COLORECTAL CANCER: ASSOCIATION BETWEEN SOCIODEMOGRAPHIC VARIABLES AND THE ADHERENCE TO CANCER SCREENING.

BACKGROUND: Colorectal cancer (CRC) is a worldwide health problem whose control depends on public policy establishment and effective prevention and screening programs. In Brazil, there are few studies related to adherence to screening methods. AIMS: The aim of this study was to evaluate the association between demographic and socioeconomic to adherence to CRC screening with fecal immunochemical test (FIT) among average-risk individuals for CRC. METHODS: In this prospective cross-sectional study, conducted between March 2015 and April 2016, 1,254 asymptomatic individuals aged 50-75 years, participating in a hospital screening campaign in Brazil, were invited to participate in the study. RESULTS: The adherence rate to FIT was 55.6% (697/1,254). In the multivariable logistic regression analysis, patients aged 60-75 years (odds ratio (OR)=1.30; 95% confidence interval (CI): 1.02-1.66; p=0.03), religious belief (OR=2.04; 95% CI: 1.34-3.11; p<0.01), previous fecal occult blood test (OR=2.07; 95% CI: 1.55-2.76; p<0.01), and full/part-time working status (OR=0.66; 95% CI: 0.49-0.89; p<0.01) were independently associated with adherence to CRC screening. CONCLUSION: The results of the present study highlight the importance of considering the labor aspects when implementing screening programs, suggesting that campaigns conducted in the workplace and repeated over the years may be more effective.

Amplicon-based NGS test for assessing MLH1 promoter methylation and its correlation with BRAF mutation in colorectal cancer patients.

Detecting MLH1 promoter methylation is highly relevant to differentiate between possible Lynch syndrome patients or patients with sporadic causes of MLH1/PMS2 deficiency in colorectal (CRC) and endometrial cancers. Here, we aimed to develop a test for assessing MLH1 promoter methylation based in next generation sequencing (NGS), and to evaluate the concordance of MLH1 methylation and BRAF-V600 mutation status in CRC. For that, we performed a series of experiments with DNA from tumor, saliva and commercial control samples and our in house developed amplicon-based NGS test. In patients' samples, MLH1 methylation above 10% was only observed in tumors with MLH1/PMS2 loss. We confirmed the reproducibility and accuracy of MLH1 promoter analysis performing a serial dilution experiment with completely methylated and unmethylated control DNAs and a comparison between two NGS platforms (Ion Proton and Illumina). In MLH1/PMS2 deficient tumors, the MLH1 methylation status was concordant with the BRAF mutation status in 90% (18/20) of the cases. Our amplicon-based NGS test showed a great sensitivity and specificity for detecting MLH1 methylation in CRC samples, with a high agreement with the evaluation of BRAF mutation. This simple and affordable test could be used as a reflex test to identify patients with sporadic causes of MLH1/PMS2 deficiency in CRC, aiding to genetic test referral and identification of Lynch syndrome patients.

Câncer colorretal: associação entre variáveis sociodemográficas e a adesão a programas de rastreamento / Colorectal cancer: association between sociodemographic variables and the adherence to cancer screening

ABSTRACT BACKGROUND Colorectal cancer (CRC) is a worldwide health problem whose control depends on public policy establishment and effective prevention and screening programs. In Brazil, there are few studies related to adherence to screening methods. AIMS: The aim of this study was to evaluate the association between demographic and socioeconomic to adherence to CRC screening with fecal immunochemical test (FIT) among average-risk individuals for CRC. METHODS: In this prospective cross-sectional study, conducted between March 2015 and April 2016, 1,254 asymptomatic individuals aged 50-75 years, participating in a hospital screening campaign in Brazil, were invited to participate in the study. RESULTS: The adherence rate to FIT was 55.6% (697/1,254). In the multivariable logistic regression analysis, patients aged 60-75 years (odds ratio (OR)=1.30; 95% confidence interval (CI): 1.02-1.66; p=0.03), religious belief (OR=2.04; 95% CI: 1.34-3.11; p<0.01), previous fecal occult blood test (OR=2.07; 95% CI: 1.55-2.76; p<0.01), and full/part-time working status (OR=0.66; 95% CI: 0.49-0.89; p<0.01) were independently associated with adherence to CRC screening. CONCLUSION: The results of the present study highlight the importance of considering the labor aspects when implementing screening programs, suggesting that campaigns conducted in the workplace and repeated over the years may be more effective.

