Transarterial radioembolization for liver tumors as neoadjuvant therapy: three case reports / Radioembolização transarterial hepática como terapia neoadjuvante: relato de três casos

ABSTRACT Transarterial radioembolization (TARE) with yttrium-90 microspheres is a palliative locoregional treatment, minimally invasive for liver tumors. The neoadjuvant aim of this treatment is still controversial, however, selected cases with lesions initially considered unresectable have been enframed as candidates for curative therapy after hepatic transarterial radioembolization. We report three cases in which the hepatic transarterial radioembolization was used as neoadjuvant therapy in an effective way, allowing posterior potentially curative therapies.

RESUMO A radioembolização transarterial hepática com microesferas de ítrio-90 é uma modalidade paliativa de tratamento locorregional minimamente invasiva. O objetivo neoadjuvante deste tratamento ainda é controverso, mas casos selecionados de lesões consideradas inicialmente irressecáveis reenquadram-se como candidatos à terapia curativa após a radioembolização transarterial hepática. Relatamos três casos em que a radioembolização transarterial hepática foi utilizada como terapia neoadjuvante de forma efetiva possibilitando aplicação posterior de terapias potencialmente curativas.

Avaliação dos efeitos da quimioterapia neoadjuvante na resposta imune celular nos tumores de mama triplo-negativos localmente avançados / Evaluation of the effects of neoadjuvant chemotherapy on the cellular immune response in locally advanced triple-negative breast tumors

Introdução: O câncer de mama triplo-negativo (CMTN) localmente avançado representa um problema de saúde pública no Brasil; e seu tratamento padrão consiste em quimioterapia neoadjuvante, com taxa de sucesso extremamente variável a depender do acesso ao tratamento oncológico adequado e do tipo de resposta patológica. Na última década, o papel do sistema imune no câncer de mama tem ganhado espaço com a demonstração do impacto favorável do infiltrado tumoral de linfócitos (TILs) e expressão gênica de resposta imune, principalmente em tumores de alta taxa de proliferação e receptor de estrógeno negativo. Objetivo: avaliar a resposta imune celular em mulheres com câncer de mama triplo-negativo localmente avançado, e submetidas a quimioterapia neoadjuvante. Métodos: estudo longitudinal com seguimento realizado entre os anos de 2015 e 2017. O estudo foi realizado no Hospital de Câncer de Pernambuco (HCP) e Laboratório de Pesquisa Translacional do Instituto de Medicina Integral Prof. Fernando Figueira (IMIP). Foram incluídas 30 mulheres, entre 18 e 60 anos de idade, com diagnóstico de CMTN localmente avançado e submetidas a quimioterapia neoadjuvante; e como grupo controle de comparação, 30 mulheres saudáveis com idade entre 18 a 60 anos sem diagnóstico prévio ou atual, e histórico familiar de CM. Coletas de sangue periférico foram realizadas antes e após a quimioterapia neoadjuvante (NAC). As análises dos níveis percentuais de TCD3+, TCD4+ e TCD8+ com expressão de CD28, FAS, PD1 e CTLA4 foram realizadas por citometria de fluxo. O teste de múltiplas comparações não paramétrico de Kruskall-wallis foi utilizado na análise de associação. Para análise pareada pré e pós tratamento, foi utilizado o teste não paramétrico de Wilcoxon. Para análise de sobrevida livre de doença (SLD), foi utilizado o teste de Log-Rank para comparação entre os grupos. Foi adotado o nível de significância estatística de p<0.05. A análise estatística foi realizada através do programa graphpad prism v6.0. Resultados: Verificou-se níveis elevados de CD3+ T CD28+, CD4+ T CD28+, CD3+ T PD1+ e CD3+ T CTLA4+ no sangue periférico dos grupos de mulheres que obteve resposta patológica completa (RC) e parcial (RP) ao tratamento neoadjuvante quando comparado ao grupo controle (p<0,05). Foram observados níveis elevados de TCD4+FAS+ no grupo de pacientes com RP ao tratamento neoadjuvante quando comparado aos grupos com RC e controle (p<0,05). Foram observados níveis mais elevados de TCD8+PD1+ no grupo de pacientes com RP comparado aos grupos com RC e controle (p<0,05). Foram encontrados níveis elevados nos índices obtidos da relação CD4+ TCD28+/CD8+ TCD28+ nos grupos de mulheres que obteve RP quando comparado aos grupos com RC e de controle. Níveis elevados da relação CD4+ TPD1+/CD8+ TPD1+ nos grupos CMTN que obteve RC e RP ao tratamento neoadjuvante quando comparado ao grupo controle (p<0,05). Verificou-se diferença significativa na análise pareada dos níveis percentuais de TCD4+ TCD8+ antes e após NAC. Também se verificou diferença significativa dos níveis de TCD3+ e TCD4+ com expressão de CD28, FAS e PD1+ e de TCD8+PD1+ antes e após no sangue periférico das mulheres com CMTN antes e após NAC. A sobrevida livre de doença em 24 meses foi de 52,1% no grupo de pacientes com níveis percentuais de TCD3 < 68,0 e de 100% no grupo com CD3+ T ≥ 68,8 (p=0,007), e de 54,1% no grupo de pacientes com níveis percentuais de TCD4+FAS+ ≥ 44,5 e de 100% no grupo com TCD4+FAS+ < 44,5 (p=0,02). Com relação TCD4+ PD1+, a sobrevida livre de doença foi 69,5% no grupo com níveis percentuais de TCD4+ PD1+ ≥ 4,5 e de 100% no grupo TCD4+PD1+ < 4,5 (p=0,01). Conclusão: Conclui-se que os níveis TCD4+/FAS+ e TCD8+/PD1+ circulantes antes do tratamento estão associadas a RC, o que sugere ser potenciais biomarcadores preditivos de resposta a NAC. As alterações nos níveis circulantes de TCD3+, TCD4+FAS+ e TCD4+PD1+ após NAC estão a associadas a sobrevida livre de doença, o que sugere que essas populações celulares e os receptores de inibição da resposta imune, FAS e PD1, estão envolvidos no prognóstico do CMTN

LLocally advanced triple-negative breast cancer (TNBC) represents a public health problem in Brazil. Its standard treatment consists of neoadjuvant chemotherapy, with an extremely variable success rate depending on access to adequate cancer treatment and the type of pathological response. In the last decade, the role of the immune system in breast cancer has gained space with the demonstration of the favorable impact of lymphocyte tumor infiltration (TILs) and genetic expression of immune response, especially in tumors with high proliferation rate and estrogen receptor negative. Objective: to evaluate the cellular immune response in women with locally advanced triple-negative breast cancer, and to undergo neoadjuvant chemotherapy. METHODS: This was a longitudinal study with follow-up performed between the years 2015 and 2017. The study was conducted at the Hospital de Cancer de Pernambuco and Translational Research Laboratory of the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP). Thirty women aged between 18 and 60 years with a diagnosis of locally advanced CMTN and submitted to neoadjuvant chemotherapy were included, and 30 healthy women aged 18 to 60 years without previous or current diagnosis and family history of TNBC were included as control group. Peripheral blood samples were collected before and after neoadjuvant chemotherapy (NAC). The analysis of the percentage levels of CD3+ T, TCD4 + and TCD8 + with expression of CD28, FAS, PD1 and CTLA4 were performed by flow cytometry. The non-parametric Kruskall-wallis multiple-comparison test was used in association analysis. For pre-and post-treatment paired analysis, the non-parametric Wilcoxon test was used. For disease-free survival analysis (SLD), the Log-Rank test was used to compare the groups. The level of statistical significance of p <0.05 was adopted. Statistical analysis was performed using the graphpad prism v6.0 program (Graphpad software, San Diego, CA). Results: High levels of CD28+ CD3+ T, CD28+CD4+ T, PD1 +CD3+T and CD3+ T CTLA4 + were observed in the peripheral blood of the groups of women with complete pathological response (CPR) and no CPR to the neoadjuvant treatment when compared to the control group (p < 0.05). High levels of FAS+CD4+ T were observed in the group of patients with RP to the neoadjuvant treatment when compared to the CR and control groups (p <0.05). Higher levels of PD1+CD8+ T were observed in the group of patients with no CRP compared to the control and CRP groups (p <0.05). High levels were found in the indices obtained from the CD28+ CD4+T / CD28+ CD8 +T ratio in the groups of women who had when compared to the RC and control groups. High levels of the PD1 + CD4 + T / PD1+ CD8+ T ratio in the CMTN groups, which obtained CPR and no CPR to the neoadjuvant treatment when compared to the control group (p <0.05). There was a significant difference in the paired analysis of the percent levels of CD4+ T and CD8+ T before and after NAC. There was also a significant difference in CD3+ T and CD4+ T levels with expression of CD28, FAS and PD1 and PD1+ CD8+ T before and after NAC in the peripheral blood of women with CMTN. The 24-month disease-free survival rate was 52.1% in the group of patients with CD3+T <68.0 and 100% in the CD3+ T ≥ 68.8 (p=0.007) and 54.1 % in the group of patients with FAS+ CD4+T ≥ 44.5 and 100% in the group with FAS+ CD4+T <44.5 (p = 0.02). With respect to PD1+ CD4+T disease-free survival was 69.5% in the group with PD1+ CD4+T ≥ 4.5 and 100% in the PD1+ CD4+T <4.5 (p = 0.01) groups. Conclusion: It is concluded that pre-treatment FAS+ CD4+ T and PD1+ CD8+ T levels are associated with CPR, suggesting potential biomarkers predictive of NAC response. Changes in the circulating levels of CD3+ T, FAS+ CD4+T and PD1+ CD4 +T after NAC are associated with disease free survival, suggesting that these cellular populations and immune response inhibitory receptors, FAS and PD1, are involved in the CMTN prognosis

