Estudio de marcadores moleculares en neoplasias mieloproliferativas

Las neoplasias mieloproliferativas (NM) son un grupo de enfermedades clonales de la célula hematopoyética madre. Entre las NM clásicas se encuentran la policitemia vera (PV), la trombocitemia esencial (TE) y la mielofibrosis primaria (MFP). Durante muchos años el diagnóstico de estas patologías se hacía por exclusión utilizando biomarcadores de clonalidad poco específicos. En el año 2005, la descripción de la mutación JAK2V617F supuso un avance importante en el diagnóstico de estas patologías. Posteriormente, se han descrito mutaciones en otros genes como mutaciones en MPL, TET2, ASXL1, IDH1, IDH2, c-CBL, EZH2, IKZF1 y LNK, en distintas neoplasias mieloides y en porcentaje variable. Aun así, ninguno de estos genes son marcadores específicos de ninguna NM y todavía existe un porcentaje elevado de pacientes con TE y MFP sin un marcador de clonalidad conocido. Además, todos estos genes se han descrito como eventos genéticos implicados en la transformación de una NM a leucemia mieloide aguda. El objetivo de este proyecto fue estudiar varios marcadores moleculares en neoplasias mieloproliferativas Philadelphia negativas. En primer lugar, se estudió la modulación de la carga alélica JAK2V617F en pacientes con PV o TE que recibieron tratamiento citoreductor y a su vez se analizó la dinámica natural de la carga alélica en pacientes que no recibieron tratamiento. Posteriormente, se analizaron la presencia de alteraciones en los genes previamente mencionados, en distintos grupos de pacientes. En primer lugar, se analizó la presencia de mutaciones en TET2, ASXL1, IDH1, IDH2 y CBL en un grupo de pacientes JAK2 y MPL negativos, para determinar la frecuencia de alteraciones de estos genes en este grupo de pacientes y determinar su valor en el diagnóstico de estas patologías. En segundo lugar, se estudió la presencia de mutaciones en estos genes incluyendo EZH2, IKZF1 y LNK para estudiar la incidencia y el valor pronóstico de estas alteraciones en las NM que progresan a mielofibrosis.

X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation

Background: Aproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects. Results: Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%). Conclusion:This tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients.

Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder

Background: There is increasing evidence that impairment of mitochondrial energy metabolism plays an important role in the pathophysiology of autism spectrum disorders (ASD; OMIM number: 209850). A significant proportion of ASD cases display biochemical alterations suggestive of mitochondrial dysfunction and several studies have reported that mutations in the mitochondrial DNA (mtDNA) molecule could be involved in the disease phenotype. Methods: We analysed a cohort of 148 patients with idiopathic ASD for a number of mutations proposed in the literature as pathogenic in ASD. We also carried out a case control association study for the most common European haplogroups (hgs) and their diagnostic single nucleotide polymorphisms (SNPs) by comparing cases with 753 healthy and ethnically matched controls.Results: We did not find statistical support for an association between mtDNA mutations or polymorphisms and ASD.Conclusions: Our results are compatible with the idea that mtDNA mutations are not a relevant cause of ASD and the frequent observation of concomitant mitochondrial dysfunction and ASD could be due to nuclear factors influencing mitochondrion functions or to a more complex interplay between the nucleus and the mitochondrion/mtDNA.

Splenectomy for refractory Evan' syndrome associated with antiphospholipid antibodies: report of two cases.

The main haematological manifestations seen in patients with antiphospholipid antibodies (aPL) are thrombocytopenia, usually mild, and haemolytic anaemia with a positive Coombs test. Owing to the shared characteristics with idiopathic thrombocytopenic purpura, similar rules are followed in the treatment of these cytopenias. Two patients with severe aPL associated cytopenias, who required splenectomy after being refractory to steroids, immunosuppressive agents, and other treatments (intravenous gammaglobulin, danazol), are described, and previously reported cases are reviewed.