RESUMO RACIONAL: O câncer colorretal (CCR) é um problema de saúde mundial cujo controle depende do estabelecimento de políticas públicas e programas de prevenção e rastreamento eficazes. No Brasil existem poucos estudos relacionados à adesão métodos de rastreamento. OBJETIVO: Avaliar a associação de características sócio-demográficas à realização de testes de sangue oculto nas fezes do tipo imunoquimicomecanizado (FIM) em população de médio risco para o desenvolvimento de câncer colorretal. MÉTODOS: Estudo observacional transversal, com coleta prospectiva de dados. Entre março de 2015 e abril de 2016, 1.254 indivíduos assintomáticos, com idade entre 50 e 75 anos, foram consecutivamente selecionados a partir de uma campanha hospitalar de rastreamento para neoplasias. RESULTADOS: As taxas de adesão ao teste FIM foi 55.6% (697/1254). Na análise de regressão logística múltipla os fatores independentes associados à adesão ao rastreamento do CCR foram: Idade entre 60-75 anos (oddsratio (OR)=1.30; intervalo de confiança de 95% (IC): 1.02-1.66; p=0.03), crença religiosa (OR=2.04; 95%IC: 1.34-3.11; p<0.01), realização prévia de exame de sangue oculto nas fezes (OR=2.07; 95%IC: 1.55-2.76; p<0.01) e vínculo empregatício em período integral ou parcial (OR=0.66; 95%IC: 0.49-0.89; p<0.01). CONCLUSÃO: Este estudo enfatiza a importância de considerar aspectos laborais ao implementar programas de rastreamento do câncer colorretal e sugere que campanhas de rastreamento implantadas no ambiente de trabalho e de maneira repetida ao longo dos anos podem ser mais efetivas.

Molecular and Dynamic Evaluation of Proteins Related to Resistance to Neoadjuvant Treatment with Chemoradiotherapy in Circulating Tumor Cells of Patients with Locally Advanced Rectal Cancer.

The heterogeneity of response to neoadjuvant chemoradiotherapy (NCRT) is still a challenge in locally advanced rectal cancer (LARC). The evaluation of thymidylate synthase (TYMS) and RAD23 homolog B (RAD23B) expression in circulating tumor cells (CTCs) provides complementary clinical information. CTCs were prospectively evaluated in 166 blood samples (63 patients) with LARC undergoing NCRT. The primary objective was to verify if the absence of RAD23B/TYMS in CTCs would correlate with pathological complete response (pCR). Secondary objectives were to correlate CTC kinetics before (C1)/after NCRT (C2), in addition to the expression of transforming growth factor-ß receptor I (TGF-ßRI) with survival rates. CTCs were isolated by ISET and evaluated by immunocytochemistry (protein expression). At C1, RAD23B was detected in 54.1% of patients with no pCR and its absence in 91.7% of patients with pCR (p = 0.014); TYMS- was observed in 90% of patients with pCR and TYMS+ in 51.7% without pCR (p = 0.057). Patients with CTC2 > CTC1 had worse disease-free survival (DFS) (p = 0.00025) and overall survival (OS) (p = 0.0036) compared with those with CTC2 ≤ CTC1. TGF-ßRI expression in any time correlated with worse DFS (p = 0.059). To conclude, RAD23B/TYMS and CTC kinetics may facilitate the personalized treatment of LARC.

Neoadjuvant hypofractionated radiotherapy and chemotherapy for extremity soft tissue sarcomas: Safety, feasibility, and early oncologic outcomes of a phase 2 trial.

BACKGROUND AND PURPOSE: Optimal treatment of extremity soft tissue sarcomas (ESTS) is controversial. The aim of this study was to evaluate neoadjuvant chemotherapy (ChT) plus concomitant hypofractionated RT (hypo-RT) in local and distant disease relapse. Here we report safety, feasibility and early outcomes. MATERIALS AND METHODS: This was a prospective, single arm study with a goal accrual of 70 patients. Between 2015 and 2018, 18 patients with histologically confirmed nonmetastatic ESTS were assigned to receive doxorubicin and ifosfamide for three neoadjuvant cycles, concomitant with hypo-RT (25 Gy in 5 fractions) followed by surgery. The primary endpoint was disease-free survival (DFS). Secondary outcomes were pathologic response, wound complications (WC), and morbidity rates. RESULTS: Median follow-up was 29 months. At last follow-up, 13/18 patients were alive without evidence of local or systemic disease (DFS 72%), 1 had died due to metastatic disease, and 3 were alive with distant metastasis. One patient presented with local relapse within the irradiated field. Mean DFS time was 48.6 months (95% CI: 37.3-59.9). Six patients (33%) had no residual viable tumor detected in pathologic specimens (3 of these myxoid liposarcomas). There was a significant difference in WC among patients with acute RT skin toxicity. Six patients (33%) developed major WC. No grade 3 or 4 ChT adverse events were reported. CONCLUSION: Despite the limited sample size, these early outcomes demonstrate that this treatment regimen is feasible and well tolerated with high rates of limb preservation, local control, and pathologic complete response, supporting further investigation in a multi-institutional setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02812654; https://clinicaltrials.gov/ct2/show/NCT02812654.

