlung des psychoonkologischen Betreuungsbedarfs, die Teilnahmebereitschaft dieser Patienten an einer psychoonkologischen Intervention festzustellen und zwei unterschiedliche Therapieverfahren (kognitiv-verhaltenstherapeutisch ausgerichtete Gesprächstherapie und Entspannungstherapie in Form einer progressiven Muskelrelaxation) mit einer Kontrollgruppe (Darreichung von Informationsmaterial über das Krankheitsbild) zu vergleichen. Es konnte ein positiver Effekt der Intervention, besonders der Gesprächstherapie, auf die Reduktion der Angst und Depression bei hoch belasteten Tumorpatienten nachgewiesen werden. Der Betreuungsbedarf derjenigen Patienten, die nur Informationsmaterial über die bösartige Krankheit erhielten, veränderte sich dagegen in der Zeit ihrer Chemotherapie nicht. Verlaufsabhängig konnte gezeigt werden, dass die Veränderung des psychoonkologischen Betreuungsbedarfs bereits kurz nach der Intervention einsetzt. Es gab aber auch Patienten, die erst im Verlauf der Intervention während der Chemotherapie einen psychoonkologischen Betreuungsbedarf entwickelten, den sie zu Beginn der Untersuchung nicht hatten. Auch diese Patienten konnten durch die psychotherapeutischen Interventionsmaßnahmen erfolgreich behandelt werden. / Gastrointestinal cancer patients who are hospitalized and receiving chemotherapy suffer from somatic, psychological, and social stresses that can be counteracted with psycho-oncological treatment. In fact, 60% of this population has been found to be in need of such services. The aim of this study was to determine how many patients in need of these services would be willing to participate in a psychosocial intervention, and to compare the outcomes of groups receiving two different therapeutic approaches (cognitive behavioral talk therapy and relaxation therapy in the form of a progressive muscle relaxation) with those of a control group, who were simply given written materials about their illness that included information on relevant psychosocial issues. The interventions, especially the talk therapy, were observed to have a positive effect on alleviating depression and anxiety in highly burdened cancer patients. The patients who only received written information about their disease showed no changes in the degree to which they needed psycho-oncological support over the time they were receiving chemotherapy. While some patients experienced improvements soon after the interventions had begun, there were also cases of patients who hadn’t initially exhibited a need for psycho-oncological support but later came to develop this need over the course of undergoing chemotherapy. These patients were also successfully treated through the psychotherapeutic interventions.

Os desfechos clínicos e oncológicos dos pacientes submetidos à ressecção endoscópica do câncer gástrico precoce (CGP), considerando os critérios de indicação, comparados à cirurgia, não foram relatados em revisões sistemáticas. A pesquisa foi desenvolvida para estabelecer os desfechos de curto e longo prazos da ressecção endoscópica comparada à cirurgia no tratamento do CGP, elevando as informações para o nível de evidência 2a, melhor respaldando a prática clínica. A revisão sistemática com metanálises foi procedida utilizando-se as bases Medline, Embase, Cochrane, LILACS, Scopus e CINAHL. Onze coortes retrospectivas foram selecionadas para análise qualitativa e quantitativa. Todos os estudos incluem pacientes com CGP e comparam os desfechos nos dois braços. Os dados envolveram 2654 pacientes que preenchiam os critérios absolutos ou expandidos para ressecção endoscópica. Diferentes modalidades de tratamento endoscópico foram avaliadas, principalmente os procedimentos de ressecção, como endoscopic mucosal resection (EMR) e endoscopic submucosal dissection (ESD). As informações basearam-se nas características dos participantes, critérios de inclusão e exclusão, tipos de intervenções e desfechos (diferentes taxas de sobrevida, eventos adversos, ressecção completa, recorrência e mortalidade). As análises dos riscos absolutos dos desfechos foram feitas com o software RevMan, computando-se as diferenças de risco (DR) das variáveis dicotômicas. Dados de DR e intervalo de confiança de 95% (IC) foram calculados utilizando-se o teste de Mantel-Haenszel e a inconsistência foi qualificada e reportada em ?2 e método Higgins (I2). A análise de sensibilidade foi feita quando a heterogeneidade era maior que 50%. Todas as análises basearam-se inicialmente no modelo de efeito fixo. Dados de sobrevida de 3 anos estavam disponíveis em seis estudos (n = 1197). Não houve DR após os dois tratamentos (DR = 0,01, IC 95% = -0,02 a 0,05). A