Unveiling the Path to Resilience: Prioritizing Mental Health, Sleep, and Nutrition in the Post-COVID Era.

The COVID-19 pandemic has disrupted daily life, impacting relationships, work, and education. This has led to increased stress, anxiety, and depression, along with altered sleep patterns and eating behaviors. Quarantine and isolation have worsened mental health, especially in children and the elderly, due to the loss of activities and physical contact. Sleep disorders and negative dreams perpetuate poor sleep quality, increasing the risk of health issues. Sedentary lifestyles and emotional effects contribute to unhealthy eating patterns and obesity, exacerbated by disrupted routines and limited outdoor activities. Addressing these challenges requires prioritizing mental health, promoting healthy sleep habits, and addressing obesity factors. The pandemic has profoundly affected human well-being, but resilience, mental health, sleep, and nutrition can enhance overall well-being and adaptability in the post-COVID era. This comprehensive opinion aims to raise awareness of the wide-ranging impacts of this pandemic on various aspects of human well-being and to emphasize the importance of implementing strategies that prioritize mental health, improve sleep habits, address eating behaviors, and foster resilience to navigate and thrive in the face of future challenges.

Healthcare Workers' Mental Health in Pandemic Times: The Predict Role of Psychosocial Risks.

Background: Healthcare workers perform an emotionally exhausting daily work activity, making them prone to occupational hazards, namely psychosocial ones. This study aims to assess the impact of psychosocial risk factors on healthcare workers' mental health. Methods: A cross-sectional study was developed between May and June of 2021 with 479 healthcare workers from Portuguese hospitals. The Depression, Anxiety and Stress Scale was used to assess mental health, and psychosocial risks were assessed through the Health and Work Survey - INSAT. Statistical analysis was performed to identify the psychosocial risk factors related to anxiety, depression, and stress. Subsequently, a multiple linear regression was performed to identify the models that better explained psychosocial risk factors' relationship with anxiety, depression, and stress. Results: Data showed a strong exposure to psychosocial risks. Work pace and intensity, work relationships, and emotional demands stood out with higher global average percentages for yes answers to "exposure and discomfort." The analysis of the ß values and p-values from the multiple linear regression shows that some cross-sectional psychosocial risks are predictors of anxiety and stress dimensions, and other psychosocial risks differ in the two mental health dimensions. However, it is important to highlight that healthcare workers still showed great joy and pleasure in performing their work activities. Conclusion: Support network development in the work environment is needed to prevent healthcare workers' emotional stress and promote their psychological well-being. Therefore, new research is essential to understand the psychosocial risks that affect healthcare workers and assess the less visible effects of work-health relationships.

Metabolomics by NMR Combined with Machine Learning to Predict Neoadjuvant Chemotherapy Response for Breast Cancer.

Neoadjuvant chemotherapy (NACT) is offered to patients with operable or inoperable breast cancer (BC) to downstage the disease. Clinical responses to NACT may vary depending on a few known clinical and biological features, but the diversity of responses to NACT is not fully understood. In this study, 80 women had their metabolite profiles of pre-treatment sera analyzed for potential NACT response biomarker candidates in combination with immunohistochemical parameters using Nuclear Magnetic Resonance (NMR). Sixty-four percent of the patients were resistant to chemotherapy. NMR, hormonal receptors (HR), human epidermal growth factor receptor 2 (HER2), and the nuclear protein Ki67 were combined through machine learning (ML) to predict the response to NACT. Metabolites such as leucine, formate, valine, and proline, along with hormone receptor status, were discriminants of response to NACT. The glyoxylate and dicarboxylate metabolism was found to be involved in the resistance to NACT. We obtained an accuracy in excess of 80% for the prediction of response to NACT combining metabolomic and tumor profile data. Our results suggest that NMR data can substantially enhance the prediction of response to NACT when used in combination with already known response prediction factors.

Breast Cancer Treatment Delay in SafetyNet Health Systems, Houston Versus Southeast Brazil.

