Programmed cell death protein 1 is a marker for neoadjuvant chemotherapy response in triple-negative breast cancer

SUMMARY OBJECTIVE: Tumor-infiltrating lymphocytes are detectable in up to 75% of triple-negative breast cancer. The composition of these infiltrates may influence prognosis and is not known regarding regulatory or effector lymphocytes. The objectives of this study were to describe and quantify the composition of the tumor-infiltrating lymphocytes before and after chemotherapy (neoadjuvant chemotherapy) and to evaluate their association with complete pathological response and overall survival. METHODS: This was a retrospective observational study. Clinical and pathological data from 38 triple-negative breast cancer patients treated with neoadjuvant chemotherapy at the University Hospital (HUCFF/UFRJ), between November 2004 and November 2018, were analyzed. The Stromal tumor-infiltrating lymphocytes (Stromal tumor-infiltrating lymphocytes) have been identified on hematoxylin and eosin-stained sections according to the guidelines of the "International tumor-infiltrating lymphocytes Working Group." Immunohistochemistry studies were performed to identify T-cell subsets (i.e., CD3, CD4, CD8, and FOXP3) and T-cell exhaustion (i.e., programmed cell death protein 1). RESULTS: Statistically significant changes in stromal tumor-infiltrating lymphocyte categories were observed before and post-neoadjuvant chemotherapy, with 32% of intermediate cases becoming high. The correlation between pre-neoadjuvant chemotherapy stromal tumor-infiltrating lymphocytes and pathological response, pre-neoadjuvant chemotherapy and post-neoadjuvant chemotherapy, and stromal tumor-infiltrating lymphocytes and overall survival was not statistically significant. However, we noticed an increase of cells that favor the antitumor activity (i.e., CD3, CD8, and CD8/FOXP3 ratio) and decreased levels of cells inhibiting tumor activities (i.e., FOXP3 and programmed cell death protein 1) post-neoadjuvant chemotherapy. Importantly, programmed cell death protein 1 expression pre-neoadjuvant chemotherapy showed an association with pathological response. CONCLUSION: In this study, we observed that chemotherapy significantly increases stromal tumor-infiltrating lymphocytes, CD8 T cells, as well as CD8/FoxP3 ratio. Most importantly, programmed cell death protein 1 expression before neoadjuvant chemotherapy positively correlates with pathological response suggesting the use of programmed cell death protein 1 as a prognostic marker before neoadjuvant chemotherapy.

Clinicopathologic profile of breast cancer patients treated with neoadjuvant chemotherapy at HUCFF/UFRJ

Introduction: The objective of this study is to describe the profile of patients from a public institution, submitted to neoadjuvant chemotherapy (NACT), comparing the verified pathological response with literature data. Methods: Observational retrospective cohort study on breast cancer patients diagnosed between September 2001 and October 2018 and treated with NACT at Hospital Universitário Clementino Fraga Filho (HUCFF/UFRJ), located in Rio de Janeiro, Brazil. The adopted neoadjuvant chemotherapy regimen was based on anthracycline and docetaxel. Results: A total of 133 patients were evaluated. The average age in this group was 54 years (28-86), 49 women (37%) were under 50 years old. The following distribution by molecular subtype was observed: overexpression or amplification of the human epidermal growth factor receptor 2 (HER2+) (13 women, 26.6%), Luminal (19 women, 38.8%), and Triple-negative (TN) (17 women, 34.6%). The HER2+ and TN subtypes had a higher incidence of cases between 40-49 years and 50-59 years. As for the initial staging, 34% were IIIA; 26%, IIB; and 19%, IIIB. Only one patient did not undergo surgery after NACT, 33 (24.8%) underwent conservative surgery, and 99 patients (74.4%) underwent mastectomy. Regarding the axillary approach, 41 (31%) underwent sentinel lymph node biopsy and 88 (66%) had an indication for lymphadenectomy. In the anatomopathological evaluation of the surgery, 12 (9.1%) patients obtained a pathologic complete response (pCR) and 113 (84.9%), partial or no response to chemotherapy. Conclusion: This research enabled the identification of clinicopathologic characteristics and outcome of patients who received neoadjuvant chemotherapy in a public university service. The predominance of advanced tumors was observed, stressing the need for public health policies for the screening of breast cancer as well as the guarantee of timely treatment for diagnosed cases. The data somewhat reflect the difficulty that the public sector encounters to carry out the most appropriate treatment. The authors expect that this article, by analyzing the profile and the adopted treatment in real-life cases and in a public university institution, can contribute to the improvement of breast cancer treatment in Brazil.