Hormone receptor-negative as a predictive factor for pathologic complete response to neoadjuvant therapy in breast cancer / Receptor hormonal negativo como fator preditivo para resposta patológica completa ao tratamento neoadjuvante de câncer de mama

ABSTRACT Objective To define a predictive factor for pathologic complete response, compare the oncologic outcomes associated with the degree of pathologic response after neoadjuvant chemotherapy, and to analyze pathologic complete response as a prognostic factor for overall survival and progression-free survival. Methods A retrospective study of patients admitted to Hospital Estadual Mário Covas and Hospital Anchieta from 2008 to 2012, with locally advanced breast cancer. Hormone receptor status, HER2 status, histologic and nuclear grade, age upon diagnosis and histological type of the tumor were analyzed. Pathologic evaluation of the tumor was subdivided into pathologic complete response, defined by the absence of tumor; intermediate response, considered as a favorable stage; and poor response, considering low-responder patients. Data obtained were submitted to statistical analysis. Results The study included 243 patients. There was an association of pathologic complete response with HER-2 negative, histological grade 3, stage III, hormone receptor negative, positive lymph node, older age and more advanced tumors. However, after multivariate analysis the only predictor of pathologic complete response was the presence of negative hormone receptor. By analyzing the prognostic factors, hormone receptor negative was considered as an independent risk factor, and pathologic complete response was considered as an independent protective factor. Conclusion Hormone receptor negative is predictive of pathologic complete response and is an isolated risk factor for lower progression-free survival and overall survival. Pathologic complete response is a protective factor for these same survival analyses.

RESUMO Objetivo Definir um fator preditivo para resposta patológica completa, comparar os resultados oncológicos associados com o grau de resposta patológica, após quimioterapia neoadjuvante, e analisar a resposta patológica completa como fator prognóstico para sobrevivência global e livre de progressão de doença. Métodos Estudo retrospectivo de pacientes admitidas no Hospital Estadual Mário Covas e Hospital Anchieta, no período de 2008 a 2012, com câncer de mama localmente avançado. Foram utilizados status dos receptores hormonais, proteína HER2, grau histológico e nuclear, idade do paciente ao diagnóstico e tipo histológico do tumor. A avaliação patológica do tumor foi subdividida em resposta patológica completa, definida com ausência de tumor; resposta intermediária, considerada como um estádio favorável; e resposta ruim, considerando os pacientes pouco respondedores. As informações obtidas foram submetidas à análise estatística. Resultados Foram incluídas 243 pacientes. Verificou-se associação de resposta patológica completa entre HER-2 negativo, grau histológico 3, estadiamento III, receptor hormonal negativo, linfonodo positivo, maior idade e tumores mais avançados. Porém, após análise multivariada, o único fator preditivo de resposta patológica completa foi presença de receptor hormonal negativo. Ao analisar fatores prognósticos, receptor hormonal negativo permaneceu como variável independente de risco, e resposta patológica completa, como variável independente de proteção. Conclusão O receptor hormonal negativo é fator preditivo isolado de resposta patológica completa e fator de risco para menor sobrevida livre de doença e sobrevida global. Já a resposta patológica completa é fator protetor para estas mesmas análises de sobrevivência.

Transhiatal esophagectomy is not associated with poor quality lymphadenectomy / Esofagectomia trans-hiatal não está associada com linfadenectomia de baixa qualidade

ABSTRACT Background: Esophageal cancer neoadjuvant therapy followed by surgery increases the likelihood of treatment success. Aim: To evaluate variables that can influence the number of retrieved lymph nodes, the number of retrieved metastatic lymph nodes and lymphnodal recurrence in esophagectomy after neoadjuvant chemoradiotherapy. Methods: Patients of a single institute were evaluated after completion of trimodal therapy. Univariate and multivariate analyses were performed to evaluate variables that can influence in the number of retrieved lymph nodes and retrieved metastatic lymph nodes. Results: One hundred and forty-nine patients were included. Thoracoscopy access was considered an independent factor for the number of lymph nodes retrieved, but was neither related to the number of positive lymph nodes retrieved nor to lymphnodal recurrence. Pathological complete response on the primary tumor and male were independent variables associated with the number of positive lymph node retrieved. Pathological complete response on the primary tumor site did not statistically influence the likelihood of a lower number of lymph nodes retrieved. Conclusion: Patients submitted to esophagectomy after neoadjuvant chemoradiotherapy, thoracoscopic access is more accurate for pathological staging, even in a complete pathological response. With a proper patient selection, transhiatal surgery may preserve the quality of lymphadenectomy of the positive lymph nodes.

RESUMO Racional: No câncer esofágico a terapia neoadjuvante seguida de procedimento cirúrgico aumenta a probabilidade de sucesso do tratamento. Objetivo: Avaliar variáveis que podem influenciar o número de linfonodos recuperados, o número de linfonodos metastáticos recuperados e a recorrência linfonodal na esofagectomia após quimiorradioterapia neoadjuvante. Métodos: Os pacientes incluídos foram aqueles que terminaram terapia trimodal. Análises univariadas e multivariadas foram realizadas para avaliar as variáveis que pudessem influenciar no número de linfonodos recuperados e nos metastáticos recuperados. Resultados: Cento e quarenta e nove pacientes foram incluídos. O acesso por toracoscopia foi considerado fator independente para o número de linfonodos recuperados, mas não teve relação com o número de linfonodos positivos recuperados, nem com recorrência linfonodal. Resposta patológica completa no tumor primário e homens foram variáveis independentes associadas ao número de linfonodos positivos recuperados. A resposta patológica completa do tumor primário não acarretou em número menor de linfonodos recuperados. Conclusão: Em pacientes submetidos à esofagectomia após quimiorradioterapia neoadjuvante o acesso toracoscópico é mais preciso para estadiamento patológico, mesmo em resposta patológica completa. Com seleção adequada a esofagectomia trans-hiatal pode preservar a qualidade da linfadenectomia dos linfonodos positivos.

Modificación del abordaje quirúrgico en tumores estromales gástricos posterior a neoadyuvancia con Imatinib / Change of surgical approach in gastrointestinal stromal tumors after neoadyuvant therapy with Imatinib

Resumen Introducción: El tratamiento de los tumores estromales gastrointestinales (GIST) de alto riesgo es quirúrgico. Su resultado podría variar al usarse neoadyuvancia. Objetivo: Evaluar si el uso de la terapia neoadyuvante con imatinib puede cambiar el abordaje quirúrgico en los tumores estromales gastrointestinales de alto riesgo. Materiales y Métodos: Se realizó un análisis retrospectivo en el Hospital Clínic de Barcelona entre enero de 2002 y mayo de 2016. Resultados: Se obtuvo un total de 8 pacientes. La edad media fue 66,1 ± 13,3 años. La ubicación del tumor fue de 37,5% (3) en el tercio superior, el 50% (4) en el tercio medio y el 12,5% (1) en el tercio inferior. Debido a la clasificación de riesgo alto, la ubicación y/o la necesidad de resecciones multiviscerales, se indicó, previa evaluación comité oncológico, realizar terapia neoadyuvante. La mediana de tiempo de neoadyuvancia fue de 30 semanas. En el 100% (8) de los casos se logró un cambio de enfoque quirúrgico después de la utilización de imatinib. En todos los casos se realizó un resección local (7 laparoscópica y 1 endolaparoscópica) con márgenes negativos La biopsia posoperatoria mostró un promedio de 51,2% de reducción del tamaño tumoral inicial, lo que resultó en una diferencia estadística (p < 0,01) con el tamaño inicial de las lesiones. Durante el seguimiento, tanto la sobrevida relacionada al tumor como la global, fue de un 100%. Conclusión: La terapia neoadyuvante podría cambiar el abordaje quirúrgico de los pacientes con GIST gástrico de riesgo intermedio o alto mediante la reducción del tamaño tumoral, permitiendo realizar cirugías más económicas y logrando resultados oncológicos adecuados.