BACKGROUND: Breast cancer outcomes among patients who use safety-net hospitals in the highly populated Harris County, Texas and Southeast Brazil are poor. It is unknown whether treatment delay contributes to these outcomes. METHODS: We conducted a retrospective cohort analysis of patients with non-metastatic breast cancer diagnosed between January 1, 2009 and December 31, 2011 at Harris Health Texas and Unicamp's Women's Hospital, Barretos Hospital, and Brazilian National Institute of Cancer, Brazil. We used Cox proportional hazards regression to evaluate association of time to treatment and risk of recurrence (ROR) or death. RESULTS: One thousand one hundred ninety-one patients were included. Women in Brazil were more frequently diagnosed with stage III disease (32.3% vs. 21.1% Texas; P = .002). Majority of patients in both populations had symptom-detected disease (63% in Brazil vs. 59% in Texas). Recurrence within 5 years from diagnosis was similar 21% versus 23%. Median time from diagnosis to first treatment defined as either systemic therapy (chemotherapy or endocrine therapy) or surgery, were comparable, 9.9 weeks versus 9.4 weeks. Treatment delay was not associated with increased ROR or death. Higher stage at diagnosis was associated with both increased ROR and death. CONCLUSION: Time from symptoms to treatment was considerably long in both populations. Treatment delay did not affect outcomes. IMPACT: Access to timely screening and diagnosis of breast cancer are priorities in these populations.

Evaluation of PD-L1 and tumor infiltrating lymphocytes in paired pretreatment biopsies and post neoadjuvant chemotherapy surgical specimens of breast carcinoma.

Herein it was evaluated the impact of PD-L1 immunohistochemical expression and stromal tumor-infiltrating lymphocyte (sTIL) counts in pretreatment needle core biopsy on response to neoadjuvant chemotherapy (NACT) for patients with breast carcinomas (BC). In 127 paired pre- and post-NACT BC specimens, immunohistochemical expression of PD-L1 was evaluated in stroma and in neoplastic cells. In the same samples sTILs were semi-quantified in tumor stroma. Post-NACT specimens were histologically rated as having residual cancer burden (RCB of any degree), or with complete pathological response (pCR). PD-L1 expression and higher sTIL counts were associated with histological grade 3 BC. PD-L1 expression was also associated with the non-luminal-HER2+ and triple negative immunohistochemical profiles of BC. Pathological complete response was associated with histological grade 3 tumors, and with the non-luminal-HER2+ and triple negative profiles. Additionally, our results support an association between PD-L1 expression and pCR to NACT. It was also observed that there is a trend to reduction of sTIL counts in the post-NACT specimens of patients with pCR. Of note, PD-L1 was expressed in half of the hormone receptor positive cases, a finding that might expand the potential use of immune checkpoint inhibitors for BC patients.

Real-world data on neoadjuvant endocrine therapy in ER-positive/HER2-negative breast cancer.

PURPOSE: Neoadjuvant endocrine therapy (NET) has been shown to be effective in ER-positive/HER2-negative breast cancer in clinical trials. However, adoption in clinical practice is still limited. Real-world data may provide useful insights into effectiveness, toxicities and quality of care, potentially rendering clinical trial results to the real-world setting. Our purpose was to report real-world data of a cohort of postmenopausal patients submitted to NET. METHODS: This prospective cohort study evaluated 146 postmenopausal female patients with ER-positive/HER2-negative breast cancer treated with NET at three tertiary hospitals between 2016 and 2018. Clinicopathological information were collected prospectively. Preoperative Endocrine Prognostic Index (PEPI) score was calculated for tumors submitted to at least 16 weeks of NET. RESULTS: Median age was 67 years old, and 87.8% had stage I-II disease. Most tumors had histological grade II (76.1%). Median pretreatment Ki67 expression was 10%. Aromatase inhibitor was used in 99.5% of patients, and median treatment duration was 21.0 weeks. No tumor progressed during NET. Breast-conserving surgery was performed in the majority of patients (63.0%), as well as sentinel lymph-node biopsy (76.7%). Pathological complete response rate was 1.0%. 43 patients (29.5%) had PEPI score 0, and 26% had PEPI scores 4-5. Posttreatment Ki67 median expression was 3.0%, and only five tumors (3.4%) showed marked increase in Ki67 expression during treatment. Seven patients (4.8%) had HER2-positive residual disease, and were treated with adjuvant chemotherapy plus trastuzumab. CONCLUSIONS: Our real-world data shows that NET is effective and safe in postmenopausal patients with ER-positive/HER2-negative breast cancer. Postmenopausal status and low-risk luminal tumor features (luminal A-like) should be used as selection criteria to ensure the best results with NET.

ESR1 Mutations Are Not a Common Mechanism of Endocrine Resistance in Patients With Estrogen Receptor-Positive Breast Cancer Treated With Neoadjuvant Aromatase Inhibitor Therapy.

Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy in estrogen receptor-positive (ER+) metastatic breast cancer and have been studied as a potential therapeutic target, as well as a predictive and prognostic biomarker. Nonetheless, the role of ESR1m as a possible mechanism of primary endocrine resistance, as well as whether it also occurs in tumors that are resistant to ET administered in early-stage disease as (neo)adjuvant, has not been adequately studied. In this study, we evaluated the prevalence of ESR1m in tumor samples from patients with ER+ breast cancer resistant to neoadjuvant aromatase inhibitor therapy. Methods: We followed a prospective cohort of patients with ER+ HER2- stages II and III breast cancer treated with neoadjuvant endocrine therapy (NET). Tumor samples from patients with a pattern of primary endocrine resistance [defined as a Preoperative Endocrine Prognostic Index (PEPI) score of ≥4] were identified and analyzed for the presence of ESR1m. Results: One hundred twenty-seven patients were included in the cohort, of which 100 (79%) had completed NET and underwent surgery. Among these patients, the PEPI score ranged from 0 to 3 in 70% (70/100), whereas 30% (30/100) had a PEPI score of 4 or more. Twenty-three of these patients were included in the analysis. ESR1 mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET. Discussion: Growing evidence supports the notion that there are different mechanisms for primary and secondary endocrine resistance. Our study suggests that ESR1 mutations do not evolve rapidly and do not represent a common mechanism of primary endocrine resistance in the neoadjuvant setting. Therefore, ESR1m should be considered a mechanism of acquired endocrine resistance in the context of advanced disease. Further research should be conducted to identify factors associated with intrinsic resistance to ET.

Association of Menopausal Status, Expression of Progesterone Receptor and Ki67 to the Clinical Response to Neoadjuvant Chemotherapy in Luminal Breast Cancer.

OBJECTIVE: To identify the biomarkers of response to neoadjuvant chemotherapy in early luminal breast cancer. METHODS: A cross-sectional study that included all patients with early or locally-advanced luminal breast cancer submitted to neoadjuvant chemotherapy between 2013 and 2014. Demographic, clinic and pathologic data were retrieved from patient records. The expressions of the estrogen receptor (ER), the progesterone receptor (PR), and Ki67 were analyzed by immunohistochemistry (IHC). The status of the human epidermal growth factor receptor 2 (HER2) was evaluated by IHC and fluorescent in situ hybridization (FISH). Independent predictors of clinic and pathologic response were evaluated by stepwise logistic regression models and receiver operating characteristic (ROC) curve analysis. RESULTS: Out of 298 patients identified, 115 were included in the analysis. Clinical complete response (cCR) was observed in 43.4% of the patients (49/113), and pathologic complete response (pCR) was observed in 7.1% (8/115) of the patients. The independent predictors of cCR were premenopausal status (p < 0.001), low PR expression (≤ 50% versus > 50%; p = 0.048), and Ki67 expression ≥ 14% (versus < 14%; p = 0.01). Patients with cCR were more commonly submitted to breast conserving surgery (34.7% versus 7.8%; p < 0.001). Increasing cut-off points for Ki67 expression were associated with an increase in specificity and a decrease in sensitivity to identify patients with cCR. CONCLUSION: Premenopausal status, lower PR expression and higher Ki67 expression were associated with a higher rate of cCR to neoadjuvant chemotherapy in luminal breast cancer.

OBJETIVO: Identificar biomarcadores de resposta à quimioterapia neoadjuvante em câncer luminal de mama. MéTODOS: Estudo transversal em que foram incluídas todas as pacientes com câncer luminal de mama em estádio inicial ou localmente avançado que foram submetidas a quimioterapia neoadjuvante nos anos de 2013 e 2014. Dados demográficos, clínicos e patológicos foram obtidos de prontuários médicos. As expressões de receptor de estrogênio (RE), de receptor de progesterona (RP), e de Ki67 foram avaliadas por imuno-histoquímica (IHQ). A expressão do receptor tipo 2 do fator de crescimento epidérmico humano (human epidermal growth factor receptor 2, HER2) foi avaliada por IHQ e hibridização in situ por imunofluorescência (HISI). Análises de regressão logística e de curva de característica de operação do receptor (COR) foram usadas para investigar fatores preditivos independentes de resposta clínica e patológica. RESULTADOS: De 298 pacientes identificadas, 115 foram incluídas na análise. Resposta clínica completa (RCc) foi observada em 43.4% das pacientes (49/113), e resposta patológica completa (RPc), em 7.1% (8/115). Os fatores preditivos independentes de RCc foram status menopausal (p < 0.001), baixa expressão de RP (≤ 50% versus > 50%; p = 0.048), e expressão de Ki67 ≥ 14% (versus < 14%; p = 0.01). Pacientes com RCc apresentaram maior probabilidade de serem submetidas a cirurgia conservadora da mama (34.7% versus 7.8%; p < 0.001). Aumento no ponto de corte para expressão de Ki67 foi associado a aumento da especificidade e redução da sensibilidade na identificação de pacientes com RCc. CONCLUSãO: Status premenopausal, baixa expressão de RP e maior expressão de Ki67 estiveram associados a maior taxa de RCc à quimioterapia neoadjuvante no câncer luminal de mama.

