Occupational exposure to pesticides dysregulates systemic Th1/Th2/Th17 cytokines and correlates with poor clinical outcomes in breast cancer patients.

Pesticides are compounds known to cause immunetoxicity in exposed individuals, which have a potential to substantially modify the prognosis of pathologies dependent on an efficient immune response, such as breast cancer. In this context, we examined the circulating cytokine profile of Th1/Th2/Th17 patterns in women occupationally exposed to pesticides and their correlation with worse prognostic outcomes. Peripheral blood samples were collected from 187 rural working women with breast cancer, occupationally exposed or not to pesticides, to quantify the levels of cytokines IL-1ß, IL-12, IL-4, IL-17-A, and TNF -α. Data on the disease profile and clinical outcomes were collected through medical follow-up. IL-12 was reduced in exposed women with tumors larger than 2 cm and in those with lymph node metastases. Significantly reduced levels of IL-17A were observed in exposed patients with Luminal B subtype tumors, with high ki67 proliferation rates, high histological grade, and positive for the progesterone receptor. Reduced IL-4 was also seen in exposed women with lymph node invasion. Our data show that occupational exposure to pesticides induces significant changes in the levels of cytokines necessary for tumor control and correlates with poor prognosis clinical outcomes in breast cancer.

Brief research report pesticide occupational exposure leads to significant inflammatory changes in normal mammary breast tissue.

Studies have documented the high occurrence of several tumors, including female breast cancer, in populations occupationally exposed to pesticides worldwide. It is believed that in addition to direct DNA damage, other molecular alterations that indicate genomic instability are associated, such as epigenetic modifications and the production of inflammation mediators. The present study characterized the profile of inflammatory changes in the breast tissue of women without cancer occupationally exposed to pesticides. In samples of normal breast tissue collected during biopsy and evaluated as negative for cancer by a pathologist, oxidative stress levels were assessed as inflammatory markers through measurements of lipoperoxides and total antioxidant capacity of the sample (TRAP) by high-sensitivity chemiluminescence, as well as levels of nitric oxide (NOx) metabolites. The levels of inflammation-modulating transcription factors PPAR-γ (peroxisome proliferator-activated receptor gamma) and NF-κB (nuclear factor kappa B) were also quantified, in addition to the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin 12 (IL-12). The levels of lipoperoxides, TRAP, and NOx were significantly lower in the exposed group. On the other hand, PPAR-γ levels were increased in the breast tissue of exposed women, with no variation in NF-κB. There was also a rise of TNF-α in exposed women samples without significant variations in IL-12 levels. These findings suggest an inflammatory signature of the breast tissue associated with pesticide exposure, which may trigger mechanisms related to mutations and breast carcinogenesis.

Excess body weight significantly affects systemic and tumor inflammatory status and correlates to poor prognosis parameters in patients with breast cancer.

Introduction: Obesity is a pro-inflammatory disease critical for developing breast cancer (BC), which impacts the profiles of systemic inflammatory mediators and determinants of different disease clinical outcomes remains little explored. Methods: A total of 195 patients diagnosed with breast cancer were included. Aiming to exclude chemotherapy interference on circulating mediators, samples were collected at diagnosis, out of the treatment period. Patients were classified as normal weight (BMI up to 24.9 kg/m2) or overweight (BMI ≥25.0 kg/m2). Serum levels of IL-4, IL-12, hydroperoxides, and nitric oxide metabolites (NOx) were measured. Also, tumor expression of inducible nitric oxide synthase (iNOS), TGF-ß1, CD4+, and CD8+ lymphocytes were evaluated. Results: IL-4 levels were significantly increased in the overweight BC group (p = 0.0329), including patients with luminal B subtype (p = 0.0443), presence of lymph node metastases (p = 0.0115) and age of diagnosis below 50 years, (p = 0.0488). IL-12 levels were significantly increased in overweight BC patients with lymph node metastases (p = 0.0115). Hydroperoxides were increased in overweight BC patients (p = 0.0437), including those with tumors smaller than 2 cm (p = 0.05). NOx levels were also increased in overweight BC patients, including those with luminal B disorders (p = 0.0443), high-grade tumors (p = 0.0351) and lymph node metastases (p = 0.0155). The expression of iNOS (p < 0.001) and TCD4+ lymphocytes (p = 0.0378) was significantly investigated in tumor biopsies from overweight BC women. Conclusions: These data provide a picture of the influence of excess body weight on inflammatory mediators' systemic and tumoral profiles, especially in patients displaying poor outcome BC.