Introduction: The treatment of high-risk gastrointestinal stromal tumors (GIST) is surgical. Results may change when using neoadjuvant. Objetive: To evaluated if the use of neoadjuvant therapy with imatinib can change the surgical approach in high risk gastrointestinal stromal tumors (GIST). Materials and Methods: A retrospective analysis was performed from a prospective collected database in Hospital Clinic of Barcelona between January 2002 and May 2016. Results: A total of 8 patients were analyzed with a mean age of 66.1 ± 13.3 years. The tumor location was upper third 37.5% (3) cases, 50% (4) in the middle third and 12.5% (1) in lower third. Because of high risk classification, location and the need of multivisceral resections, neoadjuvant therapy was indicated. The median time of neoadjuvant therapy was 30 weeks. In 87.5% (7) cases a change of surgical approach was achieved after the use of imatinib. In 100% of our series laparoscopic wedge resection was performed achieving negative margins of resection. The postoperative biopsy showed 51.2% of reduction of initial tumor size, resulting in statistical difference (p < 0.01). All patients are alive and 100% of tumor related survival was achieved. Conclusion: Neoadjuvant therapy maybe can change the surgical approach of patients with high-intermediate risk gastric GIST by reducing tumor size. This response also eventually can achieve optimal oncological outcome.

Citorreducción óptima en cáncer de ovario avanzado tratado con paclitaxel a dosis densa y carboplatino seguido de cirugía de intervalo en el Instituto Nacional de Enfermedades Neoplásicas del Perú / Optimal cytoreduction in advanced ovarian cancer treated with dose-dense paclitaxel and carboplatin followed by interval surgery at the Peruvian National Institute of Neoplastic Diseases

RESUMEN Objetivos. Determinar la tasa de citorreducción óptima en pacientes con cáncer de ovario avanzado que recibieron quimioterapia neoadyuvante con carboplatino y paclitaxel dosis densa seguido de cirugía de citorreducción de intervalo (CCI). Materiales y métodos. Estudio de una serie de casos retrospectiva de mujeres peruanas tratadas con quimioterapia neoadyuvante con carboplatino (AUC 6 mg/ml/min) y paclitaxel (80 mg/m2 semanal) seguido de CCI, en el Instituto Nacional de Enfermedades Neoplásicas durante el período 2010-2014. Resultados . Los 41 pacientes que alcanzaron cirugía de intervalo, tuvieron una mediana de edad de 59 años (rango: 47-73 años). En 37 (90,2%) pacientes se reportó histología de adenocarcinoma seroso de alto grado. Treinta y cuatro (82,9%) lograron citorreducción óptima y cinco (14,7%) respuesta patológica completa. La sobrevida libre de progresión al año y 2 años fueron 74,7% y 51,8%, respectivamente. La sobrevida global al año y 2 años fue 85,2% y 71,4%, respectivamente. El riesgo de progresión y muerte fue mayor en pacientes sin citorreducción óptima y pacientes con niveles de dosaje del antígeno carcinoembrionario 125 postoperatorio > 30 U/ml. Conclusiones . La neoadyuvancia con carboplatino y paclitaxel dosis densa logró una frecuencia elevada de citorreducción óptima. Los niveles de antígeno carcinoembrionario 125 postoperatorios y citorreducción óptima resultaron factores independientes de sobrevida libre de progresión y sobrevida global.

ABSTRACT Objectives. To determine the rate of optimal cytoreduction in patients with advanced ovarian cancer who received neoadjuvant chemotherapy with dose-dense carboplatin and paclitaxel followed by interval debulking surgery (IDS). Materials and Methods. A retrospective study of a series of cases of Peruvian women treated with neoadjuvant chemotherapy with carboplatin (6 AUC mg/mL/min) and paclitaxel (80 mg/m2 weekly) followed by IDS, at the National Institute of Neoplastic Diseases during the 2010-2014 period. Results. The 41 patients who made it to the interval surgery had a median age of 59 years (range: 47-73 years). In 37 (90.2%) patients, high-grade serous adenocarcinoma histology was reported. Thirty-four (82.9%) achieved optimal cytoreduction and five (14.7%), a complete pathological response. Progression-free survival at one year and two years was 74.7% and 51.8%, respectively. Overall survival at one year and two years was 85.2% and 71.4%, respectively. The risk of progression and death was greater in patients without optimal cytoreduction and in patients with postsurgery levels of carcinoembryonic antigen 125 > 30 U/mL. Conclusions. Neoadjuvant therapy with dose-dense carboplatin and paclitaxel achieved an elevated frequency of optimal cytoreduction. The post-surgery levels of carcinoembryonic antigen 125 and optimal cytoreduction were independent factors of progression-free survival and overall survival.

Oncological outcomes in extended time intervals between preoperative chemoradiotherapy with capecitabine and surgery in operable rectal adenocarcinoma / Resultados oncológicos en intervalos extendidos de tiempo entre quimioradioterapia preoperatoria con capecitabina y cirugía en adenocarcinoma rectal operable

Objective: To assess whether extended time intervals (8-12, 13-20 and >20 weeks) between the end of neoadjuvant chemoradiotherapy and surgery affect overall survival, disease-free survival. Materials and methods: Retrospective study in 120 patients with rectal adenocarcinoma without evidence of metastasis (T1-4/N0-2/M0) at the time of diagnosis that underwent surgery with curative intent after neoadjuvant chemoradiotherapy with capecitabine and obtained R0 or R1 resection between January 2010 to December 2014 at the National Cancer Institute of Peru. Dates were evaluated by Kaplan-Meier method, log- rank test and Cox regression analysis. Results: Of the 120 patients, 70 were women (58%). The median age was 63(26-85) years. All received neoadjuvant chemoradiotherapy. No significant difference was found between the association of the median radial (0.6, 0.7 and 0.8 cm; p=0.826) and distal edge (3.0, 3.5 and 4.0 cm; p=0.606) with time interval groups and similarly the mean resected (18.8, 19.1 and 16.0; p=0.239) and infiltrated nodules (1.05, 1.29 and 0.41); p=0.585). The median follow-up time of overall survival and desease free survival was 40 and 37 months, respectively. No significant differences were observed in overall survival (79.0%, 74.6% and 71.1%; p=0.66) and disease-free survival (73.7%, 68.1% and 73.6%; p=0.922) according to the three groups studied at the 3-year of follow-up. Conclusions: We found that widening the time intervals between the end of neoadjuvant chemoradiotherapy and surgery at 24 weeks does not affect the overall survival, disease-free survival and pathological outcomes. It allows to extend the intervals of time for future studies that finally will define the best time interval for the surgery

Objetivo: Evaluar si los intervalos de tiempo extendidos (8-12, 13-20 y >20 semanas) entre el fin de la quimioradioterapia neoadyuvante y la cirugía afectan la sobrevida global, y la sobrevida libre de enfermedad. Material y métodos: Estudio retrospectivo de 120 pacientes con adenocarcinoma rectal sin evidencia de metástasis (T1-4/N0-2/M0) al momento del diagnóstico que se sometieron a cirugía con intención curativa luego de quimioradioterapia neoadyuvante con capecitabina y tuvieron resección R0 o R1 entre enero 2010 y diciembre 2014 en el Instituto Nacioanal de Enfermedades Neoplásicas de Perú. El análisis se hizo con el método de Kaplan-Meier, la prueba log-rank y la regresión de Cox. Resultados: De 120 pacientes, 70 fueron mujeres (58%). La mediana de la edad fue 63 años (26-85 años). Todos recibieron quimioradioterapia neoadyuvante. No hubo diferencia significativa entre la asociación de las medianas de los bordes radial (0,6, 0.7 y 0,8 cm; p=0,826) y distal (3,0, 3,5 y 4,0 cm; p=0,606) con los intervalos de tiempo de los grupos y similarmente con la media de los ganglios resecados (18,8, 19,1 y 16,0; p=0,239) e infiltrados (1,05, 1,29 y 0,41; p=0,585). No se observaron diferencias significativas en sobrevida global (79,0%, 74,6% y 71,1%; p=0,66) y sobrevida libre de enfermedad (73,7%, 68,1% y 73,6%; p=0,922), en los tres grupos estudiados a 3 años de seguimiento. Conclusiones: Encontramos que aumentar los intervalos de tiempo entre el fin de la quimioradioterapia neoadyuvante y la cirugía hasta 24 semanas no afecta la sobrevida global, sobrevida libre de enfermedad ni los desenlaces patológicos. Esto permitiría extender los intervalos de tiempo en estudios futuros para definir el mejor intervalo de tiempo para la cirugía

Individualized threshold for tumor segmentation in 18F-FDG PET/CT imaging: The key for response evaluation of neoadjuvant chemoradiation therapy in patients with rectal cancer? / Individualização na segmentação tumoral de imagens de 18F-FDG PET/CT: a chave para avaliação de resposta terapêutica neoadjuvante em pacientes com câncer retal?

