Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed.

In-depth characterization has introduced new molecular subtypes of gastric cancer (GC). To identify these, new approaches and techniques are required. Liquid biopsies are trendsetting and provide an easy and feasible method to identify and to monitor GC patients. In a prospective cohort of 87 GC patients, extracellular vesicles (EVs) were isolated from 250 µL of plasma. The total RNA was isolated with TRIZOL. The total RNA amount and the relative mRNA levels of CD44, PTEN, and FASN were measured by qRT-PCR. The isolation of EVs and their contained mRNA was possible in all 87 samples investigated. The relative mRNA levels of PTEN were higher in patients already treated by chemotherapy than in chemo-naïve patients. In patients who had undergone neoadjuvant chemotherapy followed by gastrectomy, a decrease in the total RNA amount was observed after neoadjuvant chemotherapy and gastrectomy, while FASN and CD44 mRNA levels decreased only after gastrectomy. The amount of RNA and the relative mRNA levels of FASN and CD44 in EVs were affected more significantly by chemotherapy and gastrectomy than by chemotherapy alone. Therefore, they are a potential biomarker for monitoring treatment response. Future analyses are needed to identify GC-specific key RNAs in EVs, which could be used for the diagnosis of gastric cancer patients in order to determine their molecular subtype and to accompany the therapeutic response.

Gastric and esophagogastric junction cancers are heterogeneous and aggressive tumors with an unpredictable response to cytotoxic treatment. New methods allowing for the analysis of drug resistance are needed. Here, we describe a novel technique by which human tumor specimens can be cultured ex vivo, preserving parts of the natural cancer microenvironment. Using a tissue chop- per, fresh surgical tissue samples were cut in 400 μm slices and cultivated in 6-well plates for up to 6 days. The slices were processed for routine histopa- thology and immunohistochemistry. Cytokeratin stains (CK8, AE1/3) were ap- plied for determining tumor cellularity, Ki-67 for proliferation, and cleaved caspase-3 staining for apoptosis. The slices were analyzed under naive conditions and following 2–4 days in vitro exposure to 5-FU and cisplatin. The slice culture technology allowed for a good preservation of tissue morphology and tumor cell integrity during the culture period. After chemotherapy exposure, a loss of tumor cellularity and an increase in apoptosis were observed. Drug sensitivity of the tumors could be assessed. Organotypic slice cultures of gastric and es- ophagogastric junction cancers were successfully established. Cytotoxic drug effects could be monitored. They may be used to examine mechanisms of drug resistance in human tissue and may provide a unique and powerful ex vivo platform for the prediction of treatment response.

A técnica de análise de sobrevivência tem sido muito utilizada por pesquisadores na área de saúde. Neste trabalho foi usada uma distribuição em análise de sobrevivência recentemente estudada, chamada distribuição exponencial generalizada. Esta distribuição foi estudada sob todos os aspectos: para dados completos e censurados, sob a presençaa de covariáveis e considerando sua extensão para um modelo multivariado derivado de uma função cópula. Para exemplificação desta nova distribuição, foram utilizados dados reais de câncer (leucemia mielóide aguda e câncer gástrico) que possuem a presença de censuras e covariáveis. Os dados referentes ao câncer gástrico tem a particularidade de apresentar dois tempos de sobrevida, um relativo ao tempo global de sobrevida e o outro relativo ao tempo de sobrevida livre do evento, que foi utilizado para a aplicação do modelo multivariado. Foi realizada uma comparação com outras distribuições já utilizadas em análise de sobrevivência, como a distribuiçãoo Weibull e a Gama. Para a análise bayesiana adotamos diferentes distribuições a priori para os parâmetros. Foi utilizado, nas aplicações, métodos de simulação de MCMC (Monte Carlo em Cadeias de Markov) e o software Winbugs. / Survival analysis methods has been extensively used by health researchers. In this work it was proposed the use a survival analysis model recently studied, denoted as generalized exponential distribution. This distribution was studied in all respects: for complete data and censored, in the presence of covariates and considering its extension to a multivariate model derived from a copula function. To exemplify the use of these models, it was considered real cancer lifetime data (acute myeloid leukemia and gastric cancer) in presence of censored data and covariates. The assumed cancer gastric lifetime data has two survival responses, one related to the total lifetime of the patient and another one related to the time free of the disease, that is, multivariate data associated to each patient. In these applications there was considered a comparative study with standard existing lifetime distributions, as Weibull and gamma distributions.For a Bayesian analysis we assumed different prior distributions for the parameters of the model. For the simulation of samples of the joint posterior distribution of interest, we used standard MCMC (Markov Chain Monte Carlo) methods and the software Winbugs.

CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior / As metaloproteinases-2 (MMP-2) e -14 (MMP-14) e o inibidor tecidual de metaloproteinases tipo 2 (TIMP-2) participam de modo fundamental na transiÃÃo epitelial-mesenquimal e progressÃo tumoral-linfonodal de muitos tipos de cÃncer, inclusive o gÃstrico. O objetivo deste trabalho à avaliar a expressÃo das trÃs enzimas no carcinoma gÃstrico e metÃstases linfonodais e suas possÃveis participaÃÃes na progressÃo tumoral. Foram utilizados 83 casos de gastrectomias por cÃncer gÃstrico (histotipo intestinal = 53 casos; difuso = 30 casos), e seus respectivos linfonodos, dos arquivos do Departamento de Patologia e Medicina Legal/UFC. Foi realizado tissue microarray e imunohistoquÃmica com anticorpo monoclonal anti-MMP-2, anti-MMP-14 e anti-TIMP-2, avaliada atravÃs dos seguintes escores: 0 = ausÃncia de imunomarcaÃÃo ou raras cÃlulas marcadas (< 5%); 1 = marcaÃÃo discreta na maioria (> 50%) das cÃlulas tumorais ou inflamatÃrias mononucleadas (muitos dos quais identificados como macrÃfagos pelo CD68) ou marcaÃÃo moderada em minoria de cÃlulas (< 50%); 2 = marcaÃÃo moderada na maioria (> 50%) das cÃlulas tumorais ou inflamatÃrias mononucleadas ou marcaÃÃo intensa em minoria de cÃlulas (< 50%); 3 = marcaÃÃo intensa na maioria (> 50%) das cÃlulas tumorais ou inflamatÃrias mononucleadas. A expressÃo de MMP-2, MMP-14 e TIMP-2 nos mononucleares associados a tumores ocorreu com maior frequÃncia comparada à imunomarcaÃÃo em mononucleares da mucosa normal, com diferenÃa significativa em relaÃÃo a TIMP-2 (40/53 vs 12/26; *p = 0,0128, teste exato de Fisher). MMP-2 foi muito mais presente nas mulheres (p = 0,0248) enquanto TIMP-2 ocorreu predominantemente apÃs os 50 anos (p = 0,0034). A expressÃo dos trÃs biomarcadores nos carcinomas gÃstricos primÃrios foi muito superior nos mononucleares, em relaÃÃo Ãs cÃlulas neoplÃsicas, sobretudo para a MMP-2 (16/46 vs 5/46; *p = 0,0118), que tambÃm prevaleceu em mononucleares das metÃstases linfonodais em tumores dos histotipos intestinal e difuso (13/16 vs 4/19; ***p = 0,0006). Neste estudo, a expressÃo preponderante dos trÃs imunomarcadores pelos mononucleares do conjuntivo reforÃa o papel central destas cÃlulas e do microambiente tumoral na progressÃo do cÃncer gÃstrico. A maior expressÃo de TIMP-2 no sÃtio primÃrio à sugestiva do efeito inibitÃrio desta enzima sobre MMP-2 e MMP-14, que parecem participar principalmente em fases mais avanÃadas da progressÃo tumoral-linfonodal. A MMP-14, atravÃs dos mononucleares, parece estar mais envolvida na progressÃo do cÃncer gÃstrico difuso do que a MMP-2 e seu inibidor tissular.

