TLR4 deficiency upregulates TLR9 expression and enhances irinotecan-related intestinal mucositis and late-onset diarrhoea.

BACKGROUND AND PURPOSE: Severe diarrhoea, a common gastrointestinal manifestation of anticancer treatment with irinotecan, might involve single nucleotide polymorphisms (SNPs) of toll-like receptors (TLRs), described as critical bacterial sensors in the gut. Here, colorectal cancer patients carrying missense TLR4 A896G (rs4986790) or C1,196T (rs4986791) SNPs and Tlr4 knockout (Tlr4-/-) mice were given irinotecan to investigate the severity of the induced diarrhoea. EXPERIMENTAL APPROACH: Forty-six patients treated with irinotecan-based regimens had diarrhoea severity analysed according to TLR4 genotypes. In the experimental setting, wild-type (WT) or Tlr4-/- mice were given irinotecan (45 or 75 mg·kg-1 , i.p.) or saline (3 ml·kg-1 ). Diarrhoea severity was evaluated by measuring intestinal injury and inflammatory markers expression after animals were killed. KEY RESULTS: All patients with TLR4 SNPs chemotherapy-treated presented diarrhoea, whereas gastrointestinal toxicity was observed in 50% of the wild homozygous individuals. Mice injected with irinotecan presented systemic bacterial translocation and increased TLR4 immunostaining in the intestine. In line with the clinical findings, Tlr4 gene deficiency enhanced irinotecan-related diarrhoea and TLR9 expression in mice. An increased myeloperoxidase activity and Il-18 expression along with IL-10 decreased production in Tlr4-/- mice also indicated an intensified intestinal damage and inflammatory response. CONCLUSION AND IMPLICATIONS: TLR4 deficiency upregulates TLR9 expression and enhances intestinal damage and the severity of late-onset diarrhoea during irinotecan-based treatment. Identifying patients genetically predisposed to chemotherapy-associated diarrhoea is a strategy toward precision medicine.

How does genetic testing influence anxiety, depression, and quality of life? A hereditary breast and ovarian cancer syndrome suspects trial.

BACKGROUND: Emotional distress associated with genetic testing for hereditary breast and ovarian cancer syndrome (HBOC) is reported to interfere with adherence to treatment and prophylactic measures and compromise quality of life. OBJECTIVES: To determine levels of anxiety, depression, and quality of life in patients tested for pathogenic BRCA1/2 mutations and identify risk factors for the development of adverse psycho-emotional effects. METHODS: Cross-sectional observational trial involving 178 breast or ovarian cancer patients from a referral cancer hospital in Northeastern Brazil. Information was collected with the Hospital Anxiety and Depression Scale (HADS) and the World Health Organization (WHO) Quality of Life (QoL) questionnaire (WHOQOL-BREF). RESULTS: Patients suspected of HBOC had higher levels of anxiety than depression. The presence of (probably) pathogenic BRCA1/2 mutations did not affect levels of anxiety and depression. High schooling, history of psychiatric disease, and use of psychotropic drugs were directly associated with high anxiety. High schooling was too inversely associated with QoL as such a breast tumor. Anxiety and depression were directly correlated and both reduced significantly QoL. CONCLUSION: Our results highlight the importance of psychological support and screening of risk factors for anxiety and depression and low QoL in HBOC patients at the time of testing.

Disparities in Epidemiological Profile of Gastric Adenocarcinoma in Selected Cities of Brazil

Background: Despite decreasing global incidence trends, gastric cancer is still among the five most incident cancers in the world and the third cancer-related cause of death. In Brazil, differences in incidence and mortality exist depending on the geographic region studied. Objective: To describe the incidence, mortality, trends and age-period-cohort of gastric cancer in three cities of Brazil (Sao Paulo, Belem and Fortaleza), in the period 1990-2012. Mortality for gastric cancer in Brazil overall and by region was described. Methods: 33,462 incident cases of gastric cancer were identified from the population-based cancer registries and 23,424 deaths from mortality information system in residents of the three cities and in Brazil were included in the study. Data for incident cases were extracted from the Population Based Cancer Registries from the National Cancer Institute (INCA). Mortality data on gastric cancer were extracted from Information Technology Department of Brazilian Public Health Care System/Health Ministry (DATASUS/MS). Mortality and incidence age standardized rates were calculated. For trends analysis the Joinpoint Regression and age-period-cohort model were applied. Results: Belem presented the highest incidence rates for gastric adenocarcinoma. Decreasing incidence trends were identified in Sao Paulo (-7.8% in men; -6.3% in women) and in Fortaleza (-1.2% in men). Increasing incidence trends were observed for women in Belem (1.8%) and Fortaleza (1.1%). In Belem (Amazon area), there was an increased risk for gastric cancer in women born after the 1960s. Overall in Brazil mortality for gastric cancer is decreasing. Mortality trends showed significant reduction, for both sexes, in the three Brazilian cities. Conclusion: Incidence of gastric cancer is increasing in women born in the sixties in Belem (Amazon region) and Fortaleza (Northeast region). In Brazil there was increase in mortality in Northeast region and decrease in others regions. More update data on incidence for Amazon and Northeast region is needed.