Summary Introduction: The standard treatment for locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiation followed by radical surgery. Regardless the extensive use of SUVmax in 18F-FDG PET tumor uptake as representation of tumor glycolytic consumption, there is a trend to apply metabolic volume instead. Thus, the aim of the present study was to evaluate a noninvasive method for tumor segmentation using the 18F-FDG PET imaging in order to predict response to neoadjuvant chemoradiation therapy in patients with rectal cancer. Method: The sample consisted of stage II and III rectal cancer patients undergoing 18F-FDG PET/CT examination before and eight weeks after neoadjuvant therapy. An individualized tumor segmentation methodology was applied to generate tumor volumes (SUV2SD) and compare with standard SUVmax and fixed threshold (SUV40%, SUV50% and SUV60%) pre- and post-therapy. Therapeutic response was assessed in the resected specimens using Dworak's protocol recommendations. Several variables were generated and compared with the histopathological results. Results: Seventeen (17) patients were included and analyzed. Significant differences were observed between responders (Dworak 3 and 4) and non-responders for SUVmax-2 (p<0.01), SUV2SD-2 (p<0.05), SUV40%-2 (p<0.05), SUV50%-2 (p<0.05) and SUV60%-2 (p<0.05). ROC analyses showed significant areas under the curve (p<0.01) for the proposed methodology with sensitivity and specificity varying from 60% to 83% and 73% to 82%, respectively. Conclusion: The present study confirmed the predictive power of the variables using a noninvasive individualized methodology for tumor segmentation based on 18F-FDG PET/CT imaging for response evaluation in patients with rectal cancer after neoadjuvant chemoradiation therapy.

Resumo Introdução: O câncer retal (RC) é uma doença de importância global, e o tratamento padrão para o câncer retal localmente avançado compreende quimiorradiação neoadjuvante seguida de cirurgia radical. Independentemente do uso extensivo da captação tumoral mais intensa do 18F-FDG (conhecida como SUVmax) como representativo do consumo glicolítico do tumor nas imagens de PET, há uma tendência para aplicar volume metabólico. Dessa forma, o objetivo do presente estudo foi avaliar um método não invasivo de segmentação tumoral utilizando a 18F-FDG PET para predizer a resposta à quimiorradioterapia neoadjuvante em pacientes com câncer de reto. Método: A amostra consistiu em pacientes com câncer retal em estádios II e III submetidos ao exame de 18F-FDG PET/CT antes e oito semanas após a terapia neoadjuvante. Foi aplicada uma metodologia de segmentação tumoral individualizada para gerar volumes tumorais (SUV2SD). A resposta terapêutica foi avaliada nos espécimes ressecados utilizando as recomendações do protocolo de Dworak. Várias variáveis foram geradas e comparadas com os resultados histopatológicos. Resultados: Dezessete (17) pacientes foram incluídos e analisados. Foram observadas diferenças significativas entre os respondedores (Dworak 3 e 4) e não respondedores para SUVmax-2 (p<0,01), SUV2SD-2 (p<0,05), SUV40%-2 (p<0,05), SUV50%-2 (p<0,05) e SUV60%-2 (p< 0,05). As análises ROC mostraram áreas significativas sob a curva (p<0,01) para a metodologia proposta, com sensibilidade e especificidade variando de 60% a 83% e 73% a 82%, respectivamente. Conclusão: O presente estudo confirmou o poder preditivo das variáveis utilizando uma metodologia não invasiva individualizada para segmentação tumoral baseada em imagens 18F-FDG PET/CT para avaliação da resposta em pacientes com câncer retal após tratamento com quimiorradiação neoadjuvante.

Estudo comparativo entre a amputação de reto na posição clássica de Lloyd-Davies e em decúbito ventral / Comparative study between amputation of the rectum in the classic Lloyd-Davies position and in ventral decubitus

RESUMO Objetivo: avaliar benefícios e desvantagens do posicionamento em decúbito ventral em relação ao de Lloyd-Davies, de pacientes submetidos à amputação abdominoperineal de reto. Métodos: estudo retrospectivo de 56 pacientes submetidos à amputação abdominoperineal de reto por neoplasias de reto distal e de canal anal, tratados no Hospital Central da Santa Casa de Misericórdia de São Paulo entre 2008 e 2017. Resultados: a média de idade dos pacientes foi de 63,08 anos, sendo 48,2% deles mulheres e 51,8%, homens. Adenocarcinoma foi o tipo histológico em 94,6% dos casos e carcinoma espinocelular em 5,4%. A posição de Lloyd-Davies foi a adotada em 66,1% das cirurgias e a posição ventral em 33,9%. No momento da cirurgia quatro pacientes apresentavam metástases sincrônicas: hepática (um caso), pulmonar (um caso) e hepática e pulmonar simultâneas (dois casos). Tratamento neoadjuvante foi realizado em 85,7% dos pacientes. Complicações pós-operatórias tardias ocorreram em 13 pacientes operados na posição clássica e em um paciente operado em decúbito ventral. O tempo de sobrevida global para o grupo operado na posição clássica foi, em média, de 45,7 meses, enquanto que no grupo operado em decúbito ventral foi de 15,5 meses. Conclusão: o grupo da posição ventral apresentou menor necessidade de infusão de volume intravenoso intraoperatório e menos complicações pós-cirúrgicas tardias, enquanto que o grupo Lloyd-Davies obteve melhores tempos cirúrgicos e anestésicos. Recidiva, tempo livre de doença e sobrevida global devem ser avaliados em um tempo maior de seguimento.

ABSTRACT Objective: to evaluate the benefits and disadvantages of the ventral decubitus position compared with that of Lloyd-Davies in patients submitted to abdominoperineal amputation of the rectum. Methods: we conducted a retrospective study of 56 patients submitted to abdominoperineal amputation of the rectum due to distal rectal and anal canal neoplasms, treated at the Central Hospital of the Santa Casa de Misericórdia in São Paulo between 2008 and 2017. Results: patients' mean age was 63.08 years, 48.2% of them women and 51.8%, men. Adenocarcinoma was the histological type, in 94.6% of cases, and squamous cell carcinoma, in 5.4%. The position of Lloyd-Davies was adopted in 66.1% of the procedures, and the ventral position, in 33.9%. At the time of surgery, four patients had synchronous metastases: hepatic (one case), pulmonary (one case) and simultaneous liver and lung (two cases). Neoadjuvant treatment was performed in 85.7% of the patients. Late postoperative complications occurred in 13 patients operated in the classic position and in one patient operated on in the ventral decubitus position. The overall survival time for the group operated in the classic position was on average 45.7 months, while in the group operated on in the ventral decubitus position it was 15.5 months. Conclusion: the ventral position group presented less need for intraoperative intravenous volume infusion and fewer postoperative complications, whereas the Lloyd-Davies group had better surgical and anesthetic times. Relapse, disease-free time, and overall survival should be evaluated at a longer follow-up time.

