La Activación Conductual (AC) en mujeres con cáncer de mama durante la quimioterapia: análisis de la evolución de casos / Behavioral Activation Therapy (AC) in women with breast cancer undergoing chemotherapy: case evolution análisis

OBJETIVO: Valorar la utilidad de la Activación Conductual para el afrontamiento del cáncer. MÉTODO: 18 pacientes con cáncer de mama de reciente diagnóstico siguieron 6 sesiones protocolarizadas dirigidas a recuperar actividades relevantes, eliminar conductas de enfermedad y modificar patrón de evitación experiencial. El análisis funcional determinó objetivos concretos de intervención y la estimación del cambio clínico en cada caso. Se evaluó el cambio pre-post-seguimiento (trimestral). RESULTADOS: Se observa recuperación de las actividades, en particular, domésticas (p = 0,005) y ocio (p = 0,05). Es escasa la presencia de patrones de evitación, aunque se logra su reconocimiento. Las conductas de enfermedad se reconocen y reducen (p = 0,03). No hay casos de ansiedad ni depresión (HAD), pero sí sintomatología que mejora durante la intervención. CONCLUSIONES: La orientación de los pacientes oncológicos hacia el mantenimiento de actividades de la vida cotidiana relevantes durante la quimioterapia, parece mejorar el afrontamiento de la enfermedad

OBJECTIVE: To assess the utility of Behavioral Activation for coping with cancer. METHOD: 18 patients with recently diagnosed breast cancer followed 6 protocoled sessions, aimed to recover relevant activities, eliminate illness behavior and to modify experiential avoidance patterns. Functional analysis determined concrete intervention objectives and the estimation of clinically significant change for each case. Pre-post and three months follow up changes were assessed. RESULTS: Activity recovery is observed specifically related to of daily living (p = .005) and leisure activities (p = .05). The presence of avoidance patterns is scarce, although recognizable. Illness behaviors are recognized and reduced (p = .03). There were no cases of anxiety and depression (HAD), although some symptomatology is detected, it evolves favorably during the intervention. CONCLUSIONS: The guidance of oncologic patients towards maintaining relevant activities of daily living during chemotherapy, seems to improve the coping with the disease

Automating ChIP-seq experiments to generate epigenetic profiles on 10,000 HeLa cells.

Chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) is a technique of choice for studying protein-DNA interactions. ChIP-seq has been used for mapping protein-DNA interactions and allocating histones modifications. The procedure is tedious and time consuming, and one of the major limitations is the requirement for high amounts of starting material, usually millions of cells. Automation of chromatin immunoprecipitation assays is possible when the procedure is based on the use of magnetic beads. Successful automated protocols of chromatin immunoprecipitation and library preparation have been specifically designed on a commercially available robotic liquid handling system dedicated mainly to automate epigenetic assays. First, validation of automated ChIP-seq assays using antibodies directed against various histone modifications was shown, followed by optimization of the automated protocols to perform chromatin immunoprecipitation and library preparation starting with low cell numbers. The goal of these experiments is to provide a valuable tool for future epigenetic analysis of specific cell types, sub-populations, and biopsy samples.

Terapia de activación conductual en pacientes con cáncer / Behavioral activation treatment for cancer patients

Objetivo: Valorar la eficacia de la Terapia de Activación Conductual con pacientes con cáncer de pulmón y cáncer de mama durante el tratamiento oncológico. Procedimiento: Se establecen como criterio de resultado: frecuencia e intensidad de síntomas de enfermedad y/o trata-miento; afectación de la autonomía personal, actividad doméstica, laboral, ocio, relaciones familiares y sociales y alteraciones emocionales. Los datos se recogen mediante escalas estandarizadas (IK, HAD, QLQ-C30), autoinforme y entrevista clínica en cada sesión de tratamiento y en un seguimiento de tres meses. Se empleó un grupo control que ocupó el mismo número de sesiones en la evaluación de la calidad de vida. El total de participantes con cáncer de mama fueron 54 (G.C.: N = 29 / G.E.: N = 25) y con cáncer de pulmón 84 (G.C.: N = 37 / G.E.: N = 47). Resultados: Los análisis de comparación inter e intra grupos indican que entre los pacientes con cáncer de pulmón, el G.E. presenta significativamente menos pérdida de apetito, dificultades para dormir, ansiedad, depresión y mayor recuperación de actividades cotidianas y de ocio. Entre los pacientes con cáncer de mama no hay diferencias entre grupos pero el efecto tiempo resultó significativo en la evolución negativa del cansancio y la fatiga. Conclusiones: los pacientes que, durante el tratamiento con quimioterapia, mantienen sus actividades cotidianas y de ocio no presentan alteraciones emocionales. La activación conductual puede contribuir a mejorar la calidad de vida y prevenir alteraciones emocionales (AU)

