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BackgroundHaving temporary immigration status affords limited rights, workplace protections, and access to services. There is not yet research data on impacts of the COVID-19 pandemic for people with temporary immigration status in Canada.MethodsWe use linked administrative data to describe SARS-CoV-2 testing, positive tests, and COVID-19 primary care service use in British Columbia from January 1, 2020, to July 31, 2021, stratified by immigration status (Citizen, Permanent Resident, Temporary Resident). We plot the rate of people tested and the rate of people confirmed positive for COVID-19 by week from April 19, 2020, to July 31, 2021, across immigration groups.Results4.9% of people with temporary immigration status had a positive test for SARS-CoV-2 over this period, compared to 4.0% among people with permanent residency and 2.1% among people who hold Canadian citizenship. This pattern is persistent by sex/gender, age group, neighborhood income quintile, health authority, and in both metropolitan and small urban settings. At the same time we observe lower access to testing and COVID-19 related primary care among people with temporary status.InterpretationPeople with temporary immigration status in BC experience higher SARS-CoV-2 test positivity; alarmingly, this was coupled with lower access to testing and primary care. Interwoven immigration, health and occupational policies place people with temporary status in circumstances of precarity and higher health risk. Extending permanent residency status to all immigrants residing in Canada and decoupling access to health care from immigration status could reduce precarity due to temporary immigration status.

Objectives The prevalence of sickle cell disease (SCD) in Spain is markedly inferior compared with other European and Mediterranean countries. However, the diagnosis of new patients with SCD is expected to increase. In this multicenter retrospective study, we analyze the hematopoietic stem cell transplantation (HSCT) results obtained in Spain. Methods Forty-five patients who underwent a matched sibling donor (MSD) HSCT between 1999 and 2018 were included. Primary endpoint was event-free survival (EFS), and secondary endpoints included acute and chronic graft-versus-host disease (GvHD) and overall survival (OS). Results Bone marrow was the most frequent stem cell source (93.3%). Most patients received a conditioning regimen based on busulfan and cyclophosphamide (69%). Cumulative incidence of grade III-IV acute GvHD and chronic GvHD was 6.8% (95% CI: 2.3%-20.1%) and 5.4% (95% CI: 1.38%-19.9%), respectively. EFS and overall survival (OS) at 3 years post-HSCT were 89.4% (95% CI: 73.9%-95.9%) and 92.1% (95% CI: 77.2%-97.4%), respectively. All patients aged

INTRODUCTION: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. MATERIAL AND METHODS: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. RESULTS: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. CONCLUSIONS: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer.

Introduction: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. Material and methods: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. Results: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. Conclusions: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer. (C) 2016 Asociacion Espanola de Pediatria. Published by Elsevier Espana, S.L.U. All rights reserved.

INTRODUCTION: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. MATERIAL AND METHODS: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. RESULTS: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. CONCLUSIONS: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer.

Although high absolute lymphocyte count (ALC) early after transplantation is a simple surrogate for immune reconstitution, few studies to date have established the predictive factors for ALC after umbilical cord blood transplantation (UCBT). We retrospectively studied the factors associated with early lymphocyte recovery and the impact of the ALC on day +42 (ALC42) of >= 300 x 10(6)/L on outcomes in 210 consecutive pediatric and adult patients (112 males; median age, 15 years; range, 0.3 to 60 years; interquartile range, 4 to 36 years) who underwent myeloablative in vivo T cell-depleted single UCBT between 2005 and 2014 for malignant and nonmalignant disorders. In a logistic multivariate regression model, factors favoring a higher ALC42 were higher infused CD3(+) cell dose (odds ratio [OR], 2.7; 95% CI, 1.4 to 5.2; P = .004), lower antithymocyte globulin dose (OR; 2.3; 95% CI, 1.2 to 4.5; P = .01), and better HIA match (OR, 2.1; 95% CI, 1.1 to 4.1; P = .03). In multivariate analysis, lower ALC42 was associated with higher nonrelapse mortality (hazard ratio [HR], 1.76; 95% CI, 1.34 to 2.32; P = .001), whereas a higher ALC42 was associated with better disease-free survival (HR, 2.03; 95% CI, 1.15 to 3.6; P < .001) and overall survival (HR, 2.03; 95% CI, 1.17 to 3.6; P < .001). Our study suggests that the selection of better HLA-matched cord blood units containing higher CD3+ cell counts and the use of conditioning regimens with lower ATG doses could improve immune reconstitution after UCBT. (C) 2016 American Society for Blood and Marrow Transplantation.