Pathologic complete response (ypt0 ypn0) after chemotherapy and radiotherapy neoadjuvant followed by esophagectomy in the squamous cell carcinoma of the esophagus / Resposta patológica completa (ypt0 ypn0) após quimioterapia e radioterapia neoadjuvantes seguido de esofagectomia no carcinoma epidermóide avançado do esôfago: resultados e sobrevida

ABSTRACT Background: Esophageal squamous cell carcinoma is an aggressive neoplasia that requires a multidisciplinary treatment in which survival and prognosis are still not satisfactory. The complete pathologic response to neoadjuvant chemotherapy and radiotherapy is considered a good prognosis factor, and esophagectomy is indicated. Aim: Survival analysis of cases with pathologic complete response (ypT0 ypN0) to neoadjuvant chemotherapy and/or radiotherapy, submmitted to esophagectomy. Methods: Between 1983-2014, 222 esophagectomies were performed, and 177 were conducted to neoadjuvant treatment. In 34 patients the pathologic response was considered complete. Medical records of the patients were retrospectively reviewed regarding type of chemotherapy applied, amount of radiotherapy, interval between the neoadjuvant therapy and the surgery, body mass index; postoperative complications; hospital admission time and survival. Results: The average age was 55.8 years. Twenty-five patients were subjected to chemotherapy and radiotherapy, and nine to neoadjuvant radiotherapy. The total radiation dose ranged from 4400 until 5400 cGy. The chemotherapy was performed with 5FU, cisplatin, and carbotaxol, concomitantly with the radiotherapy. The esophagectomy was transmediastinal, followed by the cervical esophagogastroplasty performed on a average of 49.4 days after the neoadjuvant therapy. The hospital admission time was an average of 14.8 days. During the follow-up period, 52% of the patients submitted to radiotherapy and chemotherapy were disease-free, with 23.6% of them presenting more than five years survival. Conclusions: The neoadjuvant treatment followed by esophagectomy in patients with pathologic complete response is beneficial for the survival of patients with esophageal squamous cell carcinoma.

RESUMO Racional: O carcinoma epidermoide do esôfago é neoplasia de natureza agressiva, que requer tratamento multidisciplinar e tem taxas de sobrevida e prognóstico ainda não satisfatórios. A resposta patológica completa à neoadjuvância com quimioterapia e radioterapia é considerada fator de bom prognóstico e a esofagectomia está indicada. Objetivo: Análise de sobrevida dos casos com resposta patológica completa (ypT0 ypN0) à neoadjuvância com quimioterapia e/ou radioterapia, submetidos à esofagectomia. Métodos: Entre 1983-2014, 222 esofagectomias foram realizadas e 177 foram submetidas ao tratamento neoadjuvante. Em 34 pacientes, a resposta patológica foi considerada completa. Os prontuários dos pacientes foram revisados retrospectivamente quanto ao tipo de quimioterapia aplicada, quantidade de radioterapia, intervalo entre a terapia neoadjuvante e a operação, índice de massa corporal (IMC), complicações pós-operatórias, tempo de internação hospitalar e sobrevida. Resultados: A idade média foi de 55,8 anos. Vinte e cinco pacientes foram submetidos a quimioterapia e radioterapia e nove à radioterapia neoadjuvante. A dose total de radiação variou de 4400 até 5400 cGy. A quimioterapia foi realizada com 5FU, cisplatina e carbotaxol, concomitantemente à radioterapia. A esofagectomia foi transmediastinal, seguida da esofagogastroplastia cervical realizada em média 49,4 dias após a terapia neoadjuvante. O tempo de internação hospitalar foi em média de 14,8 dias. Durante o período de seguimento, 52% dos pacientes submetidos a radioterapia e quimioterapia estavam livres de doença, com 23,6% apresentando sobrevida maior que cinco anos. Conclusão: O tratamento neoadjuvante seguido de esofagectomia, nos pacientes com resposta patológica completa, oferece benefícios na sobrevida de portadores de carcinoma epidermoide do esôfago.

Prognostic factors affecting outcomes in multivisceral en bloc resection for colorectal cancer

OBJECTIVES: This study sought to determine the clinical and pathological factors associated with perioperative morbidity, mortality and oncological outcomes after multivisceral en bloc resection in patients with colorectal cancer. METHODS: Between January 2009 and February 2014, 105 patients with primary colorectal cancer selected for multivisceral resection were identified from a prospective database. Clinical and pathological factors, perioperative morbidity and mortality and outcomes were obtained from medical records. Estimated local recurrence and overall survival were compared using the log-rank method, and Cox regression analysis was used to determine the independence of the studied parameters. ClinicalTrials.gov: NCT02859155. RESULTS: The median age of the patients was 60 (range 23-86) years, 66.7% were female, 80% of tumors were located in the rectum, 11.4% had stage-IV disease, and 54.3% received neoadjuvant chemoradiotherapy. The organs most frequently resected were ovaries and annexes (37%). Additionally, 30.5% of patients received abdominoperineal resection. Invasion of other organs was confirmed histologically in 53.5% of patients, and R0 resection was obtained in 72% of patients. The overall morbidity rate of patients in this study was 37.1%. Ureter resection and intraoperative blood transfusion were independently associated with an increased number of complications. The 30-day postoperative mortality rate was 1.9%. After 27 (range 5-57) months of follow-up, the mortality and local recurrence rates were 23% and 15%, respectively. Positive margins were associated with a higher recurrence rate. Positive margins, lymph node involvement, stage III/IV disease, and stage IV disease alone were associated with lower overall survival rates. On multivariate analysis, the only factor associated with reduced survival was lymph node involvement. CONCLUSIONS: Multivisceral en bloc resection for primary colorectal cancer can be performed with acceptable rates of morbidity and mortality and may lead to favorable oncological outcomes.

Clinical factors of post-chemoradiotherapy as valuable indicators for pathological complete response in locally advanced rectal cancer

OBJECTIVES: Pathological complete response has shown a better prognosis for patients with locally advanced rectal cancer after preoperative chemoradiotherapy. However, correlations between post-chemoradiotherapy clinical factors and pathologic complete response are not well confirmed. The aim of the current study was to identify post-chemoradiotherapy clinical factors that could serve as indicators of pathologic complete response in locally advanced rectal cancer. METHODS: This study retrospectively analyzed 544 consecutive patients with locally advanced rectal cancer treated at Sun Yat-sen University Cancer Center from December 2003 to June 2014. All patients received preoperative chemoradiotherapy followed by surgery. Univariate and multivariate regression analyses were performed to identify post-chemoradiotherapy clinical factors that are significant indicators of pathologic complete response. RESULTS: In this study, 126 of 544 patients (23.2%) achieved pathological complete response. In multivariate analyses, increased pathological complete response rate was significantly associated with the following factors: post-chemoradiotherapy clinical T stage 0-2 (odds ratio=2.098, 95% confidence interval=1.023-4.304, p=0.043), post-chemoradiotherapy clinical N stage 0 (odds ratio=2.011, 95% confidence interval=1.264-3.201, p=0.003), interval from completion of preoperative chemoradiotherapy to surgery of >7 weeks (odds ratio=1.795, 95% confidence interval=1.151-2.801, p=0.010) and post-chemoradiotherapy carcinoembryonic antigen ≤2 ng/ml (odds ratio=1.579, 95% confidence interval=1.026-2.432, p=0.038). CONCLUSIONS: Post-chemoradiotherapy clinical T stage 0-2, post-chemoradiotherapy clinical N stage 0, interval from completion of chemoradiotherapy to surgery of >7 weeks and post-chemoradiotherapy carcinoembryonic antigen ≤2 ng/ml were independent clinical indicators for pathological complete response. These findings demonstrate that post-chemoradiotherapy clinical factors could be valuable for post-operative assessment of pathological complete response.

Transanal endoscopic operation for rectal cancer after neoadjuvant therapy

PURPOSE: In this paper we report the oncological outcomes from clinical series of patients with rectal cancer submitted to local excision after neoadjuvant therapy and discuss the indications for local excision in partial clinical responders. METHODS: We analysed a prospective database of 39 patients submitted to a transanal endoscopic operation for rectal cancer after neoadjuvant chemoradiation between 2006 and 2015, comparing clinical and pathological variables, perioperative complications, recurrence rate and overall survival. RESULTS: We obtained 15.4% ypT0, 17.9% ypT1, 35.9% ypT2 and 28.2% ypT3. After a median follow-up of 24 months, tumoral recurrence was observed in 4 patients, one of them with isolated pulmonary metastasis. R0 resection was achieved in 79.5%, and postoperative complications were observed in 30.2% patients and no perioperative mortality occur. Compromise surgical margins do not affect recurrence rate, and 94.9% of patients are alive nowadays. CONCLUSION: Local excision could be associated with low recurrence rate and good overall survival. Short hospitalization time and low level of serious complications observed could be an interesting option for patients who would not tolerate a radical procedure or for those who declined a total mesorectal excision. A strict long-term follow-up must be warranted to detect early tumoral recurrence.

