Characteristics and prognosis of young breast cancer patients treated in a public comprehensive cancer centre in Brazil: A retrospective cohort study.

BACKGROUND: The incidence of breast cancer among women under 41 years old varies worldwide, with higher rates observed in developing countries. These young women often face later-stage diagnoses. In this study, we examine a cohort of young women who were treated for breast cancer in São Paulo, Brazil. METHODS: We conducted a retrospective cohort study involving women under 41 years old. Our objective was to describe patient and treatment characteristics, with the main outcomes being overall and disease-free survival. Our analysis explored the associations between age of menarche, history of breastfeeding, use of hormonal contraceptives, and age at diagnosis. RESULTS: Our study included 493 patients with a mean follow-up of 62.8 months. The mean age of the patients was 34.6 (SD=4.19). Of the patients, 68% presented with locally advanced disease, and 19.27% were metastatic at the time of diagnosis. We observed significant associations between age of menarche and age at diagnosis (p = 0.0096), as well as age at diagnosis and breastfeeding (p = 0.0232). Chemotherapy was administered to 92.91% of the patients as part of their treatment, while 27.2% were eligible for breast-conserving surgery. During the follow-up period, 153 patients died, with disease progression being the cause of death in 73.2% of cases. The median survival time for the entire cohort is still under review, while the metastatic patients at diagnosis had a median survival time of 28.64 months (95%CI 20.21-40.89). CONCLUSION: Our findings highlight significant associations between late-stage diagnosis and overall and disease-free survival in this patient age group. Given that the majority of patients present with locally advanced breast cancer, it is crucial to implement strategies that promote early-stage diagnosis and improve survival rates.

Measurement of extracapsular extension in sentinel lymph node as a possible predictor of residual axillary disease in breast cancer.

BACKGROUND: The presence of Extracapsular Extension (ECE) in the Sentinel Lymph Node Biopsy (SLNB) is still a doubt in the literature. Some studies suggest that the presence of ECE may be related to a greater number of positive axillary lymph nodes which could impact Disease Free Survival (DFS) and Overall Survival (OS). This study searches for the clinical significance of the ECE. METHODS: Retrospective cohort comparing the presence or absence of ECE in T1-2 invasive breast cancer with positive SLNB. All cases treated surgically at the Cancer Institute of the State of São Paulo (ICESP) between 2009 and 2013 were analyzed. All patients with axillary disease in SLNB underwent AD. OUTCOMES: Identify the association between the presence and length of ECE and additional axillary positive lymph nodes, OS and DFS between both groups. RESULTS: 128 patients with positive SLNB were included, and 65 had ECE. The mean metastasis size of 0.62 (SD = 0.59) mm at SLNB was related to the presence of ECE (p < 0.008). The presence of ECE was related to a higher mean of positive sentinel lymph nodes, 3.9 (± 4.8) vs. 2.0 (± 2.1), p = 0.001. The median length of follow-up was 115 months. The OS and DFS rates had no differences between the groups. CONCLUSION: The presence of ECE was associated with additional positive axillary lymph nodes in this study. Therefore, the OS and DFS were similar in both groups after 10 years of follow-up. It is necessary for additional studies to define the importance of AD when SLNB with ECE.

Programmed cell death-1 and its ligands: Current knowledge and possibilities in immunotherapy.

Programmed Cell Death-1 (PCD-1) is a key immune checkpoint receptor, which mainly expresses on activated T, B, Dendritic (DC), Natural Killer (NK), and Treg cells. On the surface of activated T-cells, PCD-1 expression is upregulated after the recognition of peripherals antigens by T cells; subsequently, the elevated binding of PD-1 to Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2) becomes a key step for downstream inhibitory signaling. Although the role of PD-L1 has been evaluated more thoroughly by clinical research, and PD-L1 has also been used more widely in the clinical setting, PD-L2 also plays an important role in the negative regulation of T-cells, one of the necessary conditions that lead to immune tolerance. Expression of PD-L1 either in tumors or in infiltrating immune cells has been verified predominantly by Immunohistochemistry (IHC) in a variety of tumors, suggesting a role for the PD-1/PD-L1 axis as a prognostic trait and therapeutic target across multiple histotypes. The complex interplay between these factors plays a major role in the diffusion and clinical application of PD-L1 IHC assays as predictive biomarkers of response to PD-1/PD-L1 inhibitors. Checkpoint blockades are registered for the treatment of various cancers, including gynecological malignancies.

