Current status of precision medicine in pediatric oncology in Spain: a consensus report by the Spanish Society of Paediatric Haematology and Oncology (SEHOP).

The study analyzes the current status of personalized medicine in pediatric oncology in Spain. It gathers national data on the tumor molecular studies and genomic sequencing carried out at diagnosis and at relapse, the centers that perform these studies, the technology used and the interpretation and clinical applicability of the results. Current challenges and future directions to achieve a coordinated national personalized medicine strategy in pediatric oncology are also discussed. Next generation sequencing-based (NGS) gene panels are the technology used in the majority of centers and financial limitations are the main reason for not incorporating these studies into routine care. Nowadays, the application of precision medicine in pediatric oncology is a reality in a great number of Spanish centers. However, its implementation is uneven and lacks standardization of protocols; therefore, national coordination to overcome the inequalities is required. Collaborative work within the Personalized Medicine Group of SEHOP is an adequate framework for encouraging a step forward in the effort to move precision medicine into the national healthcare system.

The paediatric cancer clinical research landscape in Spain: a 13-year multicentre experience of the new agents group of the Spanish Society of Paediatric Haematology and Oncology (SEHOP).

PURPOSE: Early phase trials are crucial in developing innovative effective agents for childhood malignancies. We report the activity in early phase paediatric oncology trials in Spain from its beginning to the present time and incorporate longitudinal data to evaluate the trends in trial characteristics and recruitment rates. METHODS: Members of SEHOP were contacted to obtain information about the open trials at their institutions. The study period was split into two equal periods for analysis: 2007-2013 and 2014-2020. RESULTS: Eighty-one trials and two molecular platforms have been initiated. The number of trials has increased over the time of the study for all tumour types, with a predominance of trials available for solid tumours (66%). The number of trials addressed to tumours harbouring specific molecular alterations has doubled during the second period. The proportion of industry-sponsored compared to academic trials has increased over the same years. A total of 565 children and adolescents were included, with an increasing trend over the study period. For international trials, the median time between the first country study approval and the Spanish competent authority approval was 2 months (IQR 0-6.5). Fourteen out of 81 trials were sponsored by Spanish academic institutions. CONCLUSIONS: The number of available trials, and the number of participating patients, has increased in Spain from 2007. Studies focused on molecular-specific targets are now being implemented. Barriers to accessing new drugs for all ranges of age and cancer diseases remain. Additionally, opportunities to improve academic research are still required in Spain.

[Self-perception of health care team leaders in Andalusia. A quantitative and qualitative study]. / Autopercepción de las personas responsables en los equipos sanitarios de Andalucía. Estudio cuantitativo y cualitativo.

OBJECTIVE: To determine the perception and self-assessment on leadership among health care team leaders in Andalusia. MATERIAL AND METHODS: Design: Exploratory descriptive study using quantitative and qualitative methodology, developed between 2013 and 2015, using a questionnaire and semi-structured interviews. PLACE: Andalusia. PARTICIPANTS: All health managers from the Primary Care Management Units and Health Management Areas of the Departments of Paediatrics, Emergency and Internal Medicine, for the quantitative study. A purposive sample of 24 health managers was used for the qualitative study. METHODS: Descriptive statistical study and bivariate analysis of comparison of means. Content analysis of the semi-structured interviews: Codification, category tree, and triangulation of results. RESULTS: The best self-assessment dimension relates to support, and the worst to considering oneself as a 'good leader'. The definition of a 'good leader' includes: Honesty, trust, and attitudes of good communication, closeness, appreciation, and reinforcement of the health team members. Different leadership styles were perceived. Main difficulties for leadership are related to the economic crisis and the management of personal conflicts. CONCLUSIONS: Health managers describe an adaptive leadership style, based on personal and professional support, and using communication as the main cohesive element for the team project. More studies on leaders' perspectives are important, in order to better understand their experiences, needs and expectations.

Changes in soil microbial community functionality and structure in a metal-polluted site: The effect of digestate and fly ash applications.