Umbilical cord blood transplant recipients are exposed to an increased risk of graft failure, a complication leading to a higher rate of transplant-related mortality. The decision and timing to offer a second transplant after graft failure is challenging. With the aim of addressing this issue, we analyzed engraftment kinetics and outcomes of 1268 patients (73% children) with acute leukemia (64% acute lymphoblastic leukemia, 36% acute myeloid leukemia) in remission who underwent single-unit umbilical cord blood transplantation after a myeloablative conditioning regimen. The median follow-up was 31 months. The overall survival rate at 3 years was 47%; the 100-day cumulative incidence of transplant-related mortality was 16%. Longer time to engraftment was associated with increased transplant-related mortality and shorter overall survival. The cumulative incidence of neutrophil engraftment at day 60 was 86%, while the median time to achieve engraftment was 24 days. Probability density analysis showed that the likelihood of engraftment after umbilical cord blood transplantation increased after day 10, peaked on day 21 and slowly decreased to 21% by day 31. Beyond day 31, the probability of engraftment dropped rapidly, and the residual probability of engrafting after day 42 was 5%. Graft failure was reported in 166 patients, and 66 of them received a second graft (allogeneic, n=45). Rescue actions, such as the search for another graft, should be considered starting after day 21. A diagnosis of graft failure can be established in patients who have not achieved neutrophil recovery by day 42. Moreover, subsequent transplants should not be postponed after day 42.

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.

Aneurysmal dilatation of the sinus of Valsalva is a rare structural cardiac abnormality in children. It appears to be more common in Asia. It may be clinically silent for many years but these defects frequently coexist with other cardiac malformations, causing, when rupture occurs, unexpected symptoms that are not explained by the original defects. We report a case of ruptured aneurysm of the sinus of Valsalva in a 12-year-old boy diagnosed with ventricular septal defect in the neonatal period with an uneventful course. The boy suddenly developed acute prechordal pain, symptoms of low heart output and systolic-diastolic murmur. The diagnosis of ruptured aneurysm of the sinus of Valsalva was based on echocardiography. Surgical treatment was required to close the ventricular septal defect and repair the aorta, without valvular replacement. The postoperative course was uneventful. We conclude that is extremely important to have a degree high suspicion of this entity in previously asymptomatic children, with or without cardiac anomalies, who suddenly present this kind of heart failure and abrupt changes in cardiac auscultation.

A patient with lung adenocarcinoma had progressive myelopathy. Computed tomography of spinal cord with intravenous contrast and magnetic resonance scan were negative. At autopsy, a spinal cord metastasis was found. In patients with cancer and clinical suspicion of spinal cord metastasis, palliative treatment with radiotherapy is indicated in spite of negative radiological investigations, so as to prevent the progression of myelopathy.

Vertebral hemangioma is a benign vascular tumor predominantly involving the dorsolumbar spine. Although most of these tumors are asymptomatic, they may result in radiculopathy and/or compressive myelopathy. Plain X-ray films and computed tomography (CT) generally permit the diagnosis by showing characteristic images with hypertrophic bone trabeculation in the vertebral body. We report three patients with vertebral hemangioma in which CT was diagnostic. Magnetic resonance (MR) with low intensity field was inferior to CT for the suggestion of the diagnosis of hemangioma, but had a better definition for subarachnoid space obliteration and spinal cord compression.