Vitamin D and in vitro fertilization: a systematic review.

PURPOSE: Vitamin D (VD) action on calcium is well known, but its other properties, particularly in the human reproductive system, are not completely understood. This review aims at assessing the relationship between serum VD levels and IVF results. METHODS: A systematic review was carried out using MEDLINE, EMBASE, LILACS, Google scholar, the CAPES journal portal, and the Cochrane Library, as well as the descriptors "vitamin D" and "fertilization in vitro." The review was conducted by two authors following the PRISMA recommendations between September 2021 and February 2022. RESULTS: Eighteen articles were selected. Five of them showed a positive correlation between serum VD levels and IVF results, 12 lacked any association, and 1 exhibited a negative correlation. The 3 studies that assessed VD in the follicular fluid found a positive correlation between the serum and follicular levels. Non-Hispanic White patients seemed to suffer the consequence of vitamin D deficiency more than Asian patients. In one study alone in the VD-deficient group, there was a larger number of natural killer (NK) cells, B cells, a greater proportion of helper T cells/cytotoxic T cells (Th/Tc), and an association with a smaller number of mature oocytes. CONCLUSION: The association between serum VD levels and the post-IVF pregnancy rate is uncertain. However, VD levels might be more relevant in the White than in the Asian ethnicity and in the number of aspiration follicles, and they could act in the immune system having an impact both on embryo implantation and on pregnancy.

Hormonal and Metabolic Factors Influence the Action of Progesterone on the Endometrium of Women with Polycystic Ovary Syndrome.

Hormonal and metabolic factors may influence endometrial quality and interfere with the action of progesterone. Therefore, the aim of our study was to address this issue. Participants were recruited from an outpatient reproductive endocrinology clinic at an academic tertiary medical care centre. All subjects underwent endometrial biopsy (EB) in the follicular phase of the cycle prior to treatment. Thereafter, they were treated with micronized progesterone (400 mg/day × 10 days intravaginally) from days 14-28 of the next cycle. A second EB was performed between days 21-24 of the cycle (the second phase). The metabolic and hormonal serum levels were evaluated during the implantation window. EB samples were analysed using light microscopy for histomorphometric analysis. The endometrium of women with Polycystic Ovarian Syndrome (PCOS) in the second phase demonstrated a uniform surface epithelium with less leukocyte infiltration and an absence of apoptotic figures compared to the control group. (p < 0.021). The thickness of the surface epithelium in the second phase of the PCOS group correlated positively with free and bioavailable testosterone values. The number of stromal cells increases with increasing insulin levels. Our results suggest that histomorphometric abnormalities of the endometrium persist and are linked to androgen and insulin levels despite progesterone supplementation in PCOS.

Effects of preoperative magnetic resonance image on survival rates and surgical planning in breast cancer conservative surgery: randomized controlled trial (BREAST-MRI trial).

BACKGROUND: Breast magnetic resonance imaging (MRI) has high sensitivity in detecting invasive neoplasms. Controversy remains about its impact on the preoperative staging of breast cancer surgery. This study evaluated survival and surgical outcomes of preoperative MRI in conservative breast cancer surgery. METHODS: A phase III, randomized, open-label, single-center trial including female breast cancer participants, stage 0-III disease, and eligible for breast-conserving surgery. We compared the role of including MRI in preoperative evaluation versus radiologic exam routine with mammography and ultrasound in breast cancer conservative candidates. The primary outcome was local relapse-free survival (LRFS), and secondary outcomes were overall survival (OS), mastectomy rate, and reoperation rate. RESULTS: 524 were randomized to preoperative MRI group (n = 257) or control group (n = 267). The survival analysis showed a 5.9-years LRFS of 99.2% in MRI group versus 98.9% in control group (HR = 0.72; 95% CI 0.12-4.28; p = 0.7) and an OS of 95.3% in the MRI group versus 96.3% in the control group (HR = 1.37 95% CI 0.59-3.19; p = 0.8). Surgical management changed in 21 ipsilateral breasts in the MRI group; 21 (8.3%) had mastectomies versus one in the control group. No difference was found in reoperation rates, 22 (8.7%) in the MRI group versus 23 (8.7%) in the control group (RR = 1.002; 95% CI 0.57-1.75; p = 0.85). CONCLUSION: Preoperative MRI increased the mastectomy rates by 8%. The use of preoperative MRI did not influence local relapse-free survival, overall survival, or reoperation rates.