Soil from Trhové Dusníky (Príbram, Czech Republic) is characterized by its high polymetallic accumulations in Pb-Ag-Zn due to mining and smelting activities. In previous studies performed in our research group, we have evaluated the potential use of amendments that would reduce the mobility and availability of metals such as Hg. We have observed that the application of digestate and fly ash in metal-polluted soil has an impact in immobilizing these metals. However, until now we have lacked information about the effect of these amendments on soil microbial functionality and communities. The multi-contaminated soil was used to grow wheat in a pot experiment to evaluate the impact of digestate and fly ash application in soil microbial communities. Soil samples were collected after 30 and 60 days of treatment. The digestate application improved chemical attributes such as the content in total organic carbon (TOC), water soluble carbon (WSOC), total soluble carbon (C), total soluble nitrogen (N), and inorganic N forms (NO3(-)) as consequence of high content in C and N which is contained in digestate. Likewise, microbial activity was greatly enhanced by digestate application, as was physiological diversity. Bacterial and fungal communities were increased, and the microbial biomass was highly enhanced. These effects were evident after 30 and 60 days of treatment. In contrast, fly ash did not have a remarkable effect when compared to digestate, but soil microbial biomass was positively affected as a consequence of macro- and micro-nutrient sources applied by the addition of fly ash. This study indicates that digestate can be used successfully in the remediation of metal-contaminated soil.

Short-term dynamics of culturable bacteria in a soil amended with biotransformed dry olive residue.

Dry olive residue (DOR) transformation by wood decomposing basidiomycetes (e.g. Coriolopsis floccosa) is a possible strategy for eliminating the liabilities related to the use of olive oil industry waste as an organic soil amendment. The effects of organic fertilization with DOR on the culturable soil microbiota are largely unknown. Therefore, the objectives of this study were to measure the short-term effects of DOR and C. floccosa-transformed DOR on the culturable bacterial soil community, while at the same time documenting the bacterial diversity of an agronomic soil in the southeastern Iberian Peninsula. The control soil was compared with the same soil treated with DOR and with C. floccosa-transformed DOR for 0, 30 and 60 days. Impact was measured from total viable cells and CFU counts, as well as the isolation and characterization of 900 strains by fatty acid methyl ester profiles and 16S rRNA partial sequencing. The bacterial diversity was distributed between Actinobacteria, Alphaproteobacteria, Gammaproteobacteria, Betaproteobacteria, Bacilli, Sphingobacteria and Cytophagia. Analysis of the treatments and controls demonstrated that soil amendment with untransformed DOR produced important changes in bacterial density and diversity. However, when C. floccosa-transformed DOR was applied, bacterial proliferation was observed but bacterial diversity was less affected, and the distribution of microorganisms was more similar to the unamended soil.

[Extreme reactive thrombocytosis in a healthy 6 year-old child]. / Trombocitosis extrema reactiva en un niño sano de 6 años.

Thrombocytosis is usually a casual finding in children. Reactive or secondary thrombocytosis is the more common form, being the infections diseases the most prevalent cause of it. Regarding the number of platelets there are four degrees of thrombocytosis; in its extreme degree the number of platelets exceeds 1,000,000/mm(3). We describe a case of extreme reactive thrombocytosis in a healthy 6-year-old child. He required critical care admission for diagnosis and treatment (maximum number of platelets 7,283,000/mm(3)). We review the different causes of thrombocytosis in childhood, the differential diagnosis, and the available treatments in case of extreme thrombocytosis.

Extreme reactive thrombocytosis in a healthy 6 year-old child.

Thrombocytosis is usually found by chance in children. Reactive or secondary thrombocytosis is the more common form, with infectious diseases being the most prevalent cause of it. Regarding the number of platelets there are four degrees of thrombocytosis; in its extreme degree the number of platelets exceeds 1,000,000/mm3. We describe a case of extreme reactive thrombocytosis in a healthy 6-year-old child. He required critical care admission for diagnosis and treatment (maximum number of platelets 7,283,000/mm3). We review the different causes of thrombocytosis in childhood, the differential diagnosis, and the available treatments in case of extreme thrombocytosis.

