Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

Use of serology in a systematic screening programme for strongyloidiasis in an immigrant population.

OBJECTIVES: The aim of this cross-sectional study was to describe the results of a systematic serological screening programme for strongyloidiasis. METHODS: A prospective serological screening programme for strongyloidiasis was performed between 2009 and 2014 for all immigrant patients attending the Tropical Medicine Unit. Three formalin-ether concentrated stool samples and an ELISA for anti-Strongyloides stercoralis antibodies were used as screening tools. RESULTS: Of 659 patients screened, 79 (12%) were positive for S. stercoralis regardless of the diagnostic method used. The prevalence of infection was 42.9% in East African patients, 16.3% in Central African patients, 10.9% in those from South America, and 10% in the case of West Africa. Univariate analysis showed that infection by S. stercoralis was significantly more frequent in patients from Central Africa (p=0.026; OR 1.72, 95% CI 1.03-2.85) and East Africa (p<0.001; OR 5.88, 95% CI 1.75-19.32). Taking West Africa as the reference (as the area of lowest prevalence among the positive prevalence areas), the statistical analysis showed that the risk of infection was higher in East Africa (p=0.001; OR 6.750, 95% CI 2.127-21.423) and Central Africa (p=0.065; OR 1.747, 95% CI 0.965-3.163). CONCLUSIONS: Due to the potential complications of strongyloidiasis infection, we recommend that immigrant patients from developing countries be routinely screened for S. stercoralis, especially those from East Africa. A serological test is a highly appropriate screening tool.

Factors associated with quit attempts and smoking cessation in Brazil: findings from the International Tobacco Control Brazil Survey.

OBJECTIVES: This study aimed to identify factors associated with attempting to quit and successful smoking cessation in a population-based sample of Brazilian smokers. STUDY DESIGN: This is a prospective cohort study. METHODS: Data came from the first two waves of the International Tobacco Control Brazil Survey, conducted in 2009 and 2012/2013 in three cities: Rio de Janeiro, São Paulo, and Porto Alegre. Data were collected from 488 adults (aged ≥18 years) who smoked at Wave 1 and who were resurveyed at Wave 2. Crude and adjusted relative risks for two outcomes (making a quit attempt between Wave 1 and Wave 2 and successfully quitting by Wave 2) were estimated. Multivariable multilevel logistic regression models were used, whereby variables were added to the models in a series of blocks. RESULTS: Nearly two-thirds (65.6%) of smokers attempted to quit between waves, and 23.4% had quit at Wave 2. Intention to quit smoking at Wave 1 was the only variable associated with attempt to quit by Wave 2 (odds ratio [OR] = 2.85; 95% confidence interval [CI] 1.64-4.94; P < 0.001). Smokers of higher socio-economic status (OR high versus low = 1.80; 95% CI 1.05-3.10; P = 0.03) and lower nicotine dependence (OR low Heaviness of Smoking Index [HSI] versus high HSI = 1.94; 95% CI 1.10-3.43; P = 0.02) were more likely to successfully quit. The presence of another adult smoker at home was negatively related to successful quitting (OR = 0.50; 95% CI 0.26-0.94; P = 0.03). CONCLUSIONS: These results are generally consistent with prior research and have potential to inform governmental interventions to promote tobacco cessation, particularly among disadvantaged groups.

Sex differences in kinetic and neuromuscular control during jumping and landing.

In the present study, we analysed the kinetic profile together with the lower limb EMG activation pattern during a countermovement jump and its respective landing phase in males and females. Twenty subjects (10 males and 10 females) took part in the study. One experimental session was conducted in order to record kinetic and electromyographic (EMG) parameters during a countermovement jump (CMJ) and the subsequent landing phase. During the CMJ, males recorded a higher (p<0.001) performance than females in terms of jump height and power production. Stiffness values were lower in males than females due to greater centre of mass displacement during the countermovement (p<0.01). According to the EMG activity, males demonstrated greater (p<0.05) activation during the concentric phase of the jump. However, females revealed a higher co-contraction ratio in the plantar flexors during the push-off phase. During landings males showed higher (p<0.01) peak ground reaction forces (Fpeak), greater (p<0.05) stiffness and a higher maximal displacement of the CoM (p<0.05) than females. EMG analysis revealed greater EMG activity in the tibialis anterior (p<0.05) and rectus femoris (p=0.05) muscles in males. Higher plantar flexor co-activation during landing has also been found in males. Our findings demonstrated different neuromuscular control in males and females during jumping and landing.

Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

Chronic myeloid leukaemia in Spain: Its presentation characteristics have changed. Spanish section of the EUTOS population-based registry. / Leucemia mieloide crónica en España: sus características de presentación han cambiado. Sección española del registro poblacional EUTOS.

OBJECTIVES: To provide more reliable data on the epidemiology of chronic myeloid leukaemia (CML) in Spain than are currently available. MATERIAL AND METHODS: The EUTOS population-based project of European LeukemiaNet is a population registry of new CML cases in patients 18 years of age or older from 22 European areas. The Spanish section included the autonomous communities of Madrid, Castilla-La Mancha and Aragon, from 1-2-2010 to 31-12-2012. RESULTS: A total of 250 cases were recorded in 35 months. The overall incidence was 1.08 cases/10(5) inhabitants-year, with a predominance of men (58%) and clear differences among the communities. The incidence standardised by age was similar (overall, 1.04; men, 1.31; women, 0.81). The median age was 54 years. The incidence increased with age, reaching a peak at>65 years, although 31.7% of cases appeared between the ages of 20 and 44 years. Four percent of cases were diagnosed in advanced stages (2.4% in accelerated phase, 1.6% in blast crisis), 56% were asymptomatic, 38% had splenomegaly, and the Sokal score was high in 11% (lower than what was previously reflected in the literature). CONCLUSIONS: The current incidence of CML in Spain is higher than previously reported and similar to that of the European studies. Unlike the classical descriptions, CML presented mostly in asymptomatic form, with no splenomegaly, less leucocytosis and in stages with better prognosis.

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.

European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia.

Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life.

Whole-exome sequencing in splenic marginal zone lymphoma reveals mutations in genes involved in marginal zone differentiation.

Splenic marginal zone lymphoma (SMZL) is a B-cell neoplasm whose molecular pathogenesis remains fundamentally unexplained, requiring more precise diagnostic markers. Previous molecular studies have revealed 7q loss and mutations of nuclear factor κB (NF-κB), B-cell receptor (BCR) and Notch signalling genes. We performed whole-exome sequencing in a series of SMZL cases. Results confirmed that SMZL is an entity distinct from other low-grade B-cell lymphomas, and identified mutations in multiple genes involved in marginal zone development, and others involved in NF-κB, BCR, chromatin remodelling and the cytoskeleton.

Training-induced changes in drag-flick technique in female field hockey players.

The penalty corner is one of the most important goal plays in field hockey. The drag-flick is used less by women than men in a penalty corner. The aim of this study was to describe training-induced changes in the drag-flick technique in female field hockey players. Four female players participated in the study. The VICON optoelectronic system (Oxford Metrics, Oxford, UK) measured the kinematic parameters of the drag-flick with six cameras sampling at 250 Hz, prior to and after training. Fifteen shots were captured for each subject. A Wilcoxon test assessed the differences between pre-training and post-training parameters. Two players received specific training twice a week for 8 weeks; the other two players did not train. The proposed drills improved the position of the stick at the beginning of the shot (p < 0.05), the total distance of the shot (p < 0.05) and the rotation radius at ball release (p < 0.01). It was noted that all players had lost speed of the previous run. Further studies should include a larger sample, in order to provide more information on field hockey performance.

Effect of experimental diabetes and STZ on male fertility capacity. Study in rats.

To assess the effect of experimental Type 1 diabetes on male fertility, male Sprague Dawley rats were injected with either streptozotocine (STZ) to induce diabetes or with citrate buffer as controls. Diabetic animals and 2 control groups (STZ-resistant and buffer-injected rats) were sacrificed at 2 different times after injection: 6 weeks (6W) and 20 weeks (20W). We analyzed serum testosterone (sTT), epididymal sperm parameters, and weight of testicles and epididymides, and carried out a histological evaluation of testicular tissue. Diabetic animals presented a significant increase in teratozoospermia (20W, P < .01) and a decrease in sTT (P < .01), tubular diameter (6W, P < .05), and testicular (6W, P < .01) and epididymal (P < .01) weight. STZ-resistant animals showed significantly decreased sTT (6W, P < .01), epididymal weight (6W, P < .05), and sperm count (6W, P < .01) compared with buffer-injected controls. Experimental STZ diabetes increases teratozoospermia and decreases sTT, testicular weight (reverting at medium-term), and epididymal weight.

[Evaluation of guidelines for the assessment of success after vasectomy and needed improvements]. / Evaluación de un protocolo para el control de la vasectomía y modificaciones a realizar.