Association of menopausal status, expression of progesterone receptor and ki67 to the clinical response to neoadjuvant chemotherapy in luminal breast cancer / Associação de status menopausal, expressão de receptor de progesterona e de Ki67 à resposta clínica à quimioterapia neoadjuvante no câncer luminal de mama

Abstract Objective To identify the biomarkers of response to neoadjuvant chemotherapy in early luminal breast cancer. Methods A cross-sectional study that included all patients with early or locallyadvanced luminal breast cancer submitted to neoadjuvant chemotherapy between 2013 and 2014. Demographic, clinic and pathologic data were retrieved from patient records. The expressions of the estrogen receptor (ER), the progesterone receptor (PR), and Ki67 were analyzed by immunohistochemistry (IHC). The status of the human epidermal growth factor receptor 2 (HER2) was evaluated by IHC and fluorescent in situ hybridization (FISH). Independent predictors of clinic and pathologic response were evaluated by stepwise logistic regression models and receiver operating characteristic (ROC) curve analysis. Results Out of 298 patients identified, 115 were included in the analysis. Clinical complete response (cCR) was observed in 43.4% of the patients (49/113), and pathologic complete response (pCR) was observed in 7.1% (8/115) of the patients. The independent predictors of cCR were premenopausal status (p < 0.001), low PR expression (≤ 50% versus > 50%; p = 0.048), and Ki67 expression ≥ 14% (versus < 14%; p = 0.01). Patients with cCR were more commonly submitted to breast conserving surgery (34.7% versus 7.8%; p < 0.001). Increasing cut-off points for Ki67 expression were associated with an increase in specificity and a decrease in sensitivity to identify patients with cCR. Conclusion Premenopausal status, lower PR expression and higher Ki67 expression were associated with a higher rate of cCR to neoadjuvant chemotherapy in luminal breast cancer.

Resumo Objetivo Identificar biomarcadores de resposta à quimioterapia neoadjuvante em câncer luminal de mama. Métodos Estudo transversal em que foram incluídas todas as pacientes com câncer luminal de mama em estádio inicial ou localmente avançado que foram submetidas a quimioterapia neoadjuvante nos anos de 2013 e 2014. Dados demográficos, clínicos e patológicos foram obtidos de prontuários médicos. As expressões de receptor de estrogênio (RE), de receptor de progesterona (RP), e de Ki67 foram avaliadas por imuno-histoquímica (IHQ). A expressão do receptor tipo 2 do fator de crescimento epidérmico humano (human epidermal growth factor receptor 2, HER2) foi avaliada por IHQ e hibridização in situ por imunofluorescência (HISI). Análises de regressão logística e de curva de característica de operação do receptor (COR) foram usadas para investigar fatores preditivos independentes de resposta clínica e patológica. Resultados De 298 pacientes identificadas, 115 foram incluídas na análise. Resposta clínica completa (RCc) foi observada em 43.4% das pacientes (49/113), e resposta patológica completa (RPc), em 7.1% (8/115). Os fatores preditivos independentes de RCc foram status menopausal (p < 0.001), baixa expressão de RP (≤ 50% versus > 50%; p = 0.048), e expressão de Ki67 ≥ 14% (versus < 14%; p = 0.01). Pacientes com RCc apresentaram maior probabilidade de serem submetidas a cirurgia conservadora da mama (34.7% versus 7.8%; p < 0.001). Aumento no ponto de corte para expressão de Ki67 foi associado a aumento da especificidade e redução da sensibilidade na identificação de pacientes com RCc. Conclusão Status premenopausal, baixa expressão de RP e maior expressão de Ki67 estiveram associados a maior taxa de RCc à quimioterapia neoadjuvante no câncer luminal de mama.

Prognostic assessment of breast carcinoma submitted to neoadjuvant chemotherapy with pathological non-complete response.

