Ultra-low-dose continuous combined estradiol and dydrogesterone in postmenopausal women: A pooled safety and tolerability analysis.

Objective: To assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone (E0.5 mg/D2.5 mg) among postmenopausal women. Methods: This pooled analysis of data from three clinical studies assessed the effects of continuous combined ultra-low-dose estradiol and dydrogesterone among postmenopausal women. Participants received E0.5 mg/D2.5 mg or placebo for 13 weeks (double-blind, randomized, European study), E0.5 mg/D2.5 mg or placebo for 12 weeks (double-blind, randomized, Chinese study), or E0.5 mg/D2.5 mg for 52 weeks (open-label, European study). Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), treatment discontinuation due to a TEAE, and adverse events of special interest (AESIs). Results: Overall, 1027 women were included in the pooled analysis (E0.5 mg/D2.5 mg, n = 736; placebo, n = 291). Mean treatment exposure was 288.9 days in the E0.5 mg/D2.5 mg group and 86.6 days in the placebo group. The proportion of women experiencing ≥1 TEAE was similar in the E0.5 mg/D2.5 mg and placebo groups (50.1% vs 49.5%, respectively). TESAEs occurred in 12 (1.6%) women receiving E0.5 mg/D2.5 mg and 9 (3.1%) women receiving placebo. Discontinuation of study treatment was infrequent in both groups (E0.5 mg/D2.5 mg: 1.5%; placebo: 2.4%). The occurrence of breast pain was more common in the E0.5 mg/D2.5 mg group than in the placebo group (2.0% vs 0.3%) as was uterine hemorrhage (6.5% vs 2.4%). The incidence of acne, hypertrichoses and weight increased was similar between groups. Conclusions: Across three studies, ultra-low-dose estradiol plus dydrogesterone was well tolerated among postmenopausal women, with no increase in TEAEs or TESAEs compared with placebo.

Evaluating the cost utility of estradiol plus dydrogesterone for the treatment of menopausal women in China.

AIM: Evaluate the cost utility of menopausal hormone therapy for women in China. MATERIALS AND METHODS: A bespoke Markov cost utility model was developed to evaluate a cohort of symptomatic perimenopausal women (>45 years) with intact uterus in China in accordance with China's Pharmacoeconomic guideline. Short (5-year) and long (10-year) treatment durations were evaluated over a lifetime model time horizon with 12-month cycle duration. Societal and healthcare payer perspectives were evaluated in the context of a primary care provider/prescriber, outpatient setting with inpatient care for patients with chronic conditions. Disease risk and mortality parameters were derived from focused literature searches, and China Diagnosis-related Group cost data was included. Comprehensive scenario, univariate and probabilistic sensitivity analysis were undertaken along with independent validation. This is the first model to include MHT-related disease risks. RESULTS: According to base case results, the total cost for MHT was 22,516$ (150,106¥) and total quality adjusted life years 12.32 versus total cost of no MHT 30,824$ (205,495¥) and total quality adjusted life years 11.16 resulting in a dominant incremental cost effectiveness ratio of -7,184$ (-47,898¥) per QALY. Results hold true over a range of univariate deterministic sensitivity and scenario analyses. Probabilistic analysis showed a 91% probability of being cost effective at a willingness to pay threshold of three times Gross Domestic Product per capita in China. CONCLUSION: Contingent on the structure and assumptions of the model, combination of estradiol plus dydrogesterone MHT is potentially cost saving in symptomatic women over the age of 45 years in China.

Menopausal hormone therapy is publicly funded in many countries to alleviate symptoms of menopause; however, uptake has been comparatively slow in China. This has implications for the estimated 168 million menopausal-aged women. This analysis is the first to evaluate the cost effectiveness of menopausal hormone therapy in China using best practice principles and incorporating longer term disease risks. Menopausal hormone therapy is potentially cost saving in the context of China.

Real-World Molecular Testing and Treatment Patterns in Brazilian Patients with Newly Diagnosed Locally Advanced or Metastatic NSCLC.