The Expression of CTLA-4 in Breast Tumors and Tumor-Infiltrating Leukocytes Affects Patients' Systemic Inflammatory Status and Varies According to Their Molecular Subtypes.

Recent evidence has pointed out that the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expression is a poor prognosis factor. However, the implications of CTLA-4 expression on circulating inflammatory mediators are unclear for breast cancer. Tumor biopsies and blood samples were collected from 117 breast cancer patients. Oxidative stress parameters were evaluated in plasma samples by measuring the lipoperoxidation profile and nitric oxide metabolites (NOx). Interleukins 12 (IL-12) and 4 (IL-4) were assessed by ELISA. CTLA-4 expression was determined by immunofluorescence assessed by its labeling in tumor-infiltrating leukocytes (TILs) or breast tumors. Correlations between CTLA-4 expression in breast tumors with TCD4/TCD8 infiltrating lymphocyte and inflammation-related genes were performed using data from TIMER 2.0/TCGA databases (n = 2160). CTLA-4 expression in TILs significantly correlated to triple-negative breast tumors. Patients carrying CTLA-4-positive tumors exhibited lower plasmatic NOx levels, and those expressing CTLA-4 in TILs had reduced levels of IL-12 in plasma. No changes in either IL-4 or lipid peroxidation profiles were detected concerning any CTLA4 status. Compared to the Luminal A ones, oxidative stress parameters and cytokines were observed in patients bearing triple-negative tumors. CTLA-4 expression in all breast cancer subtypes positively correlated to TCD4/TCD8 lymphocyte infiltrates, as well as to the pro-inflammatory genes IL12A, IL4, NFKB1, NFKB2, NOS1, NOS2, and NOS3. CTLA-4 expression in both tumor and TILs can affect the systemic inflammatory status of breast cancer patients, especially antitumor molecules such as IL-12 and NOx that correlate to more aggressive disease.

Occupational Exposure to Pesticides Affects Pivotal Immunologic Anti-Tumor Responses in Breast Cancer Women from the Intermediate Risk of Recurrence and Death.

Breast cancer risk stratification is a strategy based using on clinical parameters to predict patients' risk of recurrence or death, categorized as low, intermediate, or high risk. Both low and high risk are based on well-defined clinical parameters. However, the intermediate risk depends on more malleable parameters. It means an increased possibility for either suboptimal treatment, leading to disease recurrence, or systemic damage due to drug overload toxicity. Therefore, identifying new factors that help to characterize better the intermediate-risk stratification, such as environmental exposures, is necessary. For this purpose, we evaluated the impact of occupational exposure to pesticides on the systemic profile of cytokines (IL-12, IL-4, IL-17A, and TNF-α) and oxidative stress (hydroperoxides, total antioxidants, and nitric oxide metabolites), as well as TGF-ß1, CTLA-4, CD8, and CD4 expression, investigated in tumor cells. Occupational exposure to pesticides decreased the levels of IL-12 and significantly increased the expression of TGF-ß1 and CTLA-4 in the immune infiltrate. Nevertheless, we observed a decrease in CTLA-4 in tumor samples and CD8 in infiltrating cells of intermediate overweight or obese patients with at least one metastatic lymph node at the diagnosis. These findings indicate that occupational exposure to pesticides changes the molecular behavior of disease and should be considered for intermediate-risk stratification assessment in breast cancer patients.

Corrigendum: Somatic DNA damage response and homologous repair gene alterations and its association with tumor variant burden in breast cancer patients with occupational exposure to pesticides.

[This corrects the article DOI: 10.3389/fonc.2022.904813.].

Somatic DNA Damage Response and Homologous Repair Gene Alterations and Its Association With Tumor Variant Burden in Breast Cancer Patients With Occupational Exposure to Pesticides.

