Real-life management of primary immune thrombocytopenia (ITP) in adult patients and adherence to practice guidelines.

Very few data exist on the management of adult patients diagnosed with primary immune thrombocytopenia (ITP). The objectives of this study were to describe the diagnostic and treatment patterns for ITP and to compare the findings to recent ITP guidelines. We retrospectively analyzed the medical records of adult ITP patients diagnosed with primary ITP between January 2011 and June 2012 and examined whether management strategies were consistent or not with eight recent guideline-recommended practices. Overall, median age at the diagnosis of the disease (n = 101) was 58 years and median platelet count 12 × 10(9)/L with 75.2 % of patients having symptoms of ITP. The study perceived two major shortcomings in the diagnostic approach: (1) failure to perform peripheral blood film examination in 22.8 % of patients, a test that is mandatory by all guidelines, and (2) ordinary bone marrow assessment in more than half of the patients at diagnosis (50.5 %), a test not routinely recommended by guidelines. Low appropriateness in therapeutic management of patients included (1) unjustified use of intravenous immunoglobulin in the absence of bleeding in 54.8 % of patients and (2) splenectomy not being deferred until 6-12 months from diagnosis (median 161 days). Data also reflect a trend towards the early use of thrombopoietin receptor agonists in the treatment of patients who are refractory to any first-line therapy. We have recognized important areas of inapropriateness in the diagnostic and therapeutic management of adult ITP patients. Compliance with established guidelines should be encouraged in order to improve patient outcomes.

Design and application of a 23-gene panel by next-generation sequencing for inherited coagulation bleeding disorders.

INTRODUCTION: Molecular testing of Inherited bleeding coagulation disorders (IBCDs) not only offers confirmation of diagnosis but also aids in genetic counselling, prenatal diagnosis and in certain cases genotype-phenotype correlations are important for predicting the clinical course of the disease and to allow tailor-made follow-up of individuals. Until recently, genotyping has been mainly performed by Sanger sequencing, a technique known to be time consuming and expensive. Currently, next-generation sequencing (NGS) offers a new potential approach that enables the simultaneous investigation of multiple genes at manageable cost. AIM: The aim of this study was to design and to analyse the applicability of a 23-gene NGS panel in the molecular diagnosis of patients with IBCDs. METHODS: A custom target enrichment library was designed to capture 31 genes known to be associated with IBCDs. Probes were generated for 296 targets to cover 86.3 kb regions (all exons and flanking regions) of these genes. Twenty patients with an IBCDs phenotype were studied using NGS technology. RESULTS: In all patients, our NGS approach detected causative mutations. Twenty-one pathogenic variants were found; while most of them were missense (18), three deletions were also identified. Six novel mutations affecting F8, FGA, F11, F10 and VWF genes, and 15 previously reported variants were detected. NGS and Sanger sequencing were 100% concordant. CONCLUSION: Our results demonstrate that this approach could be an accurate, reproducible and reliable tool in the rapid genetic diagnosis of IBCDs.

Relationship between calcium mobilization and platelet α- and δ-granule secretion. A role for TRPC6 in thrombin-evoked δ-granule exocytosis.

Changes in cytosolic Ca(2+) concentration ([Ca(2+)]c) regulate granule secretion in different cell types. Thrombin activates PAR1 and PAR4 receptors and promotes release of Ca(2+) from distinct intracellular stores, which, in turn, activates store-operated Ca(2+) entry (SOCE). A crucial step during platelet function is the release of physiological agonists stored in secretory granules to the extracellular compartment during activation. We aim to study the role of Ca(2+) mobilization from the extracellular compartment or from different intracellular stores in platelet granule secretion. By using flow cytometry, we have found that α- and δ-granules are secreted in thrombin-stimulated platelets in the absence of extracellular Ca(2+), and in a concentration-dependent manner. Our findings show that thrombin-stimulated granule secretion depends on Ca(2+) mobilization from intracellular stores. Analysis of the kinetics of granule secretion reveals that platelet stimulation with thrombin results in rapid release of α-granules which precedes the secretion of δ-granules. Incubation of platelets with a specific antibody, which recognizes the extracellular amino acid sequence 573-586 of TRPC6, inhibited thrombin-evoked δ-granule exocytosis. Our results indicate that the mechanisms underlying thrombin-induced α- and δ-granule secretion show differences in dependency on Ca(2+) mobilization.