OBJECTIVES: To evaluate the molecular testing and treatment patterns in a retrospective cohort of newly diagnosed treatment-naïve patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This is an observational retrospective cohort study conducted across 10 cancer centers in Brazil. Treatment-naïve patients with locally advanced or metastatic NSCLC were enrolled from January to December 2014. The following data were collected from the medical records of patients from diagnosis until the last record (death, loss to follow-up, or the end of the maximum follow-up period): demographics; medical history; smoking status; disease characteristics; previous treatments; and molecular testing patterns and results. The overall survival (OS) was also estimated. RESULTS: A total of 391 patients from 8 different Brazilian states were included, with a median age of 64.1 years (23.7-98.7), with most patients being males (60.1%). The smoking status of 74.2% of patients was a 'former' or 'current smoker'. Stage IV NSCLC at diagnosis was observed in 82.4% of patients, with 269 of them (68.8%) presenting adenocarcinoma (ADC). Among the stage IV ADC patients, 54.0% were referred for molecular testing. Among the patients with an available epidermal growth factor receptor (EGFR) mutation status, 31 (24.0%) were EGFR-positive. The first-line treatment was a platinum-based chemotherapy for 98 patients (25.1%), while non-platinum-based regimens were used in 54 patients (13.8%). OS data were available for 370 patients, with a median OS of 10.8 months. Never smokers had a significantly higher median OS versus current or former smokers (14.6 versus 9.1 months; log-rank p=0.003). Among the patients for whom molecular testing data were available, those with EGFR-positive results had a longer median OS (34.6 versus 12.8 months; log-rank p=0.003). CONCLUSION: Our findings provide relevant information for prescribers and policy decision-makers by highlighting the unmet needs of patients and the importance of molecular testing in newly diagnosed locally advanced or metastatic lung adenocarcinoma. We also highlight the respective EGFR-tyrosine kinase inhibitor treatment when the result is positive and the areas in which further efforts are required to grant access to effective treatment.

Cost-effectiveness analysis comparing companion diagnostic tests for EGFR, ALK, and ROS1 versus next-generation sequencing (NGS) in advanced adenocarcinoma lung cancer patients.

BACKGROUND: The treatment of choice for advanced non-small cell lung cancer is selected according to the presence of specific alterations. Patients should undergo molecular testing for relevant modifications and the mutational status of EGFR and translocation of ALK and ROS1 are commonly tested to offer the best intervention. In addition, the tests costs should also be taken in consideration. Therefore, this work was performed in order to evaluate the cost-effectiveness of a unique exam using NGS (next generation sequencing) versus other routinely used tests which involve RT-PCR and FISH. METHODS: The target population was NSCLC, adenocarcinoma, and candidates to first-line therapy. Two strategies were undertaken, strategy 1 corresponded to sequential tests with EGFR RT-PCR, then FISH for ALK and ROS1. Strategy 2 differed from 1 in that ALK and ROS1 translocation testing were performed simultaneously by FISH. Strategy 3 considered single test next-generation sequencing, a platform that includes EGFR, ALK and ROS1 genes. A decision tree analysis was used to model genetic testing options. From the test results, a microsimulation model was nested to estimate survival outcomes and costs of therapeutic options. RESULTS: The use of NGS added 24% extra true cases as well as extra costs attributed to the molecular testing. The ICER comparing NGS with sequential tests was US$ 3479.11/correct case detected. The NGS improved a slight gain in life years and QALYs. CONCLUSION: Our results indicated that, although precise, the molecular diagnosis by NGS of patients with advanced stage NSCLC adenocarcinoma histology was not cost-effective in terms of quality-adjusted life years from the perspective of the Brazilian supplementary health system.

