Next Generation Cytogenetics in Myeloid Hematological Neoplasms: Detection of CNVs and Translocations.

Conventional cytogenetics are the gold standard for the identification of chromosomal alterations recurrent in myeloid neoplasms. Some next-generation sequencing (NGS) panels are designed for the detection of copy number variations (CNV) or translocations; however, their use is far from being widespread. Here we report on the results of a commercial panel including frequent mutations, CNVs and translocations in myeloid neoplasms. Frequent chromosomal alterations were analyzed by NGS in 135 patients with myeloid neoplasms and three with acute lymphoblastic leukemia. NGS analysis was performed using the enrichment-capture Myeloid Neoplasm-GeneSGKit (Sistemas Genómicos, Spain) gene panel including 35 genes for mutational analysis and frequent CNVs and translocations. NGS results were validated with cytogenetics and/or MLPA when possible. A total of 66 frequent alterations included in NGS panel were detected, 48 of them detected by NGS and cytogenetics. Ten of them were observed only by cytogenetics (mainly trisomy 8), and another eight only by NGS (mainly deletion of 12p). Aside from this, 38 secondary CNVs were detected in any of the genes included mainly for mutational analysis. NGS represents a reliable complementary source of information for the analysis of CNVs and translocations. Moreover, NGS could be a useful tool for the detection of alterations not observed by conventional cytogenetics.

Benefits and harms of breast cancer mammography screening for women at average risk of breast cancer: A systematic review for the European Commission Initiative on Breast Cancer.

OBJECTIVES: Mammography screening is generally accepted in women aged 50-69, but the balance between benefits and harms remains controversial in other age groups. This study systematically reviews these effects to inform the European Breast Cancer Guidelines. METHODS: We searched PubMed, EMBASE and Cochrane Library for randomised clinical trials (RCTs) or systematic reviews of observational studies in the absence of RCTs comparing invitation to mammography screening to no invitation in women at average breast cancer (BC) risk. We extracted data for mortality, BC stage, mastectomy rate, chemotherapy provision, overdiagnosis and false-positive-related adverse effects. We performed a pooled analysis of relative risks, applying an inverse-variance random-effects model for three age groups (<50, 50-69 and 70-74). GRADE (Grading of Recommendations Assessment, Development and Evaluation) was used to assess the certainty of evidence. RESULTS: We identified 10 RCTs including 616,641 women aged 38-75. Mammography reduced BC mortality in women aged 50-69 (relative risk (RR) 0.77, 95%CI (confidence interval) 0.66-0.90, high certainty) and 70-74 (RR 0.77, 95%CI 0.54-1.09, high certainty), with smaller reductions in under 50s (RR 0.88, 95%CI 0.76-1.02, moderate certainty). Mammography reduced stage IIA+ in women 50-69 (RR 0.80, 95%CI 0.64-1.00, very low certainty) but resulted in an overdiagnosis probability of 23% (95%CI 18-27%) and 17% (95%CI 15-20%) in under 50s and 50-69, respectively (moderate certainty). Mammography was associated with 2.9% increased risk of invasive procedures with benign outcomes (low certainty). CONCLUSIONS: For women 50-69, high certainty evidence that mammography screening reduces BC mortality risk would support policymakers formulating strong recommendations. In other age groups, where the net balance of effects is less clear, conditional recommendations will be more likely, together with shared decision-making.

Moderately elevated first trimester fasting plasma total homocysteine is associated with increased probability of miscarriage. The Reus-Tarragona Birth Cohort Study.

The association between elevated early pregnancy fasting plasma total homocysteine (tHcy) and miscarriage risk was investigated prospectively in participants (n = 544) from the Reus-Tarragona Birth Cohort study. Pregnancy was confirmed before 12 gestational weeks (GW) by ultrasound scan and a fasting blood sample collected. Pregnancies with complications other than miscarriages were excluded. Miscarriages were diagnosed by ultrasound scan and gestational age at the time of miscarriage estimated by embryo size, where possible. Cases in which blood samples were collected more than a week after the miscarriage, or the miscarriage was of known cause, were excluded. Fasting plasma folate, vitamin B12, tHcy, cotinine (biomarker of smoking), red blood cell (RBC) folate, MTHFR 677C > T (rs1801133) and SLC19A1 80G>A (rs1051266) genotypes were determined. The exposed group consisted of participants with first trimester tHcy ≥ P90 (7.1 µmol/L) (n = 57) and unexposed of those with tHcy < P90 (n = 487). Adherence to folic acid supplement recommendations, plasma folate, plasma vitamin B12, RBC folate and prevalence of optimal RBC folate status (≥ 906 µmol/L) were lower in the exposed compared to unexposed group. The prevalences of the MTHFR 677 TT genotype and miscarriage were higher in the exposed group. The relative risks (95% CI) of pregnancy ending in miscarriage were 2.5 (1.1, 5.7) and 2.1 (1.0, 4.5) for participants in the high tHcy and suboptimal RBC folate groups (compared to the reference groups) respectively. Adherence to folic acid supplement recommendations was positively associated, while the MTHFR 677 TT versus CC genotype and smoking versus non-smoking were negatively associated, with RBC folate status.