Homologous recombination is a crucial pathway that is specialized in repairing double-strand breaks; thus, alterations in genes of this pathway may lead to loss of genomic stability and cell growth suppression. Pesticide exposure potentially increases cancer risk through several mechanisms, such as the genotoxicity caused by chronic exposure, leading to gene alteration. To analyze this hypothesis, we investigated if breast cancer patients exposed to pesticides present a different mutational pattern in genes related to homologous recombination (BRCA1, BRCA2, PALB2, and RAD51D) and damage-response (TP53) concerning unexposed patients. We performed multiplex PCR-based assays and next-generation sequencing (NGS) of all coding regions and flanking splicing sites of BRCA1, BRCA2, PALB2, TP53, and RAD51D in 158 unpaired tumor samples from breast cancer patients on MiSeq (Illumina) platform. We found that exposed patients had tumors with more pathogenic and likely pathogenic variants than unexposed patients (p = 0.017). In general, tumors that harbored a pathogenic or likely pathogenic variant had a higher mutational burden (p < 0.001). We also observed that breast cancer patients exposed to pesticides had a higher mutational burden when diagnosed before 50 years old (p = 0.00978) and/or when carrying BRCA1 (p = 0.0138), BRCA2 (p = 0.0366), and/or PALB2 (p = 0.00058) variants, a result not found in the unexposed group. Our results show that pesticide exposure impacts the tumor mutational landscape and could be associated with the carcinogenesis process, therapy response, and disease progression. Further studies should increase the observation period in exposed patients to better evaluate the impact of these findings.

Covariate clustering: Women with breast cancer in southwestern Paraná, Brazil / Agrupamiento covariado: mujeres con cáncer de mama en el suroeste de paraná, Brasil

Introduction: Due to the high incidence and aggressiveness of breast cancer, understanding specific factors associated with the profile of the disease is necessary. Thus, the study aimed to analyze data from 155 patients with breast cancer, grouping them according to their clinicopathological characteristics, attended at a reference hospital for Oncology, in 2015–2020, in the southwest region of Paraná, Brazil.Material and MethodsUsing multivariate statistical analysis, sample data were divided into three clusters. The heterogeneity between clusters was obtained by Ward's method. The clinicopathological variables obtained from the patients' medical records were: the presence of intratumoral emboli and lymph nodes, menopausal status, molecular subtype, histological grade, TNM staging of the disease, tumor size, age at diagnóstico, weight, height, and body mass index.ResultsIt is observed that 70% of the patients were in menopause at diagnóstico, 31.5% had tumors containing emboli, and 41% had positive lymph nodes. The prevalence of Luminal B subtype, intermediate histological grade, and TNM staging II was verified. The prevalence of the disease was higher in women aged over 50 years, representing 66% of cases. The BMI of the patients ranged from 17.63 kg/m2 to 51.26 kg/m2, with 73.55% above 25 kg/m2. Using the spatial distribution of patients, cluster analysis identified the regions with the worst averages of clinicopathological variables and the highest number of cancer cases.ConclusionThrough the statistical analysis, it was possible to determine the heterogeneity of the data, so the patients were separated into three clusters. When analyzing the obtained clusters, each one of them had specific characteristics. (AU)

Introducción: Debido a la alta incidencia y agresividad del cáncer de mama, es necesario el conocimiento de factores específicos asociados al perfil de la enfermedad. Así, el objetivo del estudio fue analizar datos de 155 pacientes con cáncer de mama, agrupándolas según sus características clínico-patológicas, atendidas en un hospital de referencia en Oncología, en el período 2015–2020, en la región suroeste de Paraná, Brasil.Material y métodosA partir de la utilización de un análisis estadístico multivariado, los datos de la muestra se dividieron en tres grupos. La heterogeneidad entre clústeres se obtuvo mediante el método de Ward. Las variables clínico-patológicas obtenidas de la historia clínica de las pacientes fueron: presencia de émbolos y ganglios linfáticos intratumorales, estado menopáusico, subtipo molecular, grado histológico, estadificación TNM de la enfermedad, tamaño tumoral, edad al momento del diagnóstico, peso, talla, e índice de masa corporal.ResultadosSe observa que el 70% de las pacientes se encontraba en menopausia al momento del diagnóstico, el 31,5% tenía tumores con émbolos y el 41% tenía ganglios positivos. Se verificó la prevalencia de subtipo luminal B, grado histológico intermedio y estadificación TNM II. La prevalencia de la enfermedad fue mayor en mujeres mayores de 50 años, lo que representa el 66% de los casos. El IMC de los pacientes osciló entre 17,63 kg/m2 y 51,26 kg/m2, con un 73,55% encima de 25 kg/m2. El análisis de clúster, utilizando la distribución espacial de pacientes, identificó las regiones con los peores promedios de variables clínico-patológicas y el mayor número de casos de cáncer.ConclusiónA través del análisis estadístico fue posible determinar la heterogeneidad de los datos, por lo que las pacientes fueron separadas en tres grupos. Al analizar los clústeres obtenidos, pudo verificarse que cada uno de ellos presentaba características específicas. (AU)

Clinical implications of lipid peroxides levels in plasma and tumor tissue in breast cancer patients.

