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.

One-year follow up on post-placental IUD insertion: A randomized clinical trial.

INTRODUCTION: Our objectives were to compare the 1-year follow-up clinical performance of the TCu380A intrauterine device (TCu380A-IUD) and levonorgestrel (LNG) 52-mg intrauterine system (IUS) inserted at post-placental period. MATERIAL AND METHODS: We conducted an open-label, parallel-group, randomized clinical trial, 1:1 with pregnant women admitted for childbirth independently of the mode of birth. Our primary outcome was expulsion up to 1 year after device placement by type of IUD and mode of delivery. During the follow up (42, 90 and 365 days (±7 days) after device placement), an ultrasound was performed to evaluate the device position. Kaplan-Meier with log-rank test was used to compare the survival curves of the TCu380A IUD and the LNG IUS. Couple-Years of Protection after insertion of both devices was calculated. RESULTS: One hundred and forty women were randomized to the TCu380A IUD (n = 70) or the LNG IUS (n = 70). By the end of the first year after device placement, 38 women experienced device expulsion (27.1%), most of them (33/38; 86.8%) within the first 42 days after delivery. The expulsions were significantly higher among users of TCu380A IUD (39.4%) than among users of the LNG IUS (22.2%; P = .039), and among those with vaginal delivery (43.8%) than among women with cesarean delivery (15%; P = .003). The 1-year cumulative continuation rate was 64.2%, significantly higher for LNG IUS (73.1%) than for TCu380A IUD (54.4%; P = .03), and among women with cesarean delivery (77.6%) than for vaginal delivery (52%; P = .00). The post-placental IUD insertion provided 356.4 Couple-Years of Protection. CONCLUSIONS: Two-thirds of women who accepted a post-placental IUD placement still used the device 1 year after childbirth. However, expulsion was the most prevalent reason for discontinuation, mainly within 42 days after device placement. The expulsion rate was significantly higher among TCu380A IUD users and among women with vaginal delivery.

[Testing the Psychometric Properties of the Helping Alliance Questionnaire (HAQ) in Different Health Care Settings]. / Psychometrische Überprüfung des Helping Alliance Questionnaire (HAQ) in unterschiedlichen Versorgungssettings.

Introduction The Helping Alliance Questionnaire developed by Luborsky was psychometricly examined for the first time and translated into German by Bassler et al. in the mid-1990s. It consists of 11 Items, which are summarized to the scales "relation to the therapist" and "satisfaction with therapeutic outcome". HAQ is now one of the most used instruments to measure therapeutic alliance. The goal of this study was to test the psychometric properties based on three large patient samples in different treatment settings. Material and methods Analyses were conducted based on 2 samples of patients in inpatient psychosomatic/psychotherapeutic rehabilitation (n=655, n=2494) and one sample in outpatient psychotherapy (n=1477). Exploratory factor analyses and for verification confirmatory factor analyses were applied. Furthermore reliability and validity analysis were conducted. Results The 2-factorial structure found in literature was replicated with an increasing stability at the end of treatment. Item 2 and 3 had inconsistent factor loadings at different points of measurement and study. Reliability and validity indices were satisfying to good. The fit of the model, on the other hand, was less satisfying and suggests a solution without Item 2 and 3. For reasons of content as well as for reasons of dissemination, it is pleaded for the maintenance of the existing item assignments in the HAQ for the present.

Differences in breast cancer survival and stage by age in off-target screening groups: a population-based retrospective study.

BACKGROUND: Age is an important prognostic factor in breast cancer. The target age to screen is under debate. OBJECTIVE: This study aimed to assess the influence of age on the diagnosis and survival among women with breast cancer. STUDY DESIGN: This was a retrospective cohort study of the Population-Based Cancer Registry of Campinas, Brazil, and included all women diagnosed from 2010 to 2014. The outcomes assessed were overall survival and stage. For statistical analyses, the Kaplan-Meier method, log-rank tests, and chi-square tests were used. RESULTS: The sample comprised 1741 women aged 40 to 79 years. Diagnoses at stages 0 to II were the more frequent. In the 40 to 49 years and 50 to 59 years age groups, the frequency of stage 0 (in situ) was 20.5% and 14.9% (P=.022), respectively, and the frequency of stage I was 20.2% and 25.8% (P=.042), respectively. The mean overall survival was 8.9 years (8.6-9.2) in the 40 to 49 years age group and 7.7 years (7.3-8.1) in the 70 to 79 years age group. The 5-year overall survival was higher in the 40 to 49 years age group than in the 50 to 59 years age group for stage 0 (in situ) (100.0% vs 95.0%; P=.036) and stage III (77.4% vs 66.2%; P=.046) diagnoses. The 5-year overall survival was higher in 60 to 69 years age group than in the 70 to 79 years age group for stages I (94.6% vs 86.5%; P=.002) and III (83.5% vs 64.9%; P=.010). In all age groups, significant differences in survival were not observed for stage 0 (in situ) vs stage I diagnoses, stage 0 vs stage II diagnoses, and stage I vs stage II diagnoses. CONCLUSION: Women aged 40 to 49 years had the highest proportion of in situ tumors, and stages III and IV accounted for about one-third of the cases in all age groups. There was no difference in the overall survival for stage 0 (in situ) vs stage I or II diagnoses in all age groups.