Pycnodysostosis. A report of 3 clinical cases

Pycnodysostosis is a rare clinical entity, first described in 1962 by Maroteaux and Lamy. It is a genetic disorder, usually diagnosed at an early age. However, the diagnosis is sometimes late, made as a result of bone fracture, given the severe bone fragility resulting from increased bone density. Oral and maxillofacial manifestations of this disease are very clear. The head is usually large, the nose beaked, the mandibular angle obtuse, and both maxilla and mandible hypoplastic. Dental abnormalities and impaction are observed, as well as alterations in eruption and frequent dental crowding. The differential diagnosis is established with osteopetrosis, cleidocranial dysplasia and idiopathic acro-osteolysis. This article reviews the clinical and radiographic characteristics of pycnodysostosis based on three clinical cases of patients with this disease.

Impacte d'un programa d'activitat física basat en el mètode Klapp i Stretching Global Actiu sobre la postura de persones adultes amb escoliosi idiopàtica

La simetria entre espatlles i l’alçada de les dues crestes ilíaques es perd quan es pateix escoliosi. Aquest empitjorament de la bona postura té conseqüències negatives per a la salut, especialment en el sistema musculoesquelètic. L’objecte principal d’aquest treball és avaluar l’impacte d’un programa d’activitat física basat en la combinació dels mètodes “Klapp” i l’“Stretching Global Actiu” sobre la postura en bipedestació de persones adultes que pateixen escoliosi idiopàtica. L’aplicació d’ambdós mètodes de forma individual no obtenen millores en aquests paràmetres en persones adultes, però en canvi en nens i nenes sí. El treball és un estudi experimental en el qual es va assignar un subjecte al grup intervenció i un subjecte al grup control. El subjecte del grup intervenció va realitzar un programa de 20 sessions de 45 – 60 minuts de treball amb aquests dos mètodes de treball físic. El subjecte del grup control va seguir la seva activitat habitual. Abans i després de la intervenció, es varen mesurar les variables dependents principals i secundaries respectivament. Els resultats obtinguts han revelat una petita millora en la simetria de les espatlles (+0,2 cms.) en el grup intervenció però no en la simetria de l’altura de les crestes ilíaques. El grup control no ha presentat canvis. Per tant, podem dir que és útil utilitzar la combinació dels dos mètodes físics per a millorar la postura en persones adultes que pateixen escoliosi idiopàtica.

Association of early repolarization with risk of cardiac mortality in the general population

Early repolarization, which is characterized by an elevation of the J-point on 12-lead electrocardiography, is a common finding that has been considered as benign for decades. However, in the last years, it has been related with vulnerability to idiopathic ventricular fibrillation and with cardiac mortality in the general population. Recently, 4 potential ECG predictors that could differentiate the benign from the malignant form of early repolarization have been suggested. Any previous study about early repolarization has been done in Spain. Aim. To ascertain whether the presence of early repolarization pattern in a resting electrocardiogram is associated with a major risk of cardiac death in a Spanish general population and to determine whether the presence of potential predictors of malignancy in a resting electrocardiogram increases the risk of cardiac mortality in patients with early repolarization pattern. Methods. We will analyse the presence of early repolarization and the occurrence of cardiac mortality in a retrospective cohort study of 4,279 participants aged 25 to 74 years in the province of Girona. This cohort has been followed during a mean of 9.8 years. Early repolarization will be stratified according to the degree of J-point elevation (≥0.1 mV or ≥0.2 mV), the morphology of the J-wave (slurring, notching or any of these two), the ST-segment pattern (ascending or descending) and the localization (inferior leads, lateral leads, or both). Association of early repolarization with cardiac death will be assessed by adjusted Cox-proportional hazards models

Available evidence and outcome of off-label use of rituximab in clinical practice

Purpose: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. Methods: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. Results: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.568.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 24 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 1230months) in 69.2%of patients showing a short-term response. Median cost per patient was 5,187.5 (IQR 5,187.57,781.3). Conclusions: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice.

