RESUMEN
BACKGROUND: An important proportion of HER2-positive metastatic breast cancer patients do not respond to trastuzumab. The combination of dasatinib and trastuzumab has shown to be synergistic in preclinical models. METHODS: We conducted a phase II trial combining dasatinib 100 mg once daily with trastuzumab 2 mg/kg and paclitaxel 80 mg/m2 weekly. Primary objective was objective response rate (ORR) and secondary included safety, other efficacy parameters and pharmacodynamics in tumour tissue, blood samples and skin biopsies. RESULTS: From June 2013 to December 2015, 29 patients were included. Median number of cycles was 12 (1-49). Only 6 patients discontinued due to adverse events. ORR was 79.3% (95% CI 60.3-92), clinical benefit rate 82.8% (95% CI 64.2-94.2). Median time to progression 23.9 months (95% CI 14.9-not reached [NR]), median progression-free survival 23.9 months (95% CI 10.3-NR). No grade 4 toxicity was seen. Grade 3 toxicities included: ejection fraction decrease, neutropenia, hyponatremia, fatigue and sensory neuropathy and one left ventricular systolic dysfunction. Phosphorylated (p)-SRC was reduced in peripheral blood mononuclear cells. Phosphorylated SRC, ERK and AKT were also reduced in epidermal keratinocytes. CONCLUSIONS: Dasatinib can be safely combined with trastuzumab and paclitaxel. The combination is active with an ORR of almost 80%. TRIAL REGISTRATION: NCT01306942, EudraCT 2010-023304-27.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Dasatinib/administración & dosificación , Paclitaxel/administración & dosificación , Trastuzumab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/metabolismo , Dasatinib/efectos adversos , Esquema de Medicación , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/efectos adversos , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Receptor ErbB-2/metabolismo , Análisis de Supervivencia , Trastuzumab/efectos adversos , Resultado del TratamientoRESUMEN
PURPOSE: GEICAM/2006-10 compared anastrozole (A) versus fulvestrant plus anastrozole (A + F) to test the hypothesis of whether a complete oestrogen blockade is superior to aromatase inhibitors alone in breast cancer patients receiving hormone adjuvant therapy. METHODS: Multicenter, open label, phase III study. HR+/HER2- EBC postmenopausal patients were randomized 1:1 to adjuvant A (5 years [year]) or A + F (A plus F 250 mg/4 weeks for 3 year followed by 2 year of A). Stratification factors: prior chemotherapy (yes/no); number of positive lymph nodes (0/1-3/≥ 4); HR status (both positive/one positive) and site. PRIMARY OBJECTIVE: disease-free survival (DFS). Planned sample size: 2852 patients. RESULTS: The study has an early stop due to the financer decision with 870 patients (437 randomized to A and 433 to A + F). Patient characteristics were well balanced. After a median follow-up of 6.24y and 111 DFS events (62 in A and 49 in A + F) the Hazard Ratio for DFS (combination vs. anastrozole) was 0.84 (95% CI 0.58-1.22; p = 0.352). The proportion of patients disease-free in arms A and A + F at 5 year and 7 year were 90.8% versus 91% and 83.6% versus 86.7%, respectively. Most relevant G2-4 toxicities (≥ 5% in either arm) with A versus A + F were joint pain (14.7%; 13.7%), fatigue (2.5%; 7.2%), bone pain (3%; 6.5%), hot flushes (3.5%; 5%) and muscle pain (2.8%; 5.1%). CONCLUSIONS: The GEICAM/2006-10 study did not show a statistically significant increase in DFS by adding adjuvant F to A, though no firm conclusions can be drawn because of the limited sample size due to the early stop of the trial. ClinicalTrials.gov: NCT00543127.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Anastrozol/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Fulvestrant/administración & dosificación , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Posmenopausia , Resultado del TratamientoRESUMEN
BACKGROUND: Retrospective data suggest an association between bevacizumab efficacy and the incidence of arterial hypertension (AHT). Additionally, epigenetic mechanisms have been related to AHT. METHODS: This prospective observational study conducted by GEICAM Spanish Breast Cancer Research Group included metastatic breast (MBC) or colorectal (mCRC) cancer patients treated with bevacizumab-containing chemotherapy as first-line treatment. Blood pressure (BP) levels were measured (conventional and 24-h Holter monitoring) at baseline and up to cycle 3. Primary endpoint assessed BP levels increase as predictive factor for progression-free survival (PFS). Germline DNA methylation profile was explored in pre-treatment blood samples; principal component analysis was used to define an epigenetic predictive score for increased BP levels. RESULTS: From Oct-2012 to Jul-2016, 143 (78 MBC and 65 mCRC) patients were included. The incidence of AHT according to guidelines was neither predictive of PFS nor of best overall tumor response (BOR). No statistically significant association was observed with systolic BP nor diastolic BP increment for PFS or BOR. Grade 3 and 4 adverse events were observed in 37 and 5% of patients, respectively. We identified 27 sites which baseline methylation status was significantly associated to BP levels increase secondary to bevacizumab-containing chemotherapy. CONCLUSIONS: Neither the frequency of AHT nor the increase of BP levels were predictive of efficacy in MBC and mCRC patients treated with bevacizumab-containing chemotherapy. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT01733628.