A higher platelet-to-lymphocyte ratio is prevalent in the presence of circulating tumor microemboli and is a potential prognostic factor for non-metastatic colon cancer.

Colorectal cancer is a common and often deadly cancer. Circulating tumor cells (CTCs) have been implicated as a potentially valuable prognosis factor. The detection of circulating tumor microemboli (CTM) and of simple blood component parameters that reflect inflammatory status, such as the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR), may provide information about tumor progression. The aim of this study was to explore the importance of CTCs, CTM, PLR, and NLR prospectively in non-metastatic colon cancer progression. CTCs were enriched using ISETⓇ (Isolation by SizE of Tumor cells) and identified by immunocytochemical exclusion of leukocytes. We evaluated CTCs and blood cell parameters in a cohort of 69 stage I-III colon cancer patients (52.2% men; median age, 61 years; age range, 19-87 years) at a baseline timepoint prior to resection surgery. The median of CTC levels at baseline was 20 cells/8 mL (0-94) and higher levels were associated with CTM presence (p = 0.02). CTM were found in 18 (26.1%) patients. Of 18 stage I patients, 33.3% had CTM and of 51 stages II or III patients, 13.7% had CTM (p = 0.08). Patients with a high PLR (>124) were mostly (75.6%) diagnosed with high-risk stages II/III cancer (stages I/low-risk II, 24.4%; p = 0.014). All 8 patients that had disease recurrence during follow-up had a high PLR (p = 0.02 vs. low PLR). NLR was not significantly associated with disease stage or recurrence. The present results indicate that CTCs and PLR analyses may be clinically useful for colon cancer management and risk stratification.

SURVIVAL OF PATIENTS WITH COLORECTAL CANCER IN A CANCER CENTER.

BACKGROUND: Hospital-based studies recently have shown increases in colorectal cancer survival, and better survival for women, young people, and patients diagnosed at an early disease stage. OBJECTIVE: To describe the overall survival and analyze the prognostic factors of patients treated for colorectal cancer at an oncology center. METHODS: The analysis included patients diagnosed with colon and rectal adenocarcinoma between 2000 and 2013 and identified in the Hospital Cancer Registry at A.C.Camargo Cancer Center. Overall 5-year survival was estimated using the Kaplan-Meier method, and prognostic factors were evaluated in a Cox regression model. Hazard ratios (HR) are reported with 95% confidence intervals (CI). RESULTS: Of 2,279 colorectal cancer cases analyzed, 58.4% were in the colon. The 5-year overall survival rate for colorectal cancer patients was 63.5% (65.6% and 60.6% for colonic and rectal malignancies, respectively). The risk of death was elevated for patients in the 50-74-year (HR=1.24, 95%CI =1.02-1.51) and ≥75-year (HR=3.02, 95%CI =2.42-3.78) age groups, for patients with rectal cancer (HR=1.37, 95%CI =1.11-1.69) and for those whose treatment was started >60 days after diagnosis (HR=1.22, 95%CI =1.04-1.43). The risk decreased for patients diagnosed in recent time periods (2005-2009 HR=0.76, 95%CI =0.63-0.91; 2010-2013 HR=0.69, 95%CI =0.57-0.83). CONCLUSION: Better survival of patients with colorectal cancer improves with early stage and started treatment within 60 days of diagnosis. Age over 70 years old was an independent factor predictive of a poor prognosis. The overall survival increased to all patients treated in the period 2000-2004 to 2010-2013.

Clinical Characteristics, Management, and Outcomes of 19 Nonpediatric Patients with Desmoplastic Small Round Cell Tumor: A Cohort of Brazilian Patients.

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive mesenchymal malignancy, usually affecting young males. There is no consensus on the best therapeutic approach. We seek to characterize a cohort of nonpediatric patients with DSRCT treated at a large Brazilian cancer center. We performed a retrospective analysis of patients with histologically confirmed DSRCT referred to our institution (2007-2020). Clinical and imaging data were extracted and summarized with descriptive statistics. Survival analyses were conducted by the Kaplan-Meier method and compared with the log-rank test. We included 19 patients with DSRCT, the median age at diagnosis was 26 years (range: 15-41 years), and 68% were male. Ninety percent presented with abdominopelvic masses, and 32% had extra-abdominal metastasis at diagnosis. Eleven patients (58%) underwent surgery, four patients (21%) received whole abdominal adjuvant radiotherapy, and five patients (26%) had hyperthermic intraperitoneal chemotherapy. Median OS was 27 months (interquartile range: 18-51 m). The five-year OS rate was 12%. Our data confirm the aggressiveness of DSRCT despite intense multimodality treatment. Outcomes of patients treated in a reference cancer center in a developing country are similar to cancer centers in developed nations. Multicenter cooperation is urgent to the development of clinical trials and to improve diagnosis and treatment efficacy.