Economic evaluation of the levonorgestrel-releasing intrauterine system for the treatment of dysfunctional uterine bleeding in Spain

To compare the cost and effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) versus combined oral contraception (COC) and progestogens (PROG) in first-line treatment of dysfunctional uterine bleeding (DUB) in Spain. STUDY DESIGN: A cost-effectiveness and cost-utility analysis of LNG-IUS, COC and PROG was carried out using a Markov model based on clinical data from the literature and expert opinion. The population studied were women with a previous diagnosis of idiopathic heavy menstrual bleeding. The analysis was performed from the National Health System perspective, discounting both costs and future effects at 3%. In addition, a sensitivity analysis (univariate and probabilistic) was conducted. RESULTS: The results show that the greater efficacy of LNG-IUS translates into a gain of 1.92 and 3.89 symptom-free months (SFM) after six months of treatment versus COC and PROG, respectively (which represents an increase of 33% and 60% of symptom-free time). Regarding costs, LNG-IUS produces savings of 174.2-309.95 and 230.54-577.61 versus COC and PROG, respectively, after 6 months-5 years. Apart from cost savings and gains in SFM, quality-adjusted life months (QALM) are also favourable to LNG-IUS in all scenarios, with a range of gains between 1 and 2 QALM compared to COC and PROG. CONCLUSIONS: The results indicate that first-line use of the LNG-IUS is the dominant therapeutic option (less costly and more effective) in comparison with first-line use of COC or PROG for the treatment of DUB in Spain. LNG-IUS as first line is also the option that provides greatest health-related quality of life to patients.

Economic evaluation of the levonorgestrel-releasing intrauterine system for the treatment of dysfunctional uterine bleeding in Spain

To compare the cost and effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) versus combined oral contraception (COC) and progestogens (PROG) in first-line treatment of dysfunctional uterine bleeding (DUB) in Spain. STUDY DESIGN: A cost-effectiveness and cost-utility analysis of LNG-IUS, COC and PROG was carried out using a Markov model based on clinical data from the literature and expert opinion. The population studied were women with a previous diagnosis of idiopathic heavy menstrual bleeding. The analysis was performed from the National Health System perspective, discounting both costs and future effects at 3%. In addition, a sensitivity analysis (univariate and probabilistic) was conducted. RESULTS: The results show that the greater efficacy of LNG-IUS translates into a gain of 1.92 and 3.89 symptom-free months (SFM) after six months of treatment versus COC and PROG, respectively (which represents an increase of 33% and 60% of symptom-free time). Regarding costs, LNG-IUS produces savings of 174.2-309.95 and 230.54-577.61 versus COC and PROG, respectively, after 6 months-5 years. Apart from cost savings and gains in SFM, quality-adjusted life months (QALM) are also favourable to LNG-IUS in all scenarios, with a range of gains between 1 and 2 QALM compared to COC and PROG. CONCLUSIONS: The results indicate that first-line use of the LNG-IUS is the dominant therapeutic option (less costly and more effective) in comparison with first-line use of COC or PROG for the treatment of DUB in Spain. LNG-IUS as first line is also the option that provides greatest health-related quality of life to patients.

Available evidence and outcome of off-label use of rituximab in clinical practice

Purpose: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. Methods: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. Results: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.5-68.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 2-4 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 12-30months) in 69.2%of patients showing a short-term response. Median cost per patient was 5,187.5 (IQR 5,187.5-7,781.3). Conclusions: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice.

Association of early repolarization with risk of cardiac mortality in the general population

Early repolarization, which is characterized by an elevation of the J-point on 12-lead electrocardiography, is a common finding that has been considered as benign for decades. However, in the last years, it has been related with vulnerability to idiopathic ventricular fibrillation and with cardiac mortality in the general population. Recently, 4 potential ECG predictors that could differentiate the benign from the malignant form of early repolarization have been suggested. Any previous study about early repolarization has been done in Spain. Aim. To ascertain whether the presence of early repolarization pattern in a resting electrocardiogram is associated with a major risk of cardiac death in a Spanish general population and to determine whether the presence of potential predictors of malignancy in a resting electrocardiogram increases the risk of cardiac mortality in patients with early repolarization pattern. Methods. We will analyse the presence of early repolarization and the occurrence of cardiac mortality in a retrospective cohort study of 4,279 participants aged 25 to 74 years in the province of Girona. This cohort has been followed during a mean of 9.8 years. Early repolarization will be stratified according to the degree of J-point elevation (≥0.1 mV or ≥0.2 mV), the morphology of the J-wave (slurring, notching or any of these two), the ST-segment pattern (ascending or descending) and the localization (inferior leads, lateral leads, or both). Association of early repolarization with cardiac death will be assessed by adjusted Cox-proportional hazards models