ABSTRACT
Up-regulation of the Hedgehog (Hh) pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer (TNBC). Sonidegib is a potent and selective oral inhibitor of Smo, a key component of the Hh signaling pathway. We designed a phase I clinical study to explore the combination of sonidegib plus docetaxel (fixed dose at 75 mg/m2) in advanced TNBC patients. The primary objective was to ascertain the combination's maximum tolerated dose and the recommended phase II dose (RP2D), based on dose limiting toxicities (DLTs) in the first 2 cycles. A standard "3 + 3" design was followed including three dose levels (DL) of sonidegib: 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3). Twelve patients were included. Sonidegib 800 mg orally q.d. plus docetaxel 75 mg/m2 given intravenously on day 1 of 21-day cycles was established as the RP2D. No DLTs were observed at any DL. The median number of administered cycles at DL3 was 8 (range: 6 to 9). Grade 3 adverse events (AEs) at DL3 were neutropenia (66.7%), CPK increase (33.3%), leukopenia (33.3%), and paresthesia (33.3%), grade 4 AEs were not reported at this DL. At the RP2D, the combination showed antitumor activity in three out of 10 patients with measurable disease. Median time to progression for the overall study was 42.5 days (95% Confidence Interval: 29-155), and 188 days at DL3. No drug-to-drug interactions between sonidegib and docetaxel were found in the PK assessment. Trial Registration: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. TRIAL REGISTRATION: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. ClinicalTrials.gov: NCT02027376.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Ductal, Breast/drug therapy , Smoothened Receptor/antagonists & inhibitors , Triple Negative Breast Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Biphenyl Compounds/administration & dosage , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , Docetaxel/administration & dosage , Female , Humans , Maximum Tolerated Dose , Middle Aged , Prognosis , Pyridines/administration & dosage , Tissue Distribution , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathologyABSTRACT
Abstract Introduction: The number of mothers with mental disorders is increasing. Motherhood entails major changes in women´s lives, potentially creating different occupational needs and an emerging field for Occupational Therapy. Objective: To identify and describe the occupational needs during occupational transition linked to motherhood, from the perspective of two women with mental disorders in Galicia, Spain. Method: Qualitative with phenomenological approach, using conversational techniques for data collection, and thematic analysis. Results: "Daily life before the change" and "I gave birth to him and he gave me my life", the emerged themes, transversely describe occupational needs experienced by participants in the occupational transition process linked to motherhood. Conclusion: We discuss the mediators of occupational transition, its complexity and a critical perspective of participants' experiences as one more experience within the diversity of motherhood; and conclude with the implications for occupational therapy.
Resumo Introdução: A quantidade de mulheres com transtorno mental que são mães está aumentando. A maternidade produz uma grande mudança na vida das mulheres, podendo gerar novas necessidades ocupacionais e constituindo um campo emergente para a terapia ocupacional. Objetivo: Identificar e descrever as necessidades ocupacionais vivenciadas durante a transição ocupacional vinculada à maternidade, segundo a perspectiva de duas mulheres com transtorno mental na Galícia, Espanha. Método: Pesquisa qualitativa com enfoque fenomenológico, empregando técnicas conversacionais para a coleta de dados e análise temática. Resultados: "No dia a dia antes da mudança" e "Eu o pari e ele me deu a vida" são os temas que descrevem de forma transversal as necessidades ocupacionais vividas pelas participantes no seu processo de transição ocupacional vinculado à maternidade. Conclusão: A discussão é realizada em torno dos mediadores da transição ocupacional e da complexidade desta e contribui com uma visão crítica, compreendendo as experiências das participantes como uma a mais entre a diversidade que representa a maternidade. Conclui-se discutindo as implicações para a terapia ocupacional.
Resumen Introducción: Las cifras de mujeres con trastorno mental que son madres están aumentando. La maternidad produce un gran cambio en la vida de las mujeres, pudiendo generar nuevas necesidades ocupacionales y constituyendo un ámbito incipiente para la terapia ocupacional. Objetivo: Identificar y describir las necesidades ocupacionales vivenciadas durante la transición ocupacional vinculada a la maternidad, desde la perspectiva de dos mujeres con trastorno mental en Galicia, España. Metodología: Cualitativa con enfoque fenomenológico, empleando técnicas conversacionales para la recogida de datos y análisis temático. Resultados: "El día a día antes del cambio" y "Yo lo parí y él me dio la vida" describen de forma transversal las necesidades ocupacionales vividas por las participantes en su proceso de transición ocupacional vinculado a la maternidad. Conclusión: La discusión se articula en torno a los mediadores de la transición ocupacional, la complejidad de la misma, y se aporta una mirada crítica entendiendo las experiencias de las participantes como una más dentro de la diversidad que representa la maternidad. Se finaliza discutiendo las implicaciones para la terapia ocupacional.
ABSTRACT
Effective quality assurance is essential in any screening programme. This article provides a unique insight into key quality indicators of five rounds of the first population-based colorectal cancer screening programme implemented in Spain (2000-2012), providing the results according to the type of screening (prevalent or first screen and incident or subsequent screen) and test (guaiac or immunochemical). The total crude participation rate increased from 17.2% (11,011) in the first round to 35.9% (22,988) in the last one. Rescreening rate was very high (88.6% in the fifth round). Positivity rate was superior with the faecal immunochemical test (6.2%) than with the guaiac-based test (0.7%) (p < 0.0001) and detection rates were also better with the immunochemical test. The most significant rise in detection rate was observed for high risk adenoma in men (45.5 per 1,000 screened). Most cancers were diagnosed at an early stage (61.4%) and there was a statistically significant difference between those detected in first or subsequent screening (52.6% and 70.0% respectively; p = 0.024). The availability of these results substantially improves data comparisons and the exchange of experience between screening programmes.
Subject(s)
Colorectal Neoplasms/epidemiology , Adult , Aged , Colorectal Neoplasms/diagnosis , Early Detection of Cancer/methods , Humans , Mass Screening , Middle Aged , Population Surveillance , Quality Indicators, Health Care , Reproducibility of Results , Spain/epidemiologyABSTRACT
The aim of this paper was to examine the distribution of fecal hemoglobin (f-Hb) concentration in a Spanish colorectal cancer screening population according to sociodemographic characteristics and analyze whether f-Hb was associated with clinical outcomes (type of lesion and its location). From September 2009 to November 2012, we sent 77,744 invitations to individuals aged 50-69 years to provide one sample of feces. f-Hb was measured on samples from 27,606 screenees (35.5%). Colonoscopy findings and pathology data were collected on the 1406 screenees with f-Hb greater than 100 ng Hb/ml (20 mg Hb/g feces). The Mann-Whitney U-test and the Kruskal-Wallis test were used to compare f-Hb (median) according to sociodemographic variables, clinical outcomes, and histological features of adenomas. f-Hb from greater than 100 ng Hb/ml was categorized into quartiles. Regression models were used to determine whether f-Hb was a risk predictor of colorectal lesions. f-Hb was associated directly with the severity of the colorectal lesions. An overlap between individuals with a negative colonoscopy and those with a low-risk adenoma was observed. High-grade dysplasia, villous histology, distal location, and increasing size were all features associated with an increased f-Hb level. f-Hb could be used in individual risk assessment to determine surveillance strategies for colorectal cancer screening.