Clinical and Molecular Assessment of Patients with Lynch Syndrome and Sarcomas Underpinning the Association with MSH2 Germline Pathogenic Variants.

Lynch syndrome (LS) is a hereditary cancer-predisposing syndrome associated most frequently with epithelial tumors, particularly colorectal (CRC) and endometrial carcinomas (EC). The aim of this study was to investigate the relationship between sarcomas and LS by performing clinical and molecular characterization of patients presenting co-occurrence of sarcomas and tumors from the LS spectrum. We identified 27 patients diagnosed with CRC, EC, and other LS-associated tumors who had sarcomas in the same individuals or families. Germline genetic testing, mismatch repair (MMR) protein immunohistochemistry, microsatellite instability (MSI), and other molecular analyses were performed. Five LS patients presenting personal or family history of sarcomas were identified (3 MSH2 carriers and 2 MLH1), with 2 having Muir-Torre phenotypes. For two MSH2 carriers we confirmed the etiology of the sarcomas (one liposarcoma and two osteosarcomas) as LS-related, since the tumors were MSH2/MSH6-deficient, MSI-high, or presented a truncated MSH2 transcript. Additionally, we reviewed 43 previous reports of sarcomas in patients with LS, which revealed a high frequency (58%) of MSH2 alterations. In summary, sarcomas represent a rare clinical manifestation in patients with LS, especially in MSH2 carriers, and the analysis of tumor biological characteristics can be useful for definition of tumor etiology and novel therapeutic options.

Sobrevida de pacientes com câncer colorretal em um Cancer Center / Survival of patients with colorectal cancer in a cancer center

ABSTRACT BACKGROUND: Hospital-based studies recently have shown increases in colorectal cancer survival, and better survival for women, young people, and patients diagnosed at an early disease stage. OBJECTIVE: To describe the overall survival and analyze the prognostic factors of patients treated for colorectal cancer at an oncology center. METHODS: The analysis included patients diagnosed with colon and rectal adenocarcinoma between 2000 and 2013 and identified in the Hospital Cancer Registry at A.C.Camargo Cancer Center. Overall 5-year survival was estimated using the Kaplan-Meier method, and prognostic factors were evaluated in a Cox regression model. Hazard ratios (HR) are reported with 95% confidence intervals (CI). RESULTS: Of 2,279 colorectal cancer cases analyzed, 58.4% were in the colon. The 5-year overall survival rate for colorectal cancer patients was 63.5% (65.6% and 60.6% for colonic and rectal malignancies, respectively). The risk of death was elevated for patients in the 50-74-year (HR=1.24, 95%CI =1.02-1.51) and ≥75-year (HR=3.02, 95%CI =2.42-3.78) age groups, for patients with rectal cancer (HR=1.37, 95%CI =1.11-1.69) and for those whose treatment was started >60 days after diagnosis (HR=1.22, 95%CI =1.04-1.43). The risk decreased for patients diagnosed in recent time periods (2005-2009 HR=0.76, 95%CI =0.63-0.91; 2010-2013 HR=0.69, 95%CI =0.57-0.83). CONCLUSION: Better survival of patients with colorectal cancer improves with early stage and started treatment within 60 days of diagnosis. Age over 70 years old was an independent factor predictive of a poor prognosis. The overall survival increased to all patients treated in the period 2000-2004 to 2010-2013.

RESUMO CONTEXTO: Estudos hospitalares recentes têm demonstrado aumento da sobrevida do câncer colorretal e melhor sobrevida para mulheres, jovens e pacientes diagnosticados em estágio precoce da doença. OBJETIVO: Descrever a sobrevida global e analisar os fatores prognósticos de pacientes tratados para câncer colorretal em um centro de oncologia. MÉTODOS: Foram incluídos pacientes com diagnóstico de adenocarcinoma de cólon e reto entre 2000 e 2013, identificados no Registro Hospitalar de Câncer do A.C.Camargo Cancer Center. A sobrevida global aos 5 anos foi estimada pelo método de Kaplan-Meier e os fatores prognósticos foram avaliados pelo modelo de Cox. As razões de risco (HR) são relatadas com intervalos de confiança (IC) de 95%. RESULTADOS: Dos 2.279 casos de câncer colorretal analisados, 58,4% eram de cólon. A taxa de sobrevida global aos 5 anos para pacientes com câncer colorretal foi de 63,5% (65,6% e 60,6% para câncer de cólon e retal, respectivamente). O risco de óbito foi elevado para pacientes na faixa etária de 50-74 anos (HR=1,24; IC95% =1,02-1,51) e ≥75 anos (HR=3,02; IC95% =2,42-3,78), para pacientes com câncer retal (HR=1,37; IC95% =1,11-1,69) e para aqueles cujo tratamento foi iniciado >60 dias após o diagnóstico (HR=1,22; IC95% =1,04-1,43). O risco diminuiu para pacientes diagnosticados em períodos recentes (2005-2009 HR=0,76; IC95% =0,63-0,91; 2010-2013 HR=0,69; IC95% =0,57-0,83). CONCLUSÃO: A sobrevida dos pacientes com câncer colorretal é maior naqueles em estágio inicial e com início do tratamento antes dos 60 dias.. Idade acima de 70 anos foi fator independente preditivo de mau prognóstico. A sobrevida global aumentou para todos os pacientes tratados no período de 2000-2004 a 2010-2013.