La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm3. Se presenta un caso de trombocitosis extrema reactiva en un niño sano de 6 años, que requirió ingreso en cuidados intensivos para tratamiento y diagnóstico (cifra máxima de plaquetas de 7.283.000/mm3). Se revisan las diferentes causas de trombocitosis en la infancia, se describe el diagnóstico diferencial y se discute sobre los diferentes tratamientos disponibles ante un caso como el descrito.

[Permanence of last generation antiretroviral in daily clinical practice]. / Permanencia del tratamiento antirretroviral de última generación en la práctica clínica diaria.

INTRODUCTION: Time of permanence is a useful measure of success in last generation antiretroviral (LGA) therapy: raltegravir, darunavir, etravirine and maraviroc. The aim of our study was to analyze the permanence of antiretroviral therapy (ART) containing at least one LGA, and to compare it with other ART used in experienced patients. METHODS: Observational case-control study. It included adult outpatients whose ART was switched between 01/05/2008 and 01/09/2009. Cases (patients with at least one LGA) were matched (1:1) with pretreated patients who switched to an ART without any LGA (controls). The primary endpoint was the permanence of ART. The follow-up was conducted from the modification of ART to a year after the closure of the inclusion period. Results were adjusted for confounding variables: CD4 and viral load (VL) at baseline, MDR HIV infection and time from the first ART. RESULTS: 112 patients were included in each group. The permanence of ART was 16.7 months (cases) vs 16.8 months (controls), although statistically significant differences were not found after adjusting for confounding variables. Toxicity was the main reason of discontinuation (53.3% in cases vs 45.2% in controls, p = 0.70). The mean decrease in the logarithm of the VL was 0.89 in cases and 0.58 in controls (p = 0.223). The increase of CD4/microL was 77 and 73 respectively (p = 0.480). CONCLUSION: The permanence of ART in patients whose treatment contains a LGA is similar to those without any LGA.

Introducción: La permanencia es una medida útil del éxito de los tratamientos antirretrovirales de última generación (AUG): raltegravir, darunavir, etravirina y maraviroc. El objetivo de nuestro estudio fue analizar la permanencia de los tratamientos antirretrovirales (TAR) que contenían al menos un AUG, y compararla con otros TAR utilizados en pacientes experimentados. Métodos: Estudio observacional, de casos y controles, de pacientes adultos externos cuyo TAR fue modificado entre 01/05/2008 y 01/09/2009. Los casos (pacientes con al menos un AUG) fueron emparejados (relación 1:1) con pacientes pretratados que cambiaron a un TAR sin AUG (controles). La variable principal fue la permanencia del TAR. El seguimiento se realizó desde la modificación del TAR hasta un año después del cierre del período de inclusión. Los resultados se ajustaron por las variables de confusión: CD4 y carga viral (CV) basales, infección VIH multirresistente y tiempo desde el primer TAR. Resultados: Se incluyeron 112 pacientes en cada grupo. El tiempo de permanencia del TAR fue 16,7 meses (casos) vs 16,8 meses (controles), sin encontrarse diferencias estadísticamente significativas ajustando por las variables de confusión. La toxicidad fue el principal motivo de discontinuación (53,3% en casos vs 45,2% en controles, p = 0,70). La media en la disminución del logaritmo de la CV fue 0,89 en los casos y 0,58 en los controles (p = 0,223). El incremento de CD4/microL fue 77 y 73 respectivamente (p = 0,480). Conclusión: La permanencia del TAR en los pacientes cuyo tratamiento contiene algún AUG es similar a la de los pacientes que no lo contienen.

Different levels of lack of improvement at 4 weeks of escitalopram treatment as predictors of poor 8-week outcome in MDD.