An insulin hypersecretion phenotype precedes pancreatic ß cell failure in MODY3 patient-specific cells.

MODY3 is a monogenic hereditary form of diabetes caused by mutations in the transcription factor HNF1A. The patients progressively develop hyperglycemia due to perturbed insulin secretion, but the pathogenesis is unknown. Using patient-specific hiPSCs, we recapitulate the insulin secretion sensitivity to the membrane depolarizing agent sulfonylurea commonly observed in MODY3 patients. Unexpectedly, MODY3 patient-specific HNF1A+/R272C ß cells hypersecrete insulin both in vitro and in vivo after transplantation into mice. Consistently, we identified a trend of increased birth weight in human HNF1A mutation carriers compared with healthy siblings. Reduced expression of potassium channels, specifically the KATP channel, in MODY3 ß cells, increased calcium signaling, and rescue of the insulin hypersecretion phenotype by pharmacological targeting ATP-sensitive potassium channels or low-voltage-activated calcium channels suggest that more efficient membrane depolarization underlies the hypersecretion of insulin in MODY3 ß cells. Our findings identify a pathogenic mechanism leading to ß cell failure in MODY3.

BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3.

Constitutively activating internal tandem duplications (ITD) of FLT3 (FMS-like tyrosine kinase 3) are the most common mutations in acute myeloid leukemia (AML) and correlate with poor prognosis. Receptor tyrosine kinase inhibitors targeting FLT3 have developed as attractive treatment options. Because relapses occur after initial responses, identification of FLT3-ITD-mediated signaling events are important to facilitate novel therapeutic interventions. Here, we have determined the growth-inhibitory and proapoptotic mechanisms of 2 small molecule inhibitors of FLT3, AG1295 or PKC412, in hematopoietic progenitor cells, human leukemic cell lines, and primary AML cells expressing FLT3-ITD. Inactivation of the PI3-kinase pathway, but not of Ras-mitogen-activated protein (MAP) kinase signaling, was essential to elicit cytotoxic responses. Both compounds induced up-regulation of proapoptotic BH3-only proteins Bim and Puma, and subsequent cell death. However, only silencing of Bim, or its direct transcriptional activator FOXO3a, abrogated apoptosis efficiently. Similar findings were made in bone marrow cells from gene-targeted mice lacking Bim and/or Puma infected with FLT3-ITD and treated with inhibitor, where loss of Puma only provided transient protection from apoptosis, but loss of Bim preserved clonal survival upon FLT3-ITD inhibition.

Postplacental Placement of Intrauterine Devices: Acceptability, Reasons for Refusal and Proposals to Increase its Use.

OBJECTIVE: To evaluate the acceptability of postplacental placement of intrauterine devices (PPIUD), reasons for refusal and suggested policies to increase its use. METHODS: Cross-sectional study conducted at the Women Hospital of the Universidade de Campinas, Campinas, SP, Brazil. Postplacental placement of intrauterine devices was offered to women admitted in labor who did not present infections, uterine malformation, twin pregnancy, preterm birth, and were at least 18 years old. In case of refusal, the parturient was asked to give their reasons and the answers were classified as misinformation about contraception or other reasons. The following were considered misinformation: fear of pain, bleeding, contraception failure and future infertility. Bivariate analysis was performed. RESULTS: Amongst 241 invited women, the refusal rate was of 41.9%. Misinformation corresponded to 50.5% of all refusals, and the reasons were: fear of pain (39.9%); fear of contraception failure (4.9%); fear of bleeding (3.9%); fear of future infertility (1.9%); other reasons for refusal were 49.5%. Parturients aged between 18 and 27 years old refused the PPIUD more frequently due to misinformation (67.4%), and older parturients (between 28 and 43 years old) refused frequently due to other reasons (63.6%) (p = 0.002). The mean age of those who declined the PPIUD due to misinformation was 27.3 ± 6.4 years old, while those who declined for other reasons had a mean age of 29.9 ± 5.9 years old (p = 0.017). CONCLUSION: The refusal of the PPIUD was high, especially amongst young women and due to misinformation. It is necessary to develop educative measures during antenatal care to counsel women about contraception, reproductive health and consequences of unintended pregnancy.