Identification of seven novel SMPD1 mutations causing Niemann-Pick disease types A and B.

Niemann-Pick disease (NPD) types A and B are autosomal, recessively inherited, lysosomal storage disorders caused by deficient activity of acid sphingomyelinase (E.C. 3.1.4.12) because of mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. Here, we present the molecular analysis and clinical characteristics of 15 NPD type A and B patients. Sequencing the SMDP1 gene revealed eight previously described mutations and seven novel mutations including four missense [c.682T>C (p.Cys228Arg), c.1159T>C (p.Cys387Arg), c.1474G>A (p.Gly492Ser), and c.1795C>T (p.Leu599Phe)], one frameshift [c.169delG (p.Ala57Leufs*20)] and two splicing (c.316+1G>T and c.1341delG). The most frequent mutations were p.Arg610del (21%) and p.Gly247Ser (12%). Two patients homozygous for p.Arg610del and initially classified as phenotype B showed different clinical manifestations. Patients homozygous for p.Leu599Phe had phenotype B, and those homozygous for c.1341delG or c.316+1G>T presented phenotype A. The present results provide new insight into genotype/phenotype correlations in NPD and emphasize the difficulty of classifying patients into types A and B, supporting the idea of a continuum between these two classic phenotypes.

Experiencia asistencial del programa de Cuidados Paliativos de la Fundación CUDECA / No disponible

Introducción/Objetivos: la Fundación CUDECA esta formada por un equipo asistencial multidisciplinar formado por médicos, enfermeros-as, trabajadora social, psicóloga y voluntarios cualificados, que atiende al paciente paliativo tanto en el Centro CUDECA, como en el propio domicilio del enfermo, consiguiendo así que se puedan cumplir los deseos de las personas en esta situación, enfermos y familiares, de permanecer en su propio hogar. Se analizan, en este estudio, los datos de 3.400 pacientes atendidos en el Programa Asistencial de Cuidados Paliativos de la Fundación CUDECA. Material y métodos: se procesaron los datos de 3.400 pacientes, incluidos en programa desde 1992 hasta 2005, mediante el programa estadístico SPSS 11.0, se realizó un estudio descriptivo de las siguientes características de los pacientes: sexo, edad de los pacientes, edad del cuidador, tiempo de permanencia en programa, tipo de tumor más frecuente y lugar de defunción de los pacientes, que figuraba codificado de la siguiente manera: domicilio, hospital, UCP (Unidad de Cuidados Paliativos), residencia y otros. Resultados: la media de edad es de 67 años. Acorde con la mayor prevalencia de tumores en pacientes mayores y también en relación con el mayor envejecimiento de la población. Predominan los varones: 59,4%. En relación a la mayor incidencia de tumores, destaca el de pulmón en varones, que es el tumor más prevalente en nuestra población. La media de estancia en programa es de 76 días. La mediana es de 36 días. Destaca el tumor de pulmón como el más frecuente con un 24%. Seguido del colorrectal con un 14%, cabeza y cuello y cáncer de mama con un 10%. La mayoría de nuestros pacientes, el 76,8%, fallecen en el domicilio. Conclusiones: la mayoría de nuestros pacientes, el 76,8% fallecen en el domicilio. Es un dato muy importante de calidad de asistencia en Cuidados Paliativos, ya que se consigue que los pacientes mueran en su ambiente familiar. Supone un importantísimo ahorro al Sistema Nacional de Salud y compañías privadas, ya que se evitan estancias prolongadas en hospital, con el ahorro que supone de coste cama/día. Los datos de alta frecuencia de cáncer de pulmón coinciden con los descritos en la literatura, ya que se trata del tumor más prevalente. En nuestra población destaca la alta frecuencia de tumores de cabeza y cuello, en posible relación al tabaco y al consumo de alcohol. La media de estancia en programa es corta, estos datos demuestran la sospecha inicial de que los pacientes son derivados a las Unidades de Cuidados Paliativos por los Servicios de Oncología en situación muy avanzada de su enfermedad, es necesario, por tanto, mejorar la coordinación entre las Unidades de Cuidados Paliativos y los Servicios de Oncología de Procedencia (AU)