The effect of prenatal smoke exposure on child neuropsychological function: a prospective mother-child cohort study.

Objective: To study prospectively the effect of prenatal smoke exposure (PSE) on child neuropsychological function and intelligence quotient (IQ).Background: PSE has been associated with adverse effects on child neurodevelopment. However, some studies reported that these associations disappear after adjustment for potential confounders.Methods: A cohortof 248 mothers-child dyad was followed from the first trimester of pregnancy until children were 7.5 years old. PSE was recorded during pregnancy by questionnaire and plasma cotinine. The Wechsler Intelligence Scale for Children, the Neuropsychological Assessment of Executive Functions for Children (ENFEN) and the School Neuropsychological Maturity Questionnaire were administered at 7.5 years of age. The effect of PSE on child IQ and neuropsychological function was assessed with ANCOVA, adjusting for obstetric, neonatal and sociodemographic factors.Results: Children whose mothers smoked throughout pregnancy scored lower in interference (ENFEN) compared to unexposed children (F = 4.1; p = .008). The results showed no differences in other executive functions, verbal and visual memory and IQ between the PSE groups.Conclusion: PSE had little effect on child neuropsychological outcome and was limited to mental flexibility. Nevertheless, these findings support further efforts aimed at encouraging mothers to quit smoking in pregnancy.

Next-Generation Sequencing Improves Diagnosis, Prognosis and Clinical Management of Myeloid Neoplasms.

Molecular diagnosis of myeloid neoplasms (MN) is based on the detection of multiple genetic alterations using various techniques. Next-generation sequencing (NGS) has been proved as a useful method for analyzing many genes simultaneously. In this context, we analyzed diagnostic samples from 121 patients affected by MN and ten relapse samples from a subset of acute myeloid leukemia patients using two enrichment-capture NGS gene panels. Pathogenicity classification of variants was enhanced by the development and application of a custom onco-hematology score. A total of 278 pathogenic variants were detected in 84% of patients. For structural alterations, 82% of those identified by cytogenetics were detected by NGS, 25 of 31 copy number variants and three out of three translocations. The detection of variants using NGS changed the diagnosis of seven patients and the prognosis of 15 patients and enabled us to identify 44 suitable candidates for clinical trials. Regarding AML, six of the ten relapsed patients lost or gained variants, comparing with diagnostic samples. In conclusion, the use of NGS panels in MN improves genetic characterization of the disease compared with conventional methods, thus demonstrating its potential clinical utility in routine clinical testing. This approach leads to better-adjusted treatments for each patient.

Evidence mapping and quality assessment of systematic reviews on therapeutic interventions for oral cancer.

Purpose: This evidence mapping aims to describe and assess the quality of available evidence in systematic reviews (SRs) on treatments for oral cancer. Materials and methods: We followed the methodology of Global Evidence Mapping. Searches in MEDLINE, EMBASE, Epistemonikos and The Cochrane Library were conducted to identify SRs on treatments for oral cancer. The methodological quality of SRs was assessed using the Assessing the Methodological Quality of Systematic Reviews-2 tool. We organized the results according to identified Population-Intervention-Comparison-Outcome (PICO) questions and presented the evidence mapping in tables and a bubble plot. Results: Fifteen SRs met the eligibility criteria, including 118 individual reports, of which 55.1% were randomized controlled clinical trials. Ten SRs scored "Critically low" methodological quality. We extracted 30 PICOs focusing on interventions such as surgery, radiotherapy, chemotherapy, targeted therapy and immunotherapy; 18 PICOs were for resectable oral cancer, of which 8 were reported as beneficial. There were 12 PICOs for unresectable oral cancer, of which only 2 interventions were reported as beneficial. Conclusion: There is limited available evidence on treatments for oral cancer. The methodological quality of most included SRs scored "Critically low". The main beneficial treatment reported by authors for patients with resectable oral cancer is surgery alone or in combination with radiotherapy or chemotherapy. Evidence about the benefits of the treatments for unresectable oral cancer is lacking. These findings highlight the need to address future research focused on new treatments and knowledge gaps in this field, and increased efforts are required to improve the methodology quality and reporting process of SRs on treatments for oral cancer.