OBJECTIVES: The evaluation of a recently established guidelines about the assessment of semen samples after vasectomy in the laboratory of the Hospital General of Albacete and to modify them to optimize the number of semen samples provided per patient but keeping in concordande with the international recommendations. PATIENTS AND METHODS: The records of seminal analysis results from vasectomies performed from January 2002 to December 2004 were reviewed. Our vasectomy guidelines are based upon those of the British Andrology Society (BAS) and those of the World Health Organization for seminal assessment. RESULTS: During the 3 years 984 patients underwent vasectomy. At follow up, 67% of them returned postvasectomy semen samples, but just 55.,5% of them get the clearance criteria; the other patient abandoned before getting them. A mean of 2 samples per patient were received, but 39.6% of them provided one and more than 23% brought more than 3 semen samples. We had 43 technical failures, 4 early recanalization (0.5%) and one late recanalization (0.1%), and 13 patients underwent revasectomy (1,7%). CONCLUSION: A high percentage of our patients failed to fulfill the clearance criteria recommended by the BAS and almost a quarter of them had to deliver more than 3 semen samples. So we find convenient to modify our guides and propose that our patients should receive 2 request forms from the practitioner for semen analysis in the 6th and the 7th month postoperatively and should return to global evaluation of both reports. In that moment most patients will be able to meet the applied criteria for success with just 2 semen samples. Those who fail to become sterile because of either technical failure or early recanalizatione may be advised to go to the urologist with just 2 semen analysis without unnecessary delay.

[Influence of the analytical process in the appearance and disappearance of the spermatozoa after vasectomy]. / Influencia del proceso analítico en la aparición y desaparición de los espermatozoides del semen tras la vasectomia.

OBJECTIVES: To evaluate if the analytical process might justify that in some patients rare non motile sperm might be seen in some but not all their post-vasectomy semen samples. PATIENTS AND METHODS: Post vasectomy ejaculates received in our Center from january 2002 to december 2004 were reviewed. We used our own guidelines for post vasectomy semen assessment based upon those of the British Andrology Society for the evaluation of post vasectomy semen samples and the World Health Organization guidelines for semen analysis. RESULTS: During the 3 years of follow up, 984 patients underwent vasectomy. We received 1.430 semen samples, 2 samples per patient on average. Regarding the pre analytical phase, 134 samples (9.4%) were not completely collected; ejaculate volumes of less than 2 mL were delivered by 269 patients (18.8%); in these cases, we were not sure whether the whole ejaculates were submitted: pre analytical conditions of 11 samples (0.8%) were inappropriate: incorrectly labeled, spilled, provided into inadequate containers... Regarding the analytical phase, 432 ejaculates (30.5%) were extremely viscous and sperm detection might have been affected; 62 semen samples (4.3%) contained many cells which obstructed the visualization of the entire microscopy field. Regarding the post analytical phase, 153 patients (20.9%) had alternative negative/positive results with rare non motile sperm. CONCLUSION: An elevated percentage of incidences involving both the pre analytical and the analytical phase were observed during post-vasectomy seminal analysis. Inadequate conditions may affect the results and justify that spermatozoa may be seen in some but not all the ejaculates of the same patient. We recommend that two semen samples per patient are required to ensure that he is correctly evaluated. We propose to report a negative result as a spermatozoa count bellow the detection limit of our analytical procedure similar to other laboratory magnitudes to minimize the effect of fluctuations in such a low count of rare non motile sperm.

Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach.

The use of the tyrosine kinase inhibitor imatinib, which blocks the enzymatic action of the BCR-ABL fusion protein, has represented a critical advance in chronic myeloid leukemia (CML) treatment. However, a subset of patients initially fails to respond to this treatment. Use of complementary DNA (cDNA) microarray expression profiling allows the identification of genes whose expression is associated with imatinib resistance. Thirty-two CML bone marrow samples, collected before imatinib treatment, were hybridized to a cDNA microarray containing 6500 cancer genes, and analyzed using bootstrap statistics. Patients refractory to interferon-alpha treatment were evaluated for cytogenetic and molecular responses for a minimum of 12 months. A set of 46 genes was differentially expressed in imatinib responders and non-responders. This set includes genes involved in cell adhesion (TNC and SCAM-1), drug metabolism (cyclooxygenase 1), protein tyrosine kinases and phosphatases (BTK and PTPN22). A six-gene prediction model was constructed, which was capable of distinguishing cytogenetic response with an accuracy of 80%. This study identifies a set of genes that may be involved in primary resistance to imatinib, suggesting BCR-ABL-independent mechanisms.

A randomized study of intermediate as compared with high doses of interferon-alpha for chronic myeloid leukemia: no differences in cytogenetic responses.