sobrevida de 5 anos (n = 2310) não demonstrou diferença significativa entre os grupos analisados (DR = 0,01, IC 95% = -0,01 a 0,03). A avaliação de 551 pacientes não evidenciou desigualdade na sobrevida de 10 anos entre as diferentes abordagens (DR = -0,02, IC 95% = -0,15 a 0,10). Dados de complicação estavam presentes em oito estudos (n = 2439), e diferença significativa foi detectada (DR = -0,08, IC 95% = -0,10 a -0,05), demonstrando melhores resultados com a endoscopia. As taxas de ressecção completa foram analisadas em 536 pacientes. Evidenciou-se diferença significativa entre o tratamento endoscópico e cirúrgico (DR = -0,13, IC 95% = -0,17 a -0,09), validando melhores resultados no último grupo. A recorrência foi avaliada em cinco pesquisas (n = 1331) e não houve diferença entre as duas formas de terapêutica (DR = 0,01, IC 95% = -0,00 a 0,02). As taxas de mortalidade foram obtidas de quatro estudos (n = 1107), e não se evidenciou diferença entre os grupos envolvidos (DR = -0,01, IC 95% = -0,02 a 0,00). Conclui-se que as taxas de sobrevida de 3, 5 e 10 anos, recorrência e mortalidade são semelhantes em ambos os grupos. Considerando-se as taxas de complicação, a abordagem endoscópica confere resultados mais apropriados e, analisando-se as taxas de ressecção completa, ela é inferior à cirurgia / Clinical and oncological outcomes of endoscopic resection of early gastric cancer (EGC), considering the indication criteria, compared to surgery, have not been reported in systematic reviews. To address the short- and long-term outcomes of endoscopic resection compared to surgery in the treatment of EGC, a systematic review was performed, establishing the available data to an unpublished 2a strength of evidence, better handling clinical practice. A systematic review and meta-analysis using Medline, Embase, Cochrane, LILACS, Scopus and CINAHL databases were done. Eleven retrospective cohort studies were selected to quantitative and qualitative synthesis. All studies included patients diagnosed with EGC that compared outcomes considering endoscopic treatment and surgery. The included records involved 2654 patients with EGC that filled the standard or expanded indications for endoscopic resection. Different endoscopic treatment modalities were analyzed, mainly mucosal resection procedures such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), compared to surgery. Information of the selected studies was extracted on characteristics of trial participants, inclusion and exclusion criteria, types of interventions and outcomes (different survival rates, adverse events, complete resection, recurrence and mortality rates). The analysis of the absolute risks of the outcomes was performed using the software RevMan, by computing risk differences (RD) of dichotomous variables. Data on RD and 95% confidence interval (CI) for each outcome were calculated using the Mantel-Haenszel test and inconsistency was qualified and reported in X2 and the Higgins method (I2). Sensitivity analysis was performed when heterogeneity was higher than 50%. All pooled analyses were initially based on fixed-effects model. Three-year survival data were available for six studies (n = 1197). There were no RD in 3-year survival data after endoscopic and surgical treatment of EGC (RD = 0.01, 95% CI = -0.02 to 0.05). Five-year survival data (n = 2310) showed no evidence of a difference between the two groups (RD = 0.01, 95% CI = -0.01 to 0.03). The data analysis, in 551 patients, showed no difference in 10-year survival rates between the approaches (RD = -0.02 and 95% CI = -0.15 to 0.10). Complication data were identified in eight studies (n = 2439). A significant difference was detected (RD = -0.08, 95% CI = -0.10 to -0.05), demonstrating better results with endoscopic approach. Complete resection data was analyzed in 536 patients. It showed significant difference in complete resection rates between endoscopic and surgical treatment of EGC (RD = -0.13, 95% CI = -0.17 to -0.09), exhibiting improved results in the surgical group. Recurrence data were analyzed in five studies (n = 1331) and there was no difference between the approaches (RD = 0.01, 95% CI = -0.00 to 0.02). Mortality data were obtained in four studies (n = 1107), and there was no difference between treatment modalities (RD = -0.01, 95% CI = -0.02 to 0.00). This systematic review concludes that 3-, 5- and 10-year survival, recurrence and mortality rates are similar for both groups. Considering procedure-related complication rates, endoscopic approach achieves significantly better results and, analyzing complete resection data, it is considered worse than surgery