Contribución al estudio del crecimiento en secciones aisladas de coleóptilos de avena, por Luis Recalde y A. Carlos Blesa.-- Algunos aspectos de la relación existente entre el metabolismo y el crecimiento, por Luis Recalde y A. Carlos Blesa.-- Utilización de azúcares por Neurospora crassa, por C. F. Heredia y A. Medina.-- Cristalquírnica de los silicatos ·laminares, por el Dr. W . F . Bradley.-- Notas.-- Reunión de la Sociedad de Ciencia del Suelo.-- Curso sobre Aplicadones Industriales de los silicatos.-- Biblografía. Esdorn, Isle: Die Nutzplanzen der Tropen und Subtropen der Weltwirtschaft. (G. Giménez-Martín).-- National Science Foundation : Founds for Research and Development in Agricultura) Experiment Stations and Agricultural Colleges in the U. S., Fiocal Y ear 1958 (Luis Jimeno).-- Algunos aspectos de la relación existente entre el metabolismo y el crecimiento, por Luis Recalde y A. Carlos.-- Los minerales de la arcilla en suelos de la provincia de Salamanca. por J. L. Martín Vivaldi, M. Sánchez Camazano y F. Lucena Conde.-- Diagenesis en sedimentos, por W. F. Bradley.-- Notas.IV Congrés International d’études Pyreneennes.-- International Soil Conference.-- IV Congreso Mundial de Fertilizantes.-- Sociedad Española de Cerámica. Sección de Refractarios.-- Sociedad Española de Mecánica del Suelo y Cimentaciones.-- Comité del Neógeno Mediterráneo y Unión Paleontológica Internacional.-- Unión Pale-ontológica Internacional (U. F. l.). Bibliografía. Baumeister, Walter: Das Natrium als Pflanzennahrstoff. El sodio oomo nutriente vegetal (Fernando González Bernáldez).-- «Japanese Potassium simposium» (P. Sánchez Conde).-- Contribución al estudio del crecimiento en secciones aisladas de coleóptilos, por Luis Recolde y A. Carlos Blesa.-- Contribución al estudio del crecimiento en secciones aisladas de coleóptilos por Luis Recalde y A. Carlos Blesa.-- Los suelos agrícolas de la ·«Maresma» y la fertilización del clavel, por J. Cardús y M. Lasala Nota sobre Jos suelos naturales de las Islas del Cabo Verde, por M. Muñoz Taboadela. Notas.-Seminario de Enseñanza Superior Científica y Técnica.--Conferencia del Profesor E. G. Willians.-- Conferencia del Dr. Fritz Baade.-- Congreso Internacional Conservero de Murcia.-- Bibliografía. Festchrift Albert, Frey-Wyssling: Beiheft zu den Zeitschriften des Schweizerischen :Ferstvercims (Gonzalo Giménez-Martín).-- Pansiot. F. P. y Rebour, H.: Mejoramiento del cultivo del olivo. Organización de las Naciones Unidas para la agricultura y la alimentación (G. Bilbao).-- Sobre la determinación de materia orgánica en suelos, por L. M. Lachica Garrido y R. Montesinos Gallego.-- Contribución al estudio de las interferencias 'mutuas del Na+, K+ y ·Ca++ en .!a valoración de estos elementos por fotometría de llama en extractos de suelos, por J. Cardús y M. Lasala.-- Alofán y otros coloides en las arcillas de Braunlehm y sus alteraciones en las Canarias occidentales, por María del Carmen Sánchez Calvo. Notas.-- Colegio Internacional de Ciencias Naturales.-- Seminario de Enseñanzas Superiores Científica y Técnica.-- Premios de Ciencias del Consejo Superior de Investigaciones Científicas correspondientes al año 1960.--Reunión Técnica de la Sección de Refractarios de la Sociedad Española de Cerámica.-- Sociedad Española de Cerámica. Conferencias del Profesor Duchaufour. Bibliografía. Tyrrel, G. W.: Principios de Petrología (J. J. Alonso).-- Contribución al estudio de los suelos de la Cordillera Cantábrica, por J. M. Albareda Herrera y F. Velasco de Pedro.-- Posiciones convencional y de equilibrio en minerales detríticos, por Josefina Benayas Casares.-- Composición mineralógica y génesis de algunos tipos de suelos calizos béticos, por G. Paneque Guerrero.-- Notas.--Necrológica: Prof. H. Stremme.-- Conferencia del Prof. E. G. Williams.--Segunda Reunión Científica de la Sociedad Española para el Estudio de Pastos--Jornadas de Arte Cerámico.