OBJETIVO: Avaliar a taxa de aceitação do dispositivo intrauterino pós-placentário (DIUPP); os motivos de recusa e propor medidas que aumentem sua aceitação. MéTODOS: Estudo de corte transversal realizado no Hospital da Mulher da Universidade Estadual de Campinas, Campinas, SP, Brasil. O DIUPP foi oferecido a mulheres admitidas em trabalho de parto que não apresentavam: infecções, malformação uterina, gravidez gemelar, parto prematuro e com idade mínima de 18 anos. Em caso de recusa, perguntou-se o motivo, e as respostas foram agrupadas em informações equivocadas sobre contracepção ou outros motivos. Considerou-se informação equivocada: medo de dor, sangramentos, falha da contracepção e prejuízo da fertilidade. Análises bivariadas foram realizadas. RESULTADOS: Entre 241 mulheres, a taxa de recusa foi de 41,9%. A desinformação correspondeu a 50,5% de todos os motivos de recusa, que foram: medo da dor (39,9%); medo da falha da contracepção (4,9%); medo de sangramento (3,9%), medo de o dispositivo intrauterino (DIU) prejudicar a fertilidade (1,9%). Outros motivos de recusa atingem 49,5%. Parturientes com idade entre 18 e 27 anos recusaram o PPIUD com mais frequência devido a desinformação (67,4%), e as mais velhas (com idade entre 28 e 43 anos) recusaram com frequência devido a outros motivos (63,6%) (p = 0,002). Houve diferença entre a idade média de quem recusou o PPIUD por desinformação (27,3 ± 6,4 anos) em comparação com outras razões (29,9 ± 5,9 anos), (p = 0,017). Além disso, ambos os grupos apresentaram altas taxas de recusa por desinformação, de 67,4 e 36,4%, respectivamente. CONCLUSãO: A recusa do DIUPP foi alta, principalmente entre as mulheres jovens e por desinformação. Diante disso, é necessário o desenvolvimento de medidas educativas durante o pré-natal e aconselhar as mulheres sobre contracepção, saúde reprodutiva e gravidez indesejada.

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.

Plasmodium falciparum expressing domain cassette 5 type PfEMP1 (DC5-PfEMP1) bind PECAM1.

Members of the Plasmodium falciparum Erythrocyte Membrane protein 1 (PfEMP1) family expressed on the surface of malaria-infected erythrocytes mediate binding of the parasite to different receptors on the vascular lining. This process drives pathologies, and severe childhood malaria has been associated with the expression of particular subsets of PfEMP1 molecules. PfEMP1 are grouped into subtypes based on upstream sequences and the presence of semi-conserved PfEMP1 domain compositions named domain cassettes (DCs). Earlier studies have indicated that DC5-containing PfEMP1 (DC5-PfEMP1) are more likely to be expressed in children with severe malaria disease than in children with uncomplicated malaria, but these PfEMP1 subtypes only dominate in a relatively small proportion of the children with severe disease. In this study, we have characterised the genomic sequence characteristic for DC5, and show that two genetically different parasite lines expressing DC5-PfEMP1 bind PECAM1, and that anti-DC5-specific antibodies inhibit binding of DC5-PfEMP1-expressing parasites to transformed human bone marrow endothelial cells (TrHBMEC). We also show that antibodies against each of the four domains characteristic for DC5 react with native PfEMP1 expressed on the surface of infected erythrocytes, and that some of these antibodies are cross-reactive between the two DC5-containing PfEMP1 molecules tested. Finally, we confirm that anti-DC5 antibodies are acquired early in life by individuals living in malaria endemic areas, that individuals having high levels of these antibodies are less likely to develop febrile malaria episodes and that the antibody levels correlate positively with hemoglobin levels.

Exame da vulva em mulheres climatéricas / Vulvar examination in climateric women

A vulva de 52 mulheres climatéricas foi avaliada através de anamnese, exame físico especial, vulvoscopia e teste de Collins no Ambulatório de Menopausa do Centro de Assistência Integral a Saúde da Mulher, Faculdade de Ciências Médicas da Universidade de Campinas, no período de julho a outubro 1990. A biópsia foi indicada quando constatada alteraçäo macroscópica, vulvoscópica e/ou teste de Collins positivo. Apenas uma paciente apresentou queixa vulvar espontânea, ao passo que 25 apresentaram queixas vulvares ao interrogatório dirigido. No exame físico especial, 11 pacientes apresentaram lesöes vulvares macroscópicas. É vulvoscopia constataram-se alteraçöes em 17 pacientes, sendo o epitélio branco a alteraçäo mais freqnente. Houve 14 casos com teste de Collins positivo. Dezoito pacientes foram submetidos a biópsia e o exame histológico foi sugestivo de infecçäo por papilomavfrus humano em oito casos. Os autores salientaram a importância do exame vulvar na assistência as mulheres climáticas e destacam a freqüência de alteraçöes sugestivas de infecçäo pelo papilomavírus humano.