An adequacy evaluation of a maternal health intervention in rural Honduras: the impact of engagement of men and empowerment of women / Evaluación de la suficiencia de una intervención de salud materna en un entorno rural de Honduras: repercusión de la participación de los hombres y el empoderamiento de las mujeres

Objective. To determine the impact that a 6-year maternal and child health project in rural Honduras had on maternal health services and outcomes, and to test the effect of level of father involvement on maternal health. Methods. This was a program evaluation conducted through representative household surveys administered at baseline in 2007 and endline in 2011 using 30 cluster samples randomly-selected from the 229 participating communities. Within each cluster, 10 households having at least one mother-child pair were randomly selected to complete a questionnaire, for a total of about 300 respondents answering close to 100 questions each. Changes in key outcome variables from baseline to endline were tested using logistic regression, controlling for mother's education and father's involvement. Results. There were improvements in most maternal health indicators, including an increase in women attending prenatal checkups (84% to 92%, P = 0.05) and institutional births (44% to 63%, P = 0.002). However, the involvement of the fathers decreased as reflected by the percentage of fathers accompanying mothers to prenatal checkups (48% to 41%, P = 0.01); the fathers' reported interest in prenatal care (74% to 52%, P = 0.0001); and fathers attending the birth (66% to 54%, P = 0.05). There was an interaction between the fathers' scores and the maternal outcomes, with a larger increase in institutional births among mothers with the least-involved fathers. Conclusions. Rather than the father's involvement being key, changes in the mothers may have led to increased institutional births. The project may have empowered women through early identification of pregnancy and stronger social connections encouraged by home visits and pregnancy clubs. This would have enabled even the women with unsupportive fathers to make healthier choices and achieve higher rates of institutional births.

Objetivo. Determinar la repercusión de un proyecto de salud maternoinfantil de 6 años de duración, en un entorno rural en Honduras, sobre los servicios de salud materna y los resultados asistenciales, y estudiar el efecto del grado de participación del padre en la salud materna. Métodos. El programa se evaluó mediante una serie de encuestas a los hogares representativos administradas al inicio de la intervención, en el 2007, y al concluir en el 2011, con 30 muestras de agrupaciones de familias elegidas al azar entre las 229 comunidades participantes. Dentro de cada agrupación, se seleccionaron aleatoriamente 10 familias compuestas al menos por una madre y un hijo para que contestasen un cuestionario, con lo cual se reunieron en total cerca de 300 personas encuestadas que respondieron casi 100 preguntas cada una. Se analizaron las variaciones en los criterios principales de valoración, entre el inicio y el final de la intervención, mediante técnicas de regresión logística, controlando el nivel educativo de la madre y la participación del padre. Resultados. Se observaron mejoras en la mayoría de los indicadores de salud materna, incluido un aumento de la cantidad de mujeres que acudieron a los controles prenatales (variación de 84% a 92%, P = 0,05) y de los partos atendidos en centros sanitarios (variación de 44% a 63%, P = 0,002). Sin embargo, se redujo la participación del padre, tal como refleja el porcentaje de padres que acompañan a la madre a los controles prenatales (variación de 48% a 41%, P = 0,01), el interés comunicado por el padre en la asistencia prenatal (variación de 74% a 52%, P = 0,0001) y el porcentaje de padres que estuvieron presentes en el parto (variación de 66% a 54%, P = 0,05). Se constató una interacción entre las puntuaciones paternas y los resultados asistenciales maternos, así como un aumento mayor de los partos en centros sanitarios en los casos en que el padre se involucraba menos. Conclusiones. Más que la participación del padre como factor clave, el aumento de los partos asistidos en centros sanitarios puede haberse debido a los cambios en las madres. Es posible que el proyecto empoderase a las mujeres y les permitiese percatarse antes de su embarazo y reforzar sus conexiones sociales con visitas domiciliarias y grupos de embarazadas. Esto habría facilitado, aun en los casos en los que el padre no se involucraba, que las mujeres tomasen decisiones más saludables, y que aumentasen las tasas de partos atendidos en centros sanitarios.

XRCC1 gene polymorphisms in a population sample and in women with a family history of breast cancer from Rio de Janeiro (Brazil)

The X-ray repair cross-complementing Group1 (XRCC1) gene has been defined as essential in the base excision repair (BER) and single-strand break repair processes. This gene is highly polymorphic, and the most extensively studied genetic changes are in exon 6 (Arg194Trp) and in exon 10 (Arg399Gln). These changes, in conserved protein sites, may alter the base excision repair capacity, increasing the susceptibility to adverse health conditions, including cancer. In the present study, we estimated the frequencies of the XRCC1 gene polymorphisms Arg194Trp and Arg399Gln in healthy individuals and also in women at risk of breast cancer due to family history from Rio de Janeiro. The common genotypes in both positions (194 and 399) were the most frequent in this Brazilian sample. Although the 194Trp variant was overrepresented in women reporting familial cases of breast cancer, no statistically significant differences concerning genotype distribution or intragenic interactions were found between this group and the controls. Thus, in the population analyzed by us, variants Arg194Trp and Arg399Gln did not appear to have any impact on breast cancer susceptibility.

