Fatores prognósticos em câncer de cólon localmente avançado tratado com ressecção extendida

The impact of clinical, pathologic, and surgical variables on the postoperative morbidity, mortality, and survival of patients undergoing extended resections of colon carcinoma were evaluated. METHODS: The medical records of 95 patients who underwent extended resections for colon carcinoma between 1953 and 1996 were reviewed. In all cases, in addition to colectomy, 1 or more organs and/or structures were resected en bloc due to a macroscopically based suspicion of tumor invasion. The clinical, pathologic, and surgical parameters were analyzed. Overall survival rates were analyzed according to the method of Kaplan and Meier. Multivariate analysis was performed using the Cox proportional hazards model. RESULTS: Eighty-six patients were treated by curative surgeries and the remaining by palliative resections. Invasion of the organs and/or adjacent structures and regional lymph nodes was found microscopically in 48 and 31 patients, respectively. The median follow-up without postoperative mortality was 47.7 months. The 5-year overall survival rates was 52.6%. The 5-year overall survival rates for patients undergoing curative and palliative surgeries was 58.3% and 0%, respectively. The mean survival time in the palliative surgery group was 3.1 months. Multivariate analysis showed that Karnofsky performance status was strongly related to the risk of postoperative complications (P = .01), and postoperative deaths were associated with the type of surgery and Karnofsky performance status at the time of admission (P = .001). CONCLUSIONS: Some patients with locally advanced colon adenocarcinomas undergoing extended resections have a 5-year overall survival rates of 58.3%. Patients could benefit from palliative-intent procedures, but these measures should cautiously be indicated and avoided in patients with low Karnofsky performance status due to high rates of postoperative mortality and poor survival.Foi avaliado o impacto de variáveis clínicas, patológicas e cirúrgicas na morbidade e mortalidade pós operatórias de pacientes submetidos à ressecção extendida de carcinoma do cólon. MÉTODOS: Prontuários médicos de 95 pacientes submetidos á ressecção extendida de carcinoma de cólon entre os anos de 1953 e 1996 foram revisados. Em todos os casos, além de colectomia, um ou mais órgãos e/ou estruturas foram ressecados em bloco devido á suspeição de invasão tumoral macroscópica. As variáveis clínicas, patológicas e cirúrgicas foram analizadas. As taxas de sobrevida global foram analizadas de acordo com o método de Kaplan and Meier. A análise multivariada foi realizada empregando-se o modelo de risco proporcional de Cox. RESULTADOS: Oitenta e seis pacientes foram tratados com cirurgia curativa e o restante com ressecção paliativa. Invasão microscópica de órgãos e/ou estruturas adjacentes e linfonodos regionais foi encontrada em 48 e 31 pacientes respectivamente. O tempo de seguimento mediano, sem mortalidade pós operatória, foi de 47.7 meses. A taxa de sobrevida global em 5 anos foi de 52.6%. A taxa de sobrevida global para pacientes submetidos à cirurgia curativa e paliativa foi de 58.3% e zero, respectivamente. A sobrevida mediana no grupo de pacientes com cirurgia paliativa foi de 3.1 meses. A análise multivariada mostrou que a performance status de Karnofsky fortemente correlacionou com risco de complicações pós operatórias (p=0.01), e que o risco de morte pós operatória estava associada com o tipo de cirurgia e a performance status de Karnofsky na admissão (p=0.001) CONCLUSÕES: Pacientes com adenocarcinoma de cólon localmente avançados submetidos à ressecção extendida têm taxa de sobrevida global em 5 anos de 58.3% Este tipo de cirurgia pode ser empregada com intuito paliativo, mas deve ter indicação criteriosa e ser evitada em pacientes com baixa performance status de Karnofsky devido às altas taxas de mortalidade pós operatória e baixa sobrevida

Identification of hereditary cancer in the general population: development and validation of a screening questionnaire for obtaining the family history of cancer