Asunto(s)
Bevacizumab , Neoplasias de la Mama , Neoplasias Colorrectales , Hipertensión , Humanos , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Femenino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Persona de Mediana Edad , Hipertensión/inducido químicamente , Estudios Prospectivos , Anciano , Masculino , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Supervivencia sin Progresión , Metilación de ADNRESUMEN
Results from multinational clinical trials are globally adopted into the routine clinical practice in most countries. Changes in the natural history and incidence of certain diseases as well as in drugs toxicities related to yearly seasons have been reported, however, variations related to climate have never been described. In our study, we assessed whether yearly seasons and climate could influence the chemotherapy toxicity profile. We analyzed the toxicities recorded in the phase III GEICAM 9906 study which was run in different geographically and climatically/seasonally regions in Spain. In this trial 1246 patients were randomized and eligible to receive FEC90 ×6 cycles or FEC90 ×4 cycles followed by eight doses of weekly paclitaxel (T). The results showed differences in hematological and non-hematological toxicities in relation to the season of the year and the climate of the area in which the treatment was administered. We found a higher hematological toxicity in warm seasons (spring and summer) and in Oceanic climate regions (Neutropenia G4: 7.8 vs. 1.0 vs. 1.0%, P < 0.0001). Asthenia was greater frequency in the summer period (FEC90: 21.1%, T: 15.3%) as well as in the Mediterranean areas (FEC: 28% T: 27.2%). Also we observed liver transaminase elevations were more frequent in the summer and in the Oceanic areas. Myalgias and secondary sensory neuropathy to paclitaxel were recorded more frequently during autumn. Climate should be considered a significant variable in toxicity to chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Características de la Residencia , Estaciones del Año , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Distribución de Chi-Cuadrado , Femenino , Humanos , Medición de Riesgo , Factores de Riesgo , España , Resultado del TratamientoRESUMEN
A nickel-ceria-yttria stabilized zirconia (Ni-CYSZ) cermet material was synthesized and tested as the anode for the direct oxidation of methane in a solid oxide fuel cell (SOFC) with YSZ as the electrolyte and strontium-doped lanthanum manganite (LSM) as the cathode. Initially, the electrochemical behavior was investigated under several load demands in wet (3% H2O) CH4 at 850 °C during 144 h using I-V curves, impedance spectra, and potentiostatic measurements. Long-term tests were subsequently conducted under 180 mA·cm-2 in wet CH4 for 236 h and dry CH4 for 526 h at 850 °C in order to assess the cell stability. Material analysis was carried out by SEM-EDS after operation was complete. Similar cell performance was observed with wet (3% H2O) and dry CH4, and this indicates that the presence of water is not relevant under the applied load demand. Impedance spectra of the cell showed that at least three processes govern the direct electrochemical oxidation of methane on the Ni-CYSZ anode and these are related to charge transfer at high frequency, the adsorption/desorption of charged species at medium frequency and the non-charge transfer processes at low frequency. The cell was operated for more than 900 h in CH4 and 806 h under load demand, with a low degradation rate of ~0.2 mV·h-1 observed during this period. The low degradation in performance was mainly caused by the increase in charge transfer resistance, which can be attributed to carbon deposition on the anode causing a reduction in the number of active centers. Carbon deposits were detected mostly on the surface of Ni particles but not near the anode/electrolyte interface or the cerium surface. Therefore, the incorporation of cerium in the anode structure could improve the cell lifetime by reducing carbon formation.