Could be FOXO3a, miR-96-5p and miR-182-5p useful for Brazilian women with luminal A and triple negative breast cancers prognosis and target therapy?

FOXO3a dysregulation is frequently implicated in tumorigenesis, and its inhibition can occur by several molecular mechanisms. Among these, post-transcriptional suppression by miRNAs has been associated with various cancers initiation. Here, we assessed the expression profiles of the most relevant miRNAs for breast tumorigenesis, using Luminal A (LA) and Triple-Negative (TN) breast cancer from Brazilian patients, by the quantitative real time-PCR method. Their potential prognostic role for the patients was also evaluated. We identified the miRNAs miR-96-5p and miR-182-5p, de-scribed as negative regulators of FOXO3A, with differential expression both in LA and TN tumors when compared to normal tissue. The miR-96-5p and miR-182-5p miRNAs were upregulated in LA (7.82 times, p < 0.005; 6.12 times, p < 0.005, respectively) and TN breast cancer samples (9.42 times, p < 0.0001; 8.51 times, p < 0.0001) compared to normal tissues. The samples with higher miR-96-5p and miR-182-5p expression (FR ≥ 4) were submitted for FOXO3a immunostaining. Reduced protein detection was observed in all of the tumors compared to normal tissues. The most prominent miRNA expression and FOXO3a protein suppression were observed in TN samples (p < 0.001), indicating the relevant role of these molecules in this tumor biology and clinical behavior. Our results corroborate the literature regarding to the relevance of FOXO3a in the breast cancer, and they open new perspectives for alternative target therapy options for Brazilian patients expressing both FOXO3a and its regulatory miRNAs.

Validation of the Residual Cancer Burden Index as a prognostic tool in women with locally advanced breast cancer treated with neoadjuvant chemotherapy.

AIMS: To correlate the 'Residual Cancer Burden' (RCB) index with overall survival (OS) and disease-free survival (DFS) in women undergoing neoadjuvant chemotherapy at the Cancer Institute of the State of São Paulo. METHODS: We analysed the medical records of patients with breast cancer who underwent neoadjuvant chemotherapy and breast surgery, from 2011 to December 2017. Variables analysed were age, clinical and pathological staging, molecular subtype, number of recurrences or metastases, number of deaths, value and class of the RCB index. We used the Kaplan-Meier and the log-rank statistics to evaluate the possible association between RCB and OS and DFS. A regression model was used to determine the independent association of the RCB with the outcomes controlling for confounding factors. RESULTS: 347 patients were included in the analysis with a mean age of 49.39 years. Initial clinical staging was T3 in 57.9% of patients and 43.8% of patients had N1 axillary status. Survival analysis showed a statistically significant better prognosis for the RCB 0 (pCR) subgroup compared with RCB 1, 2 and 3 (log rank p=0.01). In a multivariate analysis, only the RCB classification showed a statistically significant correlation with DFS (RCB 1, HR 6.9, CI 1.9 to 25.4, p=0.004; RCB 2, HR 4.2, CI 1.6 to 10.8, p=0.03; and RCB 3, HR 7.6, CI 2.76 to 20.8, p=0.00). CONCLUSION: We demonstrated a positive and significant relationship between the RCB index and the risk of relapse and death.