Descarga papilar: relação com o câncer de mama e estratégias para a sua abordagem / Nipple discharge: relation with breast cancer and its approach

A descarga papilar está presente em 5% das mulheres e ocorre em razão de causas fisiológicas, doenças benignas da mama e câncer de mama. Algumas das lesões benignas da mama estão relacionadas a um maior risco de desenvolvimento de patologia maligna mamária. A papilar para a avaliação desse sintoma mamário e sua relação com as lesões benignas importância da descarga papilar está na possibilidade de essa condição associar-se a câncer de mama. Uma avaliação clínica detalhada é fundamental para a determinação da abordagem terapêutica da paciente com descarga papilar. Foram avaliadas 23 pacientes do Serviço de Mastologia do Instituto Fernandes Figueira/Fiocruz submetidas à exérese de árvore ductal em virtude de descarga e com o câncer de mama. Das 23 pacientes analisadas, o resultado histopatológico foi de lesão benigna não proliferativa em 26,1%, lesão proliferativa sem atipias em 60,8%, hiperplasia ductal com atipias em 8,7% e câncer em 4,4%. Os resultados demonstraram que em 69,5% dos casos a histopatologia foi de lesão proliferativa de mama, que, apesar de benigna, apresenta maior risco de desenvolvimento do câncer de mama. Apesar de a descarga papilar estar na maioria dos casos relacionada à doença mamária benigna, em alguns casos esta se associa a um risco aumentado de câncer de mama. É fundamental ressaltar que pode haver uma relação entre a descarga papilar e o câncer de mama, embora este não seja a correspondência histopatológica mais freqüente da descarga papilar.

Nipple discharge is present in 5% of women and occurs due to physiological causes, benign breast disease and breast cancer. Some of benign breast lesions are associated with a higher risk of malignant breast diseases development. The importance of nipple discharge is the possibility of this condition to be associate with breast cancer. A detailed clinical evaluation is fundamental to determinate the therapeutic approach of a patient with nipple discharge. Twenthy-three patients from the Mastology Department of Fernandes Figueira Institute/Fiocruz were submitted to removal of central mammary ducts due to nipple discharge for evaluation of this symptom and its relationship with benign breast lesions and breast cancer. The histopathological results from 23 patients that have been analysed were not proliferative benign breast lesions in 26.1%, proliferative lesions without atypias in 60.8%, atypical ductal hyperplasia in 8.7% and 4 cancer in 4,4%. The results proved 69.5% of proliferative breast lesions thats presents a higher risk of breast cancer development. Although nipple discharge is associated in most of the cases with benign breast diseases sometime it is related to a higher risk of breast cancer. It is important to emphasize that it could be a relation between nipple discharge and breast cancer even if it is not the most frequent, histopathological correspondence of nipple discharge.

Burden of diarrhea among children in Honduras, 2000-2004: estimates of the role of rotavirus

OBJECTIVES: To estimate the annual burden of diarrhea and of diarrhea that is associated with rotavirus (RV) in children who are treated at public clinics and hospitals in Honduras. METHODS: Data were collected from computerized records of all children < 5 years old treated for diarrhea at clinics and hospitals operated by the Secretary of Health for the period of 2000 through 2004. A review of studies of RV in Honduras and neighboring countries provided estimates of detection rates of RV among children treated for acute diarrhea as outpatients or as inpatients. From these data, we estimated the annual number of cases of diarrhea and of rotavirus-related diarrhea in Honduras, the cumulative incidence of diarrhea and of rotavirus-related diarrhea for a child from birth to age 5 years, and the number of fatalities due to RV among children hospitalized for diarrhea. RESULTS: From 2000 through 2004, a mean of 222 000 clinic visits, 4 390 hospitalizations, and 162 in-hospital deaths due to diarrhea were recorded annually among children < 5 years of age in the public health facilities in Honduras. From our review of scientific literature on Honduras and neighboring countries, an estimated 30 percent of outpatients and 43 percent of inpatients who were treated for diarrhea would be expected to have RV. Consequently, we estimated that 66 600 outpatient visits, 1 888 hospitalizations, and 70 in-hospital deaths among children < 5 years in Honduras could be attributed to RV each year. Therefore, a child in the first five years of life has a respective risk for consultation, hospitalization, and in-hospital death of 1:1, 1:46, and 1:1 235 for diarrhea. For an episode associated with RV, the respective risks are 1:3, 1:106, and 1:2 857. These values likely underestimate the true burden of diarrhea in Honduras, since some 51 percent of children with acute diarrhea do not receive formal care for the illness, 70 percent do not receive oral rehydration...