RESUMEN
Purpose: We previously detected promising efficacy of neoadjuvant nintedanib (a multityrosine kinase inhibitor, TKI) in early HER2-negative breast cancer. In a preclinical study, we monitored stromal hypoxia with 18F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET); we found that reoxygenation of tumors (or lack of it) during a window-of-opportunity (WoO) treatment with TKIs correlated with the benefit (or lack of it) from TKI-plus-chemotherapy combinations. We studied the predictive role of 18F-FMISO-PET for the TKI nintedanib in the neoadjuvant setting in a phase II WoO randomized trial.Experimental Design: Patients were randomized to a 14-day WoO of nintedanib preceded and followed by an 18F-FMISO-PET, followed by nintedanib plus weekly paclitaxel (Arm A) or an 18F-FMISO-PET followed by weekly paclitaxel (Arm B) before surgery. The endpoint was residual cancer burden (RCB). The objective was to detect the patients with no response (RCB-III) on the basis of the baseline or evolutive 18F-FMISO-PET values/changes.Results: One-hundred and thirty HER2-negative patients were randomized. Seventeen (27.9%), 34 (55.7%), and 8 (13.1%) patients had an RCB of III, II, and I/0, respectively, in Arm A. In this arm, baseline hypoxic tumors had a 4.4-fold higher chance of experiencing RCB = 3 (P = 0.036) compared with baseline normoxic tumors. Nintedanib WoO induced tumor reoxygenation in 24.5% of the patients; those not reoxygenating showed a trend toward higher chance of experiencing RCB-III (6.4-fold; P = 0.09). In Arm B, 18F-FMISO-PET lacked predictive/prognostic value.Conclusions: Baseline hypoxic tumors (measured with 18F-FMISO-PET) do not benefit from neoadjuvant nintedanib. Clin Cancer Res; 23(6); 1432-41. ©2016 AACR.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Indoles/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Receptor ErbB-2/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Indoles/efectos adversos , Persona de Mediana Edad , Misonidazol/administración & dosificación , Misonidazol/análogos & derivados , Terapia Neoadyuvante/efectos adversos , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Tomografía Computarizada por Tomografía de Emisión de Positrones , Inhibidores de Proteínas Quinasas/efectos adversos , Hipoxia Tumoral/efectos de los fármacosRESUMEN
Cumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres (< 3 kilobases, CSTs), but not average telomere length by itself, accounts for limited tissue renewal and turnover capacity. The impact of this parameter (which can be modified with different therapies) in chemotherapy-derived toxicity has not been studied.Blood from 115 treatment-naive patients from a clinical trial in early HER2-negative breast cancer that received weekly paclitaxel (80 mg/m2 for 12 weeks) either alone or in combination with nintedanib and from 85 healthy controls was prospectively obtained and individual CSTs and average telomere lenght were determined by HT Q-FISH (high-throughput quantitative FISH). Toxicity was graded according to NCI common toxicity criteria for adverse events (NCI CTCAE V.4.0). The variable under study was "number of toxic episodes" during the 12 weeks of therapy.The percentage of CSTs ranged from 6.5%-49.4% and was directly associated with the number of toxic events (R2 = 0.333; P < 0.001). According to a linear regression model, each 18% increase in the percentage of CSTs was associated to one additional toxic episode during the paclitaxel cycles; this effect was independent of the age or treatment arm. Patients in the upper quartile (> 21.9% CSTs) had 2-fold higher number of neuropathy (P = 0.04) or fatigue (P = 0.019) episodes and >3-fold higher number of myalgia episodes (P = 0.005). The average telomere length was unrelated to the incidence of side effects.The percentage of CSTs, but not the average telomere size, is associated with weekly paclitaxel-derived toxicity.