Oxidative stress can promote the oxidation of lipoproteins and polyunsaturated fatty acids present in cell membranes; an event known as lipid peroxidation (LPO). LPO has been associated with carcinogenesis and cancer progression, however, its meaning concerning the clinicopathological aspects of human breast cancer is not clear. This study investigated LPO profiles in tumor and plasma samples from breast cancer patients (n = 140) considering their clinicopathological features (age at diagnosis, menopausal status, body mass index, tumor histological grade, tumor size, ki-67 proliferation index, presence of metastasis, chemotherapy response, the molecular subtype of cancer and overall survival status). LPO levels were estimated by tert-butyl hydroperoxide-initiated chemiluminescence. High LPO levels were found regarding poor prognosis parameters as young age at diagnosis (p = 0.006 in tissue), premenopausal patients (p = 0.012 in tissue), high-grade tumors (p = 0.010 in tissue and p = 0.002 in plasma), metastatic disease (p = 0.046 in tissue), chemoresistant tumors (p = 0.041 in tissue), disease relapse (p = 0.018 in tissue and p = 0.009 in plasma) and overall survival status (p = 0.001 in plasma). Our findings point out the clinical meaning of LPO and highlight it as an oxidative stress event linked to poor prognosis and disease aggressiveness in breast cancer patients.

Systemic lipid peroxidation profile from patients with breast cancer changes according to the lymph nodal metastasis status.

Metastasis is the leading cause of cancer death. Considering that lymph nodes are the major pathway for cancer spreading and that the metastatic process is under oxidative stress effects, this study aims to evaluate the differential lipid peroxidation profile in the blood of breast cancer patients regarding their lymph nodal status (LN). A total of 105 women diagnosed with breast cancer were included before chemotherapy started. LN was determined by assessing the histopathological analysis of patients' biopsies, and groups were categorized according to the presence (LN+, n = 48) or absence (LN-, n = 57) of metastases. Lipid peroxidation profiles (LPO) were determined in blood by high-sensitivity chemiluminescence. After patients' categorization in groups according to their clinicopathological features, LN- patients aged over 50 years presented significantly lower LPO when compared to those under 50 years. Further, LN- patients carrying HER2 positive tumors presented augmented LPO when compared to patients bearing luminal B or triple-negative tumors. LN+ group also had reduced LPO when presented intratumoral clots. The significant contribution of this study was to show that LPO correlates with specific clinical features of patients with breast cancer according to their LN status and that such profile is significantly affected by the presence of metastases.

Characterization of occupational exposure to pesticides and its impact on the health of rural women

Objective: To characterize the profile of occupational exposure to pesticides and its impact on women's health. Method: This is a prospective and descriptive study with a quantitative approach. The study population included all patients attended at Francisco Beltrao Cancer Hospital (Ceonc) from May 2015 to December 2018 (n=315). The characterization of their exposure profile was obtained through an interview using a form applied by trained researchers contained 60 questions related to women's pesticide exposure and their health status. The questions referred to past and current occupational pesticide exposure profile, intoxication, and health history from women and their families. All collected data were analyzed in the Statistical Package for the Social Sciences package (SPSS 25.0). Results: A total of 265 individuals (84.2%) have lived some part of their life in the countryside, and 70% were categorized as occupationally exposed to pesticides. Most of them (57%) were directly exposed, mainly by washing pesticide-contaminated clothes and personal protective equipment used in pesticide pulverization without glove protection. Cancer cases in the family were the main disease reported (68.3%). Further, 57% of interviewed women had a breast cancer diagnosis but no significance between breast cancer occurrence and pesticide exposure was observed. Conclusion: The form allowed us to characterize the profile of occupational pesticide exposition in rural women, alerting them to their severe contamination. This approach can be useful to characterize the occupational exposure profiles of rural workers living in other rural regions of Brazil that use pesticides.