Marcadores e mecanismos de resistência à terapia neoadjuvante e o papel das vesículas extracelulares secretadas pelas células tumorais no câncer de reto / Biomarkers and mechanisms of resistance to neoadjuvnat therapy and the role of extracelular vesicles secreted by tumor cells in rectal cancer

O câncer de reto é o segundo tumor mais comum no intestino grosso correspondendo a um terço do total de casos de câncer colorretal (CCR). Pacientes com câncer de reto em estádios II e III são tratados com radioquimioterapia neoadjuvante seguida de ressecção cirúrgica do tumor. Análises das peças cirúrgicas ressecadas mostraram que apenas 10-45% dos pacientes obtém resposta patológica completa (RCp) à terapia neoadjuvante, estando essa associada com uma diminuição da recorrência local, melhora da sobrevida livre de doença e aumento na preservação esfincteriana. Apesar da melhora na sobrevida nas últimas décadas, a resposta à terapia neoadjuvante continua variável e imprevisível e não é possível identificar e separar clinicamente os grupos de pacientes que terão ou não resposta completa ao tratamento neoadjuvante. Além disso, os mecanismos de resistência à radioquimioterapia nos tumores de reto são pouco compreendidos. Dessa forma, o objetivo principal deste estudo foi identificar marcadores e mecanismos celulares relacionados à resistência à terapia neoadjuvante em adenocarcinoma de reto e o papel das vesículas extracelulares (VEs) nesse processo. O estudo proteômico comparativo entre biópsias obtidas de tumores pré-tratamento com o tumor residual removido cirurgicamente pós-tratamento radioquimioterápico mostrou uma importante alteração no perfil de expressão proteica. Entre as proteínas que aumentam a expressão após a neoadjuvância estão as proteínas de reparo de dano de DNA, Ku70 e Ku80, e a proteína de tráfego intracelular Rab5C. Em um modelo in vitro, foi demonstrado que Rab5C orquestra um mecanismo de resistência à radioterapia nos tumores de reto através da modulação da internalização de EGFR promovida por radiação ionizante (RI). O EGRF intracelular por sua vez é essencial para regular a expressão de Ku70 e Ku80 e a resistência celular à RI. Estes dados apontam Rab5C e EGFR como potenciais alvos terapêuticos para sensibilizar células de câncer de reto resistentes ao tratamento neoadjuvante. Também foi observado que a RI promove alterações epigenéticas predominantemente de hipometilação, e entre os genes alterados estão SPG20 e TBC1D16, sendo o primeiro importante para a internalização de EGFR e o segundo para a regulação de Rab5C e modulação de EGFR. O perfil de expressão proteica foi ainda comparado entre biópsias pré-tratamento de pacientes com RCp e sem resposta patológica, e o resultado mostrou que esses dois grupos de pacientes apresentam um diferente perfil de expressão proteica. Nos pacientes com RCp as proteínas com aumento da expressão estão atuando em vias que favorecem a resposta à terapia, como a detoxificação de glutationa e degradação de glicogênio, enquanto as proteínas com aumento da expressão em pacientes sem RCp estão envolvidas em vias do metabolismo energético do tumor as quais contribuem para a resistência tumoral à terapia. As diferenças observadas nestes grupos devem ser amplamente exploradas uma vez que podem ser marcadores preditivos de resposta ao tratamento radioquimioterápico. A realização de estudos funcionais foi viabilizada pela geração de um modelo celular de tumor de reto resistente à radioterapia. Ao analisar as VEs secretadas por estas células foi observado que a RI não altera a quantidade e o tamanho médio das VEs secretadas, porém é capaz de alterar o carregamento proteico das mesmas. De fato, as VEs de células irradiadas apresentam um perfil proteico diferente quando comparadas as VEs de células não irradiadas, onde encontramos aumento da expressão de Ku70, Ku80 e Rab5C, além das metiltransferases NSUN2 e GLYM nas VEs de células pós RI. Interessantemente, as VEs secretadas por células irradiadas são capazes de transmitir a resistência à RI às células não irradiadas. Além disso os resultados mostraram que o tratamento com VEs de células irradiadas promove metilação em 98% do DNA avaliado em células SW837 em comparação ao tratamento com VEs de células não irradiadas. Os genes hipermetilados estão envolvidos em vias relacionadas ao sistema imune, como a apresentação de antígeno, sinalização de imunodeficiência primária e maturação de células dendríticas. Por fim, foi identificado que a expressão da proteína A33 está relacionada ao grau de diferenciação dos tumores colorretais, e que essa proteína está presente em VEs secretadas por células de adenocarcinoma de reto, indicando que a mesma pode ser usada para isolar VEs específicas do tecido colorretal. Os dados obtidos neste trabalho apontam mecanismos relacionados à resistência à terapia neoadjuvante no adenocarcinoma de reto e que em conjunto permitirão identificar novos alvos terapêuticos com potencial de melhorar a resposta à radioquimioterapia, além de identificar marcadores de resposta à terapia neoadjuvante antes do tratamento e dessa forma, poupar os pacientes não respondedores de terapias tóxicas e melhorar a sustentabilidade na saúde poupando os custos com drogas não eficientes para um grupo de pacientes.

Rectal cancer is the second most common cancer in large intestine, corresponding to one third of total cases of colorectal cancer (CRC). Patients with rectal cancer in stage II and III are treated with neoadjuvant chemoradiation followed by surgical resection. Analyzes of the resected tumor demonstrated that only 10-45% of the patients achieve pathological complete response (pCR) after neoadjuvant therapy, which is associated with a decrease in local recurrence, improvement of disease free survival and increase in sphincter preservation. Despite the improvement in survival in the last decades, the response to neoadjuvant therapy is still variable and unpredictable, and before the surgery it is not possible to identify and separate clinically the group of patients that will or will not have complete response to neoadjuvant treatment. Moreover, the mechanisms of resistance of rectal tumors to chemoradiation are poorly understood. Thus, the main objective of this work was to identify biomarkers and cellular mechanisms related to the resistance to neoadjuvant therapy in rectal adenocarcinomas and the role of extracellular vesicles (EVs) in this process. The comparative proteomic study between biopsy obtained from tumors pretreatment with residual tumor, post chemoradiation treatment, removed by surgery showed an important alteration in the protein expression profile. Among the proteins with increased expression after neoadjuvant therapy are the DNA repair proteins Ku70 and Ku80, and the protein involved in the intracellular trafficking, Rab5C. It was demonstrated in vitro that Rab5C orchestrates a mechanism of radioresistance in rectal tumors by modulating the EGFR internalization promoted by ionizing radiation (IR). The intracellular EGFR is essential to regulate Ku70 and Ku80 expression and the cell resistance to IR. These data pointed Rab5C and EGFR as potential therapeutic targets to sensitize rectal cancer cells resistant to neoadjuvant treatment. It was also observed that IR promotes epigenetic alterations, predominantly hypomethylation, and between the altered genes are SPG20 and TBC1D16, the first is important to EGFR internalization, while the second regulates Rab5C and modulates EGFR. The protein expression profile was further compared between biopsy pretreatment of patients with and without pCR, and the results showed that these two groups of patients present a different protein expression profile. In patients with pCR the proteins with increased expression are involved in pathways favoring the response to therapy, as glutathione-mediated detoxification and glycogen degradation, while the proteins with increased expression in patients without pCR are involved in tumor energetic metabolism pathways that contribute to tumor resistance to therapy. The observed differences in these groups should be widely explored since they may be predictive markers of response to chemoradiation treatment. The performance of functional studies was possible by generation of a cellular model of rectal tumor resistant to radiotherapy. The analysis of the EVs secreted by these cells showed that IR does not alter the amount and the medium size of secreted EVs, but is able to change their protein content. EVs from irradiated cells presented a different protein profile when compared to EVs from non-irradiated cells, where it was found the increased expression of Ku70, Ku80 and Rab5C, besides the methyltransferases NSUN2 and GLYM in EVs after irradiation. Interestingly, the EVs secreted by irradiated cells are capable of transfering resistance to IR to non-irradiated cells. Moreover, the results showed that the treatment of SW837 cells with EVs from irradiated cells promoted methylation in 98% of the analyzed DNA in comparison with the treatment with EVs from non-irradiated cells. The hypermethylated genes are involved in pathways related to immune system, as antigen presentation, primary immunodeficiency signaling and dendritic cells maturation. Lastly, it was identified that the A33 expression is related to the colorectal tumors differentiation degree, and this protein is present in EVs secreted by rectal adenocarcinoma, indicating that it may be used to isolate EVs specific from colorectal tissues. The data obtained in this work pointed to mechanisms related to resistance to neoadjuvant therapy in rectal adenocarcinoma that together will allow to identify new therapeutic targets with the potential to improve the response to chemoradiation, as well as to identify markers of response to neoadjuvant therapy before the treatment, and, in this way, avoid the non-responder patients to receive toxic therapies and improve health sustainability, sparing cost with non-efficient drugs for a group of patients.

