Feasibility and outcomes after dose reduction of immunochemotherapy in young adults with Burkitt lymphoma and leukemia: results of the BURKIMAB14 trial.

High dose-intensive or infusional intermediate-dose immunochemotherapy is highly effective treatment for Burkitt lymphoma irrespective of human immunodeficiency virus (HIV) infection. However, toxicities of these regimens are relevant, especially in older adults and elderly patients. The prospective multicenter BURKIMAB14 trial included four to six blocks of immunochemotherapy according to stage (localized: 1 and 2 non-bulky; advanced: 2 bulky, 3, 4) and age, with dose reduction in patients >55 years old. Dose-intensity of chemotherapy was reduced in patients ≤55 years old after achieving complete metabolic response (CMR). Their outcomes were compared with those of similar patients included in the former BURKIMAB08 trial, in which there was no dose reduction. CMR was attained in 86 of 107 (80%) patients (17/19 in localized stages and 69/88 in advanced stages). Patients from the BURKIMAB14 trial ≤55 years old showed similar overall survival (OS), fewer infections and cytopenias than patients from the BURKIMAB08 trial. Patients >55 years old had a significantly higher treatment- related mortality despite dose reduction of chemotherapy. With a median follow-up of 3.61 years the 4-year OS probability was 73% (range, 63-81%). Age (≤55 vs. >55 years) and stage (localized vs. advanced) had prognostic significance. No significant differences in OS were observed in HIV-positive versus HIV-negative patients. The results of BURKIMAB14 are similar to those of other dose-intensive immunochemotherapy trials. Age >55 years and advanced stage, but not HIV infection, were associated with poor survival. Dose reduction of chemotherapy in young adults in CMR is safe and does not impact outcomes (clinicaltrials gov. Identifier: NCT05049473).

Detection of kinase domain mutations in BCR::ABL1 leukemia by ultra-deep sequencing of genomic DNA.

The screening of the BCR::ABL1 kinase domain (KD) mutation has become a routine analysis in case of warning/failure for chronic myeloid leukemia (CML) and B-cell precursor acute lymphoblastic leukemia (ALL) Philadelphia (Ph)-positive patients. In this study, we present a novel DNA-based next-generation sequencing (NGS) methodology for KD ABL1 mutation detection and monitoring with a 1.0E-4 sensitivity. This approach was validated with a well-stablished RNA-based nested NGS method. The correlation of both techniques for the quantification of ABL1 mutations was high (Pearson r = 0.858, p < 0.001), offering DNA-DeepNGS a sensitivity of 92% and specificity of 82%. The clinical impact was studied in a cohort of 129 patients (n = 67 for CML and n = 62 for B-ALL patients). A total of 162 samples (n = 86 CML and n = 76 B-ALL) were studied. Of them, 27 out of 86 harbored mutations (6 in warning and 21 in failure) for CML, and 13 out of 76 (2 diagnostic and 11 relapse samples) did in B-ALL patients. In addition, in four cases were detected mutation despite BCR::ABL1 < 1%. In conclusion, we were able to detect KD ABL1 mutations with a 1.0E-4 sensitivity by NGS using DNA as starting material even in patients with low levels of disease.

Validación de la escala multifactorial mixta de engagement educativo (EMMEE) / Validation of the mixed multifactor scale of educational engagement (MMSEE)

Actualmente, el engagement educativo se considera uno de los factores más importantes a la hora de predecir un buen aprendizaje por parte de los estudiantes, así como su éxito educativo. Sin embargo, la mayoría de los instrumentos descritos, no incluyen todos los factores clave vinculados al engagement académico: motivaciones, valores, contextos de aprendizaje, estado emocional y estrategias de gestión. El objetivo de este estudio es desarrollar una escala para valorar el nivel de engagement educativo de los estudiantes en Educación Superior (EMMEE) que supere esta limitación. MÉTODO: Se realizan análisis factoriales exploratorio y confirmatorio, así como un estudio de la consistencia interna, validez convergente y discriminante en una muestra de 764 estudiantes de la Universidad de Sevilla (España), perteneciente a todas las áreas de saber y los diferentes cursos de grados. RESULTADOS: Se explora y se confirma con muy buen nivel de ajuste una estructura multifactorial de engagement educativo de cinco factores que explican una varianza cercana al 65.78%, con una excelente consistencia interna (α = .91) y con indicios significativos de validez convergente y discriminante. CONCLUSIONES: Se concluye que la EMMEE es un instrumento válido y fiable para medir el nivel de engagement de las aulas, así como mejorar el entendimiento del constructo a través de sus factores