OBJETIVOS: Estimar la carga anual por diarrea y por diarrea asociada con la infección por rotavirus (RV) en niños atendidos en clínicas y hospitales públicos de Honduras. MÉTODOS: Los datos se obtuvieron a partir de los registros computarizados de todos los niños menores de 5 años atendidos por diarrea en clínicas y hospitales operados por la Secretaría de Salud de Honduras durante el período 2000-2004. Una revisión de los estudios realizados sobre RV en Honduras y los países vecinos ofreció estimados de las tasas de detección de RV en niños tratados por diarrea aguda hospitalizados o de forma ambulatoria. Con estos datos se estimó el número anual de casos de diarrea y de diarrea asociada con la infección por RV en Honduras, la incidencia acumulativa de diarrea y de diarrea asociada con la infección por RV en niños menores de 5 años y el número de muertes debido a RV en niños hospitalizados por diarrea. RESULTADOS: Entre los años 2000 y 2004 se registraron medias anuales de 222 000 visitas médicas, 4 390 hospitalizaciones y 162 muertes hospitalarias por diarrea en niños menores de 5 años en instalaciones sanitarias públicas de Honduras. A partir de la revisión de la literatura científica relativa a Honduras y los países vecinos se estimó que 30 por ciento de los casos de diarrea atendidos ambulatoriamente y 43 por ciento de los hospitalizados podrían deberse a RV. En consecuencia, se estimó que 66 600 visitas médicas ambulatorias, 1 888 hospitalizaciones y 70 muertes hospitalarias de niños menores de 5 años pueden atribuirse a la infección por RV anualmente en Honduras. Por lo tanto, los riesgos de un niño en sus primeros 5 años de vida de asistir a una consulta, de ser hospitalizado y de morir en un hospital por diarrea son de 1:1, 1:46 y 1:1 235, respectivamente. Los riesgos asociados con la infección por RV son de 1:3, 1:106 y 1:2 857, respectivamente. Posiblemente, estos valores subestiman la carga real por diarrea en Honduras, ya...

Estudo da mecânica respiratória em pacientes submetidos à ventilação mecânica na Unidade de Pacientes Graves do Instituto Fernandes Figueira / Study of the respiratory mechanics in patients submitted to the ventilation mechanics in the Unit of Serious Patients of the Institute Fernandes Figueira

O valor médio encontrado para complacência do sistema respiratório foi de 0,42ml/cmH2O/kg, considerado muito baixo para qualquer idade. A média da resistência se mostrou elevada para qualquer faixa etária. O comprometimento da mecânica respiratória foi associado à presença de injúria pulmonar e sepse. Foram encontradas associações, com significância estatística, em relação à baixa complacência/kg e maiores alterações no índice de ventilação. A resistência alta foi relacionada aos piores índices de ventilação e mais baixas relações PaO2/FiO2. Os demais índices testados não se correlacionaram com as alterações da resistência e da complacência.Quando feita a análise morfológica das curvas obtidas, foi possível detectar sinais que traduzem informações importantes em relação à mecânica pulmonar, como sinais de obstrução expiratória e hiperdistensão alveolar. Também foram obtidos subsídios sobre a necessidade de mudanças nos parâmetros do respirador e possíveis falhas de funcionamento, como vazamento no circuito, presença de PEEP inadvertida e volumes anômalos. Conclusões: medidas quantitativas de complacência e resistência do sistema respiratório devem ser incorporadas às rotinas das unidades de terapia intensiva pediátrica, porém, devem ser analisadas com cuidado, uma vez que existem diversos artefatos que podem alterá-las. A análise qualitativa da morfologia das curvas é instrumento útil para a detecção de alterações da mecânica respiratória e mau funcionamento do ventilador mecânico.

A contribuição dos genes BRCA na predisposição hereditária ao câncer de mama / BRCA genes contribution in the hereditary predisposition for breast cancer

Aproximadamente 20 % dos casos de câncer de mama familiar estão associados a um dos genes de susceptibilidade hereditária para câncer de mama e ovário, BRCA1 e BRCA2. Recentes trabalhos têm demonstrado o mecanismo de ação destes genes com funções estabelecidas na manutenção da integridade do genoma e no controle da recombinação homóloga. A história familiar, a bilateralidade, o acometimento precoce e achados histopatológicos específicos são fatores sugestivos da presença de mutações nestes genes. Esta revisão sumariza alguns destes conhecimentos, na tentativa de colocá-los no contexto atual das funções destes genes.

Approximately 20% of the cases related to familiar breast cancer are associated to one gene of hereditary susceptibilityfor breast and ovarian cancer, BRCA1 and BRCA2. Recent works have demonstrated the mechanism of action of these genes, with functions well established for maintaining the genome integrity and for controlling homologatesrecombination. Familiar history, bilaterality, precocious diseases, as well as specific histopathologic results areindicative factors of the presence of mutation in these genes. This literature review summarizes some of thisknowledge, trying to understand them in the current functional context of these genes.