Influence of exogenous opioids on the acute inflammatory response in the perioperative period of oncological surgery: a clinical study.

BACKGROUND: Recently, opioids have been related to trigger changes in cytokine release and tumor angiogenesis processes, influencing tumor growth, metastasis, and recurrence. METHODS: This is a prospective randomized clinical study to test whether if exogenous opioids used in the anesthesia during cancer surgery can affect the systemic inflammatory and immunological patterns. Patients were randomly allocated to the OP (opioid-inclusive) or OF (opioid-free) anesthesia group. A total of 45 patients were selected, being carriers of prostate, stomach, pancreas, bile ducts, breast, colon, lung, uterus, kidneys, or retroperitoneum tumors. Plasma levels of IL-4, IL-12, IL-17A, and TNF-α, and their oxidative stress profile before and after surgery were evaluated in both groups. In vitro tests were performed by using healthy donor blood incubated with each isolated drug used in patients' anesthesia for 1 hour, the same cytokines were measured in plasma. RESULTS: There was a significant reduction in lipid peroxidation in both groups. Patients from OF group had a significant consumption of IL-12 in the perioperative period. The other cytokines evaluated did not vary. It was also observed a significant correlation between IL-12 and TNF-α levels in the OF-post group. Except for atracurium, all tested drugs led to a reduction in IL-12 levels. CONCLUSIONS: This study demonstrated that there is a reduction of IL-12 in the OF-post patients, suggesting acute consumption and that this seems to be a general mechanism of anesthetic drugs, as demonstrated in vitro. Also, these findings bring us to reflect if IL-12 changes may influence the disease progression and recurrence.

Hereditary Breast and Ovarian Cancer Screening Syndrome Profile in Women Diagnosed with Breast Cancer from Paraná State Southwest.

OBJECTIVE: This study evaluated the risk of the hereditary breast and ovarian cancer (HBOC) syndrome in patients with breast cancer by using the Family History Screening 7 (FHS-7) tool, a validated low-cost questionnaire with high sensitivity able to screen the HBOC risk in the population. METHODS: Women diagnosed with breast cancer (n = 101) assisted by the Unified Health System at the 8th Regional Health Municipal Office of the state of Paraná answered the FHS-7, and the results were analyzed using IBM SPSS Statistics for Windows, Version 25.0. software (IBM Corp., Armonk, NY, USA). RESULTS: The risk of HBOC was 19.80% (n = 20). Patients at risk exhibited aggressive tumor characteristics, such as high-grade tumors (30%), presence of angiolymphatic emboli (35%), and premenopausal at diagnosis (50%). Significant associations between the prevalence of high-grade tumors were observed in women younger than 50 years at diagnosis with HBOC (p = 0.003). CONCLUSION: Our findings suggest a possible family inheritance associated with worse clinical features in women with breast cancer in this population, indicating that HBOC investigation can be initially performed with low-cost instruments such as FHS-7.

OBJETIVO: Este estudo avaliou o risco da síndrome hereditária de câncer de mama e ovário (HBOC, na sigla em inglês) em pacientes com câncer de mama utilizando a ferramenta Familial History Screening 7 (FHS-7), um questionário validado de baixo custo e com alta sensibilidade capaz de rastrear o risco de HBOC na população. MéTODOS: Mulheres diagnosticadas com câncer de mama (n = 101) assistidas pelo Sistema Único de Saúde da 8ª Regional de Saúde do estado do Paraná responderam ao questionário FHS-7, e os resultados foram analisados pelo software IBM SPSS for Windows, Version 25.0. (IBM Corp., Armonk, NY, EUA). RESULTADOS: A ocorrência do risco de HBOC foi de 19,80% (n = 20). Pacientes em risco exibiram características agressivas do tumor como tumores de alto grau (30%), presença de êmbolos angiolinfáticos (35%) e pré-menopausa ao diagnóstico (50%). Associações significantes foram observadas entre a prevalência de tumores de alto grau e diagnóstico abaixo de 50 anos no grupo HBOC (p = 0.003). CONCLUSãO: Nossos achados sugerem uma possível herança familiar associada a piores características clínicas em mulheres com câncer de mama nessa população, indicando que a investigação de HBOC pode ser realizada, inicialmente, com instrumentos de baixo custo, como o FHS-7.