BACKGROUND: Breast cancer with pathological non-complete response (non-pCR) after neoadjuvant chemotherapy (NAC) has a worse prognosis. Despite Neo-Bioscore has been validated as an independent prognostic model for breast cancer submitted to NAC, non-pCR carcinoma was not assessed in this setting. METHODS: This is a retrospective trial that included women with localized breast cancer who underwent NAC and had non-pCR carcinoma in surgical specimen between 01/01/2013 to 12/31/2015 with a three-year follow-up. Survival analysis was performed by Kaplan-Meier estimator and hazard ratio (HR) set by log-rank test for the primary and secondary endpoints, respectively Disease-Free Survival (DFS) and Overall Survival (OS). According to Neo-Bioscore, the proposed prognostic model named Clustered Neo-Bioscore was classified into low (0-3), low-intermediate (4-5), high-intermediate (6) and high (7) risk. The prognostic accuracy for recurrence risk was assessed by time-dependent receiver operating characteristic (time-ROC) methodology. Multivariate Cox regression assessed the menopausal status, histological grade, Ki-67, estrogen receptor, HER2, tumor subtype, pathological and clinical stages. Confidence interval at 95% (CI95%) and statistical significance at set 2-sided p-value less than 0.05 were adopted. RESULTS: Among the 310 women enrolled, 267 patients (86.2%) had non-pCR carcinoma presenting size T3/T4 (63.3%), node-positive axilla (74.9%), stage III (62.9%), Ki-67 ≥ 20% (71.9%) and non-luminal A (78.3%). Non-pCR carcinoma presented worse DFS-3y (HR = 3.88, CI95% = 1.18-11.95) but not OS-3y (HR = 2.73, CI95% = 0.66-11.40). Clustered Neo-Bioscore discerned the recurrence risk for non-pCR carcinoma: low (DFS-3y = 0.86; baseline), low-intermediate (DFS-3y = 0.70; HR = 2.61), high-intermediate (DFS-3y = 0.13, HR = 14.05), and high (DFS-3y = not achieved; HR = 22.19). The prognostic accuracy was similar between Clustered Neo-Bioscore and Neo-Bioscore (0.76 vs 0.78, p > 0.05). Triple-negative subtype (HR = 3.6, CI95% = 1.19-10.92) and pathological stages II (HR = 5.35, CI95% = 1.19-24.01) and III (HR = 6.56, CI95% = 1.29-33.32) were prognoses for low-intermediate risk, whereas pathological stage III (HR = 13.0, CI95% = 1.60-106.10) was prognosis for low risk. CONCLUSIONS: Clustered Neo-Bioscore represents a novel prognostic model of non-pCR carcinoma undergoing NAC with a more simplified and appropriate score pattern in the assessment of prognostic factors.

Copy number alterations associated with clinical features in an underrepresented population with breast cancer.

BACKGROUND: As the most incident tumor among women worldwide, breast cancer is a heterogeneous disease. Tremendous efforts have been made to understand how tumor characteristics as histological type, molecular subtype, and tumor microenvironment collectively influence disease diagnosis to treatment, which impact outcomes. Differences between populations and environmental and cultural factors have impacts on the origin and evolution of the disease, as well as the therapeutic challenges that arise due to these factors. We, then, compared copy number variations (CNVs) in mucinous and nonmucinous luminal breast tumors from a Brazilian cohort to investigate major CNV imbalances in mucinous tumors versus non-mucinous luminal tumors, taking into account their clinical and pathological features. METHODS: 48 breast tumor samples and 48 matched control blood samples from Brazilian women were assessed for CNVs by chromosome microarray. Logistic regression and random forest models were used in order to assess CNVs in chromosomal regions from tumors. RESULTS: CNVs that were identified in chromosomes 1, 5, 8, 17, 19, and 21 classify tumors according to their histological type, ethnicity, disease stage, and familial history. CONCLUSION: Copy number alterations described in this study provide a better understanding of the landscape of genomic aberrations in mucinous breast cancers that are associated with clinical features.

Role of discoidin domain receptor 2 (DDR2) and microRNA-182 in survival of women with high-grade serous ovarian cancer.

The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (DDR2) and miR-182 expression with response to platinum-based chemotherapy and survival in women with high-grade serous ovarian cancer (HGSOC). We evaluated 78 women with HGSOC stages I-IV, diagnosed between 1996 and 2013, and followed up until 2016. DDR2 expression was assessed using immunohistochemistry on tissue microarray slides. The microRNAs were evaluated by qRT-PCR. DDR2 expression was high in 11 (14.1%) women. PFS was significantly lower in women with FIGO stage I/II - versus III/IV, post-surgery residual disease and high expression of DDR2. Women with postsurgery residual disease, FIGO stage I/II - versus III/IV and DDR2 expression had worse OS, but only post-surgery residual disease remained an independent prognostic factor for worse OS in multivariable analysis. miR-182 expression levels were significantly lower in patients harboring tumors with higher expression of DDR2 (p < 0.001). In this relatively large cohort of women with HSGOC, higher DDR2 expression was associated with lower miR-182 levels and worse PFS, suggesting that these molecules may be associated with mechanisms of HGSOC progression.