Objectives: CUDECA Foundation is formed by a multidisciplinary team of doctors, nurses, social workers, psychologists, and qualified volunteers who care for patients at CUDECA's center and in their homes, so that patients can stay with their families in their own houses. We analyzed the data of 3,400 patients who entered the palliative care program of CUDECA Foundation. The main objectives of CUDECA are: to offer «specialised palliative care» to patients suffering from terminal cancer, and also to support their families during illness and the bereavement process. To constitute a study, training, investigation, and awareness program regarding palliative care. Our care is offered completely free of charge to those patients and families who need it and who live in Malaga province, Spain. Methods: We analyzed the data of 3400 patients who entered the palliative program of CUDECA Foundation using the statistical program SPSS 11.0. A descriptive study was performed of the following patient characteristics: sex, median age, median age of caregiver, time in the program, and place of death, which was coded with the following variables -nursing home, hospital, palliative care unit (PCU), home, other. Results: The majority of our patients, 76.8%, died in their homes. Median age of patients: 67 years. Median age of caregiver: 55 years. Males predominated (59.4%) in the prevalence of tumours, especially of the lungs. Mean time in the program: 76 days. Lung cancer was the most frequent malignancy (24%), followed by colorectal cancer (14%), and head and neck tumours (10%). Conclusions: Mean age of patients was high due to the greater prevalence of tumours in older patients and also in relation to population ageing. Mean time in the program was not very long (76 days); as patients are sent to palliative care units by oncology departments when disease is advanced, coordination between palliative care units and oncology departments. The high frequency of lung cancer is consistent with the data described in the literature, as this is the tumour with the highest prevalence. A majority of our patients, 76.8 %, died in their homes. This is avery important quality-of-life issue in palliative care, as we allowed patients to die with their families and in their homes according to their own wishes (AU)

Mejoría de la disnea tras el tratamiento con citrato de fentanilo oral transmucoso en paciente con cáncer de pulmón avanzado / Dyspnea improvement following treatment with oral transmucosal fentanyl citrate in a patient with advanced lung cancer

La disnea es un síntoma muy frecuente en medicina paliativa, especialmente en pacientes con diagnostico de cáncer de pulmón, que afecta seriamente la calidad de vida de los pacientes. Presentamos un caso clínico, de un paciente con disnea secundaria a un cáncer de pulmón avanzado, resistente a tratamiento convencional con morfina, donde la disnea se controla con el uso del citrato de fentanilo oral transmucoso. Se realiza una revisión amplia de la literatura donde apenas hay estudios del uso del citrato de fentanilo oral transmucoso en el tratamiento de la disnea, si hemos encontrado estudios con el uso del fentanilo nebulizado en el tratamiento de la disnea, con buenos resultados. Sería interesante la realización de ensayos fase II-III que respondieran a esta pregunta (AU)

Dyspnea is a frequent symptom in palliative medicine, and may seriously affect patient quality of life. We report a case of dyspnea in a patient with advanced lung cancer resistant to conventional treatment with morphine, which was controlled with oral transmucosal fentanyl citrate. We performed a systematic review of the literature, and found little evidence on the use of oral transmucosal fentanyl citrate in the treatment of dyspnea; however, we did find some evidence on the use of nebulized fentanyl with positive results. It is important that new phase II-III clinical studies are designed to answer this question (AU)

Un caso de feocromocitoma intratorácico en una gestante en el tercer trimestre / A case of intrathoracic pheochromocytoma in a third trimester pregnancy

La asociación de feocromocitoma y gestación es rara; su diagnóstico es difícil dada su similitud con la preeclampsia. El pronóstico maternofetal es determinado por el diagnóstico precoz y el manejo multidisciplinario. El diagnóstico se establece por la elevación de catecolaminas en orina de 24 h y las técnicas de imagen. La extirpación del tumor, previo bloqueo adrenérgico, se realiza en función de la edad gestacional antes o después del parto.Así, se reduce de forma considerable la mortalidad maternofetal, que es muy alta cuando se desconoce el diagnóstico (AU)

No disponible

Diagnosis of secondary myelodysplastic syndromes (MDS) following autologous transplantation should not be based only on morphological criteria used for diagnosis of de novo MDS.

