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Introduction: Cancer and blood disorders in children are rare. The progressive improvement in survival over the last decades largely relies on the development of international academic clinical trials that gather the sufficient number of patients globally to elaborate solid conclusions and drive changes in clinical practice. The participation of Spain into large international academic trials has traditionally lagged behind of other European countries, mainly due to the burden of administrative tasks to open new studies, lack of financial support and limited research infrastructure in our hospitals. Methods: The objective of ECLIM-SEHOP platform (Ensayos Clínicos Internacionales Multicéntricos-SEHOP) is to overcome these difficulties and position Spain among the European countries leading the advances in cancer and blood disorders, facilitate the access of our patients to novel diagnostic and therapeutic approaches and, most importantly, continue to improve survival and reducing long-term sequelae. ECLIM-SEHOP provides to the Spanish clinical investigators with the necessary infrastructural support to open and implement academic clinical trials and registries. Results: In less than 3 years from its inception, the platform has provided support to 20 clinical trials and 8 observational studies, including 8 trials and 4 observational studies where the platform performs all trial-related tasks (integral support: trial setup, monitoring, etc.) with more than 150 patients recruited since 2017 to these studies. In this manuscript, we provide baseline metrics for academic clinical trial performance that permit future comparisons. Conclusions: ECLIM-SEHOP facilitates Spanish children and adolescents diagnosed with cancer and blood disorders to access state-of-the-art diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Purpose: Despite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain. Methods: All members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center. Results: 22 phase I and II trials were open as of May 2015: 15 for solid tumors (68 %) and 7 for hematological malignancies (32 %). Fourteen (64 %) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5 years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits. Conclusions: Clinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential to cure patients with an inherited bone marrow failure syndrome (IBMFS). However, the procedure involves the risk of treatment-related mortality and may be associated with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks. IBMFS are rare, whereas case reports and small series in the literature illustrate highly heterogeneous practices in terms of indications for HSCT, timing, stem cell source and conditioning regimens. A consensus meeting was therefore held in Vienna in September 2012 on behalf of the European Group for Blood and Marrow Transplantation to discuss HSCT in the setting of IBMFS. This report summarizes the recommendations from this expert panel, including indications for HSCT, timing, stem cell source and conditioning regimen. [ABSTRACT FROM AUTHOR]

Outcomes of unrelated cord blood transplants (UCBT) were assessed in 172 consecutive children, median age 5 years (range: 0.5-18), with haematological malignancies treated at nine Spanish hospitals between February 1996 and April 2009. Data were collected from the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON) database. ALL was diagnosed in 125 patients, AML in 43 and myelodysplastic syndrome in 4. Myeloid engraftment (ANC⩾0.5 × 109/L) occurred in 87.2% at a median of 22 days and was associated with the total nucleated cell (TNC) dose infused and use of a TT-containing conditioning regimen. Cumulative incidence of relapse was 20% at 1 year post transplant and 29% at 3 years, being higher in patients with a diagnosis of ALL, very high risk disease and GVHD grades 0-1. Cumulative incidence of non-relapse mortality (NRM) was 19% at 100 days post transplant and 39% at 1 year. BU-FLU-TT-ATG-conditioned patients had lower NRM. Disease-free survival (DFS) was 40% at 2 years post transplant (for patients transplanted since 2006). On multivariate analysis, TNC dose infused, AML and BU-FLU-TT-ATG-conditioning regimen increased the probability of DFS. It is of paramount importance to select cord blood units with the highest cell dose. As the BU-FLU-TT-ATG-conditioning regimen was associated with better DFS owing to lower NRM, further prospective studies testing this regimen are warranted. [ABSTRACT FROM AUTHOR]

HLA matching is a critical determinant of outcomes for patients who have undergone umbilical cord blood transplantation (UCBT). Data have been published on the importance of donor/recipient HLA mismatch direction on UCBT outcomes. HLA mismatch in the graft-versus-host (GVH) direction is defined as a donor homozygous at an HLA locus, while the recipient shares one HLA Ag with the donor. HLA mismatch in the host-versus-graft (HVG) direction is defined as a recipient homozygous with the donor sharing one HLA Ag. In our study we focused on confirming, using an independent population, whether transplantation outcomes would be different when HLA mismatch direction was considered. We analyzed 1565 patients who received a single-unit UCBT for malignant disease. Median age was 15 years and 72% of patients were transplanted for leukemia. In multivariate analysis, using the 5/6 HLA-matched population as reference, one or two HLA mismatches in the GVH or HVG direction were not associated with non-relapse related mortality and survival. On the basis of our results, there is no evidence to support a change in the current practice for cord blood unit selection. [ABSTRACT FROM AUTHOR]