The Predictive Value of Dyadic Coping in the Explanation of PTSD Symptoms and Subjective Well-Being of Work Accident Victims.

Objective: Work accidents may be considered dyadic stressors in so far as they not only affect the worker, but also the couple's relationship. Dyadic coping, as the process by which couples manage the stress experienced by each partner, can strengthen individual health and well-being as well as couple relationship functioning. Accidents at work have progressively been studied from a perspective that focuses on their negative effects on PTSS, anxiety, and depression. However, to a large extent, the dyadic coping processes and results following a work accident are still to be identified and clarified. In this study, we examined the predictive value of dyadic coping in the explanation of PTSS and subjective well-being of work accident victims. Method: This study comprised a sample of 62 individuals involved in work accidents within the last 24 months (61.3% males) and their partners (N = 124; M = 46.25 years, SD = 11.18). All participants responded to the Dyadic Coping Inventory and the work accident victims also answered the PTSD Checklist - Civilian (PCL-C) and the Mental Health Continuum - Short Form (MHC-SF). Two hierarchical multiple regression analyses were performed using two different variable set models: Model 1 comprised the control variables gender and age, and Model 2 included the workers' and the partners' dyadic coping variables. Results: Results showed that dyadic coping reported by both workers and their respective partners (Model 2) was a significant predictor of workers' PTSS (p < 0.01) and subjective well-being (p < 0.001), explaining 31.2% of the variance in PCL-C and 68.7% in MHC-SF results. More specifically, the partners' supportive dyadic coping (by the self) and delegated dyadic coping (by the partner) were significant predictors of the workers' lower PTSS and virtually all the dyadic copying strategies of both the workers' and their partners' were significant predictors of the workers' higher subjective well-being. Conclusion: Dyadic coping of both the workers and their partners predicts the workers' PTSS and subjective well-being. These findings point to the need to work with couples who have experienced a work accident, with a view to improving the workers' mental health outcomes.

Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer.

RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1-6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.

Predictors of Pathological Complete Response in Women with Clinical Complete Response to Neoadjuvant Chemotherapy in Breast Carcinoma.

OBJECTIVE: There is insufficient information on predictors of pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast carcinoma that also presented clinical complete response (cCR) evaluated in breast, axilla and breast and axilla. METHODS: This retrospective study included 310 women with breast carcinoma who received NAC from 1/1/13 to 12/31/15 with follow-up until 8/31/16. The factors analyzed to predict pCR and cCR were menopausal status, Ki67, estrogen receptor, histologic grade, molecular subtype, tumor size, axilla status, and stage. RESULTS: The cCR/pCR rates were 53.2/16.5% (breast), 76.3/36.8% (axilla) and 50.6/13.9% (breast and axilla). Molecular subtype and HER2-positive were independent predictors to confirm pCR in women with cCR, mainly triple negative (TN) in breast (OR 22.81, 95% CI 7.13-72.96) and breast and axilla (OR 36.06, 95% CI 8.77-148.26), but not in axilla. Ki67 ≥50% expression was predictor of cCR in breast (OR 2.00, 95% CI 1.31-3.06) and breast and axilla (OR 1.67, 95% CI 1.10-1.45). CONCLUSION: TN subtype and HER2-positive were the main independent predictors of pCR in women who also had cCR to NAC in breast and breast and axilla, but none was predictor in axilla. The Ki67 ≥50% was the independent predictor of cCR in breast and breast and axilla.

WT1, p53 and p16 expression in the diagnosis of low- and high-grade serous ovarian carcinomas and their relation to prognosis.

OBJECTIVE: To evaluate the diagnostic and prognostic value of the immunohistochemical expression of WT1, p53 and p16 in low- (LGSOCs) and high-grade serous ovarian carcinomas (HGSOCs). RESULTS: HGSOC had a significantly higher proportion of advanced stage disease, higher CA125 levels, higher proportion of post-surgery residual disease and higher recurrence or disease progression. WT1 was expressed in 71.4% of LGSOCs and in 57.1% of HGSOCs (p = 0.32). Focal and/or complete absence of p53 expression with negative p16 expression was found in 90.5% of LGSOCs, in contrast to the 88.1% of HGSOCs with diffuse or complete absence of p53 expression with positive p16 expression (<0.001). The IHC p53/p16 index and the morphological classification were closely matched (k = 0.68). In the univariate analysis, FIGO stage, post-surgery residual disease and histological grade were significantly associated with progression-free survival (PFS) and overall survival (OS). The IHC p53/p16 index was associated only with PFS. WT1 was not associated with PFS or OS. According to the multivariate analysis, advanced FIGO stage and presence of post-surgery residual disease remained independent prognostic factors for worst PFS, however these features had only a trend association with OS. METHODS: 21 LGSOC and 85 HGSOC stage I-IV cases were included. The morphological classification was assessed according to the World Health Organization (WHO) criteria. Immunohistochemistry (IHC) was performed in tissue microarray slides. IHC p53/p16 index was compared with the morphological classification. CONCLUSIONS: The IHC p53/p16 index was a good marker for the differentiation of LGSOC and HGSOC, but the morphologic classification showed a better association with survival. FIGO stage and post-surgery residual disease remained the only independent prognostic factors for survival.