BACKGROUND: Several post-hoc studies have shown that lack of early improvement reduces the chance of later response or remission. This post-hoc analysis evaluates different cut-off points of non-improvement at 4 weeks of escitalopram treatment to predict 8-week non-response and non-remission. METHOD: This study consisted of MDD patients with an absence of improvement (<30% reduction in baseline score of the HAMD-17) at Week 4 of escitalopram treatment (10mg/day) that continued escitalopram treatment (10-20mg/day) for a further 4-week period (n=251). Predictive, sensitivity and specificity values for the several definitions of non-improvement (≤ 25%, ≤ 20% and ≤ 15% reduction in the HAMD-17 baseline total score) at 4 weeks were calculated. RESULTS: Overall, 70.1% (176/251) of patients did not achieve response at Week 8 and 84.5% (212/251) did not achieve remission. The predictive value for non-response was high (71.4-74.3%) for all cut-off points of non-improvement tested. The respective values for non-remission were placed between 85.0% and 87.2%. LIMITATIONS: This was a post-hoc subgroup analysis. The only drug assessed was escitalopram. CONCLUSIONS: Our data indicate that an absence of improvement, <30% reduction in the HAMD-17, after 4 weeks of escitalopram treatment should prompt clinicians to consider a change in treatment strategy. Similar findings were previously reported for other antidepressants.

Three or four fractions per week in postoperative high-dose-rate brachytherapy for endometrial carcinoma. The long-term results on vaginal relapses and toxicity.

BACKGROUND: High-dose-rate brachytherapy (HDR-BT) is an accepted part of treatment for endometrial carcinoma and is usually performed in 1-2 fractions per week using different total doses and doses per fraction. To reduce the overall treatment time, HDR-BT was administered with a 3-4 days/week schedule. PATIENTS AND METHODS: From June 2003 to December 2008, 164 patients with stage I-IIIc endometrial carcinoma were treated with HDR-BT (4-5 Gy per fraction). The patients were divided into two groups; Group 1 (40/164 patients) was treated with HDR-BT alone (6 fractions; 4 fractions/week) and Group 2 (124/164 patients) was treated with both (External Beam Radiotherapy [EBRT] + HDR-BT: 3 fractions/week). Complications were analyzed using RTOG scores for rectum and bladder and the objective scores of LENT-SOMA for vaginal complications. RESULTS: The mean followup was 48 months. In Group 1, 35 % of patients underwent treatment in ≤10 days and 65 % in >10 days. In Group 2, 53.2 % received treatment in ≤5 days and in 46.8 % in >5 days. Vaginal relapse was observed in only two patients (1.2 %), both having received adjuvant EBRT + HDR-BT. Acute vaginal toxicity appeared in 8.5 % and late vaginal toxicity in 20.7 % of patients with 13.4 % being G1, 6.7 % G2 and only 0.6 % being G4. No statistically significant differences were found in complications in either brachytherapy group regardless of the overall time. CONCLUSION: In our series, three fractions given in 3-5/days after EBRT or six fractions in 10 days, is a safe regimen in terms of complications and local control.

[Testosterone-deficiency as a risk factor for hip fracture in eldery men]. / Déficit de testosterona como factor de riesgo de fractura de cadera en hombres de edad avanzada.

OBJECTIVES: Progressive loss of bone mineral density weakens the bones and increases the probability of osteoporotic fractures. It is well known that sex steroids play a role in the maintenance of bone density. This fact makes us think there might be a correlation between sex steroid levels and osteoporotic hip fractures. MATERIAL AND METHODS: A case-control study was performed. The cases were 54 men who suffered from hip fracture. They were compared with 54 age-matched male control subjects. Levels of total testosterone, sex hormone binding globuline, albumin and oestradiol were measured in all subjects in order to calculate free testosterone and bio-testosterone levels. RESULTS: Men who suffered from hip fracture had lower serum total testosterone (8.74 nmol/L versus 11.16 nmol/L; p=0.116) and lower free testostenone (155.1pmol/L versus 204.4pmol/L; p=0.02) than control subjects. Bio-testosterone levels were lower in patients with hip fracture (2.69 nmol/L versus 3.89 nmol/L; p=0.002), being the latter the best fracture predictor (OR: 1.58). CONCLUSIONS: In our study population, men with hip fractures had significantly lower levels of calculated free testosterone and bio-testosterone. These findings suggest that free testosterone and bio-testosterone levels are independent predictors for osteoporotic hip fracture in eldery men.