-- Congresos, Reuniones y visitas a Centros.—Pensionados.—Bibliografía. Teuscher, H.; Adler, R. y la colaboración de Jerome P. Seaton Reinhold Publishing Corporation: The soil and its fertility (Valentín Hernando).-- Tincknell, R. C. y López Ritas, J.: Estudio de los suelos venezolanos con fines de diagnóstico (José M. Pozuelo).--Estudio de la correlación de N-materia orgánica en suelos de vega y en terreno de olivar, por A. Hoyos y M. Rodríguez Prada.-- Contribución al estudio del crecimiento en secciones aisladas de coleóptilo de avena, por Luis Recalde y A. Carlos Blesa.--Experiencias de digestibilidad con cerdos retintos de tipo ibérico, por Julio Boza López.-- Notas.--Reunión Técnica de Pontevedra Nota relativa a las empresas dedicadas a trabajos de asesoramiento de la Dirección.-- Posición de los países mediterráneos en el Mercado Común. Bibliografía. Termier, H. y Termier, C.: Erosión et Sedimentation (J. J. A1onso).-- Brügel, W.: Einfuhrung in die Ultrarotspektroskopie (Mª. C. Sánchez Calvo).-- Contribución al estudio del crecimiento en secciones aisladas de coleoptilo de avena, por Luis Recalde y A. Carlos Blesa.-- Aspectos químicos y microbianos del ensilado de alfafa con el empleo de diversos conservaodres, por Francisco Villalón y Andrés Suárez.-- Formas ácido-alcohol resistentes en el ciclo vegetativo de Azotobácter, por V. Callao y E. Hernández Giménez.--Proceso de génesis y degradación de vermiculita: Yacimiento de Santa Olalla (Huelva), por F. González García y G. García Ramos.-- Estudio edafológico y agriobiológico de la Huerta de Murcia.—Notas.-Reunión Bioquímica de Santander.--Conferencia del prof. Hernández-Pacheco.- Cusillo sobre Introducción al estudio de la Biocenótica litoral de los alrededores de Santander.-- ll Reunión Técnica de la Sección de Refractario.-- Bibliografía. Torres Martíncz, Manuel, y otros: El regadío murciano, problema nacional (G. Bilbao).-- Estudio del efecto de la época de aplicación del nitrato en la. producción de remolacha, por V. Herntmdo, L. Jimeno y A. Guerra.-- Influencia de la relación K/Ca y K/Na en la producción de remolacha, por V. Hernamlo, L. Jimeno y A. Guerra.-- Mineralogía de las arcillas de algunos suelos volcánicos de Chile, por José García Vicente y Eduardo Besoain.-- Sobre la fertilización nitrogenada de la agricultura española, por José Mª Albareda Herrera.-- Notas.-Cursillo sobre la Vegetación de la Zona Cantábrica, por el Profesor Dr. Francisco Bellot Rodríguez.-- Cursillo sobre técnicas Citogenéticas en la mejora de plantas, por el Profesor Dr. Ing. E. Sánchez-Monge.-- Sociedad Española de Cerámica.—Bibliografía. Heinrick, E. WM.: Petrografía microscópica (J. Benayas).--Acción de algunos herbicidas sobre la brotadura y crecimiento de los i:oubércu- ].os del «Cyperus esculentus» Ten. Vár. «Aureus» Richt, por Ernesto Vieitez.-- El balance de agua de los suelos, por José Martín Aranda.-- Suelos de origen volcánico (Portugal), por Trinidad Aleisandre.-- Notas.-Estudio geológico de la zona costera de Santander, entre el Fas y el Saja.-- Cursillo sobre introducción a la Biocenótica Animal terrestre, por el Doctor S. V. P.eris.-- II Reunión Científica de la Sociedad Española para el Estudio de .los Pastos.-- Coloquio Internacional sobre las obras públicas en terrenos yesíferos.-- II Reunión del grupo Español de Sedimentología.-- Los suelos de la cuenca media del río Termes, por Sánchez Camazano y A. García Rodríguez.-- El balance de agua de los suelos, por José Martín Aranda.-- Abonado en remolacha en la vega de Granada, por Eduardo Esteban Velasco.-- Notas.--Reunión General de la División de Ciencias Matemáticas, Médicas y de la Naturaleza.--Sesiones de trabajo de los Patronatos de la División.-- Sociedad Española de Mecánica del Suelo y Cimentaciones.-- Curso de Tecnología Cerámica.-- Bibliografía.-Teidorovich, G. l.: Authigenic Minerals in Sedimentary Rocks (J. Benays), 2019-09.- CopyBook.- Libnova.- Biblioteca ICA