One of the challenges for Latin American countries is to include in their healthcare systems technologies that can be applied to hereditary cancer detection and management. The aim of the study is to create and validate a questionnaire to identify individuals with possible risk for hereditary cancer predisposition syndromes (HCPS), using different strategies in a Cancer Prevention Service in Brazil. The primary screening questionnaire (PSQ) was developed to identify families at-risk for HCPS. The PSQ was validated using discrimination measures, and the reproducibility was estimated through kappa coefficient. Patients with at least one affirmative answer had the pedigree drawn using three alternative interview approaches: in-person, by telephone, or letter. Validation of these approaches was done. Kappa and intraclass correlation coefficients were used to analyze data’s reproducibility considering the presence of clinical criteria for HCPS. The PSQ was applied to a convenience sample of 20,000 women of which 3121 (15.6%) answered at least one affirmative question and 1938 had their pedigrees drawn. The PSQ showed sensitivity and specificity scores of 94.4% and 75%, respectively, and a kappa of 0.64. The strategies for pedigree drawing had reproducibility coefficients of 0.976 and 0.850 for the telephone and letter approaches, respectively. Pedigree analysis allowed us to identify 465 individuals (24.0%) fulfilling at least one clinical criterion for HCPS. The PSQ fulfills its function, allowing the identification of HCPS at-risk families. The use of alternative screening methods may reduce the number of excluded at-risk individuals/families who live in locations where oncogenetic services are not established.Research supported by Barretos Cancer Hospital. EIP has a grant from FAPESP (FAPESP, SP, Brazil, #2013/24633-2). N Campacci is supported by a PhD fellowship from FAPESP (FAPESP, SP, Brazil, #2015/02444-9).info:eu-repo/semantics/publishedVersio

Hereditary breast and ovarian cancer: assessment of \ud point mutations and copy number variations in \ud Brazilian patients

Background \ud Germ line mutations in BRCA1 and BRCA2 (BRCA1/2) and other susceptibility genes have \ud been identified as genetic causes of hereditary breast and ovarian cancer (HBOC). To identify \ud the disease-causing mutations in a cohort of 120 Brazilian women fulfilling criteria for \ud HBOC, we carried out a comprehensive screening of BRCA1/2, TP53 R337H, CHEK2 \ud 1100delC, followed by an analysis of copy number variations in 14 additional breast cancer \ud susceptibility genes (PTEN, ATM, NBN, RAD50, RAD51, BRIP1, PALB2, MLH1, MSH2, \ud MSH6, TP53, CDKN2A, CDH1 and CTNNB1). \ud Methods \ud Capillary sequencing and multiplex ligation-dependent probe amplification (MLPA) were \ud used for detecting point mutations and copy number variations (CNVs), respectively, for the \ud BRCA1 and BRCA2 genes; capillary sequencing was used for point mutation for both variants \ud TP53 R337H and CHEK2 1100delC, and finally array comparative genomic hybridization \ud (array-CGH) was used for identifying CNVs in the 14 additional genes. \ud Results \ud The positive detection rate in our series was 26%. BRCA1 pathogenic mutations were found \ud in 20 cases, including two cases with CNVs, whereas BRCA2 mutations were found in 7 \ud cases. We also found three patients with the TP53 R337H mutation and one patient with the \ud CHEK2 1100delC mutation. Seven (25%) pathogenic mutations in BRCA1/2 were firstly \ud described, including a splice-site BRCA1 mutation for which pathogenicity was confirmed by \ud the presence of an aberrant transcript showing the loss of the last 62 bp of exon 7. \ud Microdeletions of exon 4 in ATM and exon 2 in PTEN were identified in BRCA2-mutated and \ud BRCA1/2-negative patients, respectively. \ud Conclusions \ud In summary, our results showed a high frequency of BRCA1/2 mutations and a higher \ud prevalence of BRCA1 (64.5%) gene. Moreover, the detection of the TP53 R337H variant in \ud our series and the fact that this variant has a founder effect in our population prompted us to \ud suggest that all female breast cancer patients with clinical criteria for HBOC and negative for \ud BRCA1/2 genes should be tested for the TP53 R337H variant. Furthermore, the presence of \ud genomic structural rearrangement resulting in CNVs in other genes that predispose breast \ud cancer in conjunction with BRCA2 point mutations demonstrated a highly complex genetic \ud etiology in Brazilian breast cancer families.Fundação de Amparo à Pesquisa do Estado de São Paulo (2008/57887- 9).Conselho Nacional de Desenvolvimento Científico e Tecnológico (408833/2006-8