Aim: In this research was evaluated the efficacy of the behavioural activation therapy in patients suffering lung cancer and breast cancer along the oncologic treatment. Measures: The variables used as outcome criterion were: frequency and intensity of the illness symptoms and/o medical treatment; affectation of personal autonomy, daily life activity, leisure, work activity, family and social relationships and emotional disturbances. Data were collected through standardized scales (IK, HAD, QLQ-C30), self-report and clinical interview in each of the treatment sessions and three months follow-up. The control group underwent the same number of sessions of assessment. The total number of participants with breast cancer was 54 (control group 29 and experimental group 25) and lung cancer 84 (control group 37 and experimental group 47. Results: The subjects of the experimental group of lung cancer showed a higher recovery of daily life activities and leisure and less difficulty sleeping, anxiety, depression and less loss of appetite. In the breast cancer no differences were found between groups but the effect of time was significant in the variables tiredness and fatigue. Conclusions: The patients that, during chemotherapy treatment, maintain their daily activities and leisure activities do not show emotional disturbances. The behavioural activation can contribute to improving the quality of life and prevent emotional disturbances in cancer (AU)

Final overall survival results and effect of prolonged (≥ 1 year) first-line bevacizumab-containing therapy for metastatic breast cancer in the ATHENA trial.

The ATHENA study expanded on the safety and efficacy data derived from first-line trials of bevacizumab combined with standard chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC). In ATHENA, 2,264 patients received first-line bevacizumab-containing therapy in routine oncology practice. Overall survival (OS) data are now mature; additional analyses from this large data set can provide insights into treatment duration and the effect of prolonged bevacizumab exposure, where data are currently limited. Patients with HER2-negative LR/mBC received first-line bevacizumab with standard chemotherapy until disease progression, unacceptable toxicity, or physician/patient decision. We performed subgroup analyses on data from patients treated for ≥12 months and those who continued single-agent bevacizumab after stopping chemotherapy. After median follow-up of 20.1 months, median OS was 25.2 months (95% confidence interval [CI] 24.0-26.3 months) in the entire population. Median OS was 30.0 months (95% CI 28.5-32.7 months) in 1,205 patients who continued bevacizumab after discontinuation of chemotherapy and 18.4 months (95% CI 17.2-19.7 months) in 1,058 patients who discontinued bevacizumab before or at the same time as stopping chemotherapy. Bevacizumab treatment was continued for ≥12 months in 473 patients (21%). In most, bevacizumab was administered as monotherapy for extended periods after stopping chemotherapy. In the subgroup of patients treated for ≥12 months, the median time to onset of grade 3-5 adverse events was 5.0 months. There was no evidence that first onset of adverse events of special interest, except for proteinuria, was more common in later than earlier cycles. No relationship was detected between development of hypertension and OS. Findings from these analyses suggest that patients with LR/mBC can receive bevacizumab for prolonged periods without major toxicity or progression of disease. In the absence of progression, continuation of single-agent bevacizumab appears to be a reasonable approach, with minimal toxicity and the possibility of long-term disease control.

A randomized phase II study of raltitrexed and gefitinib versus raltitrexed alone as second line chemotherapy in patients with colorectal cancer. (1839IL/0143).

PURPOSE: To determine the efficacy of the addition of gefitinib to raltitrexed in patients with colorectal cancer (CRC) that have progressed after first line chemotherapy. The study also sought to explore the safety of the combination and to investigate biomarkers predictive outcome. METHODS: A total of 76 patients were randomized to raltitrexed (3 mg/m(2) i.v.) every 21 days plus either daily gefitinib (250 mg p.o.) or placebo. The primary endpoint of the study was progression free survival (PFS). Tumor tissues were collected to determine the expression of EGFR, pEGFR, pMAPK, and pAkt. RESULTS: Both groups were well balanced with regard to prognostic factors. Treatment was well tolerated with no increased in toxicity except diarrhea and skin rash in the combination group. There were no differences in PFS between the combination arm [63 days (95% CI: 57-84)] compared to the raltitrexed alone arm [72 days (95% CI: 59-132)], or overall survival 361 days (95% CI: 283-533 days) versus 291 days (95% CI: 255-539 days) respectively. The objective response rate was 7.9% (3 patients) (CI 95%: 1,66-21,38) versus 5.3% (2 patients) (CI 0,64-17,75), respectively. The biomarker studies were not conclusive. CONCLUSION: The combination of raltitrexed and gefitinib was well tolerated although was not associated with improved progression free survival in patients with refractory CRC.

Oncogenic RAS alters the global and gene-specific histone modification pattern during epithelial-mesenchymal transition in colorectal carcinoma cells.

