Helicobacter pylori causes chronic gastritis, peptic ulceration and gastric cancer. This bacterium is one of the most prevalent in the world, but affects mostly the populations with a lower socioeconomical status. While it causes gastric and duodenal ulcers in only 20% of infected patients, less then 1% will develop gastric adenocarcinoma. In fact, H. pylori is the most important risk factor in developing gastric cancer. Epidemiological studies have shown that 80% of gastric cancer patients are H. pylori positive. The outcome of the infection with this bacterium depends on bacterial factors, diet, genetic background of the host, and coinfection with other microorganisms. The most important cofactor in H. pylori induced disease is the host immune response, even though the exact mechanism of how the bacterium is causing disease is unknown. The structural complexity of Helicobacter bacteria makes us believe that different bacterial factors interact with different components of the innate immunity. However, as a whole bacterium it may need mainly the TLR2 receptor to trigger an immune response. The type of adaptive immunity developed in response to Helicobacter is crucial in determining the consequences of infection. It is now known for decades that a susceptible host will follow the infection with a strong Th1 immune response. IFNγ, IL-12, IL-1β and TNF-α are the key components of a strong adaptive Th1 response. This is further supported by our work, where deficient T-bet (a master regulator for Th1 response) mice were protected against gastric cancer, despite maintaining an infection at similar levels to wild type mice. On the other hand, a host that is resistant to Helicobacter develops an infection that is followed by a Th2 response sparing the mucosa from severe inflammation. Human studies looking at single nucleotide polymorphism of cytokines, like IL-1β, IL-10 and TNF-α have clearly demonstrated how genotypes that result in high levels of IL-1β and TNF-α, but low IL-10 expression may confer a 50-fold higher risk in developing gastric cancer. The outcome of Helicobacter infection clearly relies on the immune response and genetic background, however the coinfection of the host with other pathogens should not be ignored as this may result in modulation of the adaptive immunity. In studying this, we took advantage of the Balb/C mice that are known to be protected against Helicobacter induced inflammation by mounting a strong Th2 polarization. We were able to switch their adaptive immunity to Th1 by coinfected them with a T. gondii infection (a well known Th1 infection in mice). The dual infected mice developed severe gastritis, parietal cell loss and metaplastic changes. These experiments have clearly shown how unrelated pathogens may interact and result in different clinical outcomes of the infected host. A strong immune response that results in severe inflammation will also cause a cascade of apoptotic changes in the mucosa. A strict balance between proliferation and apoptosis is needed, as its disruption may result in uncontrolled proliferation, transformation and metaplasia. The Fas Ag pathway is the leading cause of apoptosis in the Helicobacter-induced inflammation. One mechanism for escaping Fas mediating apoptosis is upregulation of MHCII receptor. Fas Ag and MHCII receptor interaction inhibits Fas mediated apoptosis by an impairment of the Fas Ag receptor aggregation when stimulated by Fas ligand. Because H. pylori infection is associated with an upregulation of the MHCII levels on gastric epithelial cells, this indeed may be one mechanism by which cells escape apoptosis. The link between chronic inflammation and cancer is well known since the past century. Helicobacter infection is a prime example how a chronic inflammatory state is causing uncontrolled cell proliferation that results in cancer. The cell biology of “cancer” is regarded not as an accumulation of cells that divide without any control, but rather as an organ formed of cancer stem cells, tumor stromal support cells, myofibroblasts and endothelial cells, which function as a group. The properties of the cancer stem cells are to self-renew and differentiate into tumor cells thus maintaining the tumor grow, emphasizing that a striking similarity exists between cancer stem cells and tissue stem cells. We looked into what role would BMDCs play in chronic inflammation that causes cancer. Using the mouse model of Helicobacter induced adenocarcinoma we discovered that gastric cancer originates from a mesenchymal stem cell coming from bone marrow. We believe that chronic inflammation, in our case of the stomach, sets up the perfect stage for bone marrow stem cells to migrate to the stomach where they are exposed to inflammatory stimuli and transform into cancer stem cells. One of the mechanism by which the MSC migrate to the inflammation site is the CXCR4/SDF-1 axis. Our work sheds new light on Helicobacter induced gastric cancer pathogenesis. I hope that our findings will promote the development of new therapies in the fight against this deadly disease.

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

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