Qualidade de vida de mulheres com câncer de mama em tratamento quimioterápico adjuvante e neoadjuvante / Quality of life of women with breast cancer undergoing adjuvant and neoadjuvant chemotherapy

Trata-se de uma pesquisa observacional, longitudinal, descritiva e analítica, cujo objetivo foi avaliar a qualidade de vida de mulheres com câncer de mama em tratamento quimioterápico adjuvante e neoadjuvante. A pesquisa foi realizada em um Hospital público, universitário no Estado do Paraná. A amostra foi por conveniência, sendo incluídas 67 mulheres que iniciaram o tratamento quimioterápico no período de maio de 2013 a maio de 2015. A coleta de dados ocorreu em três etapas com a aplicação do questionário de caracterização sociodemográfica e clínica na primeira etapa e os questionários da European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire Core 30 - QLQ-C30 e Quality of Life Questionnaire - Breast Cancer - QLQ-BR23 em todas as etapas. Os dados obtidos foram organizados em tabelas elaboradas no programa Microsoft® Excel 2010 e, efetuada a análise descritiva, com distribuição de frequência e de medidas descritivas, expressas em média, desvio padrão, valores mínimos e máximos e testes estatísticos de associação entre variáveis (Friedman, Diferença Mínima Significativa, Spearman, Kruskal-Wallis e Mann Whitney). Os valores de p!0,05 foram considerados estatisticamente significativos. Os resultados demonstraram que a média de idade foi de 51,3 anos, 61,2% são casadas e 64,2% possuem de um a três filhos, 43,3% estudaram menos de nove anos. Quanto a renda familiar e per capita possuíam média de 2,8 e 1,1 salários mínimos, respectivamente. O estadio clínico III foi o mais frequente, em 82% das mulheres, com o tratamento quimioterápico neoadjuvante predominante em 79,1%, o protocolo baseado em antracíclinos e taxanos em 76,1%, e mais de 50% iniciaram a quimioterapia dentro do prazo estipulado de 60 dias para os tratamentos neoadjuvante e adjuvante. Na avaliação da qualidade de vida as análises reportaram diferenças significativas na função física e função emocional. Na escala de sintomas a fadiga e náuseas e vômitos e sintomas da mama. Na comparação entre as modalidades neoadjuvante e adjuvante as diferenças foram significativas na função física, desempenho pessoal e função cognitiva e nos sintomas dor, dispneia e sintomas da mama, denotando que as mulheres em terapêutica neoadjuvante foram mais afetadas. A associação entre as variáveis qualidade de vida global e estadiamento apresentou-se significativa na primeira e na terceira etapa, enquanto a associação do estadiamento com a função física e com a fadiga foram significativas na terceira e primeira etapa, respectivamente, fato evidenciado pelos estadios avançados encontrados nesta pesquisa. Na associação das variáveis função emocional com filhos houve significância na terceira etapa. Estes resultados evidenciam que as mulheres são afetadas em vários domínios, e que há a necessidade de atende-las de forma direcionada e integral para manter sua qualidade de vida. Para tal, a assistência deve estar voltada para além dos sintomas físicos, englobando os aspectos funcionais, físicos, emocionais, cognitivos e sociais acometidos em decorrência da doença e da terapêutica.

This is an observational, longitudinal, descriptive and analytical study, with the objective of evaluating the quality of life of women with breast cancer undergoing adjuvant and neoadjuvant chemotherapy. The survey was conducted in a public university hospital in the state of Paraná, Brazil. The sample was for convenience, being included 70 women who started chemotherapy from May 2013 to May 2015. Data collection took place in three phases with the application of socio-demographic and clinical characterization questionnaire in the first and questionnaires of the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire Core 30 (QLQ-C30) e Quality of Life Questionnaire - Breast Cancer (QLQ-BR23) in all three phases. The data acquired were organized in Microsoft Excel 2010 spreadsheets and performed a descriptive analysis with frequency distribution and descriptive measures, expressed as mean, standard deviation, minimum and maximum values and statistical tests of association between variables (Friedman, Minimum Significant Difference, Spearman, Kruskal-Wallis and Mann Whitney). Values of p!0.05 were considered statistically significant. The results showed that the average age is 51.3 years, 61.2% are married and 64.2% have one to three children, 43.3% attended school for less than nine years. As for household and per capita incomes, the average is 2.8 to 1.1 minimum wages, respectively. The clinical stage III was the most frequent, in 82% of women, with neoadjuvant chemotherapy treatment prevalent in 79.1%, the protocol based on anthracyclines and taxanes in 76.1%, and over 50% started chemotherapy within the stipulated period of 60 days for neoadjuvant and adjuvant treatments. In the assessment of quality of life analyzes reported significant differences in physical and emotional function. In the symptom scale, associated with fatigue, nausea, vomiting and breast symptons. Comparing the groups neoadjuvant and adjuvante, there were significant differences in physical function, personal performance and cognitive function, as well as in the symptoms pain, dyspnea and breast symptoms, denoting that women in neoadjuvant therapy were more affected. The association between overall quality of life and staging showed significant in the first and third phases, while the association of staging with physical function and fatigue were significant in the third and first phases, respectively, fact evidenced by the advanced stages found in this study. In the association of emotional function with children there was significance in the third stage. These results show that women are affected in various aspects, and that there is the need to attend them in a targeted and comprehensive manner to maintain their quality of life. For this purpose, assistance must be focused beyond physical symptoms, encompassing functional, physical, emotional, cognitive and social aspects affected by the disease and their therapy.

Agregação familiar da doença renal crônica secundária à hipertensão arterial ou diabetes mellitus: estudo caso-controle / Family clustering of secondary chronic kidney disease with hypertension or diabetes mellitus. A case-control study

No Brasil, a hipertensão e o diabetes mellitus tipo 2 são responsáveis por 60% dos casos de doença renal crônica terminal em terapia renal substitutiva. Estudos americanos identificaram agregação familiar da doença renal crônica, predominante em afrodescendentes. Um único estudo brasileiro observou agregação familiar entre portadores de doença renal crônica quando comparados a indivíduos internados com função renal normal. O objetivo deste artigo é avaliar se existe agregação familiar da doença renal crônica em familiares de indivíduos em terapia renal substitutiva causada por hipertensão e/ou diabetes mellitus. Estudo caso-controle tendo como casos 336 pacientes em terapia renal substitutiva portadores de diabetes mellitus ou hipertensão há pelo menos 5 anos e controles amostra pareada de indivíduos com hipertensão ou diabetes mellitus e função renal normal (n = 389). Os indivíduos em terapia renal substitutiva (casos) apresentaram razão de chance de 2,35 (IC95% 1,42-3,89; p < 0,001) versus controles de terem familiares com doença renal crônica terminal, independente da raça ou doença de base. Existe agregação familiar da doença renal crônica na amostra estudada e esta predisposição independe da raça e da doença de base (hipertensão ou diabetes mellitus).

In Brazil hypertension and type 2 diabetes mellitus are responsible for 60% of cases of end-stage renal disease in renal replacement therapy. In the United States studies have identified family clustering of chronic kidney disease, predominantly in African-Americans. A single Brazilian study observed family clustering among patients with chronic kidney disease when compared with hospitalized patients with normal renal function. This article aims to assess whether there is family clustering of chronic kidney disease in relatives of individuals in renal replacement therapy caused by hypertension and/or diabetes mellitus. A case-control study with 336 patients in renal replacement therapy with diabetes mellitus or hypertension for at least 5 years (cases) and a control matched sample group of individuals with hypertension or diabetes mellitus and normal renal function (n = 389). Individuals in renal replacement therapy (cases) had a ratio of 2.35 (95% CI 1.42-3.89, p < 0.001) versus the control group in having relatives with chronic renal disease, irrespective of race or causative illness. There is family clustering of chronic kidney disease in the sample studied, and this predisposition is irrespective of race and underlying disease (hypertension or diabetes mellitus).