BRCA1, Ki67, and ß-Catenin Immunoexpression Is Not Related to Differentiation, Platinum Response, or Prognosis in Women With Low- and High-Grade Serous Ovarian Carcinoma.

OBJECTIVE: The purpose of this study was to compare the immunohistochemical expression of BRCA1, Ki67, and ß-catenin in women with low-grade (LGSOC) and high-grade serous ovarian carcinomas (HGSOC) and their relationship with clinicopathological features, response to platinum-based chemotherapy, and survival. METHODS: For this study, 21 LGSOC and 85 HGSOC stage I to IV cases, diagnosed and treated from 1996 to 2013 and followed-up until December 2016, were included. BRCA1, Ki67, and ß-catenin expression was assessed using tissue microarray-based immunohistochemistry. RESULTS: Women with HGSOC were significantly more likely to have advanced-stage disease (P < 0.001), higher CA125 levels (P < 0.001), postsurgery residual disease (P < 0.01), and higher rates of disease progression and recurrence (P = 0.001). The percentage of women with HGSOC whose tumors expressed Ki67 was significantly higher compared with women with LGSOC (P < 0.001). The expression of BRCA1 and ß-catenin did not differ between LGSOC and HGSOC (P = 0.12 and P = 1.00, respectively). The clinicopathological features and the response to platinum-based chemotherapy did not differ according to the BRCA1, Ki67, and ß-catenin expression in either group. In HGSOC, only International Federation of Gynecology and Obstetrics stage was independently associated with poor survival (PFS and OS). CONCLUSIONS: Ki67 expression was significantly higher in HGSOC. BRCA1 and ß-catenin expression did not differ between LGSOC and HGSOC samples. BRCA1, Ki67, and ß-catenin expression was neither related to clinicopathological features, response to platinum-based chemotherapy, nor survival. Only International Federation of Gynecology and Obstetrics stage remained associated with poor survival in women with HGSOC.

Multidisciplinary Approach to Neoadjuvant Endocrine Therapy in Breast Cancer: A Comprehensive Review.

Breast cancer is the most common type of cancer and the leading cause of cancer-related death among women worldwide. Hormone receptor-positive (HR+) tumors represent the most common form of this disease, with more than 70% of breast cancers expressing these receptors. Response and benefit to neoadjuvant chemotherapy (NCT) varies according to HR expression, with lower responses in luminal tumors as compared with hormone receptor-negative (HR-) and human epidermal growth factor receptor 2-positive (HER2+) tumors. Neoadjuvant endocrine therapy (NET) is an option for selected patients with HR+ locally advanced breast cancer. Neoadjuvant endocrine therapy has a favorable toxicity profile, and is associated with benefits such as having low cost and being more easily available even for cancer care professionals outside major urban areas or tertiary centers. These factors are particularly relevant, as 70% of breast cancer deaths occur in women from low-income and middle-income countries. Additionally, NET is being increasingly explored, not simply to allow for less extensive surgery, but also as a scientific tool, with the use of biomarkers to predict outcomes in adjuvant trials and for the individual patient. This review details the current and most relevant evidence about NET for breast cancer as well as the future directions of this field.