The association among HER2, MET and FOXP3 expression and tumor regression grading in gastric adenocarcinoma.

Although the introduction of the perioperative chemotherapy on the management of gastric cancer has improved patients survival, heterogeneity of clinical outcomes has been evidenced in parallel to different histopathological regression pattern of gastric cancer cells. Thus, this study evaluated the tumor regression grading (TRG) in a series of post-treatment gastric tumors and its associations with HER2, MET, and FOXP3 expression. Material of 54 gastric cancer samples was available for TRG evaluation and immunohistochemistry. We found that total and subtotal pathologic response were significantly associated to the intestinal subtype (p = 0.04) and that well-differentiated tumors were significantly correlated with total or partial response (p = 0.019). Although not associated with the TRG, FOXP3 expression in gastric tumors was associated to poorly differentiated tumors (p = 0.03), to the diffuse and mixed subtypes together (p = 0.04) and to the presence of vascular infiltration (p = 0.04), while HER2 overexpression was associated to better differentiated cases (p = 0.04) and to the absence of vascular infiltration (p = 0.02). MET expression, however, showed no association with the analyzed clinicopathological factors. This study highlights the role of tissue differentiation on pathological response to neoadjuvant chemotherapy in gastric cancer and shows no impact between FOXP3, HER2 and MET expression in terms of TRG.

Histopathological regression of gastric adenocarcinoma after neoadjuvant therapy: a critical review.

As the perioperative chemotherapy has been widely implemented on the management of gastric cancer patients, heterogeneity of clinical outcomes has been evidenced in parallel to different histopathological regression pattern of gastric cancer cells. Tumor histological response to preoperative therapy has been graded by various systems in order to categorize the amount of regressive changes induced by chemotherapy in relation to residual tumor. In this context, tumor regression grading (TRG) systems might provide important prognostic information as the variety of tumor response may imply on different clinical outcomes with impact in survival rates. Moreover, gastric cancer behavior varies enormously upon individual factors such as histological classification and tumor anatomic site of involvement that have been shown to affect the TRG interpretation. On the other hand, some studies have assessed the role of molecular markers as a predictor of tumor response to neoadjuvant chemotherapy in terms of TRG. Thus, the aim of this review is to evaluate how TRG has been interpreted in gastric cancer, discuss their clinical and prognostic relevance and also address the molecular markers involved in this process.

Correlação entre resposta objetiva e a expressão gênica e imunoistoquímica empacientes com cânceres gástricos irressecáveis ou metastáticos submetidos à quimioterapia paliativa á base de platina e fluoropirimidinas

Introdução: O câncer gástrico (CG) é o segundo em mortalidade no mundo. Frequentemente o diagnóstico se dá em estádios avançados quando a sobrevida em 5 anos não chega a 20%. A quimioterapia (QT) paliativa, apesar de seu benefício comprovado, não promove regressão tumoral em mais da metade dos pacientes e isso, acompanhado pelos efeitos colaterais, pode impactar negativamente a qualidade de vida desses indivíduos. No entanto, não há marcadores biológicos de resposta à quimioterapia em CG. Objetivo: Obter, a partir da expressão gênica, uma assinatura gênica ou imunoistoquímica (IHQ) que permita predizer a resposta objetiva (RO) à QT. Metodologia: Estudo clínico, prospectivo, não randomizado, envolvendo pacientes com CG localmente avançados ou metastáticos, candidatos à QT paliativa baseada em platina e fluoropirimidinas. Os pacientes foram seguidos durante todo o tratamento e periodicamente avaliados radiologicamente de forma a se estabelecer, pelos critérios RECIST 1.1, a resposta ao tratamento. Foram considerados respondedores (R+) os pacientes com RO e não-respondedores (R-) aqueles sem RO. Amostras tumorais obtidas por endoscopia digestiva alta antes do tratamento foramsubmetidas à extração de RNA total, que, após quantificação, amplificação emarcação do mRNA, era hibridizado em lâminas de microarray de oligonucleotídeos, contendo 60.000 sequências gênicas. A imunoistoquímica foi realizada utilizando-se anticorpos primários para HER2, ERCC1, Topoisomerase II eTimidilato-sintetase nos espécimes tumorais coletados. Após obtenção dos dados domicroarray, verificou-se a sua correlação com o status de R+ e R-. Resultados: DeJaneiro de 2010 a Dezembro de 2012, foram incluídos 28 pacientes no estudo,desses, somente 24 eram aptos para as avaliações de RO, sendo 15 R+ e 9 R-, comtaxa de RO de 62,5%. Predominaram pacientes do sexo masculino, com idade médiade 56 anos, apresentando tumores distais, do tipo intestinal e ECOG 2. A sobrevidaglobal (SG)...