Secondary myelodysplastic syndromes (MDS) are increasingly being reported after autologous transplantation. Transient dysplastic changes have also been observed after this type of treatment. However, to the best of our knowledge no systematic morphological analysis has been performed to determine the influence of stem cell transplantation on bone marrow morphology. In 53 patients undergoing autologous transplantation, we evaluated the bone marrow, before and 6 and 12 months after the transplant, in order to analyze the appearance of dyshemopoietic changes, assessed according to a pre-established score. We also studied 25 bone marrow samples obtained at the time of diagnosis, prior to treatment, but we did not find morphological atypia. Six months after transplant, cellularity and thrombopoiesis had decreased in 38% and 49% of patients respectively, although 1 year after the process they were normal in most cases. Myelodysplasia was already present in bone marrow before transplantation and continued to be in evidence for a long time afterwards. This suggests that chemotherapy and radiotherapy used prior to transplantation are responsible for dysplastic changes. The myeloid line was the most affected with 100% of patients showing dysgranulopoiesis 1 year after autografting. Cytopenias were observed in 51% and 44% of patients 6 and 12 months after transplantation. Moreover, concomitant presence of cytopenia and myelodysplasia was observed in 37.7% of patients at 6 months after transplantation and 25% at 12 months, and therefore they could be diagnosed with MDS. These data contrast with the incidence of secondary MDS reported in earlier publications. According to these findings, the value of the French-American-British Co-operative Group criteria for the diagnosis of MDS following autologous transplantation is questionable. Moreover, since dyshemopoietic features are almost always present after autologous transplant, morphological criteria are not useful for early recognition of patients with secondary MDS after transplantation.

Platelet serotonin is a mediator potentially involved in anaphylactic reaction to neuromuscular blocking drugs.

A platelet serotonin release test was performed on blood from 10 patients who had suffered from an IgE-dependent allergic reaction to a neuromuscular blocking drug. The results were compared with those of a leukocyte histamine release test. The upper limit of serotonin release induced by neuromuscular blockers was estimated to be 2.3% in non-allergic patients. The test was positive in six patients and was consistent with histamine release in five. Serotonin release induced by neuromuscular blockers comprised 2.9-25% of total platelet serotonin content. We conclude that serotonin is one of the mediators associated with histamine release during anaphylaxis to neuromuscular blockers. Platelet serotonin release tests may be useful for the investigation of anaphylactic responses to neuromuscular blocking drugs.

Clinical evaluation of in vitro leukocyte histamine release in allergy to muscle relaxant drugs.

We have evaluated the in vitro leukocyte histamine release tests for the diagnosis of allergy to muscle relaxant drugs in 40 patients (Group A) and a control group of 44 subjects with negative leukocyte histamine release (Group B). Non-IgE dependent histamine release, expressed as a percentage of the total blood histamine, was 3.94% +/- 0.49 in Group B. The upper limit of positivity was estimated to be 5% (mean + 2 SD). Leukocyte histamine release tests were positive in 65% of the patients from Group A. The concordance between LHR and QAS-RIA was 64%. The maximal histamine release was observed at dilutions of 10(-2)-10(-4) in 20 of the 26 positive cases. The maximal histamine release was 43.8% +/- 23.3. The spontaneous histamine release was as low as 1.7% +/- 1.1. Cross-reactivity among the 5 different muscle relaxant drugs has been investigated and compared by intradermal testing. The muscle relaxant drugs which gave the lower skin reaction (M2) and the drug responsible for shock (M1) were selected for the study of in vitro leukocyte histamine release. Of 20 M2. All of the 10 cases had negative ID tests with M2. Three of these patients subsequently underwent general anesthesia with the muscle relaxant chosen as harmless (M2) without any clinical reaction.