Cystic Fibrosis is the most frequent hereditary disease in Caucasians. Its clinical presentation may be very variable. Neonatal cholestasis is a typical but rare primary clinical manifestation that usually occurs in the first 3 weeks of life. It is often associated with meconium ileus. We present the case of an infant with cystic fibrosis whose primary clinical manifestation was cholestasis and liver failure at the age of 6 weeks.

Previous research on semantic dementia (SD) has demonstrated a link between conceptual representations and ability on a range of 'non-semantic' tasks, both verbal and nonverbal. In all cases, SD patients perform well on items that conform to the underlying statistical 'surface' structure of the domain in question but poor performance on items that are atypical with respect to these statistics. For such items, there is a strong tendency for the patients' erroneous responses to reflect the more typical pattern. To date, most research on this topic has been conducted with Englishspeaking patients, and where extended to non-English languages, directly comparable aspects of each language have been probed. In this study we tested the generalisation of this theory by probing performance on an aspect of Spanish with no analogue in English (grammatical gender). As predicted, Spanish SD patients provided the correct gender to high frequency words or where the phonology of the noun strongly predicted the gender. For low frequency, atypical nouns, however, the patients made many more errors (preferring the statistically typical gender). As expected, performance on nouns with atypical grammatical gender was strongly correlated with the degree of semantic impairment across the case-series of SD patients. The results not only provide another example of the critical relationship between semantic memory and 'non-semantic' cognition, but also indicate that this theoretical framework generalises to novel aspects of non-English languages - suggesting that the phenomenon is based on brain-general mechanisms.

Myeloproliferative disease; Paediatrics Enfermedad mieloproliferativa; Pediatría Malaltia mieloproliferativa; Pediatria Open Access funding enabled and organized by Projekt DEAL.

PURPOSE Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129 ). RESULTS Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.

Acute lymphoblastic leukaemia; Children Leucemia linfoblástica aguda; Niños Leucèmia limfoblàstica aguda; Nens Acute graft-versus-host disease (aGvHD) continues to be a leading cause of morbidity and mortality following allogeneic haematopoietic stem cell transplantation (HSCT). However, higher event-free survival (EFS) was observed in patients with acute lymphoblastic leukaemia (ALL) and grade II aGvHD vs. patients with no or grade I GvHD in the randomised, controlled, open-label, international, multicentre Phase III For Omitting Radiation Under Majority age (FORUM) trial. This finding suggests that moderate-severity aGvHD is associated with a graft-versus-leukaemia effect which protects against leukaemia recurrence. In order to optimise the benefits of HSCT for leukaemia patients, reduction of non-relapse mortality—which is predominantly caused by severe GvHD—is of utmost importance. Herein, we review contemporary prophylaxis and treatment options for aGvHD in children with ALL and the key challenges of aGvHD management, focusing on maintaining the graft-versus-leukaemia effect without increasing the severity of GvHD. This study received funding from the St. Anna Children's Cancer Research Institute, Vienna, Austria.

Genetic subgroups; Immune reconstitution; Pretransplantation infections Subgrupos genéticos; Reconstitución inmune; Infecciones previas al trasplante Subgrups genètics; Reconstitució immune; Infeccions prèvies al trasplantament Background Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. Objective We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. Methods HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Results Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P < .001). The 2-year event-free survival (EFS) was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (P < .001). Genetic subgroups did not differ in 2-year OS (P = .1) and EFS (P = .073). In multivariate analysis, pretransplantation infections and use of MMRDs were associated with less favorable OS and EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), 73 of 152 patients in the IR cohort were alive and well without Ig dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor–deficient SCID, myeloablative conditioning, matched donor HSCT, and naive CD4 T lymphocytes >0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. Conclusion Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.