Association of Folate and Vitamins Involved in the 1-Carbon Cycle with Polymorphisms in the Methylenetetrahydrofolate Reductase Gene (MTHFR) and Global DNA Methylation in Patients with Colorectal Cancer.

Folate, vitamin B2, vitamin B6, vitamin B12, choline, and betaine are nutrients involved in the 1-carbon cycle that can alter the levels of DNA methylation and influence genesis and/or tumor progression. Thus, the objective of this study was to evaluate the association of folate and vitamins involved in the 1-carbon cycle and MTHFR polymorphisms in global DNA methylation in patients with colorectal cancer gene. The study included 189 patients with colorectal adenocarcinoma answering a clinical evaluation questionnaire and the Food Frequency Questionnaire (FFQ) validated for patients with colon and rectal cancer. Blood samples were collected for evaluation of MTHFR gene polymorphisms in global DNA methylation in blood and in tumor. The values for serum folate were positively correlated with the equivalent total dietary folate (total DFE) (rho = 0.51, p = 0.03) and global DNA methylation (rho = 0.20, p = 0.03). Individuals aged over 61 years (p = 0.01) in clinicopathological staging III and IV (p = 0.01) and with + heterozygous mutated homozygous genotypes for the MTHFR A1298C gene had higher levels of global DNA methylation (p = 0.04). The association between dietary intake of folate, serum folate, and tumor stage were predictive of global DNA methylation in patients' blood. The levels of serum folate, the dietary folate and the status of DNA methylation can influence clinicopathological staging.

Molecular and Kinetic Analyses of Circulating Tumor Cells as Predictive Markers of Treatment Response in Locally Advanced Rectal Cancer Patients.

Neoadjuvant chemoradiation (NCRT) followed by total mesorectal excision is the standard treatment for locally advanced rectal cancer (LARC). To justify a non-surgical approach, identification of pathologic complete response (pCR) is required. Analysis of circulating tumor cells (CTCs) can be used to evaluate pCR. We hypothesize that monitoring of thymidylate synthase (TYMS) and excision repair protein, RAD23 homolog B (RAD23B), can be used to predict resistance to chemotherapy/radiotherapy. Therefore, the aims of this study were to analyze CTCs from patients with LARC who underwent NCRT plus surgery for expression of TYMS/RAD23B and to evaluate their predictive value. Blood samples from 30 patients were collected prior to NCRT (S1) and prior to surgery (S2). CTCs were isolated and quantified by ISET®, proteins were analyzed by immunocytochemistry, and TYMS mRNA was detected by chromogenic in situ hybridization. CTC counts decreased between S1 and S2 in patients exhibiting pCR (p = 0.02) or partial response (p = 0.01). Regarding protein expression, TYMS was absent in 100% of CTCs from patients with pCR (p = 0.001) yet was expressed in 83% of non-responders at S2 (p < 0.001). Meanwhile, RAD23B was expressed in CTCs from 75% of non-responders at S1 (p = 0.01) and in 100% of non-responders at S2 (p = 0.001). Surprisingly, 100% of non-responders expressed TYMS mRNA at both timepoints (p = 0.001). In addition, TYMS/RAD23B was not detected in the CTCs of patients exhibiting pCR (p = 0.001). We found 83.3% of sensitivity for TYMS mRNA at S1 (p = 0.001) and 100% for TYMS (p = 0.064) and RAD23B (p = 0.01) protein expression at S2. Thus, TYMS mRNA and/or TYMS/RAD23B expression in CTCs, as well as CTC kinetics, have the potential to predict non-response to NCRT and avoid unnecessary radical surgery for LARC patients with pCR.

Mutation Detection in Tumor-Derived Cell Free DNA Anticipates Progression in a Patient With Metastatic Colorectal Cancer.