Real-world molecular testing and treatment patterns in brazilian patients with newly diagnosed locally advanced or metastatic NSCLC

OBJECTIVES: To evaluate the molecular testing and treatment patterns in a retrospective cohort of newly diagnosed treatment-naïve patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This is an observational retrospective cohort study conducted across 10 cancer centers in Brazil. Treatment-naïve patients with locally advanced or metastatic NSCLC were enrolled from January to December 2014. The following data were collected from the medical records of patients from diagnosis until the last record (death, loss to follow-up, or the end of the maximum follow-up period): demographics; medical history; smoking status; disease characteristics; previous treatments; and molecular testing patterns and results. The overall survival (OS) was also estimated. Results: A total of 391 patients from 8 different Brazilian states were included, with a median age of 64.1 years (23.7-98.7), with most patients being males (60.1%). The smoking status of 74.2% of patients was a 'former' or 'current smoker'. Stage IV NSCLC at diagnosis was observed in 82.4% of patients, with 269 of them (68.8%) presenting adenocarcinoma (ADC). Among the stage IV ADC patients, 54.0% were referred for molecular testing. Among the patients with an available epidermal growth factor receptor (EGFR) mutation status, 31 (24.0%) were EGFR-positive. The first-line treatment was a platinum-based chemotherapy for 98 patients (25.1%), while non-platinum-based regimens were used in 54 patients (13.8%). OS data were available for 370 patients, with a median OS of 10.8 months. Never smokers had a significantly higher median OS versus current or former smokers (14.6 versus 9.1 months; log-rank p=0.003). Among the patients for whom molecular testing data were available, those with EGFR-positive results had a longer median OS (34.6 versus 12.8 months; log-rank p=0.003). Conclusion: Our findings provide relevant information for prescribers and policy decision-makers by highlighting the unmet needs of patients and the importance of molecular testing in newly diagnosed locally advanced or metastatic lung adenocarcinoma. We also highlight the respective EGFR-tyrosine kinase inhibitor treatment when the result is positive and the areas in which further efforts are required to grant access to effective treatment.

Cost effectiveness analysis of plasma genotyping versus tumor genotyping in detection of advanced non-small-cell lung cancer with epidermal growth factor receptor and T790M mutation under the Brazilian private healthcare system perspective / Custo-efetividade do uso da biópsia líquida versus biópsia tecidual para detecção de câncer de pulmão de não pequenas células avançado com receptor do fator de crescimento epidérmico e mutação T790M sob a perspectiva do sistema suplementar de saúde do Brasil

Objective: Comparing the costs and effectiveness of plasma genotyping versus tumor genotyping for detecting the T790M mutation in advanced non-small cell lung cancer (NSCLC) with a mutation in the epidermal growth factor receptor (EGFR) and that progressed after use of an EGFR tyrosine kinase inhibitor (EGFR-TKI), from the perspective of the private healthcare system in Brazil. Methods: Patients with a post-EGFR-TKI T790M mutation are eligible for a second-line treatment with a third-generation EGFR-TKI (osimertinib). In order to estimate the costs associated with the diagnosis method for the T790M mutation, a decision tree model has been used. Resource use was estimated by a team of experts, and the direct costs were estimated based on official databases. Results: Plasma genotyping provided a R$391 reduction per patient, due to the reduced cost with complications; it prevented 40.96% of the patients from undergoing an invasive procedure and 31.91% of the patients from having any kind of complication. Conclusion: Data found support a new paradigm for treating the resistance to EGFR-TKIs, with plasma genotyping as the first diagnostic choice, what can help to define the treatment and to reduce the costs of Brazilian private healthcare system.

Objetivo: Comparar os custos e efetividade da biópsia líquida versus biópsia tecidual para detecção da mutação T790M no câncer de pulmão de não pequenas células (CPNPC) avançado com mutação no receptor do fator de crescimento epidérmico (EGFR) e que progrediram após o uso de um inibidor do sítio da tirosina cinase associada ao EGFR (EGFR-TKI), sob a perspectiva do sistema suplementar de saúde do Brasil. Métodos: Pacientes com mutação EGFR-T790M pós-EGFR-TKI são elegíveis ao tratamento de segunda linha com um EGFR-TKI de terceira geração (osimertinibe). Para a estimativa dos custos relacionados ao método de diagnóstico de mutação T790M, foi elaborado um modelo de árvore de decisão. A utilização de recursos foi estimada por painel de especialistas e os custos diretos foram estimados utilizando-se bases de dados oficiais. Resultados: A biópsia líquida proporcionou redução de R$ 391 por paciente, devido a uma redução no custo com complicações; evitou que 40,96% dos pacientes passassem por um procedimento invasivo e que 31,95% dos pacientes tivessem algum tipo de complicação. Conclusão: Os dados observados embasam um novo paradigma para o manejo da resistência aos EGFR-TKIs, com genotipagem pelo plasma como primeira opção diagnóstica, o que pode auxiliar na melhor definição do tratamento e reduzir custos ao sistema de saúde suplementar brasileiro.