Subcutaneous bortezomib in newly diagnosed patients with multiple myeloma nontransplant eligible: Retrospective evaluation.

Bortezomib-melphalan-prednisone combination is one of the standards of care for nontransplant eligible patients with newly diagnosed multiple myeloma. However, bortezomib intravenous (twice weekly for 4 cycles then weekly for 5 cycles) results in ~13% of patients with grade 3-4 peripheral neuropathy. Bortezomib subcutaneous (SQ) and weekly delivery, improves tolerability without impairment of efficacy. The aim of this study was to evaluate the safety and effectiveness of SQ bortezomib-based combinations in nontransplant eligible patients with newly diagnosed myeloma in a real-world setting. A total of 135 patients (median age [range] = 76 [58-89], International Staging System-III = 54%, median follow-up = 14.8 months [1-40], Intensive group [twice weekly bortezomib] = 65%, Optimized group [weekly bortezomib] = 35%) were included and evaluable for safety, whereas 121 were evaluable for effectiveness. Overall response rate (95% CI) was 61% (53%, 71%) (complete response = 27%, very good partial response = 13%, and partial response = 21%) and median progression-free survival was 22.2 months (95% CI: 16.1-not reached). The 3-year overall survival was 75%. The most frequent grade 3-4 adverse events were thrombocytopenia (18%), neutropenia (17%), and anemia (11%). Peripheral neuropathy of any grade was observed in 44% of patients (2% with grade 3). Comparison between regimens (Intensive vs Optimized) showed similar overall response rate (57% vs 70%) and PFS (25 vs 19 months). A similar safety profile was observed between regimens. Thus, SQ bortezomib showed similar effectiveness and better tolerability as compared with results from intravenous bortezomib studies, and showing no differences either in effectiveness or safety in different bortezomib-based combinations.

Evidence mapping based on systematic reviews of therapeutic interventions for gastrointestinal stromal tumors (GIST).

BACKGROUND: Gastrointestinal Stromal Tumours (GISTs) are the most common mesenchymal tumours. Currently, different pharmacological and surgical options are used to treat localised and metastatic GISTs, although this research field is broad and the body of evidence is scattered and expanding. Our objectives are to identify, describe and organise the current available evidence for GIST through an evidence mapping approach. METHODS: We followed the methodology of Global Evidence Mapping (GEM). We searched Pubmed, EMBASE, The Cochrane Library and Epistemonikos in order to identify systematic reviews (SRs) with or without meta-analyses published between 1990 and March 2016. Two authors assessed eligibility and extracted data. Methodological quality of the included systematic reviews was assessed using AMSTAR. We organised the results according to identified PICO questions and presented the evidence map in tables and a bubble plot. RESULTS: A total of 17 SRs met eligibility criteria. These reviews included 66 individual studies, of which three quarters were either observational or uncontrolled clinical trials. Overall, the quality of the included SRs was moderate or high. In total, we extracted 14 PICO questions from them and the corresponding results mostly favoured the intervention arm. CONCLUSIONS: The most common type of study used to evaluate therapeutic interventions in GIST sarcomas has been non-experimental studies. However, the majority of the interventions are reported as beneficial or probably beneficial by the respective authors of SRs. The evidence mapping is a useful and reliable methodology to identify and present the existing evidence about therapeutic interventions.

Maternal Folate Status and the BHMT c.716G>A Polymorphism Affect the Betaine Dimethylglycine Pathway during Pregnancy.