Evaluation of circulating microRNA profiles in Brazilian women with polycystic ovary syndrome: A preliminary study.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrinopathy, which etiology encompasses complex genetic traits associated with epigenetic factors, including differences in microRNA (miRNA) expression in a variety of tissues. The circulating form of these molecules is raising attention in the syndrome not only as potential biomarkers of PCOS but also as possible therapeutic targets. The aim of this study was to explore the circulating miRNA profiles present in a cohort of Brazilian women with and without PCOS and to evaluate the potential role of miRNAs in the pathophysiology of the syndrome. METHODS: Cross-sectional study of 36 well-characterized PCOS women and 16 healthy controls. Clinical, hormone and metabolic data were recorded and evaluated. The expression profile of the 201 circulating miRNA selected were analyzed by taqman quantitative real time polymerase chain reactions (RT-PCR) using a customized Open Array platform. Statistical and bioinformatic analyzed were performed. RESULTS: Circulating miR-21-5p, miR-23a-3p and miR-26a-5p were upregulated, and miR-103a-3p, miR-376a-3p, miR-19b-3p and miR-222-3p were downregulated in women with PCOS compared to healthy normo-ovulatory controls. miR-21-5p, miR-103a-3p and miR-376a-3p levels correlated positively with androgen levels. These miRNAs, in combination, were related to pathways involved in insulin signaling, steroids biosynthesis and endothelial regulation as well as in folliculogenesis. CONCLUSION: In this study, we identified a specific circulating miRNA signature in Brazilian women with PCOS. According to our data, circulating miR-21-5p, miR-23a-3p, miR-26a-5p, miR-103a-3p, miR-376a-3p, miR-19b-3p and miR-222-3p may represent potential candidates for differential diagnosis of PCOS in the future.

Does temporomandibular disorder correlate with menopausal symptoms?

OBJECTIVE: To assess the correlation between menopausal symptoms and pain caused by temporomandibular disorder (TMD) and the impact of sociodemographic factors on the association. METHODS: In this cross-sectional study, a total of 74 women with TMD symptoms were enrolled and divided into three groups according to the Stages of Reproductive Aging Workshop + 10 (STRAW + 10) criteria: G1 (n = 25, late menopausal transition), G2 (n = 30, early postmenopause), and G3 (n = 19, late postmenopause). Sociodemographic data were collected, along with data on menopausal symptoms (Blatt-Kupperman menopausal index) and TMD-induced pain (craniomandibular index). Statistical analysis was performed using a chi-squared test and linear correlation tests (Spearman and Pearson). RESULTS: Analysis of the three groups showed that TMD-induced pain was more intense in G1 than in G3 (P = 0.0426, r  = 0.2364, r2 = 0.05589), and menopausal symptoms correlated with the intensity of TMD-induced pain (P = 0.0004, r  = 0.4020). This correlation was more significant during the late menopausal transition (G1: P  = 0.0267, r  = 0.4427, r2 = 0.1960). In G2, women with fewer than 4 years of schooling had a higher total Blatt- Kupperman menopausal index score (17.0 ±â€Š85.0) and craniomandibular index (0.29 ±â€Š0.23) than women with more than 4 years of schooling (P  = 0.02 for both indices). CONCLUSIONS: Our results suggest that TMD-induced pain and menopausal symptoms are correlated, and more strongly so in the late menopausal transition. Additionally, sociodemographic factors, such as schooling, have a major influence on symptoms in early postmenopause. Performing the TMD evaluation during the climacteric period may be important.

The oncological safety of autologous fat grafting: a systematic review and meta-analysis.

OBJECTIVE: To present a systematic review of the literature and a meta-analysis evaluating the oncological safety of autologous fat grafting (AFG). SUMMARY BACKGROUND DATA: AFG for breast reconstruction presents difficulties during follow-up radiological exams, and the oncological potential of grafted fat is uncertain. Previous studies confirmed that the fatty tissue could be transferred under a good condition suitable would not interfere with mammographic follow-up, although the issue of oncological safety remains. METHODS: We reviewed the literature published until 01/18/2021. The outcomes were overall survival (OS), disease-free survival (DFS), and local recurrence (LR). We included studies that evaluated women with breast cancer who undergone surgery followed by reconstruction with AFG. We synthesized data using the inverse variance method on the log-HR (log of the hazard ratio) scale for time-to-event outcomes using RevMan. We assessed heterogeneity using the Chi2 and I2 statistics. RESULTS: Fifteen studies evaluating 8541 participants were included. The hazard ratios (HR) could be extracted from four studies, and there was no difference in OS between the AFG group and control (HR 0.9, 95% CI 0.53 to 1.54, p = 0.71, I2 = 58%, moderate certainty evidence), and publication bias was not detected. The HR for DFS could be extracted from six studies, and there was no difference between the AFG group and control (HR 1.01, 95% CI 0.73 to 1.38, p = 0.96, I2 = 0%, moderate certainty evidence). The HR for LR could be extracted from ten studies, and there was no difference between the AFG group and control (HR 0.86, 95% CI 0.66 to 1.12, p = 0.43, I2 = 1%, moderate certainty evidence). CONCLUSION: According to the current evidence, AFG is a safe technique of breast reconstruction for patients that have undergone BC surgery and did not affect OS, DFS, or LR.