Today, educational engagement is considered one of the most important factors in predicting good student learning and educational success. However, most of the instruments described do not include all the key factors linked to academic engagement: motivations, values, learning contexts, emotional state and management strategies. The aim of this study is to develop a scale to assess the level of educational engagement in High-er Education students (MMSEE) that overcomes this limitation. METHODS: Exploratory and confirmatory factorial analyses, as well as a study of internal consistency, convergent and discriminant validity, were carried out on a sample of 764 students from the University of Seville (Spain), belonging to all areas of knowledge and different degree courses. RESULTS: A multifactorial structure of educational engagement with five factors that explain a variance close to 65.78%, with an excellent internal consistency (α = .91) and with significant indicators of convergent and discriminant validity is explored and confirmed with a very good level of adjustment. CONCLUSIONS: It is concluded that MMSEE is a valid and reliable instrument to measure the level of engagement of classrooms, as well as to improve the under-standing of the construct through its factors

Detection of Suicidal Ideation on Social Media: Multimodal, Relational, and Behavioral Analysis.

BACKGROUND: Suicide risk assessment usually involves an interaction between doctors and patients. However, a significant number of people with mental disorders receive no treatment for their condition due to the limited access to mental health care facilities; the reduced availability of clinicians; the lack of awareness; and stigma, neglect, and discrimination surrounding mental disorders. In contrast, internet access and social media usage have increased significantly, providing experts and patients with a means of communication that may contribute to the development of methods to detect mental health issues among social media users. OBJECTIVE: This paper aimed to describe an approach for the suicide risk assessment of Spanish-speaking users on social media. We aimed to explore behavioral, relational, and multimodal data extracted from multiple social platforms and develop machine learning models to detect users at risk. METHODS: We characterized users based on their writings, posting patterns, relations with other users, and images posted. We also evaluated statistical and deep learning approaches to handle multimodal data for the detection of users with signs of suicidal ideation (suicidal ideation risk group). Our methods were evaluated over a dataset of 252 users annotated by clinicians. To evaluate the performance of our models, we distinguished 2 control groups: users who make use of suicide-related vocabulary (focused control group) and generic random users (generic control group). RESULTS: We identified significant statistical differences between the textual and behavioral attributes of each of the control groups compared with the suicidal ideation risk group. At a 95% CI, when comparing the suicidal ideation risk group and the focused control group, the number of friends (P=.04) and median tweet length (P=.04) were significantly different. The median number of friends for a focused control user (median 578.5) was higher than that for a user at risk (median 372.0). Similarly, the median tweet length was higher for focused control users, with 16 words against 13 words of suicidal ideation risk users. Our findings also show that the combination of textual, visual, relational, and behavioral data outperforms the accuracy of using each modality separately. We defined text-based baseline models based on bag of words and word embeddings, which were outperformed by our models, obtaining an increase in accuracy of up to 8% when distinguishing users at risk from both types of control users. CONCLUSIONS: The types of attributes analyzed are significant for detecting users at risk, and their combination outperforms the results provided by generic, exclusively text-based baseline models. After evaluating the contribution of image-based predictive models, we believe that our results can be improved by enhancing the models based on textual and relational features. These methods can be extended and applied to different use cases related to other mental disorders.

Incidence and outcome after first molecular versus overt recurrence in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia included in the ALL Ph08 trial from the Spanish PETHEMA Group.