The effect of the betaine: homocysteine methyltransferase BHMT c.716G>A (G: guanosine; A: adenosine) single nucleotide polymorphism (SNP) on the BHMT pathway is unknown during pregnancy. We hypothesised that it impairs betaine to dimethylglycine conversion and that folate status modifies its effect. We studied 612 women from the Reus Tarragona Birth Cohort from ≤12 gestational weeks (GW) throughout pregnancy. The frequency of the variant BHMT c.716A allele was 30.8% (95% confidence interval (CI): 28.3, 33.5). In participants with normal-high plasma folate status (>13.4 nmol/L), least square geometric mean [95% CI] plasma dimethylglycine (pDMG, µmol/L) was lower in the GA (2.35 [2.23, 2.47]) versus GG (2.58 [2.46, 2.70]) genotype at ≤12 GW (p < 0.05) and in the GA (2.08 [1.97, 2.19]) and AA (1.94 [1.75, 2.16]) versus GG (2.29 [2.18, 2.40]) genotypes at 15 GW (p < 0.05). No differences in pDMG between genotypes were observed in participants with possible folate deficiency (≤13.4 nmol/L) (p for interactions at ≤12 GW: 0.023 and 15 GW: 0.038). PDMG was lower in participants with the AA versus GG genotype at 34 GW (2.01 [1.79, 2.25] versus 2.44 [2.16, 2.76] and at labour, 2.51 [2.39, 2.64] versus 3.00 [2.84, 3.18], (p < 0.01)). Possible deficiency compared to normal-high folate status was associated with higher pDMG in multiple linear regression analysis (ß coefficients [SEM] ranging from 0.07 [0.04], p < 0.05 to 0.20 [0.04], p < 0.001 in models from early and mid-late pregnancy) and the AA compared to GG genotype was associated with lower pDMG (ß coefficients [SEM] ranging from -0.11 [0.06], p = 0.055 to -0.23 [0.06], p < 0.001). CONCLUSION: During pregnancy, the BHMT pathway is affected by folate status and by the variant BHMT c.716A allele.

Angiopoietin-like protein 8 (ANGPTL8) in pregnancy: a brown adipose tissue-derived endocrine factor with a potential role in fetal growth.

Angiopoietin-like protein 8 (ANGPTL8), a protein implicated in lipid and glucose homeostasis, is present only in mammals, suggesting that it is involved in processes unique to these vertebrates such as pregnancy and homeothermy. We explored the role of ANGPTL8 in maternal-fetal crosstalk and its relationship with newborn adiposity. In a longitudinal analysis of healthy pregnant women, ANGPTL8 levels decreased progressively during pregnancy although remained higher than levels in the postpartum period. In a cross-sectional observational study of women with or without gestational diabetes mellitus (GDM), and their offspring, ANGPTL8 levels were higher in venous cord blood than those in maternal blood and were significantly lower in GDM patients than those in healthy women. Infants small for gestational age and with low-fat mass had the highest ANGPTL8 cord blood levels. Studies in vitro revealed that ANGPTL8 was secreted by brown adipocytes and its expression was increased in experimental models of white-to-brown fat conversion. In addition, ANGPTL8 induced the expression of markers of brown adipocytes. The high levels of ANGPTL8 found in fetal life together with its relationship with newborn adiposity and brown adipose tissue point to ANGPTL8 as a potential new player in the modulation of the thermogenic machinery during the fetal-neonatal transition.

Cancer randomized trials showed that dissemination bias is still a problem to be solved.

OBJECTIVE: The objective of the present study was to determine the publication rate of cancer randomized controlled trial (RCTs) and to analyze the determinants of the publication, as well as to estimate the possible existence of a location and time lag bias. We also described the bibliometric characteristics of the publications. STUDY DESIGN AND SETTING: We conducted an observational study that identified publications resulting from RCTs involving cancer-related drug products. These studies were authorized and registered by the Spanish Agency of Medicines and Medical Devices between 1999 and 2003. RESULTS: We identified 168 publications of 303 RCTs, resulting in a publication rate of 55.4% after a mean follow-up of 12 years. The only factor associated to the likelihood of nonpublication was the study setting favoring only national RCTs (odds ratio 2.7; 95% confidence interval 1.5-4.8). Type of sponsor did not seem to be associated, although the largest volume of nonpublished trials is international, industry-sponsored. Positive results seemed to be associated to a publication in a higher impact factor journal and a shorter time-to-publication. CONCLUSIONS: About half of the cancer RCTs during the target period have not been published. The national setting is a factor associated to nonpublication, whereas the direction of results determines its dissemination (impact factor and timely publication).

The MUK five protocol: a phase II randomised, controlled, parallel group, multi-centre trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs. cyclophosphamide, bortezomib (Velcade) and dexamethasone (CVD) for first relapse and primary refractory multiple myeloma.