The Crosstalk between Melatonin and Sex Steroid Hormones.

Melatonin, an indolamine mainly released from the pineal gland, is associated with many biological functions, namely, the modulation of circadian and seasonal rhythms, sleep inducer, regulator of energy metabolism, antioxidant, and anticarcinogenic. Although several pieces of evidence also recognize the influence of melatonin in the reproductive physiology, the crosstalk between melatonin and sex hormones is not clear. Here, we review the effects of sex differences in the circulating levels of melatonin and update the current knowledge on the link between sex hormones and melatonin. Furthermore, we explore the effects of melatonin on gonadal steroidogenesis and hormonal control in females. The literature review shows that despite the strong evidence that sex differences impact on the circadian profiles of melatonin, reports are still considerably ambiguous, and these differences may arise from several factors, like the use of contraceptive pills, hormonal status, and sleep deprivation. Furthermore, there has been an inconclusive debate about the characteristics of the reciprocal relationship between melatonin and reproductive hormones. In this regard, there is evidence for the role of melatonin in gonadal steroidogenesis brought about by research that shows that melatonin affects multiple transduction pathways that modulate Sertoli cell physiology and consequently spermatogenesis, and also estrogen and progesterone production. From the outcome of our research, it is possible to conclude that understanding the correlation between melatonin and reproductive hormones is crucial for the correction of several complications occurring during pregnancy, like preeclampsia, and for the control of climacteric symptoms.

Uterus procurement from deceased donor for transplantation.

Women with absolute uterine factor infertility cannot get pregnant. The current experience in uterine transplantation is limited and the use of a deceased donor uterus in this area is incipient after some initial unsuccessful attempts. The birth of healthy babies through this modality in four different centers has given a new impetus to the use of this transplantation technique. We aimed to develop a technique for uterus procurement and preparation for transplantation from a brain dead donor. Fifteen uteri were retrieved from multi-organ donor patients, 10 of these were used in bench surgeries with the proposed technique. All procedures were performed after obtaining family's consent. This study allowed the clinical use of two of the 15 organs that were procured for transplantation. One of these organs resulted in the first live birth worldwide using a uterus transplanted from a deceased donor, a landmark in reproductive medicine. Another outcome was the optimization of the surgical technique involving less manipulation of the uterine vascular pedicles. The success of this novel technique suggests that the proposed model can be replicated and optimized further to facilitate the transplantation of uterus from deceased donors.

Pretreatment with melatonin improves ovarian tissue cryopreservation for transplantation.

BACKGROUD: Melatonin has anti-inflammatory and antioxidative actions at the mitochondrial level. This indole-containing molecule may protect ovarian grafts during the process of cryopreservation. Therefore, we aimed to determine whether melatonin pretreatment improves rat ovarian graft quality. METHODS: Twenty-six female rats were allocated to two study groups of thirteen animals each: 1) control group: ovaries cryopreserved using the standard protocol; and 2) melatonin group: ovaries cryopreserved in a medium with melatonin. Ten rats of each group were submitted to 24-h freezing, and whole ovaries autologous and avascular transplantation with retroperitoneal placement. After postoperative (PO) day 15, daily vaginal smears were obtained for estrous cycle characterization. Between PO days 30 and 35, the animals were euthanized and ovarian grafts were recovered for histological and immunohistochemical (Ki-67, cleaved caspase-3, TUNEL, von Willebrand factor, estrogen, and progesterone receptors) analyses. The ovaries of the three remaining rats from each group were studied immediately after thawing to assess the effects of cryopreservation. ANOVA and Tukey's tests were used and the rejection level of the null hypothesis was set at 0.05 or 5% (p < 0.05). RESULTS: Melatonin promoted faster restart of the estrous cycle and increased the expression of mature follicles, collagen type I, von Willebrand factor, Ki-67, and cleaved caspase-3 on corpora lutea and estrogen receptors in the ovaries as compared to control. There was a reduction in apoptosis by TUNEL on follicles, corpora lutea, and collagen type III. CONCLUSION: Based on the evaluated parameters, melatonin may promote the quality of ovarian grafts. Reproductive function enhancement should be further studied.