Na realização da colangiopancreatografia endoscópica retrógrada a cateterização da papila duodenal maior é passo fundamental na obtenção do acesso biliar profundo e correlaciona -se com complicações biliopancreáticas das quais a pancreatite aguda pós-CPER é a mais comum. Os objetivos deste trabalho foram: a) comparar o índice de sucesso na canulação seletiva da via biliar com uso do canulótomo e canulótomo com fio guia; b) comparar, entre ambos os grupos, as dosagens séricas de amilase, lipase e proteína C reativa; c) avaliar a incidência de pancreatite nos grupos em estudo. No período de julho de 2002 a outubro de 2003 foram realizadas 341 CPER em três Instituições de nível terciário, destas foram randomizados prospectivamente e de maneira consecutiva 300 pacientes para cateterização papilar com canulótomo (Grupo I) e canulótomo com fio guia (Grupo II). Os procedimentos endoscópicos foram realizados pelo autor nas três Instituições. Procedeu-se a caracterização do perfil técnico-laboratorial e avaliação da incidência de pancreatite através de métodos clínicolaboratoriais e imagenológicos, para ambos os grupos. Todos os pacientes do estudo foram mantidos internados por 24 horas após a CPRE. A cateterização inadvertida do ducto pancreático foi semelhante para os dois grupos (p= 0,161). A fistulopapilotomia foi mais freqüente no grupo I (p= 0,011), porém apresentou significativamente menor incidência de pancreatite aguda no grupo II (p= 0,041). As dosagens séricas de amilase coletadas quatro, 12 e 24 horas após CPER foram significativamente maior no grupo I (p= 0,0087; p= 0,045; p= 0,0474; respectivamente). As dosagens séricas de lipase e proteína C-reativa após a CPER foram similares para ambos os grupos. O tempo de manipulação pancreática apresentou elevação similar nas dosagens séricas de amilase após a CPRE, porém todas as dosagens de lipase coletadas após a CPER foram significativamente maior no grupo I para a categorização de um a cinco minutos (p= 0,025; p= 0,032; p= 0,049). O número de cateterizações pancreáticas categorizadas em uma a cinco vezes apresentou elevação significativamente maior no grupo I, para as amostras de amilase, lipase e proteína C-reativa coletadas quatro, 12 e 24 horas após a CPER (amilase: p=0,006; p= 0,0023; p= 0,0095/lipase: p= 0,13; p= 0,018; p= 0,028 / PC-R: p= 0,005; p= 0,01; p= 0,01). As papilotomias realizadas no grupo II apresentaram significativamente maior elevação das dosagens séricas de amilase coletadas 12 e 24 horas após a CPER (p= 0,033; p= 0,049). As dosagens séricas de lipase e proteína C-reativa apresentaram elevações similares tanto na papilotomia como na fistulopapilotomia. A pancreatite aguda pós-CPER foi significativamente maior no grupo I (p= 0,037). Conclusões: a) O acesso biliar através do cateter com fio guia proporcionou maior índice de sucesso na canulação biliar seletiva; b) No perfil laboratorial estudado a dosagem de amilase se mostrou com diferença significante na comparação entre os grupos estudados. O mesmo não ocorreu nas dosagens de lipase e PC-R; c) O uso do fio guia foi um fator de prevenção na ocorrência da pancreatite aguda pós-CPRE / During the endoscopic retrograde cholangiopancreatography (ERCP) the main step is the cannulation of major duodenal papilla to obtain deep bile duct access, and it is correlated to pancreaticobiliary complications being acute pancreatitis the most frequent. The aims were: a) compare the rate of success to achieve selective cannulation of common bile duct using a single cannula and cannula with guide-wire; b) compare the amylase, lypase and Creactive protein serum level between the groups; c) evaluate the incidence of pancreatitis in the groups. From July 2002 to October 2003 there were performed 341 ERCP on three institutions of tertiary level. From them, 300 patients were randomized, on a prospective and consecutive fashion to major duodenal papilla cannulation using single cannula (Group I) and cannula with guide wire (Group II). The author himself performed all the endoscopic procedures on the three institutions. The characterization of technicallaboratory profile and evaluation of the incidence of pancreatitis were proceeded by clinical-laboratory and image methods to both groups. All patients were hospitalized by 24 hours after ERCP. The cannulations of pancreatic duct were similar to both groups (p=0,161). The fistulosphincterotomy was more frequent in group I (p=0,011), but group II presented significant lower incidence of acute pancreatitis (p=0,041). The amylase serum were collected 4, 12 and 24 hours after ERCP and were significantly higher in group I (p=0,0087; p=0,045; p=0.0474, respectively). The