BACKGROUND: Disease recurrence occurs in 20% to 40% of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who are treated with chemotherapy and tyrosine kinase inhibitors (TKIs). In the current study, the authors report the incidence, treatment, and outcome after first disease recurrence in young and older adults treated in the ALL Ph08 trial (ClinicalTrials.gov identifier NCT01491763). METHODS: Patients aged 18 to 55 years with de novo Ph+ ALL were treated with imatinib concurrently with standard-dose induction and consolidation therapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) when possible. In patients with first disease recurrence, the authors analyzed the type of recurrence, timing, location, presence of kinase domain mutations, type of treatment, and outcomes. RESULTS: Of the 125 patients, 28 patients (22%) developed disease recurrence before (4 patients) or after (24 patients) HSCT, with the recurrences being molecular in 11 patients (39%) and overt in 17 patients (61%). T315I was the most common mutation noted at the time of disease recurrence. Change in TKI was the most frequent treatment for patients with molecular disease recurrence whereas rescue chemotherapy and TKI change followed by second allo-HSCT when possible were performed for the most part in patients with overt disease recurrence. A total of 20 patients (71%) achieved response. The median disease-free survival (DFS) and overall survival (OS) were 8.5 months and 15.3 months, respectively. A trend for better DFS and OS was observed in patients with molecular recurrence compared with those with overt recurrence (median of 16.9 months vs 6.3 months [P = .05] and 28.7 months vs 11.5 months [P = .05] for DFS and OS, respectively). CONCLUSIONS: Disease recurrence was frequent in young and older adults with Ph+ ALL who were treated with imatinib and chemotherapy with HSCT. Although the majority of patients responded to rescue therapy, their outcomes were poor, especially with regard to overt disease recurrence.

The poor prognosis of low hypodiploidy in adults with B-cell precursor acute lymphoblastic leukaemia is restricted to older adults and elderly patients.

The prognostic significance of low-hypodiploidy has not been extensively evaluated in minimal residual disease (MRD)-oriented protocols for adult acute lymphoblastic leukaemia (ALL). We analysed the outcome of hypodiploid adult ALL patients treated within Programa Español de Tratamientos en Hematología (PETHEMA) protocols. The 5-year cumulative incidence of relapse (CIR) of low-hypodiploid B-cell precursor (BCP)-ALL was significantly higher than that of high-hypodiploids (52% vs. 12%, P = 0.013). Low-hypodiploid BCP-ALL patients aged ≤35 years showed superior survival (71% vs. 21%, P = 0.026) and lower 5-year CIR (17% vs. 66%, P = 0.090) than low-hypodiploids aged >35 years. Older adults and elderly low-hypodiploid BCP-ALL patients show dismal prognosis although achieving an end-induction good MRD response.

Presence of acute and chronic renal failure in patients with paroxysmal nocturnal hemoglobinuria: results of a retrospective analysis from the Spanish PNH Registry.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disease. With the advent of eculizumab treatment, renal function has substantially improved, although no data from real-world clinical practice are available. An observational, retrospective, multicenter study was conducted in Spain on clinical data obtained from outpatient visits of patients with PNH (Spanish PNH Registry) who had experienced acute (ARF) or chronic (CRF) renal failure. Of the 128 patients registered (April 2014), 60 were diagnosed with classic PNH. Twenty-seven (45.0%) patients with a mean age of 48.5 (±16.2) years had renal failure, ARF or CRF, and were included in this study. Near half of the patients (n = 13; 48.1%) presented with ARF alone, 33.3% (n = 9) had CRF with episodes of ARF, while 18.5% (n = 5) were diagnosed with CRF alone. For patients with diagnosis of PNH and renal failure (n = 27), the median time to the first ARF episode was 6.5 (CI 95%; 2.2, 14.9) years, whereas the median to the diagnosis of CRF was 14.5 (CI 95%; 3.8, 19.2) years after the diagnosis of PNH. Patients with ARF (n = 22) were treated with eculizumab and did not experience new episodes of ARF, except for one patient with sepsis. Of the patients with CRF, two received treatment without experiencing further episodes of ARF. Sixteen patients who completed treatment (11 with ARF and 5 with ARF + CRF) recovered from the episode of ARF or from CRF. Of the remaining patients treated with eculizumab, one patient improved from stages III to II, three patients stabilized without showing disease progression, and one patient progressed from stages III to IV. Treatment with eculizumab in PNH patients has beneficial effects on renal function, preventing ARF and progression to CRF.

Clinical characteristics of patients with central nervous system relapse in BCR-ABL1-positive acute lymphoblastic leukemia: the importance of characterizing ABL1 mutations in cerebrospinal fluid.