The presence of different forms of histone covalent modifications, such as phosphorylation, acetylation and methylation in localized promoter regions are markers for chromatin packing and transcription. Activation of RAS signalling pathways through oncogenic RAS mutations is a hallmark of colorectal cancer. Overexpression of Harvey-Ras oncogene induces epithelial-mesenchymal transition (EMT) in Caco-2 cells. We focused on the role of epigenetic modifications of histone H3 and its dependence on RAS signal transduction pathways and oncogenic transformation. Using cell lines stably overexpressing oncogenic Harvey-RAS with EMT phenotype, we studied the acquired changes in the H3 histone modification patterns. Two genes show inverse protein expression patterns after Ha-RAS overexpression: Cyclin D1, a cell cycle-related gene, and the EMT marker-gene E-cadherin. We report that these two genes demonstrate matching inverse histone repression patterns on their promoter, while histone markers associated with an active state of genes were affected by the RAS-activated signalling pathway MEK-ERK-MSK1. Furthermore, we show that though the level of methyltransferases enzymes was increased, the status of H3 three-methylation at lysine 27 (H3K27me(3)), associated with gene repression on the promoter of Cyclin D1, was lower. Together, these results suggest that histone covalent modifications can be affected by oncogenic RAS pathways to regulate the expression of target genes like Cyclin D1 or E-cadherin and that the dynamic balance of opposing histone-modifying enzymes is critical for the regulation of cell proliferation.

Novel therapeutic approaches to the treatment of metastatic breast cancer.

Metastatic breast cancer is ultimately an incurable disease, although recent data have shown that its incidence is decreasing and that patients with metastatic breast cancer live longer. This improvement in survival seems to be linked with the introduction of new therapeutic agents, novel combinations of existing therapies and targeted therapies. Our increasing understanding of the molecular biology of metastatic disease has allowed the development of therapies aimed at specific molecular targets. Some of these have already been approved for the treatment of metastatic breast cancer in combination with cytotoxics, and others have shown promising results regarding disease-free survival, overall response rates and time to disease progression. Given the enormous amount of information about drug discovery in cancer, it is important to be familiar with the present state of the treatment of metastatic breast cancer. The purpose of this review is to provide an update on the development of some of the most promising novel agents and treatment strategies in metastatic breast cancer.

Calidad de Vida en Pacientes oncológicos un año después de finalizado el tratamiento / Quality of life in cancer patients a year one year after tan the treatment was finished

Objective: To describe the Quality of Life (QL) parameters one year after than the oncology treatment was finished. Methods: 53 patients were assessed using semi-structured interviews, standardized questionnaires and records covered by the patient and doctor. Results: The total scores of QL were high. However, a high prevalence of chronic symptoms as pain (39.6%), fatigue (37.75), sleep disturbances (32.1%), lost of appetite (18,9%) and depressing mood (41,1%) was described by the patients. Moreover, the emotional state, daily life and leisure activities were the aspects of the patients life more affected through that year. Conclusions: The total score of QL is an unspecific figure but no the others variables that have a great effect on the oncology patient through the treatment. On these specific variables intervention are required (AU)

Objetivo: Describir los parámetros y los predictores de la CV un año después de finalizado el tratamiento oncológico. Método: Se evaluaron un total de 53 pacientes mediante entrevistas semiestructuradas, cuestionarios estandarizados y autoregistros cumplimentados por los pacientes y el médico. Resultados: Las valoraciones generales de calidad de fueron altas. Se encontró una alta prevalencia de síntomas experimentados de forma continua como el dolor (39,6%), cansancio (37,7%), alteraciones de sueño (32,1%) y pérdida de apetito (18,9%). El estado de ánimo deprimido fue referido por un 41,1% de los pacientes. Los cambios emocionales, en las actividades domésticas y en el ocio fueron los aspectos más alterados de la rutina del paciente. En las valoraciones de CV realizadas por el paciente y el médico influyeron diversas y distintas variables. Conclusiones: Las valoraciones globales de CV son puntuaciones inespecíficas mientras que son aspectos concretos y distintos en cada momento del proceso oncológico los que afectan a la CV de los pacientes y sobre los que se requerirían intervenciones específicas (AU)

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor Atorvastatin mediated effects depend on the activation status of target cells in PLP-EAE.