BACKGROUND: Multiple myeloma is a plasma cell tumour with an annual incidence in the UK of approximately 40-50 per million i.e. about 4500 new cases per annum. The triple combination cyclophosphamide, bortezomib (Velcade®) and dexamethasone (CVD) is an effective regimen at relapse and has emerged in recent years as the standard therapy at first relapse in the UK. Carfilzomib has good activity as a single agent in the relapsed setting, and it is expected that efficacy will be improved when used in combination with dexamethasone and cyclophosphamide. METHODS: MUK Five is a phase II open label, randomised, controlled, parallel group, multi-centre trial that will compare the activity of carfilzomib, cyclophosphamide and dexamethasone (CCD) with that of CVD, given over an equivalent treatment period (24 weeks), in participants with multiple myeloma at first relapse, or refractory to no more than 1 line of treatment. In addition, the study also aims to assess the utility of a maintenance schedule of carfilzomib in these participants. The primary objective of the trial is to assess whether CCD provides non-inferior activity in terms of ≥ VGPR rates at 24 weeks, and whether the addition of maintenance treatment with carfilzomib to CCD provides superior activity in terms of progression-free survival, as compared to CCD with no maintenance. Secondary objectives include comparing toxicity profiles, further summarizing and comparing the activity of the different treatment arms and analysis of the effect of each treatment arm on minimal residual disease status. DISCUSSION: The development of carfilzomib offers the opportunity to further explore the anti-tumour efficacy of proteasome inhibition and, based on the available evidence, it is important and timely to obtain data on the activity, toxicity and tolerability of this drug. In contrast to ongoing phase III trials, this phase II trial has a unique subset of participants diagnosed with multiple myeloma at first relapse or refractory to no more than 1 line of treatment and will also evaluate the utility of maintenance with carfilzomib for up to 18 months and investigate minimal residual disease status to provide information on depth of response and the prognostic impact thereof. TRIAL REGISTRATION: The trial is registered under ISRCTN17354232, December 2012.

Interobserver variance in myelodysplastic syndromes with less than 5 % bone marrow blasts: unilineage vs. multilineage dysplasia and reproducibility of the threshold of 2 % blasts.

Previous studies have shown the reproducibility of the 2008 World Health Organization (WHO) classification in myelodysplastic syndromes (MDS), especially when multilineage dysplasia or excess of blasts are present. However, there are few data regarding the reproducibility of MDS with unilineage dysplasia. The revised International Prognostic Scoring System R-IPSS described two new morphological categories, distinguishing bone marrow (BM) blast cell count between 0-2 % and >2- < 5 %. This distinction is critical for establishing prognosis, but the reproducibility of this threshold is still not demonstrated. The objectives of our study were to explore the reliability of the 2008 WHO classification, regarding unilineage vs. multilineage dysplasia, by reviewing 110 cases previously diagnosed with MDS, and to study whether the threshold of ≤2 % BM blasts is reproducible among different observers. We used the same methodology as in our previous paper [Font et al. (2013) Ann Hematol 92:19-24], by encouraging investigators to include patients with <5 % BM blasts. Samples were collected from 11 hospitals and were evaluated by 11 morphologists. Each observer evaluated 20 samples, and each sample was analyzed independently by two morphologists. Discordance was observed in 36/108 suitable cases (33 %, kappa test 0.503). Diagnosis of MDS with unilineage dysplasia (refractory cytopenia with unilineage dysplasia (RCUD), refractory anemia with ring sideroblasts (RARS) or unclassifiable MDS) was assessed in 33 patients, by either of the two observers. We combined this series with the cases with RCUD or RARS included in our 2013 paper, thus obtaining 50 cases with unilineage dysplasia by at least one of the observers. The whole series showed very low agreement regarding RCUD (5/23, 21 %) and RARS (5/28, 18 %). Regarding BM blast count, the threshold of ≤2 % was not reproducible (discordance rate 32/108 cases, kappa test 0.277). Our study shows that among MDS WHO 2008 categories, interobserver discordance seems to be high in cases with unilineage dysplasia. We also illustrate that the threshold of ≤2 % BM blasts as settled by the R-IPSS may be not easy to reproduce by morphologists in real practice.