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Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias de la Mama/genética , Acortamiento del Telómero , Telómero/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Femenino , Humanos , Hibridación Fluorescente in Situ , Indoles/administración & dosificación , Indoles/efectos adversos , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/métodos , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversosRESUMEN
PURPOSE: To determine the frequency of breast cancer (BC) patients with hereditary risk features in a wide retrospective cohort of patients in Spain. METHODS: a retrospective analysis was conducted from 10,638 BC patients diagnosed between 1998 and 2001 in the GEICAM registry "El Álamo III", dividing them into four groups according to modified ESMO and SEOM hereditary cancer risk criteria: Sporadic breast cancer group (R0); Individual risk group (IR); Familial risk group (FR); Individual and familial risk group (IFR) with both individual and familial risk criteria. RESULTS: 7,641 patients were evaluable. Of them, 2,252 patients (29.5%) had at least one hereditary risk criteria, being subclassified in: FR 1.105 (14.5%), IR 970 (12.7%), IFR 177 (2.3%). There was a higher frequency of newly diagnosed metastatic patients in the IR group (5.1% vs 3.2%, p = 0.02). In contrast, in RO were lower proportion of big tumors (> T2) (43.8% vs 47.4%, p = 0.023), nodal involvement (43.4% vs 48.1%, p = 0.004) and lower histological grades (20.9% G3 for the R0 vs 29.8%) when compared to patients with any risk criteria. CONCLUSIONS: Almost three out of ten BC patients have at least one hereditary risk cancer feature that would warrant further genetic counseling. Patients with hereditary cancer risk seems to be diagnosed with worse prognosis factors.
Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Adulto , Neoplasias de la Mama/epidemiología , Femenino , Asesoramiento Genético , Humanos , Persona de Mediana Edad , Prevalencia , Pronóstico , Sistema de Registros , Estudios Retrospectivos , España/epidemiologíaRESUMEN
El artículo es un estudio retrospectivo para conocer la sensibilidad antibiótica de los aislados de Neisseria gonorhoeae de muestras genitales de pacientes durante los últimos 4 años en el área de Cuenca (España) para así establecer cuáles serían las mejores pautas de tratamiento para esta enfermedad en nuestra región. De un total de 26 cepas aisladas de Neisseria gonorrhoeae, la resistencia a fluorquinolonas fue del 61,54%. Todas las cepas fueron sensibles a cefotaxima, por lo que consideramos que el tratamiento empírico de elección de las infecciones gonocócicas no complicadas en nuestro medio debería ser las cefalosporinas de tercera generación (AU)
A retrospective study was conducted to determine the antibiotic susceptibility of Neisseria gonorrhoeae isolates from genital samples of patients over the last four years in Cuenca (Spain), in order to establish what would be the best treatment regimens for this disease in our region. Of a total of 26 isolates of Neisseria gonorrhoeae, fluoroquinolone resistance was 61.54%. All strains were susceptible to cefotaxime, so we believe that the choice of empirical treatment of uncomplicated gonococcal infections should be third generation cephalosporins in our region (AU)
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Humanos , Masculino , Femenino , Neisseria gonorrhoeae/aislamiento & purificación , Neisseria gonorrhoeae/patogenicidad , Farmacorresistencia Microbiana , Farmacorresistencia Microbiana/fisiología , Pruebas de Sensibilidad Microbiana/instrumentación , Pruebas de Sensibilidad Microbiana/métodos , Pruebas de Sensibilidad Microbiana/tendencias , Cefalosporinas/uso terapéutico , Ceftriaxona/uso terapéutico , Cefixima/uso terapéutico , Farmacorresistencia Microbiana , Pruebas de Sensibilidad Microbiana , Estudios RetrospectivosRESUMEN
El artículo es un estudio retrospectivo para conocer la prevalencia de parasitaciones intestinales en niños de acogida saharauis en la provincia de Cuenca (España). Se incluyeron un total de 157 muestras de 90 pacientes durante un período de cinco años. Encontramos que los pacientes presentaban un porcentaje de parasitación del 37,37%. Sería conveniente realizar un protocolo para el diagnóstico y tratamiento de las parasitaciones intestinales en estos niños (AU)
We performed a retrospective study to find out the prevalence of intestinal parasite infestation in foster children from the Sahara in Cuenca (Spain). We included 157 samples from 90 patients over a five-year period. It was found that 37.37% of the children were infected with pathological parasites. It would be advisable to develop a protocol for the diagnosis and treatment of intestinal parasite infestation in these children (AU)