Background: The observation of tumor-derived cell-free DNA (ctDNA) in plasma brought new expectations to monitor treatment response in cancer patients. Case presentation: In an exploratory case of a 57-year-old man diagnosed with metastatic sigmoid adenocarcinoma, we used a hotspot panel of cancer-associated gene mutations to identify tumor-specific mutations in the primary tumor and metastasis. RESULTS: Five mutations were detected (KRAS, p.Gly12Val; TP53, p.Arg175His; RB1, p.Ile680Thr; ALK, p.Gly1184Glu; and ERBB2, p.Lys860Lys), of which three were detected in both tissue types (primary tumor and metastasis). All five mutations were monitored in the ctDNA of six serial plasma samples. Only KRAS and TP53 mutations were detected at a high frequency in the first plasma sample. After 1 month of chemotherapy the allele frequencies of both mutations fell below the detection limit. From the third month of systemic treatment onward, the allele frequencies of both mutations were detectable in plasma, displaying a continual increase thereafter. The remaining three mutations were not detected in plasma samples. Signs of disease progression in ctDNA during the treatment period were evident while computed tomography (CT) measurements suggested stable metastatic lesions throughout the treatment. Conclusions: Liquid biopsies revealed tumor heterogeneity and predicted tumor progression, demonstrating the potential of ctDNA analysis to be a sensitive and specific tool for monitoring treatment responsivity and for early identification of treatment resistance.

Comparison between an immunochemical fecal occult blood test and a Guaiac based fecal occult blood test in detection of adenomas and colorectal cancer

Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Brazil does not have an official well established program for screening colorectal cancer. The aim of this study was to compare Guaiac Based Fecal Occult Blood Test (G-FOBT) to a kind of an Immunochemical Fecal Occult Blood Test (I-FOBT), in search of cancer or advanced adenoma. Methods: Prospective and cross-sectional study. Asymptomatic and average-risk individuals (n = 1500) aged from 50 to 75 years old were invited to participate in the study. The primary endpoint was positivity rate and the secondary endpoints were adherence rate and significant endoscopic findings. All participants received both tests with follow-up colonoscopy if either test was positive. Results: Adherence rate of G- FOBT was 756/1500 (50.4%) while for I- FOBT it was 960/1500(64%). The positivity ratio in the I- FOBT was 94/960 (9.8%) and in the G-FOBT was 20/771 (2.6%). The Positive Predict Value (PPV) for the I- FOBT counted 16/77 (21.0%) while for the G- FOBT it was 6/18 (33.0%), considering significant lesions. Regarding the colorectal cancer findings, the detection in the colonoscopy guided from the positivity of fecal occult blood tests was 5/77 (6.5%) in I- FOBT and 2/18 (11.1%) on the G- FOBT. Conclusions: The positivity, the adherence rate and the capacity to detect significant lesions were higher in I-FOBT. Considering the findings of the study we could conclude that I-FOBT was superior to G- FOBT. Trial registration: This study was reviewed and approved by the Institutional Review Board of A.C.Camargo Cancer Center, São Paulo, Brazil, number: 1877/14

Estrogen Receptor ß as a Prognostic Marker of Tumor Progression in Colorectal Cancer with Familial Adenomatous Polyposis and Sporadic Polyps.

The incidence of colorectal cancer (CRC) is lower in women than in men, and sex steroids can be considered contributing factors because oral contraception usage and estrogen replacement therapy are associated with decreased risk. Conversely, colorectal polyp development in familial adenomatous polyposis (FAP) begins during puberty. The objectives were to evaluate the relationship between the expression of these hormone receptors and adenoma-carcinoma progression, CRC stage and overall survival. We studied 120 A.C. Camargo Cancer Center patients diagnosed with either FAP-associated or spontaneous adenomatous polyps or CRC to determine the immunohistochemical expression levels of estrogen receptor (ER)-α, ER-ß and the progesterone and androgen receptors (480 analyses). The ER-ß expression levels differed between the groups: the group with FAP polyps had lower ER-ß expression than that of the sporadic polyp group. With transformation of the sporadic polyps to cancer, there was a considerable decrease in ER-ß expression (from 90% with strong expression to 80% with absent or weak expression) (p < 0.001). The ER-ß expression was lower in T3/T4 tumors than in T1/T2 tumors (p = 0.015). The 5-year overall survival of CRC patients positively expressing ER-ß exceeded that of patients without detectable expression levels (74.8% vs. 44.3%, respectively; p = 0.035). There was no significant expression of the androgen or progesterone receptor or ER-α among the groups. Differences in ER-ß expression represent a potential mechanism through which estrogen might alter the susceptibility to colon cancer, thereby confirming the possibility of a protective role of estrogen against colorectal carcinogenesis.

Oestrogen receptor beta isoform expression in sporadic colorectal cancer, familial adenomatous polyposis and progressive stages of colorectal cancer.