To address the prognostic value of minimal residual disease (MRD) before unrelated cord blood transplantation (UCBT) in children with acute lymphoblastic leukemia (ALL), we analyzed 170 ALL children transplanted in complete remission (CR) after myeloablative conditioning regimen. In all, 72 (43%) were in first CR (CR1), 77 (45%) in second CR (CR2) and 21 (12%) in third CR (CR3). The median interval from MRD quantification to UCBT was 18 days. All patients received single-unit UCBT. Median follow-up was 4 years. Cumulative incidence (CI) of day-60 neutrophil engraftment was 85%. CI of 4 years relapse was 30%, incidence being lower in patients with negative MRD before UCBT (hazard ratio (HR)=0.4, P=0.01) and for those transplanted in CR1 and CR2 (HR=0.3, P=0.002). Probability of 4 years leukemia-free survival (LFS) was 44%, (56, 44 and 14% for patients transplanted in CR1, CR2 and CR3, respectively (P=0.0001)). Patients with negative MRD before UCBT had better LFS after UCBT compared with those with positive MRD (54% vs 29%; HR=2, P=0.003). MRD assessment before UCBT for children with ALL in remission allows identifying patients at higher risk of relapse after transplantation. Approaches that may decrease relapse incidence in children given UCBT with positive MRD should be investigated to improve final outcomes. [ABSTRACT FROM AUTHOR]

Attempts to optimize outcomes in cord blood transplantation (CBT) by using new conditioning regimens and standardization of cord blood unit selection are warranted. In all, 88 patients (18 children and 70 adults) with hematological malignancy from nine Spanish institutions underwent a single-unit CBT after an i.v. BU-based myeloablative conditioning regimen. All evaluable patients except one engrafted. The overall cumulative incidence (CI) of myeloid engraftment was 94% at a median time of 19 days. In multivariate analysis, nonadvanced disease stage was the only factor with a favorable impact on myeloid engraftment. The CI of acute GVHD grades II-IV and chronic extensive GVHD were 24% each. The CI of nonrelapse mortality at 100 days, 180 days and 5 years was 14, 23 and 44%, respectively. The 5-year CI of relapse was 18%, whereas disease-free survival (DFS) was 46%, 39% and 11% for patients transplanted in early, intermediate and advanced stages of the disease, respectively. Our study shows high rates of engraftment with fast neutrophil recovery in patients undergoing single-unit CBT using a BU-based conditioning regimen. Long-term DFS can be achieved in a substantial number of patients with high-risk hematological malignancies, particularly when transplanted in an early stage of the disease. [ABSTRACT FROM AUTHOR]

We report on the outcome of children with advanced primary myelodysplastic syndrome (MDS) transplanted from an HLA-matched sibling (MSD) or an unrelated donor (UD) following a preparative regimen with busulfan, cyclophosphamide and melphalan. Ninety-seven patients with refractory anemia with excess blasts (RAEB, n=53), RAEB in transformation (RAEB-T, n=29) and myelodysplasia-related acute myeloid leukemia (MDR-AML, n=15) enrolled in the European Working Group of MDS in Childhood (EWOG-MDS) 98 study and given hematopoietic stem cell transplantation (HSCT) were analyzed. Median age at HSCT was 11.1 years (range 1.4-19.0). Thirty-nine children were transplanted from an MSD, whereas 58 were given the allograft from a UD (n=57) or alternative family donor (n=1). Stem cell source was bone marrow (n=69) or peripheral blood (n=28). With a median follow-up of 3.9 years (range 0.1-10.9), the 5-year probability of overall survival is 63%, while the 5-year cumulative incidence of transplantation-related mortality (TRM) and relapse is 21% each. Age at HSCT greater than 12 years, interval between diagnosis and HSCT longer than 4 months, and occurrence of acute or extensive chronic graft-versus-host disease were associated with increased TRM. The risk of relapse increased with more advanced disease. This study indicates that HSCT following a myeloablative preparative regimen offers a high probability of survival for children with advanced MDS. [ABSTRACT FROM AUTHOR]