We investigated the frequency, predictors, and evolution of acute lymphoblastic leukemia (ALL) in patients with CNS relapse and introduced a novel method for studying BCR-ABL1 protein variants in cDNA from bone marrow (BM) and cerebrospinal fluid (CSF) blast cells. A total of 128 patients were analyzed in two PETHEMA clinical trials. All achieved complete remission after imatinib treatment. Of these, 30 (23%) experienced a relapse after achieving complete remission, and 13 (10%) had an isolated CNS relapse or combined CNS and BM relapses. We compared the characteristics of patients with and without CNS relapse and further analyzed CSF and BM samples from two of the 13 patients with CNS relapse. In both patients, classical sequencing analysis of the kinase domain of BCR-ABL1 from the cDNA of CSF blasts revealed the pathogenic variant p.L387M. We also performed ultra-deep next-generation sequencing (NGS) in three samples from one of the relapsed patients. We did not find the mutation in the BM sample, but we did find it in CSF blasts with 45% of reads at the time of relapse. These data demonstrate the feasibility of detecting BCR-ABL1 mutations in CSF blasts by NGS and highlight the importance of monitoring clonal evolution over time.

Blastic plasmacytoid dendritic cell neoplasm frequently shows occult central nervous system involvement at diagnosis and benefits from intrathecal therapy.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid neoplasm which shows a high rate of central nervous system (CNS) recurrence and overall survival (OS) of <1 year. Despite this, screening for CNS involvement is not routinely performed at diagnosis and intrathecal (IT) prophylaxis is not regularly administered in BPDCN. Here, we prospectively evaluated 13 consecutive BPDCN patients for the presence of CNS involvement by flow cytometry. Despite none of the patients presented with neurological symptoms, occult CNS involvement was detected in 6/10 cases evaluated at diagnosis and 3/3 studied at relapse/progression. BPDCN patients evaluated at diagnosis received IT treatment -either CNS prophylaxis (n = 4) or active therapy (n = 6)- and all but one remain alive (median follow-up of 20 months). In contrast, all three patients assessed at relapse/progression died. The potential benefit of IT treatment administered early at diagnosis on OS and CNS recurrence-free survival of BPDCN was further confirmed in a retrospective cohort of another 23 BPDCN patients. Our results show that BPDCN patients studied at diagnosis frequently display occult CNS involvement; moreover, they also indicate that treatment of occult CNS disease might lead to a dramatically improved outcome of BPDCN.

Paroxysmal nocturnal hemoglobinuria: a single Spanish center's experience over the last 40 yr.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease. To date, many reviews and series have been described. We report the experience of our center by presenting a review of 56 PNH patient cases with an average age at diagnosis of 38 yr and follow-ups beginning at approximately 40 yr; the median survival rate was 11 yr. The average clonal size upon diagnosis was 48%, presenting a variable evolution. Thrombotic episodes and cancer were five each, and the main causes of death among our patients were equal at 8.9%. Radiological study by magnetic resonance imaging is presented as a fundamental technique for estimating the deposit of iron levels in the liver and kidney, as well as in some decisive cases at the start of eculizumab therapy. Sixteen patients have been treated with eculizumab so far in our series, and being a safe drug, it provides improvement in the patients' quality of life, and the disappearance of clinical symptoms, and avoids the emergence of new thrombosis.

Treatment of young patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia using increased dose of imatinib and deintensified chemotherapy before allogeneic stem cell transplantation.

The main outcomes of the Programa Español para Tratamiento de Hemopatías (PETHEMA)-acute lymphoblastic leukaemia (ALL)-Ph-08 trial were described and compared with those of the historical PETHEMA-CSTIBES02 trial. The trials differed in imatinib dose (600 vs. 400 mg/d) and amount of chemotherapy (one vs. two consolidation cycles) before stem cell transplantation (SCT). All patients (n = 29) enrolled in the ALL-Ph-08 trial achieved complete remission (CR) (vs. 90% in CSTIBES02), and SCT was performed in CR in 90% (vs. 78%). The reduction in early death, relapse before SCT and transplant-related mortality observed in the ALL-Ph-08 trial resulted in an improved 2-year event-free survival (63% vs. 37%, P = 0·009).