Introduction: Gastric cancer (GC) is the 2nd leading cause of death by malignancies in the world. It is frequently diagnosed in advanced stages when curative intent is not possible and palliative chemotherapy (CT) is the only option. Despite its benefits, most patients do not respond to CT and will suffer from its adverse events. Until presently, there are no predictive markers of response to CT in GC. Objectives: To obtain a genomic signature to identify patients who will respond to palliative CT. Methods: We enrolled patients with unresectable or metastatic GC, admitted at Haroldo Juaçaba Cancer Hospital, in a prospective, non-randomized, open label,clinical trial, candidates for palliative platinum and fluoropyrimidine-based CT. During treatment, patients performed periodic radiological evaluation to accessobjective response (OR) according to RECIST 1.1 criteria. Patients were deemed “Responders” (R) in case of OR and “Non-Responders” (NR) in case of progressive or stable disease. Before initial CT, tumor samples were obtained by biopsies during digestive endoscopy and then they were submitted to total RNA extraction, mRNA amplification and labelling, and hybridization onto a oligonucleotide microarray platform containing 60,000 gene sequences. Immnunohistochemical expression of HER2, ERCC1, TS, TOPO II alpha and cadherin-E in tumor samples was correlated with OR. Results: From December 2009 to October 2011, 28 patients were admitted to this trial. The patients mean age was 56 years-old and had mostly distal and intestinal-type tumors and ECOG 2. The response rate was 62,5% with no complete responses (15 R and 9 NR). The overall survival was 12,5% and progression free survival (PFS) was 37% with a median follow up time of 7,2 months. There were 59 genes differentiallygenes differentially expressed between R and NR. A cutoff of fold>[2] selected the 23 most differentially expressed genes. Analysis of the immunohistochemical...

Correlação entre resposta objetiva e a expressão gênica e imunoistoquímica em pacientes com cânceres gástricos metastáticos submetidos à quimioterapia paliativa à base de platina e fluoropirimidinas / Correlation of objetive response with gene expression and imunohistochemical pattern in patients with metastatic gastric cancer treated with platinum plus fluoropyrimidin-based chemotherapy

Introdução: O câncer gástrico (CG) é o segundo em mortalidade no mundo. Frequentemente o diagnóstico se dá em estádios avançados quando a sobrevida em 5 anos não chega a 20%. A quimioterapia (QT) paliativa, apesar de seu benefício comprovado, não promove regressão tumoral em mais da metade dos pacientes e isso, acompanhado pelos efeitos colaterais, pode impactar negativamente a qualidade de vida desses indivíduos. No entanto, não há marcadores biológicos de resposta à quimioterapia em CG. Objetivo: Obter, a partir da expressão gênica, uma assinatura gênica ou imunoistoquímica (IHQ) que permita predizer a resposta objetiva (RO) à QT. Metodologia: Estudo clínico, prospectivo, não randomizado, envolvendo pacientes com CG localmente avançados ou metastáticos, candidatos à QT paliativa baseada em platina e fluoropirimidinas. Os pacientes foram seguidos durante todo o tratamento e periodicamente avaliados radiologicamente de forma a se estabelecer, pelos critérios RECIST 1.1, a resposta ao tratamento. Foram considerados respondedores (R+) os pacientes com RO e não-respondedores (R-) aqueles sem RO. Amostras tumorais obtidas por endoscopia digestiva alta antes do tratamento foram submetidas à extração de RNA total, que, após quantificação, amplificação e marcação do mRNA, era hibridizado em lâminas de microarray de oligonucleotídeos, contendo 60.000 sequências gênicas. A imunoistoquímica foi realizada utilizando-se anticorpos primários para HER2, ERCC1, Topoisomerase II e Timidilato-sintetase nos espécimes tumorais coletados. Após obtenção dos dados do microarray, verificou-se a sua correlação com o status de R+ e R-. Resultados: De Janeiro de 2010 a Dezembro de 2012, foram incluídos 28 pacientes no estudo, desses, somente 24 eram aptos para as avaliações de RO, sendo 15 R+ e 9 R-, com taxa de RO de 62,5%....