lypase and C-reactive protein after ERCP were similar to both groups. The time of pancreatic manipulation presented similar elevation of amylase serum after ERCP, therefore all lypase serum after ERCP were significantly higher in group I for the categorization of 1 to 5 minutes (p=0,025; p=0,032;p=0,049). The number of pancreatic cannulations categorized in 1 to 5 times presented significant higher elevation in group I, to the samples of amylase, lypase and C-reactive protein serum collected 4, 12 and 24 hours after ERCP (amylase: p=0,006; p=0,0023; p=0,0095/ lypase: p=0,13; p=0,018;p=0,028/ C-RP: p=0,005; p=0,01; p=0,01). The endoscopic papillotomy performed in group II presented significant higher elevation of amylase serum collected at 12 and 24 hour post ERCP (p=0,033;p=0,049). The lypase and C-reactive protein serum presented similar elevation such as in papillotomy as in fistulosphincterotomy. The acute pancreatitis post ERCP were significantly higher in group I (p=0,037). Conclusion: a) The biliar access by cannula with guide wire offered a higher success to selective biliar cannulation; b) the laboratory profile of amylase serum showed a significant difference between the groups. It did not occur with lypase and C-reactive protein serum levels; c) the use of guide wire was a preventing factor of acute pancreatitis post ERCP

Os desfechos clínicos e oncológicos dos pacientes submetidos à ressecção endoscópica do câncer gástrico precoce (CGP), considerando os critérios de indicação, comparados à cirurgia, não foram relatados em revisões sistemáticas. A pesquisa foi desenvolvida para estabelecer os desfechos de curto e longo prazos da ressecção endoscópica comparada à cirurgia no tratamento do CGP, elevando as informações para o nível de evidência 2a, melhor respaldando a prática clínica. A revisão sistemática com metanálises foi procedida utilizando-se as bases Medline, Embase, Cochrane, LILACS, Scopus e CINAHL. Onze coortes retrospectivas foram selecionadas para análise qualitativa e quantitativa. Todos os estudos incluem pacientes com CGP e comparam os desfechos nos dois braços. Os dados envolveram 2654 pacientes que preenchiam os critérios absolutos ou expandidos para ressecção endoscópica. Diferentes modalidades de tratamento endoscópico foram avaliadas, principalmente os procedimentos de ressecção, como endoscopic mucosal resection (EMR) e endoscopic submucosal dissection (ESD). As informações basearam-se nas características dos participantes, critérios de inclusão e exclusão, tipos de intervenções e desfechos (diferentes taxas de sobrevida, eventos adversos, ressecção completa, recorrência e mortalidade). As análises dos riscos absolutos dos desfechos foram feitas com o software RevMan, computando-se as diferenças de risco (DR) das variáveis dicotômicas. Dados de DR e intervalo de confiança de 95% (IC) foram calculados utilizando-se o teste de Mantel-Haenszel e a inconsistência foi qualificada e reportada em ?2 e método Higgins (I2). A análise de sensibilidade foi feita quando a heterogeneidade era maior que 50%. Todas as análises basearam-se inicialmente no modelo de efeito fixo. Dados de sobrevida de 3 anos estavam disponíveis em seis estudos (n = 1197). Não houve DR após os dois tratamentos (DR = 0,01, IC 95% = -0,02 a 0,05). A sobrevida de 5 anos (n = 2310) não demonstrou diferença significativa entre os grupos analisados (DR = 0,01, IC 95% = -0,01 a 0,03). A avaliação de 551 pacientes não evidenciou desigualdade na sobrevida de 10 anos entre as diferentes abordagens (DR = -0,02, IC 95% = -0,15 a 0,10). Dados de complicação estavam presentes em oito estudos (n = 2439), e diferença significativa foi detectada (DR = -0,08, IC 95% = -0,10 a -0,05), demonstrando melhores resultados com a endoscopia. As taxas de ressecção completa foram analisadas em 536 pacientes. Evidenciou-se diferença significativa entre o tratamento endoscópico e cirúrgico (DR = -0,13, IC 95% = -0,17 a -0,09), validando melhores resultados no último grupo. A recorrência foi avaliada em cinco pesquisas (n = 1331) e não houve diferença entre as duas formas de terapêutica (DR = 0,01, IC 95% = -0,00 a 0,02). As taxas de mortalidade foram obtidas de quatro estudos (n = 1107), e não se evidenciou diferença entre os grupos envolvidos (DR = -0,01, IC 95% = -0,02 a 0,00). Conclui-se que as taxas de sobrevida de 3, 5 e 10 anos, recorrência e mortalidade são semelhantes em ambos os grupos. Considerando-se as taxas de complicação, a abordagem endoscópica confere resultados mais apropriados e, analisando-se as taxas de ressecção completa, ela é inferior à cirurgia / Clinical and oncological outcomes of endoscopic