A técnica de análise de sobrevivência tem sido muito utilizada por pesquisadores na área de saúde. Neste trabalho foi usada uma distribuição em análise de sobrevivência recentemente estudada, chamada distribuição exponencial generalizada. Esta distribuição foi estudada sob todos os aspectos: para dados completos e censurados, sob a presençaa de covariáveis e considerando sua extensão para um modelo multivariado derivado de uma função cópula. Para exemplificação desta nova distribuição, foram utilizados dados reais de câncer (leucemia mielóide aguda e câncer gástrico) que possuem a presença de censuras e covariáveis. Os dados referentes ao câncer gástrico tem a particularidade de apresentar dois tempos de sobrevida, um relativo ao tempo global de sobrevida e o outro relativo ao tempo de sobrevida livre do evento, que foi utilizado para a aplicação do modelo multivariado. Foi realizada uma comparação com outras distribuições já utilizadas em análise de sobrevivência, como a distribuiçãoo Weibull e a Gama. Para a análise bayesiana adotamos diferentes distribuições a priori para os parâmetros. Foi utilizado, nas aplicações, métodos de simulação de MCMC (Monte Carlo em Cadeias de Markov) e o software Winbugs. / Survival analysis methods has been extensively used by health researchers. In this work it was proposed the use a survival analysis model recently studied, denoted as generalized exponential distribution. This distribution was studied in all respects: for complete data and censored, in the presence of covariates and considering its extension to a multivariate model derived from a copula function. To exemplify the use of these models, it was considered real cancer lifetime data (acute myeloid leukemia and gastric cancer) in presence of censored data and covariates. The assumed cancer gastric lifetime data has two survival responses, one related to the total lifetime of the patient and another one related to the time free of the disease, that is, multivariate data associated to each patient. In these applications there was considered a comparative study with standard existing lifetime distributions, as Weibull and gamma distributions.For a Bayesian analysis we assumed different prior distributions for the parameters of the model. For the simulation of samples of the joint posterior distribution of interest, we used standard MCMC (Markov Chain Monte Carlo) methods and the software Winbugs.

Orientador: Ana Elizabete Silva / Banca: Maria Inês Moura Pardini / Banca: Fátima Pereira de Souza / Resumo: O câncer gástrico é a segunda causa de morte por câncer no mundo e o quinto tipo com maior prevalência no Brasil, sendo previstos 21.800 casos novos em 2008. Esta neoplasia apresenta etiologia bastante complexa, envolvendo fatores genéticos e ambientais. Os fatores etiológicos de maiores destaques incluem a infecção pela bactéria Helicobacter pylori, a ingestão de determinados alimentos, como defumados, enlatados e com elevada quantidade de sal, além do estilo de vida dos indivíduos, associado ao consumo de cigarro e álcool. Uma lesão pré-cancerosa importante no desenvolvimento da neoplasia gástrica é a metaplasia intestinal, podendo aumentar o seu risco em até 10 vezes. Atualmente é reconhecida a participação de alterações epigenéticas como metilação aberrante do DNA, que atua de forma igualmente relevante e complementar no processo de desenvolvimento e progressão do câncer. Vários genes com papel importante no controle do ciclo celular, reparo do DNA, apoptose, angiogênese e adesão celular podem apresentar expressão alterada devido metilação aberrante de sua região promotora, assim a investigação do padrão de metilação de genes envolvidos com o processo neoplásico pode ser uma estratégia interessante para a indicação de marcadores moleculares que possam auxiliar no diagnóstico precoce do câncer. Desta forma, no presente trabalho foi investigado o padrão de metilação dos genes WT1 e RARß em metaplasia intestinal (35 amostras) e suas respectivas mucosas gástricas normais, em comparação com o câncer gástrico (8 amostras) também com suas respectivas mucosas normais, através da técnica MS-PCR (Methylation Specific PCR). Devido à participação da infecção pela H. pylori na carcinogênese gástrica, foi investigada molecularmente a presença dessa bactéria nas amostras...(Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Worldwide, the gastric cancer is the second cause of death by cancer. In Brazil, it is the fifth type with more abundant, foreseen 21.800 new cases in 2008. This neoplasia presents very complex etiology involving genetic and environmental factors. The main etiologic factors include: infection by H. pylori, intake of specific foods such as curing food, canned food, and high consumption of salt wealthy food, besides people life style associated to alcohol and cigarette consumptions. An important previous-cankered lesion in development of gastric neoplasia is the intestinal metaplasia, what can increase your risk in ten times. At this moment, it is recognized the participation of epigenetic alterations like ADN aberrant methylation, which actuate in a same way considerable and complementary in development process and cancer evolution. Many genes with important role in control of cellular cycle, ADN repair, apoptosis, angiogenesis and cellular adhesion can present changed expression due aberrant metthylation of your promoter region. In this manner, the investigation of metithyation pattern of genes involved with the neoplasic process can be an interesting strategy for the indication of molecular markers that can help in cancer precocious diagnosis. Thus, in this present study were investigated the metthylation pattern of RARß and WT1genes (35 samples) and their respective normal mucous gastrics by technic MSPCR (Methylation Specific PCR). Due to participation of infection by H. pylori in gastric carcinogenesis, it was too molecular investigated the presence of this bacterium in the studied samples and the possible association with the metthylation pattern presented by both genes. The results showed high pattern of methylation in both valued lesions, that is, 97% and 100%, respectively of methylated samples in metaplasia group ...(Complete abstract click electronic access below) / Mestre

Visame pasaulyje skrandžio vėžys yra didelė problema, kasmet diagnozuojama apie 875000 naujų atvejų ir 645000 miršta nuo šios ligos. Lietuvos vėžio registro duomenimis, 2005 m. Lietuvoje sergamumas skrandžio vėžiu buvo 35,0 vyrų ir 22,1 moterų tarpe 100000 gyventojų. Šis susirgimas vis dar dažniausiai diagnozuojamas vėlyvose stadijose, kuomet radikali operacija jau nėra galima. Skrandžio vėžio vystymasis yra kompleksinis ir šiuo metu dar pilnai neišaiškintas procesas. Nauji tyrimai patvirtino, kad epigenetinė pažaida – TPEF/HPP1 geno metilinimas yra dažnas reiškinys tulžies ir šlapimo pūsles, kolorektalinio vėžio atvejais. Vis dėlto, nebuvo pakankamai duomenų apie TPEF/HPP1 geno metilinimo reikšmę skrandžio kancerogenezėje. Atliktame tyrime nustatyta, kad TPEF/HPP1 geno metilinimas gali būti ankstyvas šio pažeidimo požymis. Taip pat galima daryti prielaidą, kad TPEF/HPP1 genas yra skrandžio naviką slopinantis genas. Kitas svarbus skrandžio vėžio rizikos faktorius yra H. pylori sąlygotas atrofinis gastritas. Tyrimo metu nustatytas didelis vyresnių nei 55 m. dispepsija sergančių pacientų infekuotumas H. pylori. Statistiškai patikimo skirtumo tarp atrofijos ir žarninės metaplazijos dažnumo dispepsija sergantiems pacientams Taivanyje, Lietuvoje, Latvijoje negauta. Buvo nustatyta stipri koreliacija tarp skrandžio atrofijos ir žarninės metaplazijos. Klinikinėje praktikoje atrofinis gastritas patvirtinamas histologiškai (pagal 1994 m. Hiūstone modifikuotą Sidnėjaus klasifikaciją)... [toliau žr. visą tekstą] / INTRODUCTION Gastric cancer is rampant in many countries around the world and it accounts for approximately 875000 new cases and 645000 deaths annually [Jemal A et al, 2004]. While overall incidence of gastric cancer is falling, in many countries of the world it remains one the most frequent causes of cancer related deaths. According to GLOBOCAN age-standardized cancer incidence data, in Germany 15.1 