Reacciones adversas a medicamentos en el Hospital La Paz registradas en el conjunto mínimo básico de datos (CMBD) durante 2003 / Adverse drug reactions recorded in the Minimum Basic Data Set of the Hospital La Paz in 2003

Objetivo: Las reacciones adversas medicamentosas (RAM) son un problema de salud pública, cuya magnitud es difícil de cuantificar debido a su infranotificación. Nuestro objetivo fue identificar y describir las RAM registradas en el conjunto mínimo básico de datos (CMBD) del Hospital La Paz durante 2003.Pacientes y métodos: Estudio transversal. Se seleccionaron los episodios codificados, según la CIE-9-MC, como tales en los informes de alta de todos los pacientes hospitalizados durante 2003. Se describieron y analizaron las variables sociodemográficas, las categorías diagnósticas y los tipos de fármacos, entre otras. Resultados: De las 50.929 altas registradas en el CMBD, se detectaron 1.092 episodios con al menos una RAM (2,1 por ciento). De éstos, 217 (0,4 por ciento del total) tuvieron como causa principal del ingreso una RAM. Los servicios con mayor número de pacientes ingresados por esta causa fueron los de oncología médica y medicina interna. Hallamos diferencias significativas (p < 0,001) entre la estancia media de los pacientes ingresados por una RAM (8,1 días) y los que la presentaron durante su hospitalización (18,2 días). Conclusiones: El CMBD es una herramienta útil para la identificación, la cuantificación y el análisis de las RAM (AU)

Overexpression of complement receptors and related antigens on the surface of bone marrow mast cells in patients with systemic mastocytosis.

Depending on their stage of maturation and other factors, mast cell (MC) subsets differ from each other in terms of the expression of complement-associated antigens. This study analysed the expression of various complement-related cell surface antigens (CD11b/CR3, CD11c/CR4, CD35/CR1, CD55/DAF, CD59/MIRL, CD88/C5aR) on bone marrow mast cells (BMMC) in patients suffering from systemic mastocytosis (SM), other haematological diseases and non-haematological disorders (control groups). Expression of complement-associated cell surface antigens was analysed by flow cytometry. There were clear immunophenotypic differences between BMMC obtained from patients with SM and those from the control subjects: the percentage of patients expressing surface CD11c, CD35 and CD88 was significantly higher in patients with SM (76%, 100%, 54%) than in the control subjects (58%, 11%, 18%) (P < 0.05). In addition, the levels of CD11c, CD35 and CD88 expressed per MC (sites per cell) were significantly higher (P < 0.05) in SM than in the control group. Expression of the complement regulatory molecules CD55 and CD59 was detected in BMMC in all patients analysed. However, the levels of CD59 per BMMC were higher in patients with SM as compared with the control subjects, which could help to explain the formation of BMMC aggregates in the former group of individuals. Together, our results showed that BMMC in systemic mastocytosis overexpressed the cell surface membrane receptors involved in binding of complement components and complement-mediated cell activation. Whether this pathological expression of complement receptors is of pathophysiological significance remains to be determined.

Changes in the pool of bile acids in hepatocyte nuclei during rat liver regeneration.

BACKGROUND/AIMS: To investigate changes in nuclear bile acids (BAs) during rat liver regeneration. METHODS: Nuclei were isolated from control rat livers and after two-thirds partial hepatectomy (PH). BAs in bile, liver homogenate and nuclei were measured by gas chromatography-mass spectrometry. Nuclear translocation of radiolabeled BAs was determined using fresh isolated hepatocytes from control donors. RESULTS: Liver BA concentrations were transiently reduced after PH. Relative increases in: -MCA at 1 day, deoxycholic acid at 7 days and cholic acid (CA) at 3 and 14 days were found. Nuclear BAs accounted for <0.5% of liver BAs. Contamination with cytosolic BAs during nuclei isolation was <4%. Unconjugated- and conjugated-CA were able to reach the nucleus with similar efficiency. The pattern of nuclear BAs--CA (80%) and ursodeoxycholic acid (UDCA) (8.5%) being the most abundant--did not match that found in liver or bile. A transient decrease in CA/UDCA ratio, in absence of significant change in total BA content, was observed in nuclei after PH. "Flat" BA species were only detected in homogenate, but not in nuclei, at 1 day after PH. CONCLUSIONS: BA pool in nuclei of rat hepatocytes, whose composition is different to that of total liver BA pool, undergoes important changes during liver regeneration.