COVID-19: The question of genetic diversity and therapeutic intervention approaches.

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), is the largest pandemic in modern history with very high infection rates and considerable mortality. The disease, which emerged in China's Wuhan province, had its first reported case on December 29, 2019, and spread rapidly worldwide. On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic and global health emergency. Since the outbreak, efforts to develop COVID-19 vaccines, engineer new drugs, and evaluate existing ones for drug repurposing have been intensively undertaken to find ways to control this pandemic. COVID-19 therapeutic strategies aim to impair molecular pathways involved in the virus entrance and replication or interfere in the patients' overreaction and immunopathology. Moreover, nanotechnology could be an approach to boost the activity of new drugs. Several COVID-19 vaccine candidates have received emergency-use or full authorization in one or more countries, and others are being developed and tested. This review assesses the different strategies currently proposed to control COVID-19 and the issues or limitations imposed on some approaches by the human and viral genetic variability.

Chimarrão consumption and prognostic factors in breast cancer: Correlation with antioxidants and blood caffeine levels.

Breast cancer is the second most common malignancy among women. Ilex paraguariensis A. St. Hil, known as yerba mate, is widely consumed in southern Brazil as a hot infusion drink known as chimarrão. This herb has a complex chemical composition and is rich in antioxidants, which may interfere in the course of chronic inflammatory diseases as breast cancer. This study investigated the impact of chimarrão consumption on the clinicopathological profile of women with breast cancer attended at Francisco Beltrão Cancer Hospital, Paraná, Brazil. Blood antioxidants and caffeine profiles were assessed. Decreases in reduced glutathione and metallothionein levels, and increase in catalase activity were observed among breast cancer patients that were chimarrão consumers. The levels of circulating caffeine in breast cancer patients with luminal A tumors were higher than those in patients with luminal B and HER-2 subtypes. Furthermore, overweight patients presented higher caffeine levels than the eutrophic ones. It was found positive associations between chimarrão intake and high body mass index, and chimarrão intake and menopause at diagnosis. Altogether, these findings suggest that chimarrão consumption affects the blood antioxidants of breast cancer patients, and that the caffeine present in this mixture may favor the development of tumor of good prognosis. HIGHLIGHTS: Chimarrão consumption may affect the course of chronic inflammatory diseases, as breast cancer. Chimarrão intake changed blood antioxidants in breast cancer patients who were current consumers when compared to the non-consumers ones. High levels of caffeine were detected in patients bearing luminal A tumors, suggesting a protective role.

Hereditary Breast and Ovarian Cancer Screening Syndrome Profile in Women Diagnosed with Breast Cancer from Paraná State Southwest / Perfil do rastreamento da síndrome hereditária de câncer de mama e ovário em mulheres diagnosticadas com câncer de mama na região sudoeste do Paraná

Abstract Objective This study evaluated the risk of the hereditary breast and ovarian cancer (HBOC) syndrome in patients with breast cancer by using the Family History Screening 7 (FHS-7) tool, a validated low-cost questionnaire with high sensitivity able to screen the HBOC risk in the population. Methods Women diagnosed with breast cancer (n=101) assisted by the Unified Health System at the 8th Regional Health Municipal Office of the state of Paraná answered the FHS-7, and the results were analyzed using IBM SPSS Statistics for Windows, Version 25.0. software (IBM Corp., Armonk, NY, USA). Results The risk of HBOC was 19.80% (n=20). Patients at risk exhibited aggressive tumor characteristics, such as high-grade tumors (30%), presence of angiolymphatic emboli (35%), and premenopausal at diagnosis (50%). Significant associations between the prevalence of high-grade tumors were observed inwomen younger than 50 years at diagnosis with HBOC (p=0.003). Conclusion Our findings suggest a possible family inheritance associated with worse clinical features in women with breast cancer in this population, indicating that HBOC investigation can be initially performed with low-cost instruments such as FHS-7.