We studied surveillance, incidence and outcome of viral infections in children undergoing allogeneic hematopoietic cell transplantation (HCT) in the main pediatric transplant units in Spain. We prospectively collected data from first year post-HCT in every consecutive allogeneic HCT performed during 3 years (N=215): first HCT=188 and second HCT=27; median age=6.6 years (0.1-20.7). Most patients had acute leukemia (N=137) and 135 recipients (63%) were CMV seropositive. A total of 46 patients underwent cord blood transplant, 133 patients underwent HCT from alternative donors (62%) and 101 patients received anti-thymocyte globulin. Observational time was completed in 137 patients, whereas the remaining 78 died after a median survival time of 99 days (3-352). CMV was monitored in all patients; adenovirus (ADV) and human herpesvirus 6 (HHV-6) were monitored in 101 and 33 patients, respectively. We found 145 viral infections in 103 patients: CMV (n=42), ADV (n=32), HHV-6 (n=7), polyomavirus (n=20), EBV (n=6), VZV (n=17) and others (n=8). CMV infection was significantly higher in seropositive patients (25 vs 7%) (P=0.02). Extensive chronic GVHD (cGVHD) was significantly associated with an increased rate of viral infections (12 of 16 patients with cGVHD had infections vs 91 of 199 without GVHD) (P=0.035). In total, 10 patients (4.6%) died of viral infections (CMV=5, ADV=3, respiratory=2). We found a high incidence of viral infection, but mortality was low. [ABSTRACT FROM AUTHOR]

HCT is currently the treatment of choice for children with severe primary immunodeficiencies (PIDs). Frequently, these patients lack an HLA-identical sibling donor, and umbilical cord blood (UCB) transplantation may be an option; however, experience in this field remains scant. Fifteen children with PID (SCID 11, X-linked lymphoproliferative syndrome 2, Omenn's syndrome 1, Wiskott–Aldrich syndrome 1) received a UCB transplant. The donor was unrelated in 14 cases and related in 1. Median age at transplant was 11.6 months (range, 2.9–68.0) and median weight 7 kg (range, 4–21). Thirteen patients were conditioned with busulphan and cyclophosphamide and 2 with fludarabine and melphalan. Nine patients received antithymocyte globulin. Median NC × 107/kg infused was 7.9 (range, 2.9–25.0) and median CD34 × 105/kg 2.9 (range, 1.0–7.9). All patients engrafted. Median days to >0.5 × 109/l neutrophils was 31. Eight patients developed acute graft-versus-host disease (GvHD) grades II–IV and one chronic GvHD. Viral and fungal infections were frequent. Four patients died: three from GvHD grade IV complicated by infection and one from progressive interstitial lung disease. Five-year survival was 0.73±0.12. All surviving patients presented complete immunologic reconstitution. No patient is intravenous immunoglobulin (IVIg) replacement therapy-dependent. UCB transplantation is a valid option for children with PID who lack an HLA-identical sibling donor.Bone Marrow Transplantation (2008) 41, 627–633; doi:10.1038/sj.bmt.1705946; published online 17 December 2007 [ABSTRACT FROM AUTHOR]

Summary: Malignant diseases (MD) occurring after stem cell transplantation (SCT) are of particular concern as increasing number of patients survive and remain free of their original disease. The cumulative incidence at 15 years is 10–12%. The B-cell proliferative disorders (BCLP) are the most common MD in the first year after SCT; the incidence probability is 1% in allogeneic transplants but is much higher (until 14%) after HLA-identical, T-cell-depleted SCT in which Campath 1G or ATG are given. BCLP develop because of reactivation of the EBV and a depressed cellular immunity. Prediction of risk of BCLP can be made by frequent monitoring of EBV load in patients with risk factors. The most effective therapies are the early administration of anti-CD20 monoclonal antibody and adoptive immunotherapy with in vitro generated EBV-specific cytotoxic T cells. Myelodysplasia and acute myeloid leukemia with very poor prognosis have been described in 4–18% of patients with non-Hodgkin lymphoma and Hodgkin disease, 12–24 months after autologous SCT. The risk of development of solid tumors increases over time and the cumulative incidence among children who underwent an SCT at less than 10 years of age is 6–11% at 15 years. There are few studies evaluating quality of life (QOL) in children and adolescents who had received an SCT. The findings of these studies can be summarized as follows: (a) The majority of long survivors enjoy good QOL and return successfully to school or work. (b) A minority (10–15%) complain of physical problems or present moderate cognitive or psychological dysfunctions. (c) The importance of family, other social support and psychological adjustments is generally recognized. More extensive, longitudinal and comparative studies with other alternative therapies are required. [ABSTRACT FROM AUTHOR]