males and 8.8 females per 100.000 persons developed gastric cancer in 2002, in Lithuania – 25.3 males and 13.0 females, in Latvia – 24.6 males and 11.1 females, respectively. According to the data of Lithuanian Cancer Registry, gastric cancer incidence was 35.0 in male, 22.1 in female per 100.000 persons in 2005, 30.4 in male, 17.8 in female in 2004, respectively [Kurtinaitis J, 2004]. At present, primary or secondary prevention is likely to be the most effective means of reducing the incidence and mortality from this disease. However, to be successful, this strategy depends upon knowledge of the etiological factors and pathogenetic mechanisms involved in gastric carcinogenesis. Helicobacter pylori (H. pylori) has been categorized as a group I carcinogen by the International Agency for Research on Cancer and World Health Organization (WHO) in 1994. Development of gastric cancer is a complex and poorly understood process. It is clear that besides chronic gastritis caused by H. pylori, dietary factors, high salt and nitrate intake, smoking and, possibly, alcohol consumption are... [to full text]

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Le T-DM1 est un immunoconjugué composé de l'anticorps trastuzumab qui cible HER2 lié au DM1, un agent anti-tubuline dérivé de la maytansine. Malgré son efficacité, la résistance acquise au T-DM1 a été démontré lors des tests précliniques et chez certains patients. Nous avons développé des lignées résistantes à partir de la lignée de cancer du sein MDA-MB-361 et de la lignée de cancer de l'œsophage OE-19, que nous avons exposées au T-DM1 à doses croissantes pendant une longue durée en absence ou en présence de ciclosporine A (CsA). A partir de ces conditions nous avons obtenus les lignées “TR” qui ont été exposées uniquement au T-DM1 et “TCR” qui ont été exposées au T-DM1 et CsA. Nous avons observé une augmentation de la vitesse de migration et une diminution de la force d'adhésion chez OE-19 TCR associées à une sensibilité accrue à un inhibiteur de RHOA. Aussi, la voie des prostaglandines était dérégulée chez OE-19 TR et TCR, avec une forte augmentation de l'expression de COX-2 et de prostaglandine E2 dans la lignée OE-19 TR. La sensibilité à l'aspirine, un inhibiteur des cyclooxygenases 1-2, était accrue chez les deux lignées OE-19 résistantes par rapport à la lignée parentale. En conclusion nous avons démontré que différentes voies de signalisation peuvent être impliquées dans la résistance au T-DM1. Nos résultats restent à être validés chez les patients. Nous suggérons que cibler la voie de régulation de la composition du cytosquelette ou la voie des prostaglandines pourrait permettre d'obtenir un effet thérapeutique dans le cas de cancers résistants au T-DM1 / T-DM1 is an antibody-drug conjugate composed of the monoclonal antibody trastuzumab linked to DM1, a potent tubulin binding agent. Despite its efficacy in the treatment of HER2-positive breast cancer patients, acquired resistance to T-DM1 was observed during clinical trials. In order to study resistance mechanisms to T-DM1, we developed resistance models using OE-19 (esophageal) and MDA-MB-361 (breast) cancer cell lines in the absence or presence of ciclosporin A (CsA), an inhibitor of MDR1 mediated efflux. Resistant cells selected with T-DM1 alone are named “TR” and cells selected in the presence of T-DM1 and CsA are called “TCR”. OE-19 TCR cells showed modifications in adhesion gene expression, migration and adhesion strength, combined with an increased sensitivity to a RHOA inhibitor. Also, OE-19 TR cells presented an overexpression of COX-2 associated with an increased amount of PGE2 in the supernatant. A deregulation of the genes involved in the prostaglandin pathways was found in OE-19 TR and TCR cells, associated with increased sensitivity to aspirin. In conclusion, we found two signaling pathways deregulated in cell lines resistant to T-DM1. These results need to be validated using samples from patients resistant to T-DM1. Targeting the adhesion or the prostaglandin pathway could be of benefit for patients with T-DM1 resistant cancers