Gefitinibe na Primeira Linha de Tratamento para o Câncer de Pulmão de não Pequenas Células / Gefitinib as Non-Small Cell Lung Cancer First Line Treatment

Introdução: os inibidores de tirosina quinase (TKIs - tyrosine kinase inhibitor) são o tratamento de primeira linha no câncer de pulmão de não pequenas células (CPNPC) localmente avançado ou metastático com mutação do EGFR (receptor do fator de crescimento epidérmico - epidermal growth factor receptor). Esta revisão compara o tratamento do CPNPC com o gefitinibe, um TKI de primeira geração, versus o tratamento quimioterápico. Método: foi realizada revisão de literatura com palavras-chave relevantes e análise descritiva dos resultados. Resultados: os pacientes com CPNPC e mutação do EGFR apresentaram melhora da sobrevida livre de progressão (SLP), taxa de resposta objetiva (TRO) e taxa de controle da doença (TCR) em relação à quimioterapia citotóxica. A taxa de eventos adversos graves, eventos adversos que levaram à descontinuação do tratamento e os que levaram à redução de dose foram menores com o gefitinibe. O gefitinibe também foi relacionado à melhora da qualidade devida. Conclusão: o uso do gefitinibe em primeira linha no tratamento do CPNPC com mutação EGFR demonstrou superioridade de eficácia, segurança e qualidade de vida, quando comparado ao tratamento quimioterápico.

Introduction: tyrosine kinase inhibitors (TKIs) are the first line treatment for EGFR (epidermal growth factor receptor) mutated non-small cells lung cancer (NSCLC) locally advanced or metastatic. The aim of this review is to compare the treatment of NSCLC with the first-generation EGFR-TKI gefitinib versus chemotherapy . Methods: a review of the literature was performed using relevant keywords and descriptive analysis of the results. Results: patients with NSCLC and EGFR mutation showed improved progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) compared cytotoxic chemotherapy. The rate of serious adverse events, adverse events leading to discontinuation of treatment and that led to dose reduction were lower with gefitinib. Quality of life improvement was also related to the treatment with gefitinib. Conclusion: the use of gefitinib as first-line treatment of EGFR mutated NSCLC showed improved efficacy, safety and quality of life when compared to chemotherapy.

Resultados maternos e perinatais em pacientes com disfunção sistólica grave / Maternal and perinatal outcome in patients with severe systolic dysfunction

OBJETIVO: O objetivo deste trabalho é avaliar os resultados maternos e perinatais em gestantes com disfunção sistólica grave de ventrículo esquerdo acompanhadas em hospital terciário durante a gestação, parto e puerpério imediato. MÉTODOS: Doze pacientes com disfunção ventricular grave, definida por fração de ejeção <40 por cento em ecocardiograma realizado durante a gestação, foram avaliadas retrospectivamente. Os dados incluíram ocorrência de complicações clínicas e obstétricas, características do parto e resultados neonatais. As complicações clínicas consideradas foram aparecimento ou piora da dispnéia, arritmia, acidente vascular cerebral, tromboembolismo pulmonar, edema agudo de pulmão, parada cardíaca e morte. RESULTADOS: A média da fração de ejeção das pacientes foi 28,9+-6,47 por cento (mediana: 30 por cento). Quatro pacientes iniciaram o pré-natal em classe funcional III e oito com classe I ou II. Dez pacientes apresentaram piora da dispnéia durante a gravidez. A complicação clínica mais comum foi edema agudo de pulmão (Três pacientes). Três das quatro pacientes que iniciaram o pré-natal em classe funcional III apresentaram boa evolução da gravidez; a outra apresentou parto prematuro devido à piora dos sintomas. Houve dois partos vaginais e 10 cesáreas. Dez dos 13 recém-nascidos foram pequenos para idade gestacional. Uma paciente, que já tinha indicação de transplante cardíaco antes da gestação, apresentou descompensação clínica durante a gravidez e evoluiu para edema agudo de pulmão e choque cardiogênico, realizando o transplante dois meses após o parto. Não houve morte materna ou neonatal. CONCLUSÕES: Embora o número de gestações avaliadas tenha sido pequeno, deve-se rever a indicação de abortamento terapêutico em gestantes com disfunção ventricular esquerda grave, uma vez que todas as gestações evoluíram até a viabilidade. Os recém-nascidos destas mães apresentaram grande incidência de restrição do crescimento intra-uterino...