Guía de práctica clínica para el diagnóstico y el tratamiento de las infecciones bacterianas y micóticas en pacientes oncológicos mayores de 15 años con neutropenia febril posquimioterapia de alto riesgo / Recommendations for diagnosis and treatment of bacterial and fungal infections in cancer patients older than 15 years with febrile neutropenia after high-risk chemotherapy: A Clinical Practice Guideline

Objetivos: El tratamiento actual de las neoplasias busca mejorar la sobrevivencia mediante la aplicación de esquemas de quimioterapia intensificada, que produce una neutropenia más profunda y duradera, que favorece el desarrollo de infecciones bacterianas y micóticas invasoras. Este artículo resume las recomendaciones de una guía para el diagnóstico y tratamiento de las infecciones bacterianas y micóticas en pacientes oncológicos mayores de 15 años con neutropenia febril posquimioterapia de alto riesgo. Métodos: Guía de práctica clínica basada en la evidencia. Se realizó la definición de preguntas clínicas, la búsqueda sistemática de literatura, la evaluación crítica de la evidencia y la formulación de recomendaciones. Se desarrolló una evaluación económica sobre la eficiencia de dos esquemas diferentes de tratamiento antimicótico. Resultados: El presente documento incluye recomendaciones para el diagnóstico de infecciones bacterianas y micóticas en paciente con neutropenia, el uso de profilaxis antibiótica y antimicótica, el tratamiento antibiótico empírico, y el tratamiento antimicótico empírico y anticipado en pacientes mayores de 15 años, acorde con la microbiología del contexto colombiano. Conclusiones: La implementación oportuna de las recomendaciones de la guía acorde con el contexto clínico de cada paciente debe contribuir a mejorar la supervivencia y morbilidad infecciosa de los pacientes con neutropenia febril derivada de la quimioterapia.

Objective: Current cancer treatment is intended to improve survival by implementing intensified chemotherapy strategies, which increases the likelihood of neutropenia and favors the development of bacterial and invasive fungal infections. This paper summarizes clinical practice guideline recommendations for the diagnosis and treatment of bacterial and fungal infections in patients older than 15 years with febrile neutropenia after high risk chemotherapy. Methods: Evidence-based clinical practice guideline. A set of clinical questions was defined, a literature search performed, critical appraisal of the evidence, as the development of recommendations. An economic assessment was carried out on two alternative schemes for fungal therapy. Results: This article includes recommendations for the diagnosis of bacterial and fungal infections in neutropenic patients, prophylaxis for bacterial and fungal infections, empiric antimicrobial treatment, empiric and anticipated antifungal therapy in patients over 15 years, according to the microbiology setting in Colombia. Conclusions: Timely implementation of these recommendations according to each clinical context, should contribute to improve survival and reduce infection-derived morbidity in patients with chemotherapy-induced febrile neutropenia.

Description of the protocols for randomized controlled trials on cancer drugs conducted in Spain (1999-2003).

OBJECTIVE: To describe the characteristics of randomized controlled clinical trials (RCT) on cancer drugs conducted in Spain between 1999 and 2003 based on their protocols. METHODS: We conducted an observational retrospective cohort study to identify the protocols of RCTs on cancer drugs authorized by the Agencia Española del Medicamento y Productos Sanitarios (AEMPS) (Spanish Agency for Medicines and Medical Devices) during 1999-2003. A descriptive analysis was completed and the association between variables based on the study setting and sponsorship were assessed. RESULTS: We identified a total of 303 protocols, which included 176,835 potentially eligible patients. Three-quarter of the studies were internationally-based, 61.7% were phase III, and 76.2% were sponsored by pharmaceutical companies. The most frequently assessed outcomes were response rate (24.7%), overall survival (20.7%), and progression-free survival (14.5%). Of all protocols, 10.6% intended to include more than 1000 patients (mean: 2442, SD: 2724). Compared with their national counterparts, internationally-based studies were significantly larger (p<0.001) and were more likely to implement centralized randomization (p<0.001), blinding of the intervention (p<0.001), and survival as primary outcome (p<0.001). Additionally, most internationally-based studies were sponsored by pharmaceutical companies (p<0.01). In a high percentage of protocols, the available information was not explicit enough to assess the validity of each trial. Compared to other European countries, the proportion of Spanish cancer drugs protocols registered at www.clinicaltrials.gov (7%) was lower. CONCLUSION: RCTs on cancer drugs conducted in Spain between 1999 and 2003 were more likely to be promoted by pharmaceutical companies rather than by non-profit national groups. The former were more often part of international studies, which generally had better methodological quality than national ones. There are some worldwide on-going initiatives that aim to increase the transparency and quality of future research.