Resumo Objetivo Este estudo avaliou o risco da síndrome hereditária de câncer de mama e ovário (HBOC, na sigla em inglês) em pacientes com câncer de mama utilizando a ferramenta Familial History Screening 7 (FHS-7), um questionário validado de baixo custo e com alta sensibilidade capaz de rastrear o risco de HBOC na população. Métodos Mulheres diagnosticadas com câncer de mama (n=101) assistidas pelo Sistema Único de Saúde da 8ª Regional de Saúde do estado do Paraná responderam ao questionário FHS-7, e os resultados foram analisados pelo software IBM SPSS for Windows, Version 25.0. (IBM Corp., Armonk, NY, EUA). Resultados A ocorrência do risco de HBOC foi de 19,80% (n=20). Pacientes em risco exibiram características agressivas do tumor como tumores de alto grau (30%), presença de êmbolos angiolinfáticos (35%) e pré-menopausa ao diagnóstico (50%). Associações significantes foram observadas entre a prevalência de tumores de alto grau e diagnóstico abaixo de 50 anos no grupo HBOC (p=0.003). Conclusão Nossos achados sugerem uma possível herança familiar associada a piores características clínicas em mulheres com câncer de mama nessa população, indicando que a investigação de HBOC pode ser realizada, inicialmente, com instrumentos de baixo custo, como o FHS-7.

Carcinoma de Células de Merkel Metastático: Relato de Caso / Metastatic Merkel cell Carcinoma: Case Report / Carcinoma de Células de Merkel Metastásico: Relato de Caso

Introdução: O carcinoma de células de Merkel é um raro tumor neuroendócrino cutâneo, que se origina das células responsáveis pela sensibilidade tátil, possui caráter agressivo, evolução rápida e difícil tratamento. Relato do caso: Paciente do sexo masculino, 49 anos, caucasiano, que, ao atendimento dermatológico, apresentou nódulo indolor, infiltrando tecidos profundos, não ulcerado e localizado na região do braço esquerdo. O resultado da biópsia incisional foi positivo para carcinoma de células de Merkel. Após ressecção da lesão, os exames complementares evidenciaram doença metastática na axila e parede torácica. Com o tratamento quimioterápico, houve um benefício inicial com redução tumoral, porém, não durável, uma vez que foram reveladas novas áreas com metástases tumorais em regiões superiores do corpo, sendo submetido a novo procedimento cirúrgico, o qual, após novo regime quimioterápico, não obteve sucesso. Conclusão: Na ocasião do tratamento desse paciente, os anticorpos monoclonais, como o avelumab, não estavam disponíveis. O diagnóstico precoce com cirurgia de exérese da lesão imediata, antes do acometimento de outras regiões, permanece sendo a melhor opção para um prognóstico favorável ao paciente. Contudo, a despeito disso, com as limitações à época do tratamento, o paciente evoluiu a óbito.

Introduction: The Merkel cell carcinoma is a rare cutaneous neuroendocrine tumor that originates from cells responsible for tactile sensitivity, it has an aggressive character, fast evolution and difficult treatment. Case report: 49 years Caucasian male patient, with a painless nodule, infiltrating deep tissue, not ulcerated and located in left arm identified during the dermatological consultation. The result of the incisional biopsy was positive for Merkel cell carcinoma. After resection of the lesion, complementary exams revealed metastatic disease in the axilla and chest wall. The chemotherapy treatment brought an initial improvement with tumor reduction, however, it was not durable, because new areas with tumor metastases in upper regions of the body were revealed, the patient was submitted to an another surgical procedure, after which a new chemotherapy regimen failed. Conclusion:At the time of the treatment of this patient, monoclonal antibodies, such as avelumab, were not available. Early diagnosis with immediate lesion excision surgery, before the involvement of other regions, remains the best option for a better prognosis. However, regardless of this, because of the limitations at the time of the treatment, the patient died.

Introducción: El carcinoma de células de Merkel es un tumor neuroendocrino cutáneo raro, que se origina en células responsables de la sensibilidad táctil, tiene un carácter agresivo, una evolución rápida y un tratamiento difícil. Relato del caso: Paciente masculino, de 49 años, caucásico, que en atención dermatológica encontró nódulo indoloro, infiltrando tejidos profundos, no ulcerados y ubicados en la región del brazo izquierdo. El resultado de la biopsia incisional fue positivo para el carcinoma de células de Merkel. Después de la resección de la lesión, los exámenes complementarios mostraron enfermedad metastásica en la axila y la pared torácica. Con el tratamiento de quimioterapia, hubo un beneficio inicial con la reducción del tumor, sin embargo, no es duradero, ya que se revelaron nuevas áreas con metástasis tumorales en las regiones superiores del cuerpo, que se sometieron a un nuevo procedimiento quirúrgico, que después de un nuevo régimen de quimioterapia no tuvo éxito. Conclusión: En el momento del tratamiento de este paciente, los anticuerpos monoclonales, como avelumab, no estaban disponibles. El diagnóstico temprano con cirugía para la escisión de la lesión inmediata, antes de la participación de otras regiones, sigue siendo la mejor opción para un pronóstico favorable para el paciente. Sin embargo, a pesar de esto, con las limitaciones al momento del tratamiento, el paciente falleció.