OBJECTIVE: The objective of this study was to evaluate maternal and fetal outcome in patients with severe left ventricle systolic dysfunction followed in a terciary-care hospital. METHODS: We retrospectively evaluated 12 pregnant women with severe systolic dysfunction, defined as a ejection fraction <40 percent. Follow-up data included functional class evaluation, ocurrency of cardiac and obstetric events, labor data and neonatal outcome. Cardiac events were defined as new onset of arrhythmias, stroke, pulmonary thrombosis, pulmonary edema, cardiac arrest, and death. RESULTS: The mean ejection fraction was 28,9±6,47 percent. Four patients were in the NYHA class III, and 8 in class I or II on presentation. Ten patients had deteriorated during pregnancy. The most common cardiac event was pulmonary edema (3 patients). Three of the four patients with class III on presentation had a good evolution during pregnancy, and the other one had preterm delivery due to worsening symptons. There were 2 vaginal espontaneous deliveries and 10 cesarean sections. Small-for-gestational-age birthweigth ocurred in 10 pregnancies. There was no maternal or neonatal death. CONCLUSIONS: Pregnancy in patients with severe left ventricle systolic dysfunction increases the risk of maternal complications and compromises fetal growth. It is important to follow this women in a tertiary-care hospital.

[Maternal and perinatal outcome in patients with severe systolic dysfunction]. / Resultados maternos e perinatais em pacientes com disfunção sistólica grave.

OBJECTIVE: The objective of this study was to evaluate maternal and fetal outcome in patients with severe left ventricle systolic dysfunction followed in a tertiary-care hospital. METHODS: We retrospectively evaluated 12 pregnant women with severe systolic dysfunction, defined as a ejection fraction<40%. Follow-up data included functional class evaluation, occurrence of cardiac and obstetric events, labor data and neonatal outcome. Cardiac events were defined as new onset of arrhythmias, stroke, pulmonary thrombosis, pulmonary edema, cardiac arrest, and death. RESULTS: The mean ejection fraction was 28.9+/-6.47%. Four patients were in the NYHA class III, and 8 in class I or II on presentation. Ten patients had deteriorated during pregnancy. The most common cardiac event was pulmonary edema (3 patients). Three of the four patients with class III on presentation had a good evolution during pregnancy, and the other one had preterm delivery due to worsening symptoms. There were 2 vaginal spontaneous deliveries and 10 cesarean sections. Small-for-gestational-age birthweight occurred in 10 pregnancies. There was no maternal or neonatal death. CONCLUSIONS: Pregnancy in patients with severe left ventricle systolic dysfunction increases the risk of maternal complications and compromises fetal growth. It is important to follow this women in a tertiary-care hospital.

Acao da prometazina sobre a massa ossea de mulheres menopausadas / The effect of promethazine on bone mineral density in postmenopausal women

Foram estudadas 57 mulheres na pos-menopausa, cujas idades variaram entre 35 e 70 anos de idade, com media etaria de 57,52 e idade menopausal de 1 a 37 anos com media de 10,72 mais ou menos 7,42, cujas densitometrias osseas apresentassem indice t com niveis...