BACKGROUND: Among the sex hormones, oestrogen may play a role in colorectal cancer, particularly in conjunction with oestrogen receptor-ß (ERß). The expression of ERß isoform variants and their correlations with familial adenomatous polyposis (FAP) syndrome and sporadic colorectal carcinomas are poorly described. METHODS: This study aimed to investigate the expression levels of the ERß1, ERß2, ERß4 and ERß5 isoform variants using quantitative RT-PCR (921 analyses) in FAP, normal mucosa, adenomatous polyps and sporadic colorectal carcinomas. RESULTS: Decreased expression of ERß isoforms was identified in sporadic polyps and in sporadic colorectal cancer as well as in polyps from FAP syndrome patients compared with normal tissues (p < 0.001). In FAP patients, ERß1 and ERß5 isoforms showed significant down-expression in polyps (p < 0.001) compared with matched normal tissues. However, no differences were observed when sporadic colorectal carcinomas were compared to normal mucosa tissues. These findings suggest an association of the ERß isoform variants in individuals affected by germline mutations of the APC gene. Progressively decreased expression of ERß was found in polyps at early stages of low-grade dysplasia, followed by T1-T2 and T3-T4 tumours (p < 0.05). In sporadic colorectal cancer, the loss of expression was an independent predictor of recurrence, and ERß1 and ERß5 expression levels were associated with better disease-free survival (p = 0.002). CONCLUSION: These findings may provide a better understanding of oestrogens and their potential preventive and therapeutic effects on sporadic colorectal cancer and cancers associated with FAP syndrome.

A proposal of Brazilian Society of Surgical Oncology (BSSO/SBCO) for standardizing cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) procedures in Brazil: pseudomixoma peritonei, appendiceal tumors and malignant peritoneal mesothelioma / Proposta de padronização da Sociedade Brasileira de Cirurgia Oncológica (BSSO/SBCO) para procedimentos de citorredução cirúrgica (CRS) e quimioterapia intraperitoneal hipertérmica (HIPEC) no Brasil: pseudomixoma peritoneal, tumores do apêndice cecal e mesotelioma peritoneal maligno

ABSTRACT Cytoreductive surgery plus hypertermic intraperitoneal chemotherapy has emerged as a major comprehensive treatment of peritoneal malignancies and is currently the standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome as well as malignant peritoneal mesothelioma. Unfortunately, there are some worldwide variations of the cytoreductive surgery and hypertermic intraperitoneal chemotherapy techniques since no single technique has so far demonstrated its superiority over the others. Therefore, standardization of practices might enhance better comparisons between outcomes. In these settings, the Brazilian Society of Surgical Oncology considered it important to present a proposal for standardizing cytoreductive surgery plus hypertermic intraperitoneal chemotherapy procedures in Brazil, with a special focus on producing homogeneous data for the developing Brazilian register for peritoneal surface malignancies.

RESUMO A cirurgia citorredutora com quimioterapia intraperitoneal hipertérmica emergiu como um importante tratamento das neoplasias peritoneais e é, atualmente, o padrão de atendimento para neoplasias epiteliais do apêndice associadas à síndrome de pseudomixoma peritoneal, bem como para o mesotelioma peritoneal maligno difuso. No mundo, existem algumas variações reconhecidas das técnicas de cirurgia citorredutora e quimioterapia intraperitoneal hipertérmica, entretanto nenhuma técnica até agora demonstrou sua superioridade sobre o outra. Portanto, a padronização destes procedimentos poderia melhorar a prática clínica e permitir a comparação adequada entre os resultados. Neste cenário, a Sociedade Brasileira de Cirurgia Oncológica considera importante a apresentação de uma proposta de padronização de procedimentos de cirurgia citorredutora com quimioterapia intraperitoneal hipertérmica no Brasil, com um foco especial na produção de dados homogêneos para o desenvolvimento do registro brasileiro das neoplasias peritoneais.

Neoadjuvant Hypofractionated Radiotherapy and Chemotherapy in High-Grade Extremity Soft Tissue Sarcomas: Phase 2 Clinical Trial Protocol.