Interferon-alpha (IFN-alpha) is a therapy of unquestionable efficacy in chronic myeloid leukemia (CML) patients. The best dose of IFN-alpha in the treatment of CML still remains controversial. Our primary objective was to compare cytogenetic responses in patients treated with intermediate versus high doses of IFN-alpha. A multicenter randomized controlled trial was conducted involving 109 patients with untreated CML in chronic phase from 26 Spanish hospitals. Patients were assigned to receive either an intermediate (2.5 MU/m(2) per day) or high (5 MU/m(2) per day) target dose of IFN-alpha. Hydroxyurea was allowed in both groups. In total, 108 patients were analyzed, 53 in the intermediate- and 55 in the high-dose group. Median follow-up was 47.5 months. The dose of IFN-alpha actually given was lower in the intermediate-dose group (3.83 MU/day) than in the high-dose group (6.6 MU/day) ( p<0.001). The rate of complete cytogenetic response was 24.5% in the intermediate- and 12.7% in the high-dose group (NS). A partial cytogenetic response was obtained in 7.5% and 10.9%, respectively. Cox analysis did not reveal any influence of the randomization arm on cytogenetic response rate. Ten patients in each group discontinued IFN-alpha because of toxicity. Albeit not our primary objective, no differences were found in terms of survival or transformation rate between both groups. Median survival was 73 months; 64% of patients remained free of transformation at 5 years. In terms of cytogenetic response, intermediate doses of IFN-alpha are as effective as high doses in the treatment of CML.

[Lung involvement in tularemia]. / Afectación pulmonar en la tularemia.

We present three cases of pneumonia by Francisella Tularensis recently diagnosed. We also review this disease with the literature. All the studied patients were adults; two of them had epidemiological antecedents because of being in contact with hares. They present a clinical-radiological symptoms compatible with the pneumonic case described in the literature. The diagnosis was realized through serology in two cases and hemocultive in the other one. All patients had a positive answer to the antibiotic treatment, two cases with gentamicine and the other one with macrolide. There are not references about the subject in the bibliographical research we have realized in Medline. We did not find information in the Spanish base (IME), perhaps that these were the first cases found in the Spanish literature.

High expression of the ILT2 (LIR-1) inhibitory receptor for major histocompatibility complex class I molecules on clonal expansions of T large granular lymphocytes in asymptomatic patients.

BACKGROUND AND OBJECTIVES: The lymphoproliferative disorders of large granular lymphocytes (LGLD) are divided into two groups: T-cell type and NK-cell type. These entities may be either asymptomatic or associated with autoimmune manifestations (especially cytopenias). A number of surface receptors, expressed by NK-cells and some T-lymphocyte subsets repress cytotoxicity and cytokine production upon ligation with HLA class I molecules and are clonally expressed in theses lymphoproliferative disorders. These cytotoxic lymphocytes can lyse erythroid progenitors in vitro, and the physiologic lower levels of HLA class I antigens on the erythroid lineage may contribute to this form of autoimmunity. It is conceivable that the clinical outcome of T-LGLD might be influenced by the expression of MHC class I inhibitory receptors. DESIGN AND METHODS: We analyzed the surface expression of these molecules, lectin-like heterodimers (CD94/NKG2A) or killer immunoglobulin (Ig)-like receptors (KIR) and another Ig-like inhibitory receptor, termed ILT2 or LIR-1 in CD8+ cells from 12 cases of ab T-LGLD using specific monoclonal antibodies. RESULTS: None of the LGLD cases had anemia and 11 of 12 patients remain asymptomatic. KIR and CD94/NKG2A expression was detected on CD8+ populations only in some cases of T-LGLD. By contrast, our observations revealed that ILT2 expression was markedly higher in CD8+ cells from LGLD patients than from healthy donors. INTERPRETATION AND CONCLUSIONS: Expression of the ILT2 inhibitory receptor for HLA class I molecules on LGLD cells might indeed contribute to preventing their autoreactivity. Further studies are required to evaluate the expression/function of the ILT2 receptor in patients who eventually become symptomatic. The development of cytopenias in LGLD patients must involve other self-reactive activating receptors. Analysis of the expression and function of triggering NKR in LGLD needs to be carefully addressed.

Basilar artery thrombosis in a child heterozygous for factor V Leiden mutation.

Activated protein C resistance, usually because of factor V Leiden mutation, is considered to be the most common hereditary prothrombotic condition. A 9-year-old male with a basilar artery stroke and activated protein C resistance is described. The patient, found to be heterozygous for factor V Leiden mutation, is one of several recent reports that suggest that activated protein C resistance is an important risk factor for spontaneous arterial thrombosis in infancy and childhood.