Evaluation of MLH1 variants of unclear significance

Inactivating mutations in the MLH1 gene cause the cancer predisposition Lynch syndrome, but for small coding genetic variants it is mostly unclear if they are inactivating or not. Nine such MLH1 variants have been identified in South American colorectal cancer (CRC) patients (p.Tyr97Asp, p.His112Gln, p.Pro141Ala, p.Arg265Pro, p.Asn338Ser, p.Ile501del, p.Arg575Lys, p.Lys618del, p.Leu676Pro), and evidence of pathogenicity or neutrality was not available for the majority of these variants. We therefore performed biochemical laboratory testing of the variant proteins and compared the results to protein in silico predictions on structure and conservation. Additionally, we collected all available clinical information of the families to come to a conclusion concerning their pathogenic potential and facilitate clinical diagnosis in the affected families. We provide evidence that four of the alterations are causative for Lynch syndrome, four are likely neutral and one shows compromised activity which can currently not be classified with respect to its pathogenic potential. The work demonstrates that biochemical testing, corroborated by congruent evolutionary and structural information, can serve to reliably classify uncertain variants when other data are insufficient.Barretos Cancer Hospital was partially funded by FINEP‐CT‐INFRA, Grant Number: 02/2010, Radium Hospital Foundation (Oslo, Norway), Helse Sør‐Øst (Norway); Deutsche Forschungsgemeinschaft, Grant Number: PL688/2‐1info:eu-repo/semantics/publishedVersio

Risk perception among Brazilian individuals with high risk for colorectal cancer and colonoscopy

<p>Abstract</p> <p>Background</p> <p>Risk perception is considered a motivating factor for adopting preventive behaviors. This study aimed to verify the demographic characteristics and cancer family history that are predictors of risk perception and to verify if risk perception is a predictor of colonoscopy adherence.</p> <p>Methods</p> <p>Individuals with a family colorectal cancer history as indicated by a proband with cancer were interviewed by telephone. They responded to a questionnaire covering demographic characteristics, colonoscopy history and four questions on risk perception. Tests of multiple linear regression and logistic regression were used to identify associations between dependent and independent variables.</p> <p>Results</p> <p>The 117 participants belonged to 62 families and had a mean age of 45.2 years. The majority of these individuals were female (74.4%) and from families who met the Amsterdam Criteria (54.7%). The average risk perception was 47.6%, with a median of 50%. The average population perception of individual risk was 55.4%, with a median of 50%. Variables associated with a higher risk perception were age, gender, religion, school level, income, and death of a family member. The variable predicting colonoscopy was receiving medical information regarding risk (odds ratio OR 8.40).</p> <p>Conclusions</p> <p>We found that family cancer history characteristics (number of relatives with cancer, risk classification) are associated with adequate risk perception. Risk perception does not predict colonoscopy in this sample. The only variable that predicted colonoscopy was receiving medical information recommending screening.</p

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

Background: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. Methods: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. Results: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. Conclusion: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.Radium Hospital Foundation (Oslo, Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, Helse Sør-Øst (Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, the French Association Recherche contre le Cancer (ARC) in the analysis, and interpretation of data, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (Gefluc) in the analysis, and interpretation of data, the Association Nationale de la Recherche et de la Technologie (ANRT, CIFRE PhD fellowship to H.T.) in the analysis, and interpretation of data and by the OpenHealth Institute in the analysis, and interpretation of data. Barretos Cancer Hospital received financial support by FINEP-CT-INFRA (02/2010)info:eu-repo/semantics/publishedVersio