Indications for the use of next-generation antiretroviral drugs in current clinical practice.

OBJECTIVE: To describe the indications for use, in medical practice, of next-generation antiretroviral drugs (NGA): darunavir, raltegravir, maraviroc and etravirine. METHOD: An observational, transversal and descriptive study conducted in adult patients who have started to receive a NGA between May 2008 and April 2009. The variables associated with the use of NGA were defined as follows: a) Variables related to efficacy: resistance confirmed by geno/phenotype tests or potencial resistance as a result of extensive exposure to antiretroviral agents, and/or severe immunological deterioration (CD4 less than 200 cells/mcl). b) Variables related to safety: prior toxicity to classic antiretroviral drugs and/or comorbidity which compromises their use. c) Combined efficacy and safety variable (main variable): prioritizing the variables which were detected, the patients were classified into three groups: multiresistant geno/phenotype (multi-G/P), multiresistant as a result of treatment history and other situations. Data was obtained from electronic medical records, laboratory tests, and records of interviews and drugs dispensed by the Pharmacy Service. RESULTS: Seventy three patients, 40% of whom had an undetectable viral load and 38.4% who showed severe immunological deterioration, were included in the study. Multi-G/P occurred in 45% and multiresistance as a result of treatment history was found in 33% of patients. Patients classified as belonging to the "other situations" category were characterized by having a greater viral load and a poorer immunological status. In 90% of the patients without multi-G/P two or more variables associated with the use of NGA were detected. DISCUSSION: The medical reality of using NGA shows that they play a role in clinical situations which are very different, specific and difficult to manage.

[Emotional climate in Primary Health Care teams. A qualitative approach]. / El clima emocional en los equipos de atención primaria. Una aproximación cualitativa.

OBJECTIVE: The social interactions met in the Primary Health Care work teams are driven by important emotional aspects that affect the environment, results and the satisfaction of the professional and the patients. The objective of this work is to describe the emotional climate of Primary Care work teams, looking for the perceptions of different professional category and different work groups (selected by the quality of their emotional climate). METHODS: A qualitative methodology was used: 2 nominal groups and 2 focal groups, with 18 physicians and nurses working in the Andalusian Primary Health Care system. The information was recorded and then a content analysis was made. RESULTS: Health care professionals identify the following explanatory dimensions: professional relationship (high scored), shared work project, professional recognition, leadership, burnout and personal attitudes, as well as work conditions. Different opinions were recorded among physicians and nurses, especially when the group had a bad emotional atmosphere. CONCLUSIONS: More studies on the emotional climate in Primary Health Care are needed in order to propose strategies to improve satisfaction and quality of work life among professionals.

Social and occupational functioning impairment in patients in partial versus complete remission of a major depressive disorder episode. A six-month prospective epidemiological study.

PURPOSE: To evaluate social and occupational functioning in patients in partial remission (PR) compared with patients in complete remission (CR) of a major depressive disorder (MDD) episode. SUBJECTS AND METHODS: This is a six-month prospective study. PR was defined as a score more than 7 and less or equal to 15 in the Hamilton Depression Rating Scale, and CR as less or equal to 7. All patients had been on acute antidepressant treatment during the previous three months and no longer met criteria for MDD. Functioning was assessed by the Social and Occupational Functioning Assessment Scale (SOFAS). RESULTS: Mean (S.D.) patient age was 50.5 (14.5) years (N=292) and 77% were female. At baseline, partial remitters showed greater impairment in social and occupational functioning than complete remitters (62.8 [12.6] versus 80.4 [10.5], respectively; P<.0001). After six months, only 47% PR versus 77% CR reached normal functioning, and SOFAS ratings for PR were below normal range (76.2 [12.3] PR versus 84.6 [9.4] CR; P<.0001). PR reported three times more days absent from work due to sickness than CR (63 days versus 20 days; P<.001). CONCLUSION: We conclude that PR of an MDD episode is associated with significant functional impairment that persists even after nine months of antidepressant treatment. Our results underline the importance of treating the patient until achieving full remission.