Multidisciplinary Approach to Neoadjuvant Endocrine Therapy in Breast Cancer: A Comprehensive Review / Abordagem multidisciplinar em hormonioterapia neoadjuvante no câncer de mama: uma revisão

ABSTRACT Breast cancer is the most common type of cancer and the leading cause of cancer-related death among women worldwide. Hormone receptor-positive (HRþ) tumors represent the most common form of this disease, with more than 70% of breast cancers expressing these receptors. Response and benefit to neoadjuvant chemo-therapy (NCT) varies according to HR expression, with lower responses in luminal tumors as compared with hormone receptor-negative (HR-) and human epidermal growth factor receptor 2-positive (HER2þ) tumors. Neoadjuvant endocrine therapy (NET) is an option for selected patients with HRþ locally advanced breast cancer. Neoadjuvant endocrine therapy has a favorable toxicity profile, and is associated with benefits such as having low cost and being more easily available even for cancer care professionals outside major urban areas or tertiary centers. These factors are particularly relevant, as 70% of breast cancer deaths occur in women from low-income and middle-income countries. Additionally, NET is being increasingly explored, not simply to allow for less extensive surgery, but also as a scientific tool, with the use of biomarkers to predict outcomes in adjuvant trials and for the individual patient. This review details the current and most relevant evidence about NET for breast cancer as well as the future directions of this field.

RESUMO O câncer de mama é o mais comum, e a principal causa de mortalidade por câncer em mulheres de todo o mundo. Os tumores com receptor hormonal (RH) positivo representam o tipo mais comum desta doença. O benefício e as taxas de resposta à quimioterapia neoadjuvante variam de acordo com a expressão de RH, sendo mais baixa nos tumores luminais em comparação com tumores HER2 positivos ou triplo-negativos. A hormonioterapia neoadjuvante, uma opção para pacientes selecionados com tumores RH positivo localmente avançados, apresenta melhor perfil de tolerabilidade e segurança, e está associada com benefícios adicionais, como baixo custo e fácil acesso. Estes fatores são relevantes, uma vez que 70% das mortes por câncer de mama acontecem em mulheres de países pobres ou em desenvolvimento. Além disso, a hormonioterapia neoadjuvante vem sendo explorada como uma ferramenta científica, ao possibilitar o estudo de biomarcadores que podem predizer desfechos tanto para pacientes individuais quanto para ensaios clínicos em adjuvância. Este artigo de revisão detalha o conhecimento atual e as evidências mais relevantes sobre hormonioterapia neoadjuvante em câncer de mama, assim como perspectivas futuras nesta área.

The Computational Fluid Dynamics Rupture Challenge 2013--Phase II: Variability of Hemodynamic Simulations in Two Intracranial Aneurysms.

With the increased availability of computational resources, the past decade has seen a rise in the use of computational fluid dynamics (CFD) for medical applications. There has been an increase in the application of CFD to attempt to predict the rupture of intracranial aneurysms, however, while many hemodynamic parameters can be obtained from these computations, to date, no consistent methodology for the prediction of the rupture has been identified. One particular challenge to CFD is that many factors contribute to its accuracy; the mesh resolution and spatial/temporal discretization can alone contribute to a variation in accuracy. This failure to identify the importance of these factors and identify a methodology for the prediction of ruptures has limited the acceptance of CFD among physicians for rupture prediction. The International CFD Rupture Challenge 2013 seeks to comment on the sensitivity of these various CFD assumptions to predict the rupture by undertaking a comparison of the rupture and blood-flow predictions from a wide range of independent participants utilizing a range of CFD approaches. Twenty-six groups from 15 countries took part in the challenge. Participants were provided with surface models of two intracranial aneurysms and asked to carry out the corresponding hemodynamics simulations, free to choose their own mesh, solver, and temporal discretization. They were requested to submit velocity and pressure predictions along the centerline and on specified planes. The first phase of the challenge, described in a separate paper, was aimed at predicting which of the two aneurysms had previously ruptured and where the rupture site was located. The second phase, described in this paper, aims to assess the variability of the solutions and the sensitivity to the modeling assumptions. Participants were free to choose boundary conditions in the first phase, whereas they were prescribed in the second phase but all other CFD modeling parameters were not prescribed. In order to compare the computational results of one representative group with experimental results, steady-flow measurements using particle image velocimetry (PIV) were carried out in a silicone model of one of the provided aneurysms. Approximately 80% of the participating groups generated similar results. Both velocity and pressure computations were in good agreement with each other for cycle-averaged and peak-systolic predictions. Most apparent "outliers" (results that stand out of the collective) were observed to have underestimated velocity levels compared to the majority of solutions, but nevertheless identified comparable flow structures. In only two cases, the results deviate by over 35% from the mean solution of all the participants. Results of steady CFD simulations of the representative group and PIV experiments were in good agreement. The study demonstrated that while a range of numerical schemes, mesh resolution, and solvers was used, similar flow predictions were observed in the majority of cases. To further validate the computational results, it is suggested that time-dependent measurements should be conducted in the future. However, it is recognized that this study does not include the biological aspects of the aneurysm, which needs to be considered to be able to more precisely identify the specific rupture risk of an intracranial aneurysm.