Anti-neutrophil antibodies (anti-MPO-ANCAs) are associated with poor prognosis in breast cancer patients.

Anti-neutrophil antibodies are capable of activating neutrophils in sterile environments, releasing extracellular traps containing myeloperoxidase (MPO) and anti-MPO antibodies (MPO-ANCAs or anti-MPO-ANCAs), which have been implicated in the pathogenesis of several diseases. The present study evaluated systemic and tumor tissue levels of anti-MPO-ANCAs breast cancer patients, and its relation to clinicopathological characteristics. Anti-MPO-ANCAs were measured in serum and tissue samples of 150 patients by enzyme-linked immunoassay. Samples were pooled according to clinicopathological characteristics of patients. Higher anti-MPO-ANCAs levels were detected in groups presenting negative clinicopathological characteristics, such as high histological grade tumors and risk factors such as body mass index, menopausal status and early onset at diagnosis. The present data highlights anti-MPO-ANCAs as associated to poor prognosis in breast cancer, a role beyond its actually discussed role in autoimmunity and vasculitis.

Toxicoproteomics Disclose Pesticides as Downregulators of TNF-α, IL-1ß and Estrogen Receptor Pathways in Breast Cancer Women Chronically Exposed.

Deleterious effects have been widely associated with chronic pesticide exposure, including cancer development. In spite of several known consequences that pesticides can trigger in the human body, few is known regarding its impact on breast cancer women that are chronically exposed to such substances during agricultural work lifelong. In this context, the present study performed a high-throughput toxicoproteomic study in association with a bioinformatics-based design to explore new putative processes and pathways deregulated by chronic pesticide exposure in breast cancer patients. To reach this goal, we analyzed comparatively non-depleted plasma samples from exposed (n = 130) and non-occupationally exposed (n = 112) women diagnosed with breast cancer by using a label-free proteomic tool. The list of proteins differentially expressed was explored by bioinformatics and the main pathways and processes further investigated. The toxicoproteomic study revealed that women exposed to pesticides exhibited mainly downregulated events, linked to immune response, coagulation and estrogen-mediated events in relation to the unexposed ones. Further investigation shown that the identified deregulated processes and pathways correlated with significant distinct levels tumor necrosis factor alpha and interleukin 1 beta in the blood, and specific clinicopathological characteristics pointed out by bioinformatics analysis as adipose-trophic levels, menopause and intratumoral clots formation. Altogether, these findings reinforce pesticides as downregulators of several biological process and highlight that these compounds can be linked to poor prognosis in breast cancer.

Low Plasmatic 25-hydroxyvitamin D at Diagnosis is Associated with Axillary Invasion, Chemoresistance and Metastasis in Women with Breast Cancer.

PURPOSE: In this study, we investigated the circulating levels of 25-hydroxyvitamin D (25[OH]D) in Brazilian women with breast cancer in samples collected at diagnosis, and correlated these with clinicopathological parameters relevant to disease prognosis. METHODS: This study involved 147 women diagnosed with infiltrative ductal carcinoma whose peripheral blood samples were collected, to have 25(OH)D levels measured in plasma. RESULTS: Our findings indicated that circulating 25(OH)D levels at diagnosis were insufficient in patients with breast cancer. Further, 25(OH)D reduced plasmatic levels at diagnosis correlated significantly with poor prognosis parameters, including axillar positivity, chemoresistance and metastasis. Patients bearing triple-negative tumors also presented reduced 25(OH)D in plasma when compared to those who carried Luminal tumors. Our data suggest relevant correlations when 25(OH)D is reduced in plasma at diagnosis, such as advanced disease with axillar positivity, chemoresistance with advanced disease, early age at diagnosis with high histological grade and dead with axilla positivity. CONCLUSIONS: Altogether, our findings reinforce that 25(OH)D reduction can be a plausible marker of disease prognosis in breast cancer.