Low folate status enhances pregnancy changes in plasma betaine and dimethylglycine concentrations and the association between betaine and homocysteine.

BACKGROUND: Folate, choline, and betaine participate in homocysteine metabolism. It is not known whether they interact during pregnancy. OBJECTIVE: The objective was to investigate how folate status affects choline, betaine, and dimethylglycine during pregnancy. DESIGN: Fasting plasma folate, cobalamin, free choline, betaine, dimethylglycine, and total homocysteine (tHcy) were measured longitudinally at <12, 15, 24-27, and 34 gestational weeks (GW); at labor (nonfasting); and in the cord in participants (n = 522) from the Reus-Tarragona Birth Cohort (NUTrició i Creixement Intrauterí Retardat phase). Timing, dose, and duration of folic acid supplement use were recorded. Folate status was classified as below (low) or above (high) median plasma folate at baseline (27.6 nmol/L) and at 24-27 GW (11.4 nmol/L). Associations between folate or betaine with tHcy were investigated by using multiple linear regression analysis. RESULTS: Plasma betaine decreased by 34.8% (1.0%) throughout pregnancy, and dimethylglycine increased by 39.7% (2.7%) between 24-27 GW and labor (all P < 0.001). Compared with high folate status, low status was associated with a higher dimethylglycine/betaine ratio from 15 GW and with lower plasma betaine and higher dimethylglycine from 24 to 27 GW, for the rest of pregnancy. Regression analysis showed that by 24-27 GW, both plasma folate and betaine were inversely associated with tHcy when folate status was low and that the association between betaine and tHcy depended on folate status at 24-27 and 34 GW (interaction terms: P < 0.001 and P < 0.01). Betaine was inversely associated with tHcy at labor regardless of folate status. CONCLUSION: Low folate status enhances the reduction in betaine and the increase in dimethylglycine during pregnancy and strengthens the association between betaine and tHcy. This trial was registered at clinicaltrials.gov as NCT01778205.

Estudio de la estructura factorial de la escala de calidad de vida FACIT-P para los pacientes con cáncer de próstata / A study of the FACIT-P quality of life factorial structure for prostate cancer patients

Objetivo: Realizar el análisis de la estructura de dominios de la escala FACIT-P (4.ª versión), instrumento diseñado para medir el constructo de calidad de vida en pacientes con cáncer de próstata (CP). Métodos: El método seleccionado para delimitar las variables latentes fue el de máxima verosimilitud. La estructura factorial escogida para buscar variables latentes partió de una rotación ortogonal tipo varimax. Resultados: En los pacientes evaluados, más de la mitad procedían de Bogotá, la gran mayoría solo había cursado primaria, y de acuerdo con la escala Gleason, una cuarta parte presentaba un CP de grado intermedio o alto. Los dominios incluidos fueron: 1. aspectos que representan dolor y molestias; 2. elementos relacionados con autonomía y capacidad de desempeño; 3. aspectos de red social, familiar y satisfacción; 4. elementos relacionados con depresión y ansiedad; 5. síntomas específicos del cáncer de próstata. Conclusiones: La estructura de dominios que muestra el instrumento en pacientes colombianos con CP mostró una organización de variables latentes plausible, y similares al constructo de la escala original. A(Objetivo: Realizar el análisis de la estructura de dominios de la escala FACIT-P (4.ª versión), instrumento diseñado para medir el constructo de calidad de vida en pacientes con cáncer de próstata (CP). Métodos: El método seleccionado para delimitar las variables latentes fue el de máxima verosimilitud. La estructura factorial escogida para buscar variables latentes partió de una rotación ortogonal tipo varimax. Resultados: En los pacientes evaluados, más de la mitad procedían de Bogotá, la gran mayoría solo había cursado primaria, y de acuerdo con la escala Gleason, una cuarta parte presentaba un CP de grado intermedio o alto. Los dominios incluidos fueron: 1. aspectos que representan dolor y molestias; 2. elementos relacionados con autonomía y capacidad de desempeño; 3. aspectos de red social, familiar y satisfacción; 4. elementos relacionados con depresión y ansiedad; 5. síntomas específicos del cáncer de próstata. Conclusiones: La estructura de dominios que muestra el instrumento en pacientes colombianos con CP mostró una organización de variables latentes plausible, y similares al constructo de la escala original.