The role of support measures in the Intensive Care Unit for bone marrow transplant recipients has been controversial. Data from 176 pediatric bone marrow transplants were retrospectively analyzed to ascertain the probability, causes, risk factors and survival for life-threatening complications requiring intensive care. Ninety-two patients underwent allogeneic BMT and 84 autologous BMT between January 1991 and December 1995. Thirty-one ICU admissions were recorded. The most frequent causes were acute respiratory failure (n = 15, mostly interstitial pneumopathies), septic shock (n = 5) neurological disorders (n = 5) and heart failure (n = 2). The cumulative incidence of an ICU admission at 20 months post-transplant in patients with an allogeneic BMT was 25.7% (CI: 16.4–35.1), compared with 10.8% (CI: 4.2–17.5) in those with an autologous graft (P = 0.04). ICU admission frequency was maximum during the first 2 months post-transplant. All complications in patients with autologous transplants appeared during the first 5 months post-transplant. Among patients with allogeneic grafts, four were later admitted to the ICU, at 7, 9, 12 and 20 months post-transplant, respectively. The main risk factor for ICU admission was acute GVHD grades III–IV. No differences were found between patients with allogeneic transplants with GVHD grades 0–II and those undergoing autologous transplant. In contrast, differences were highly significant between patients undergoing allogeneic transplants with GVHD grades III–IV and those with GVHD grades 0–II or autologous transplants. No differences were observed between allogeneic and autologous transplants in terms of causes for ICU admission, duration of stay, hours on mechanical ventilation, hours on inotropic drug therapy and numbers of organs failing. Neither were differences found in ICU discharge survival between patients with allogeneic (50%, CI: 29.1–70.9) and autologous (66.7%, CI: 29... [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the outcome of children with acute lymphoid leukemia (ALL) in second remission who have undergone high-dose chemotherapy and radiotherapy and autologous bone marrow transplantation (ABMT) with monoclonal antibody purged marrow, and to determine the main prognostic factors. From 1987 to 1992, 55 children with ALL in second remission underwent ABMT. The conditioning regimen consisted of total body irradiation (TBI) plus cyclophosphamide in 21 patients and TBI plus cyclophosphamide plus cytarabine or VP-16 in 28 patients; the remaining six patients were treated with chemotherapy alone (cyclophosphamide and busulfan, and/or VP-16). The marrow was purged using monoclonal antibodies and complement or magnetic microspheres in all cases. All patients engrafted. Three patients (5%) died early post transplant from infections. Twenty-six patients (47%) relapsed (median 150 days); 26 patients (47%) are alive and in complete remission (CR) at a median of 36 months. The Kaplan–Meier estimation showed a probability of event-free survival (EFS) of 46 ± 0.007%. In the univariate analysis, first CR length and conditioning with TBI plus two or more cytotoxic drugs were found to be the most significant predictors of EFS. ABMT with purged marrow is a treatment modality which offers a chance of cure in children with ALL after relapse, including children who relapse early. [ABSTRACT FROM AUTHOR]

Tiller demography was compared in two populations of Spartina maritima present at similar elevations in the coastal saltmarshes of Odiel (Huelva, S.W. Spain). The successional population consisted of colonizing tussocks in a littoral lagoon, and the non-successional population comprised a stable sward that had fringed a major channel for 40 years. At both sites S. maritima was replaced by Arthrocnemum perenne at higher elevation, where sediments were less reducing. Rapid, consistent sediment accretion confirmed the successional nature of the lagoon site but there was little net accretion in the stable sward. Census of permanent quadrats at the successional site chronicled moving concentric ‘waves’ of high tiller density as tussocks expanded. Initially high densities declined after one year to low values at the end of the second year but they had almost recovered after 3 years. The decline represented a combination of reduced numbers of births and increased numbers of deaths. Tiller densities were substantially higher in the stable sward and showed relatively small fluctuations with time. The underlying risk of tiller mortality was similar in the two populations for much of the time but after two years there was increased mortality, mainly associated with flowering, at the successional site; very few tillers flowered in the sward. This mortality contributed to a shift to a younger age structure in the successional population. Data aggregated over consecutive 3-monthly periods were examined for density dependence. None was found in the successional population. In the sward population there was evidence of density-dependent adult and juvenile mortality of tillers, particularly over the first 18 months of the study, when there were compensatory responses to subtle variations in density. The lack of density dependence and relatively low peak density of about 2000 m-2 near to the leading edges of the expanding tussocks at the successional site suggest that tiller placement there was regulated mainly by physiological mechanisms affecting rhizome growth and bud development in well integrated clones. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the increasing rate of pediatric patients diagnosed with mycobacterium disease (MDT) after stem cell transplantation (SCT).