Is there a beneficial effect of gamma-linolenic acid supplementation on body fat in postmenopausal hypertensive women? A prospective randomized double-blind placebo-controlled trial.

OBJECTIVE: Systemic arterial hypertension and obesity are major public health problems that increase risks of serious cardiovascular diseases and kidney failure as well as increase mortality. Substances that can alleviate these problems are desirable. We evaluated the beneficial effects of nutritional supplementation with gamma-linolenic acid in postmenopausal hypertensive women. METHODS: This was a prospective, double-blind, placebo-controlled, randomized study involving 96 postmenopausal women. Participants were divided into two groups either receiving 1,000 mg of borage oil rich in gamma-linolenic acid + vitamin E (drug) or only vitamin E (placebo) capsules for 6 months. They were followed up monthly to assess the impact on systemic blood pressure and body composition. To verify group homogeneity, Fisher's exact and Student t tests were performed. To evaluate differences in various parameters between the two groups and at various times, repeated measures analysis of variance was performed, with Bonferroni correction. RESULTS: The power of the test was calculated based on the difference in the mean systolic blood pressure between baseline and after 6 months of treatment in the placebo group and in the drug group. A 92.9% test power was found with a 95% confidence interval. There was a significant reduction in the systolic and diastolic pressure as well as a significant change in waist-hip ratio (P < 0.01) in the drug group as compared with the placebo group. CONCLUSIONS: Supplementation with borage oil rich in gamma-linolenic acid had significant beneficial short-term effects without showing any adverse effect. There remains a need for further studies to evaluate long-term benefits.

Nutritional and dietary aspects in polycystic ovary syndrome: insights into the biology of nutritional interventions.

Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder, which affects 5-17% of reproductive age women and is often associated with obesity and metabolic impairment. Common treatment strategies are based on exercise, diet and nutrient supplementation since PCOS is often linked with obesity and metabolic impairment. Studies have recommended that nutrition is a key factor in the health maintenance of women with PCOS, however, little is known about the subject in the context of such a disease. This narrative review aims to identify dietary and nutritional aspects of PCOS and discuss the role of nutrients in management of polycystic ovary syndrome in view of clinical trials.

Prevalence of metabolic disturbances among women with polycystic ovary syndrome in different regions of Brazil.

OBJECTIVE: To describe the prevalence of metabolic disturbances in a large cohort of women with polycystic ovary syndrome (PCOS) in southeastern Brazil and to compare the findings with other cohorts of Brazilian women with PCOS. METHODS: A retrospective study analyzing clinical and laboratory data of 462 women with PCOS treated at an outpatient clinic in a tertiary hospital in southeastern Brazil. Prevalence of insulin resistance, glucose intolerance, type 2 diabetes, dyslipidemia, central obesity, hypertension, and metabolic syndrome was compared to that of other cohorts of age and body mass index-matched Brazilian women with PCOS. RESULTS: Women with PCOS had a median age of 25.0 (21.0-29.0) years and BMI of 28.7 (23.9-34.0) kg/m2 . Prevalence of insulin resistance, glucose intolerance, and type 2 diabetes varied from 39.6% to 55.0%, 7.2% to 28.1%, and 2.0% to 4.1%, respectively. Prevalence of central obesity, dyslipidemia due to decreased high-density lipoprotein cholesterol, hypertriglyceridemia, and metabolic syndrome ranged from 57.8% to 66.4%, 54.1% to 70.4%, 22.9% to 35.1%, and 27.4% to 38.3%, respectively, which did not differ among regions in Brazil. CONCLUSION: Prevalence of metabolic disturbances was high among Brazilian women with PCOS. This study suggests that, from a public health perspective, authorities in Brazil should be aware of and encourage screening for metabolic dysfunction in women with PCOS in all regions of the country.