The effect of Atorvastatin on transcriptional activity in murine experimental autoimmune encephalomyelitis (EAE) induced by PLP peptide 139-151 was analyzed by DNA microarray technique in lymph nodes and spinal cord at onset (10 days), height (20 days) and first remission (30 days) of disease. Fourteen genes were selectively influenced by Atorvastatin in EAE mice. They are mainly related to immune cell functions and regulation of cell-to-cell interaction. Interestingly, seven genes were also differentially regulated in CFA-injected control mice. But qualitative and quantitative differences to EAE mice argue for a dependency of statin effects on the activation status of target cells. Differential regulation of the newly detected candidate genes of statin effects COX-1 and HSP-105 and the previously known statin-responsive genes ICAM-1 and CD86 was confirmed by Western blot and immunohistochemistry. Flow cytometric analysis of lymph node cells revealed that the effect of Atorvastatin treatment in non-immunized healthy animals resembled the effect of immunization with PLP peptide regarding changes of T helper cells, activated B cells and macrophages. In EAE mice, these effects were partially reversed by Atorvastatin treatment. Monitoring of expression of the newly identified candidate genes and patterns of lymphocyte subpopulations might predict the responsiveness of multiple sclerosis patients to statin treatment.

Calidad de vida informada por pacientes oncológicos paliativos. Relaciones con el informe médico y estado emocional / Quality of life as reported by palliative cancer patients. Relationship with medical report and emotional state

Objetivo: analizar la utilidad clínica de los datos acerca de la calidad de vida (QL) informada por pacientes oncológicos en situación paliativa. Sujetos y Método: 107 pacientes del Servicio de Oncología del Hospital de Cabueñes de Gijón (España) cumplimentaron los cuestionarios QL-CA-AFex, HAD y Duke-UNC y un protocolo clínico. Los sujetos se asignaron aleatoriamente a distintos grupos de seguimiento (uno, dos, tres o seis meses). Se utilizaron coeficientes de correlación para analizar la relación entre la QL y la situación clínica, estado emocional y apoyo social. Se empleó el ANOVA para estudiar las diferencias en la QL en función de las variables analizadas. Resultados: la QL no se deterioró con la progresión de la enfermedad. Los aspectos más relacionados con la QL fueron los síntomas y, en segundo lugar, los aspectos psicológicos. Se comprobó la capacidad del QL-CA-AFex para discriminar entre grupos de pacientes realizados en función de diversas variables clínicas

Aim: to analyse the clinical usefulness of data regarding quality of life (QL) as reported by oncology patients in a palliative situation. Subjects and Method: 107 patients from the cancer department of Cabueñes Hospital in Gijón (Spain) completed the questionnaires QL-CA-Afex, HAD and Duke-UNC and a clinical protocol. In a second evaluation, the subjects were assigned at random to different assessment groups (one, two, three or six months). Correlation coefficients were used to analyse the relationship between the QL and the clinical situation, emotional state and social support. The ANOVA was used to study the differences in the QL with regard to the variables analysed. Results: The quality of life did not diminish as the disease progressed. The aspects most closely related to the QL were the symptoms of illness and, secondly, psychological aspects. The validity of the QL-CA-Afex when distinguishing between groups of patients formed according to various clinical variables was tested

Identification of quantitative trait loci controlling cortical motor evoked potentials in experimental autoimmune encephalomyelitis: correlation with incidence, onset and severity of disease.

Experimental autoimmune encephalomyelitis (EAE) is a polygenic chronic inflammatory demyelinating disease of the nervous system, commonly used as an animal model of multiple sclerosis. Previous studies have identified multiple quantitative trait loci (QTLs) controlling different aspects of disease pathogenesis. However, direct genetic control of cortical motor evoked potentials (cMEPs) as a straightforward measure of extent of demyelination or synaptic block has not been investigated earlier. Here, we examined the genetic control of different traits of EAE in a F2 intercross population generated from the EAE susceptible SJL/J (SJL) and the EAE resistant C57BL/10.S (B10.S) mouse strains involving 400 animals. The genotypes of 150 microsatellite markers were determined in each animal and correlated to phenotypic data of onset and severity of disease, cell infiltration and cMEPs. Nine QTLs were identified. Three sex-linked QTLs mapped to chromosomes 2, 10 and 18 linked to disease severity in females, whereas QTLs on chromosomes 1, 8 and 15 linked to the latency of the cMEPs. QTLs affecting T-lymphocyte, B-lymphocyte and microglia infiltration mapped on chromosomes 8 and 15. The cMEP-associated QTLs correlated with incidence, onset or severity of disease, e.g. QTL on chromosome 8, 32-48 cM (EAE 31) (LOD 6.9, P<0.001), associated to cMEP latencies in non-immunized mice and correlated with disease onset and EAE 32 on chromosome 15 linked to cMEP latencies 15 days post-immunization and correlated with disease severity. Additionally, applying tissue microarray technology, we identified QTLs associated to microglia and lymphocytes infiltration on chromosomes 8 and 15, which are different from the QTLs controlling cMEP latencies. There were no alterations in the morphological appearance of the myelin sheaths. Our findings suggest a possible role of myelin composition and/or synaptic transmission in susceptibility to EAE.