BACKGROUND: Neoadjuvant radiotherapy (RT) and chemotherapy are applied to large, high-grade extremity soft tissue sarcomas to treat metastatic disease earlier and sterilize margins to perform R0 surgery. However, preoperative RT increases wound complication rates (rWC), delaying adjuvant chemotherapy or preventing it from being administered altogether. Hypofractionated neoadjuvant RT can be offered in this situation, concomitant to chemotherapy, allowing patients to receive chemotherapy as a preoperative treatment in less time with an acceptable rWC. OBJECTIVE: The objectives of this protocol are to maintain low rates of morbidity and mortality compared to literature data, improving survival rates and avoiding poor responders from receiving unnecessary adjuvant chemotherapy. METHODS: This noncontrolled, single-arm, phase 2 clinical trial recruited patients aged over 18 years with high-grade soft tissue sarcomas in the girdles or extremities. Three neoadjuvant chemotherapy (ifosfamide and doxorubicin) cycles were administered with 5 days of hypofractionated RT (25 Gy in 5 fractions) in the second cycle of doxorubicin only. Viable cell counts in the surgical specimen were measured, and patients in whom this value was less than 30% continued to receive an additional 3 full chemotherapy cycles as adjuvant treatment. RESULTS: Primary endpoint will be disease-specific survival measured by the evaluation of local and distant recurrence after neoadjuvant treatment. The secondary endpoints will be wound complication and amputation rates and chemotherapy toxicity. We also will record the viable cell rates after the schema and correlate this with survival. CONCLUSIONS: As seems with other solid tumors, hypofractionated RT has comparable efficacy and safety as conventional fractionation. This modality of treatment combined with chemotherapy could increase the pathological response rates and improve the outcomes of select patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02812654; https://clinicaltrials.gov/ct2/show/NCT02812654 (Archived by WebCite at http://www.webcitation.org/6qC3puBOy).

Prognostic value of factors associated with hypoxia and lipid metabolism in patients with colorectal cancer

Background: Colorectal cancer (CRC) is a neoplasia with high incidence and mortality rates. It had been suggested that the inflammatory response is an important CRC prognostic factor. The disordered and accelerated proliferation of neoplastic cells decreases the oxygen and nutrient supply, generating a microenvironment characterized by hypoxia, necrosis and inflammation. This study aimed to evaluate the impact of factors associated with hypoxia, such as HIF1A (hypoxia-inducible factor 1-alpha) and VEGF (vascular endothelial growth factor), and with lipid metabolism, including PPARG (peroxisome proliferator-activated receptor-gamma), LXRA (liver X receptor-alpha) and LXRB (liver X receptor-beta), on the overall survival (OS) of CRC patients. Methods: This was a cohort study of 101 patients with high-risk stage II-III (TNM) CRC located above the peritoneal reflection. They were treated between 1990 and 2004 at the AC Camargo Cancer Center. Immunohistochemical analyses of HIF1A, VEGF, PPARG, LXRA and LXRB protein expression were performed using tissue microarrays (TMAs). Results: There was an association between the presence of vascular invasion and the lack of VEGF expression (p = 0. 028) as well as with positive HIF1A expression and lymphatic invasion (p = 0.045). The 5-year and 10-year OS rates were 76.6% and 60.2%, respectively. Patients with PPARG-positive tumors had a higher OS (p = 0.018). There were no correlations between the positive expression of VEGF, HIF1A, LXRA or LXRB and OS. The Cox regression model demonstrated that the risk of death was 2.72-fold higher in patients with PPARG-negative tumors (95% CI = 1.08­6.85). Conclusion: The PPARG expression was an independent prognostic factor for CRC tumors and might be used for risk stratification to stage II and stage III CRC patients (AU)

Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome.

Lynch syndrome (LS) accounts for 3-5% of all colorectal cancers (CRC) and is inherited in an autosomal dominant fashion. This syndrome is characterized by early CRC onset, high incidence of tumors in the ascending colon, excess of synchronous/metachronous tumors and extra-colonic tumors. Nowadays, LS is regarded of patients who carry deleterious germline mutations in one of the five mismatch repair genes (MMR), mostly in MLH1 and MSH2, but also in MSH6, PMS1 and PMS2. To comprehensively characterize 116 Brazilian patients suspected for LS, we assessed the frequency of germline mutations in the three minor genes MSH6, PMS1 and PMS2 in 82 patients negative for point mutations in MLH1 and MSH2. We also assessed large genomic rearrangements by MLPA for detecting copy number variations (CNVs) in MLH1, MSH2 and MSH6 generating a broad characterization of MMR genes. The complete analysis of the five MMR genes revealed 45 carriers of pathogenic mutations, including 25 in MSH2, 15 in MLH1, four in MSH6 and one in PMS2. Eleven novel pathogenic mutations (6 in MSH2, 4 in MSH6 and one in PMS2), and 11 variants of unknown significance (VUS) were found. Mutations in the MLH1 and MSH2 genes represented 89% of all mutations (40/45), whereas the three MMR genes (MSH6, PMS1 and PMS2) accounted for 11% (5/45). We also investigated the MLH1 p.Leu676Pro VUS located in the PMS2 interaction domain and our results revealed that this variant displayed no defective function in terms of cellular location and heterodimer interaction. Additionally, we assessed the tumor phenotype of a subset of patients and also the frequency of CRC and extra-colonic tumors in 2,365 individuals of the 116 families, generating the first comprehensive portrait of the genetic and clinical aspects of patients suspected of LS in a Brazilian cohort.