Hysteresis loops exhibited by the thermal properties of undoped and 0.8 at.% W-doped nanocrystalline powders of VO2 synthesized by means of the solution combustion method and compacted in pellets, are experimentally measured by photothermal radiometry. It is shown that: (i) the W doping reduces both the hysteresis loops of VO2 and its transition temperature up to 15 °C. (ii) The thermal diffusivity decreases (increases) until (after) the metallic domains become dominant in the VO2 insulating matrix, such that its variation across the metal-insulation transition is enhanced by 23.5% with W-0.8 at.% doping. By contrast, thermal conductivity (thermal effusivity) increases up to 45% (40%) as the metallic phase emerges in the VO2 structure due to the insulator-to-metal transition, and it enhances up to 11% (25%) in the insulator state when the local rutile phase is induced by the tungsten doping. (iii) The characteristic peak of the VO2 specific heat capacity is observed in both heating and cooling processes, such that the phase transition of the 0.8 at.% W-doped sample requires about 24% less thermal energy than the undoped one. (iv) The impact of the W doping on the four above-mentioned thermal properties of VO2 mainly shows up in its insulator phase, as a result of the distortion of the local lattice induced by the electrons of tungsten. W doping at 0.8 at.% thus enhances the VO2 capability to transport heat but diminishes its thermal switching efficiency. [ABSTRACT FROM AUTHOR]

Hysteresis loops exhibited by the thermal properties of undoped and 0.8 at.% W-doped nanocrystalline powders of VO2 synthesized by means of the solution combustion method and compacted in pellets, are experimentally measured by photothermal radiometry. It is shown that: (i) the W doping reduces both the hysteresis loops of VO2 and its transition temperature up to 15 °C. (ii) The thermal diffusivity decreases (increases) until (after) the metallic domains become dominant in the VO2 insulating matrix, such that its variation across the metal-insulation transition is enhanced by 23.5% with W-0.8 at.% doping. By contrast, thermal conductivity (thermal effusivity) increases up to 45% (40%) as the metallic phase emerges in the VO2 structure due to the insulator-to-metal transition, and it enhances up to 11% (25%) in the insulator state when the local rutile phase is induced by the tungsten doping. (iii) The characteristic peak of the VO2 specific heat capacity is observed in both heating and cooling processes, such that the phase transition of the 0.8 at.% W-doped sample requires about 24% less thermal energy than the undoped one. (iv) The impact of the W doping on the four above-mentioned thermal properties of VO2 mainly shows up in its insulator phase, as a result of the distortion of the local lattice induced by the electrons of tungsten. W doping at 0.8 at.% thus enhances the VO2 capability to transport heat but diminishes its thermal switching efficiency. [ABSTRACT FROM AUTHOR]

Bone Marrow Transplantation (2002) 30, S16–S18. doi:10.1038/sj.bmt.1703745 [ABSTRACT FROM AUTHOR]

Objectives: Having 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., Methods: We 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 rates of people tested and confirmed positive for COVID-19 by week from April 19, 2020 to July 31, 2021 across immigration groups. We use logistic regression to estimate adjusted odds ratios of a positive SARS-CoV-2 test, access to testing, and primary care among people with temporary status or permanent residency, compared with people who hold citizenship., Results: A total of 4,146,593 people with citizenship, 914,089 people with permanent residency, and 212,215 people with temporary status were included. Among people with temporary status, 52.1% had "male" administrative sex and 74.4% were ages 20-39, compared with 50.1% and 24.4% respectively among those with citizenship. Of people with temporary status, 4.9% tested positive for SARS-CoV-2 over this period, compared with 4.0% among people with permanent residency and 2.1% among people with citizenship. Adjusted odds of a positive SARS-CoV-2 test among people with temporary status were almost 50% higher (aOR 1.42, 95% CI 1.39, 1.45), despite having half the odds of access to testing (aOR 0.53, 95% CI 0.53, 0.54) and primary care (aOR 0.50, 95% CI 0.49, 0.52)., Conclusion: Interwoven immigration, health, and occupational policies place people with temporary status in circumstances of precarity and higher health risk. Reducing precarity accompanying temporary status, including regularization pathways, and decoupling access to health care from immigration status can address health inequities., (© 2023. The Author(s).)