resection of early gastric cancer (EGC), considering the indication criteria, compared to surgery, have not been reported in systematic reviews. To address the short- and long-term outcomes of endoscopic resection compared to surgery in the treatment of EGC, a systematic review was performed, establishing the available data to an unpublished 2a strength of evidence, better handling clinical practice. A systematic review and meta-analysis using Medline, Embase, Cochrane, LILACS, Scopus and CINAHL databases were done. Eleven retrospective cohort studies were selected to quantitative and qualitative synthesis. All studies included patients diagnosed with EGC that compared outcomes considering endoscopic treatment and surgery. The included records involved 2654 patients with EGC that filled the standard or expanded indications for endoscopic resection. Different endoscopic treatment modalities were analyzed, mainly mucosal resection procedures such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), compared to surgery. Information of the selected studies was extracted on characteristics of trial participants, inclusion and exclusion criteria, types of interventions and outcomes (different survival rates, adverse events, complete resection, recurrence and mortality rates). The analysis of the absolute risks of the outcomes was performed using the software RevMan, by computing risk differences (RD) of dichotomous variables. Data on RD and 95% confidence interval (CI) for each outcome were calculated using the Mantel-Haenszel test and inconsistency was qualified and reported in X2 and the Higgins method (I2). Sensitivity analysis was performed when heterogeneity was higher than 50%. All pooled analyses were initially based on fixed-effects model. Three-year survival data were available for six studies (n = 1197). There were no RD in 3-year survival data after endoscopic and surgical treatment of EGC (RD = 0.01, 95% CI = -0.02 to 0.05). Five-year survival data (n = 2310) showed no evidence of a difference between the two groups (RD = 0.01, 95% CI = -0.01 to 0.03). The data analysis, in 551 patients, showed no difference in 10-year survival rates between the approaches (RD = -0.02 and 95% CI = -0.15 to 0.10). Complication data were identified in eight studies (n = 2439). A significant difference was detected (RD = -0.08, 95% CI = -0.10 to -0.05), demonstrating better results with endoscopic approach. Complete resection data was analyzed in 536 patients. It showed significant difference in complete resection rates between endoscopic and surgical treatment of EGC (RD = -0.13, 95% CI = -0.17 to -0.09), exhibiting improved results in the surgical group. Recurrence data were analyzed in five studies (n = 1331) and there was no difference between the approaches (RD = 0.01, 95% CI = -0.00 to 0.02). Mortality data were obtained in four studies (n = 1107), and there was no difference between treatment modalities (RD = -0.01, 95% CI = -0.02 to 0.00). This systematic review concludes that 3-, 5- and 10-year survival, recurrence and mortality rates are similar for both groups. Considering procedure-related complication rates, endoscopic approach achieves significantly better results and, analyzing complete resection data, it is considered worse than surgery

Na realização da colangiopancreatografia endoscópica retrógrada a cateterização da papila duodenal maior é passo fundamental na obtenção do acesso biliar profundo e correlaciona -se com complicações biliopancreáticas das quais a pancreatite aguda pós-CPER é a mais comum. Os objetivos deste trabalho foram: a) comparar o índice de sucesso na canulação seletiva da via biliar com uso do canulótomo e canulótomo com fio guia; b) comparar, entre ambos os grupos, as dosagens séricas de amilase, lipase e proteína C reativa; c) avaliar a incidência de pancreatite nos grupos em estudo. No período de julho de 2002 a outubro de 2003 foram realizadas 341 CPER em três Instituições de nível terciário, destas foram randomizados prospectivamente e de maneira consecutiva 300 pacientes para cateterização papilar com canulótomo (Grupo I) e canulótomo com fio guia (Grupo II). Os procedimentos endoscópicos foram realizados pelo autor nas três Instituições. Procedeu-se a caracterização do perfil técnico-laboratorial e avaliação da incidência de pancreatite através de métodos clínicolaboratoriais e imagenológicos, para ambos os grupos. Todos os pacientes do estudo foram mantidos internados por 24 horas após a CPRE. A cateterização inadvertida do ducto pancreático foi semelhante para os dois grupos (p= 0,161). A fistulopapilotomia foi mais freqüente no grupo I (p= 0,011), porém