Preoperative imatinib for patients with primary unresectable or metastatic/recurrent gastrointestinal stromal tumor

OBJECTIVES: Despite its rising popularity, reports on the use of preoperative imatinib mesylate (IM) in patients with advanced gastrointestinal stromal tumor (GIST) are limited. This study aims to explore the clinical efficacy of preoperative IM in patients with primarily unresectable or metastatic/recurrent GIST. METHODS: Between September 2009 and February 2014, patients with primarily unresectable or metastatic/recurrent GIST treated by a single medical team were recruited and considered for preoperative IM therapy. Re-examination was conducted regularly and abdominal enhanced CT data, blood biochemistry and responses to IM were recorded. RESULTS: A total of 18 patients were enrolled, including 13 with a primary tumor (7 stomach, 3 small bowel, 2 rectal and 1 pelvic tumor) and 5 with recurrent or metastatic GIST (2 with liver metastasis, 2 with anastomotic recurrence and 1 with pelvic GIST). The median follow-up time was 9.5 months (range of 3-63). The median tumor sizes before and after initiation of IM treatment were 9.1 cm and 6.0 cm (p = 0.003) based on the CT findings, respectively. All patients showed a decrease in tumor burden and the median tumor size reduction was 35%. Sixteen of the 18 patients showed a partial response to IM and two possessed stable disease. Nine of the 18 patients (50%) underwent surgical resection of primary or metastatic/recurrent tumors, with a median of 7 months of IM therapy. One case each of multivisceral resection and tumor recurrence were noted. CONCLUSIONS: IM as a preoperative therapy is feasible and safe for unresectable or metastatic/recurrent GIST that can effectively decrease tumor size, facilitating resection. .

Qualidade de vida em mulheres no climatério atendidas na Atenção Primária / Quality of life of postmenopausal women attended at Primary Health Care / Calidad de vida de las mujeres en climaterio tratadas en la Atención Primaria

A vivência do climatério está cada vez mais presente, e demanda estratégias que melhorem a qualidade de vida das mulheres nesse período. A pesquisa objetivou avaliar a qualidade de vida de mulheres na fase do climatério, com ou sem uso da terapia de reposição hormonal (TRH). Estudo epidemiológico longitudinal, com amostra de 99 mulheres para cada grupo. Avaliaram-se as características sociodemográficas, clínicas e comportamentais. Foram aplicados à amostra a Menopause Rating Scale (MRS) e o Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). Utilizaram-se os testes t de student, Qui-quadrado e Tukey. As usuárias de TRH apresentaram média etária de 50,76 ± 3,63 anos, e as não usuárias de 48,95 ± 6,27anos (p=0,01). Relataram maior frequência de sintomas climatéricos de intensidade leve a moderada. Os aspectos sociais apresentaram escore abaixo de 50 para os dois grupos. Houve diferenças entre os grupos em relação aos componentes do SF-36 e MRS para estado geral de saúde, capacidade funcional, menor capacidade, depressão, insônia e fenômenos vasomotores.

The experience of menopause is increasingly present, and demand strategies to improve the quality of life of women during this period. This research aimed to evaluate the quality of life for women in the climacteric phase, with or without the use of hormone replacement therapy (HRT). This is a longitudinal epidemiological study of a sample of 99 women per group. It was evaluated the sociodemographic, clinical and behavioral characteristics. It was used the Menopause Rating Scale (MRS) and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). For data analysis, it was used the Student t test, chi-square and Tukey. HRT users had an average age of 50.76 ± 3.63 years, and nonusers of 48.95 ± 6,27anos (p = 0.01). It was identified a higher frequency of moderate climacteric symptoms of mild intensity. The social aspects evidenced scores below 50 for the two groups. There were differences between groups with respect to the components of the SF-36 and MRS to general health, functional capacity, lower capacity, depression, insomnia and vasomotor phenomena.

La experiencia de la menopausia es cada vez más presente, demandando estrategias para mejorar la calidad de vida de las mujeres durante este periodo. Esa investigación tuvo como objetivo evaluar la calidad de vida de las mujeres en la fase climatérica, con o sin el uso de la terapia de reemplazo hormonal (TRH). Trata-se dé un estudio epidemiológico longitudinal, con una muestra de 99 mujeres por grupo. Fueran evaluadas las características sociodemográficas, clínicas y de comportamiento. Fueran aplicados a la muestra el Menopause Rating Scale (MRS) e el Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). Utilizaran-se los testes t de Student, Qui-quadrado e Tukey. Las usuarias de TRH tenían una edad media de 50,76 ± 3,63 años, y las no usuarias de 48,95 ± 6,27anos (p = 0,01). Fue reportada una mayor frecuencia de síntomas climatéricos intensidad leve o moderada. Los aspectos sociales tuvieran puntuaciones por debajo de 50 para los dos grupos. Hubo diferencias entre los grupos con respecto a los componentes del SF-36 y el MRS para la salud en general, la capacidad funcional, la capacidad más baja, la depresión, el insomnio y los fenómenos vasomotores.

Quimioterapia neoadjuvante e resposta patológica: coorte retrospectiva / Neoadjuvant chemotherapy and pathologic response: a retrospective cohort

OBJETIVO: Avaliar a taxa de resposta patológica completa atingida pelas pacientes com diagnóstico de câncer de mama localmente avançado submetidas à quimioterapia neoadjuvante baseada no esquema doxorrubicina/ciclofosfamida seguido de paclitaxel. MÉTODOS: Coorte retrospectiva de pacientes admitidas no Hospital de Câncer de Barretos com câncer de mama localmente avançado entre 2006 e 2008 submetidas ao protocolo de doxorrubicina/ciclofosfamida seguido de paclitaxel (4 ciclos de doxorrubicina 60mg/m² e ciclofosfamida 600mg/m² a cada 21 dias; 4 ciclos de paclitaxel 175mg/m² a cada 21 dias). As seguintes variáveis foram avaliadas: idade, menopausa, performance status, estadiamento clínico inicial, dados antropométricos, quimioterapia (dose - duração), perfil de toxicidade, estadiamento clínico pós-tratamento, cirurgia, resposta patológica completa, sobrevida livre de doença e características anatomopatológicas (tipo e grau histológico, perfil hormonal e comprometimento linfonodal). A análise estatística foi realizada considerando-se o nível de significância de 5%. RESULTADOS: Das 434 pacientes avaliadas, 136 foram excluídas por erro no estadiamento ou por terem recebido outro tipo de quimioterapia. A mediana de idade foi 50 anos, todas com performance status 0-1. A mediana do tamanho clínico inicial do tumor foi 65mm e a mediana do tamanho clínico final do tumor foi 22mm. Apresentaram resposta patológica completa 51 (17,1%) pacientes. Aquelas que apresentavam perfil hormonal negativo ou que eram triplo-negativas (Her-2 e perfil hormonal negativos) tiveram impacto favorável na resposta patológica completa. CONCLUSÃO: Quimioterapia neoadjuvante com doxorrubicina/ciclofosfamida seguidas de paclitaxel ofereceu taxa de resposta patológica completa na população estudada de acordo com a literatura. Pacientes triplo-negativas tiveram maior chance de atingir essa resposta.

OBJECTIVE: To evaluate the complete pathologic response attained by patients diagnosed with locally advanced breast cancer submitted to neoadjuvant chemotherapy based on the doxorubicin/cyclophosphamide regimen followed by paclitaxel. METHODS: A retrospective cohort of patients with locally advanced breast cancer, admitted to the Hospital de Câncer de Barretos between 2006 and 2008 submitted to the doxorubicin/cyclophosphamide protocol followed by paclitaxel (4 cycles of doxorubicin 60mg/m² and cyclophosphamide 600mg/m² every 21 days; 4 cycles of paclitaxel 175mg/m² every 21 days). The following variables were assessed: age, menopause, performance status, initial clinical staging, anthropometric data, chemotherapy (dose - duration), toxicity profile, post-treatment staging, surgery, pathologic complete response rate, disease-free survival, and pathological characteristics (type and histological degree, hormonal profile and lymph node involvement). Statistical analysis was performed using a 5% level of significance. RESULTS: Of the 434 patients evaluated, 136 were excluded due to error in staging or because they had received another type of chemotherapy. Median age was 50 years, all with performance status 0-1. Median initial clinical size of tumor was 65mm and the median final clinical size of the tumor was 22mm. Fifty-one (17.1%) patients experienced a pathologic complete response. Those with a negative hormonal profile or who were triple-negative (negative Her-2 and hormonal profile) experienced a favorable impact on the pathologic complete response. CONCLUSION: Neoadjuvant chemotherapy with doxorubicin/cyclophosphamide followed by paclitaxel provided a pathologic complete response in the population studied in accordance with that observed in the literature. Triple-negative patients had a greater chance of attaining this response.