Difficulties in the collection of hematopoietic stem and progenitor cells (HSPCs) from Fanconi anemia (FA) patients have limited the gene therapy in this disease. We have investigated (ClinicalTrials.gov, NCT02931071) the safety and efficacy of filgrastim and plerixafor for mobilization of HSPCs and collection by leukapheresis in FA patients. Nine of eleven enrolled patients mobilized beyond the threshold level of 5 CD34+ cells/μL required to initiate apheresis. A median of 21.8 CD34+ cells/μL was reached at the peak of mobilization. Significantly, the oldest patients (15 and 16 years old) were the only ones who did not reach that threshold. A median of 4.27 million CD34+ cells/kg was collected in 2 or 3 aphereses. These numbers were markedly decreased to 1.1 million CD34+ cells/kg after immunoselection, probably because of weak expression of the CD34 antigen. However, these numbers were sufficient to facilitate the engraftment of corrected HSPCs in non-conditioned patients. No procedure-associated serious adverse events were observed. Mobilization of CD34+ cells correlated with younger age, higher leukocyte counts and hemoglobin values, lower mean corpuscular volume, and higher proportion of CD34+ cells in bone marrow (BM). All these values offer crucial information for the enrollment of FA patients for gene therapy protocols., Graphical abstract, Mobilization and collection of HSPCs from FA patients with sufficient HSPC reserve is a safe and efficient procedure, incorporating filgrastim and plerixafor as mobilization agents. Adequate HSPC mobilization correlates with younger age, higher leukocyte counts and hemoglobin values, lower mean corpuscular volume, and higher BM CD34+ cell numbers.

Cellular immune response; Immunology; Stem cells Respuesta inmune celular; Inmunología; Células madre Resposta immune cel·lular; Immunologia; Cèl·lules mare Fanconi anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage–associated stress molecules such as natural killer group 2 member D ligands (NKG2D-Ls). These ligands could then interact with the activating NKG2D receptor expressed in cytotoxic NK or CD8+ T cells, which may result in progressive HSPC depletion. Our results indeed demonstrated upregulated levels of NKG2D-Ls in cultured FA fibroblasts and T cells, and these levels were further exacerbated by mitomycin C or formaldehyde. Notably, a high proportion of BM CD34+ HSPCs from patients with FA also expressed increased levels of NKG2D-Ls, which correlated inversely with the percentage of CD34+ cells in BM. Remarkably, the reduced clonogenic potential characteristic of FA HSPCs was improved by blocking NKG2D–NKG2D-L interactions. Moreover, the in vivo blockage of these interactions in a BMF FA mouse model ameliorated the anemia in these animals. Our study demonstrates the involvement of NKG2D–NKG2D-L interactions in FA HSPC functionality, suggesting an unexpected role of the immune system in the progressive BMF that is characteristic of FA. This work was supported by the “Ministerio de Ciencia e Innovación y Competitividad y Fondo Europeo de Desarrollo Regional (FEDER)” (SAF2015-68073-R, SAF2015-64152-R, and RTI2018-097125-B-I00); Next Generation EU; Plan de Recuperación Transformación y Resilencia (Instituto de Salud Carlos III; TERAV) (RD12/0019/0023); Programs of the European Commission (HEALTHF5-2012-305421 and EUROFANCOLEN); the “Ministerio de Sanidad, Servicios Sociales e Igualdad” (EC11/060 and EC11/550 “Comunidad de Madrid” (AvanCell, B2017/BMD-3692); and the ICREA-Academia program.

[Background]: Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients., [Methods]: This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes., [Results]: Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT, TERC, RTEL1, CTC1 and ACD. In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening., [Conclusion]: Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed., Funded by grants PI14–01495 and PI17–01401 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain supported by FEDER funds) and by one ACCI project from CIBERER and one grant to the FPI cohort from CIBERES., We acknowledge support of the publication fee by the CSIC Open Access Publication Support initiative through its Unit of Information Resources for Research (URICI).