Objective: To analyze the dominion structure of the FACIT-P scale (4th version), an instrument designed to measure the quality of life construct in prostate cancer (PC) patients. Methods: The selected method sought to achieve greatest possible verisimilitude for discrimination of latent variables. The factorial structure chosen to single out latent variables was based upon varimax orthogonal rotation. Results: More than half the number of patients evaluated came from Bogota; a large majority had only primary school education; on the Gleason scale, one fourth suffered from intermediate or high grade PC. Dominions included aspects related to: 1. Pain and discomfort; 2. Independence and performance capacity; 3. Social network, family life and contentment; 4. Depression and anxiety; 5. Specific symptoms related to prostate cancer.Conclusions: The dominion structure produced by the instrument among Colombian PC patients revealed a plausible latent variable organization that resembled the original scale construct.

Aproximaciones complementarias y alternativas al cuidado de la salud en niños con cáncer: estudio con grupos focales / Alternative and complimentary approaches for health care in children with cancer: focus croup study

Objetivos: Este estudio busca conocer cuáles son los tipos de aproximaciones complementarias y alternativas al cuidado de la salud que utilizan los padres o los cuidadores de niños con cáncer que son atendidos en el Instituto Nacional de Cancerología de Bogotá, así como los mecanismos de acción que se adjudican a tales intervenciones. Métodos: Se realizó un estudio con una metodología cualitativa de grupos focales, para explorar los tipos de intervenciones usados, así como los mecanismos de acción propuestos. Resultados: Se armaron 5 grupos focales, que contaron con un total de 45 participantes (padres o cuidadores de niños con diagnóstico de cáncer). Los tipos de intervenciones referidos se relacionan, más que todo, con el grupo de terapias biológicas. Dentro de esta categoría se destaca, como mecanismo de acción, el refuerzo del sistema inmune. Conclusiones: Parece haber un perfil de utilización de estas aproximaciones al cuidado de la salud que es diferente en niños y adultos. Algunos de estos métodos no aparecen reportados en la literatura. Hay diversos mecanismos de acción sugeridos para las terapias biológicas, varios de los cuales han sido reportados en estudios efectuados en otras culturas. Es necesario cuantificar la frecuencia de utilización de estas intervenciones en la población pediátrica.

Objectives: This study seeks to identify what kinds of complimentary approaches and health care alternatives are used by parents or caregivers of children with cancer treated at the National Cancer Institute in Bogotá, as well as the mechanisms of action which allow them to be achieved. Methods: The study was based on qualitative methodology with focus groups in which types of intervention and proposed mechanisms of action were explored. Results: Five focus groups were formed, with a total of 45 participants (parents or caregivers of children with cancer). The most widely discussed intervention topics were those related to biological therapy; with immune system reinforcement appearing as the primary mechanism of action. Conclusions: A distinction appears to exist in the use of health care approaches - some of which are not reported on in the literature - between children and adults. Diverse mechanisms of action for biological therapy have been suggested, mostly in reports from studies carried out in other cultures. It is necessary that the frequency with which these interventions are used be quantified among the pediatric population.

Validation of the FACT-G scale for evaluating quality of life in cancer patients in Colombia.

PURPOSE: To validate the FACT-G scale for measuring quality of life of patients with cancer in Colombia. METHODS: The analysis included factor analysis, confirmatory analysis, Rasch analysis, convergent validity, internal consistency (473 patients diagnosed with cancer), test-retest reliability (97 patients evaluated at two different time points) and sensitivity to change (25 patients evaluated before and after an intervention). RESULTS: A four-factor structure has been found ("Physical well-being", "Social-family well-being", "Functional well-being" and "Emotional well-being"). Two subscales ("Emotional well-being" and "Social-family well-being") have misfitting items. Cronbach's alpha was 0.89 for the whole scale. None of the items had significant impact on the scale's alpha when removed. Lin's concordance correlation coefficient indicated test-retest reliability (rho c: 0.64-0.76) adequate to the uses of the tool. Regarding sensitivity to change, repeated measures analysis demonstrated significant change of the score after an intervention [F(3, 72) = 39.89, P = 0.000]. Except for the domain "Social-family well-being", Pearson's correlation coefficient between equivalent domain scores on FACT-G and the EORTC QLQC-30 ranged from 0.5 to 0.7. CONCLUSIONS: The FACT-G scale measures a four-factor construct. Results indicate that the FACT-G scale is an instrument that performs consistently over time, with evidence of responsiveness. The finding of misfitting items in two subscales ("Social-family well-being", and "Emotional well-being") imposes caution in interpreting the scores of these domains.