apresentou significativamente menor incidência de pancreatite aguda no grupo II (p= 0,041). As dosagens séricas de amilase coletadas quatro, 12 e 24 horas após CPER foram significativamente maior no grupo I (p= 0,0087; p= 0,045; p= 0,0474; respectivamente). As dosagens séricas de lipase e proteína C-reativa após a CPER foram similares para ambos os grupos. O tempo de manipulação pancreática apresentou elevação similar nas dosagens séricas de amilase após a CPRE, porém todas as dosagens de lipase coletadas após a CPER foram significativamente maior no grupo I para a categorização de um a cinco minutos (p= 0,025; p= 0,032; p= 0,049). O número de cateterizações pancreáticas categorizadas em uma a cinco vezes apresentou elevação significativamente maior no grupo I, para as amostras de amilase, lipase e proteína C-reativa coletadas quatro, 12 e 24 horas após a CPER (amilase: p=0,006; p= 0,0023; p= 0,0095/lipase: p= 0,13; p= 0,018; p= 0,028 / PC-R: p= 0,005; p= 0,01; p= 0,01). As papilotomias realizadas no grupo II apresentaram significativamente maior elevação das dosagens séricas de amilase coletadas 12 e 24 horas após a CPER (p= 0,033; p= 0,049). As dosagens séricas de lipase e proteína C-reativa apresentaram elevações similares tanto na papilotomia como na fistulopapilotomia. A pancreatite aguda pós-CPER foi significativamente maior no grupo I (p= 0,037). Conclusões: a) O acesso biliar através do cateter com fio guia proporcionou maior índice de sucesso na canulação biliar seletiva; b) No perfil laboratorial estudado a dosagem de amilase se mostrou com diferença significante na comparação entre os grupos estudados. O mesmo não ocorreu nas dosagens de lipase e PC-R; c) O uso do fio guia foi um fator de prevenção na ocorrência da pancreatite aguda pós-CPRE / During the endoscopic retrograde cholangiopancreatography (ERCP) the main step is the cannulation of major duodenal papilla to obtain deep bile duct access, and it is correlated to pancreaticobiliary complications being acute pancreatitis the most frequent. The aims were: a) compare the rate of success to achieve selective cannulation of common bile duct using a single cannula and cannula with guide-wire; b) compare the amylase, lypase and Creactive protein serum level between the groups; c) evaluate the incidence of pancreatitis in the groups. From July 2002 to October 2003 there were performed 341 ERCP on three institutions of tertiary level. From them, 300 patients were randomized, on a prospective and consecutive fashion to major duodenal papilla cannulation using single cannula (Group I) and cannula with guide wire (Group II). The author himself performed all the endoscopic procedures on the three institutions. The characterization of technicallaboratory profile and evaluation of the incidence of pancreatitis were proceeded by clinical-laboratory and image methods to both groups. All patients were hospitalized by 24 hours after ERCP. The cannulations of pancreatic duct were similar to both groups (p=0,161). The fistulosphincterotomy was more frequent in group I (p=0,011), but group II presented significant lower incidence of acute pancreatitis (p=0,041). The amylase serum were collected 4, 12 and 24 hours after ERCP and were significantly higher in group I (p=0,0087; p=0,045; p=0.0474, respectively). The lypase and C-reactive protein after ERCP were similar to both groups. The time of pancreatic manipulation presented similar elevation of amylase serum after ERCP, therefore all lypase serum after ERCP were significantly higher in group I for the categorization of 1 to 5 minutes (p=0,025; p=0,032;p=0,049). The number of pancreatic cannulations categorized in 1 to 5 times presented significant higher elevation in group I, to the samples of amylase, lypase and C-reactive protein serum collected 4, 12 and 24 hours after ERCP (amylase: p=0,006; p=0,0023; p=0,0095/ lypase: p=0,13; p=0,018;p=0,028/ C-RP: p=0,005; p=0,01; p=0,01). The endoscopic papillotomy performed in group II presented significant higher elevation of amylase serum collected at 12 and 24 hour post ERCP (p=0,033;p=0,049). The lypase and C-reactive protein serum presented similar elevation such as in papillotomy as in fistulosphincterotomy. The acute pancreatitis post ERCP were significantly higher in group I (p=0,037). Conclusion: a) The biliar access by cannula with guide wire offered a higher success to selective biliar cannulation; b) the laboratory profile of amylase serum showed a significant difference between the groups. It did not occur with lypase and C-reactive protein serum levels; c) the use of guide wire was a preventing factor of acute pancreatitis post ERCP