Search

Background: Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. Methods: After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. Results: After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. Conclusion: Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.

In first-line treatment of Hodgkin lymphoma (HL), Deauville scores 1-3 define complete metabolic remission. Interim 18F-FDG PET is also used for relapse-treatment adaptation; however, PET response criteria are not validated for relapse treatment. Methods: We performed a pairwise comparative analysis of early response to first- and second-line treatments in 127 patients with classic HL who experienced relapse. The patients participated in the prospective, multicenter EuroNet-PHL-C1 study. Residual uptake was measured retrospectively using the qPET method, a validated semiautomatic quantitative extension of the Deauville score. Empiric cumulative distribution functions of the qPET values were used to systematically analyze the response to first- and second-line treatments. Results: Individual patients responded variably to first- and second-line treatments. However, the empiric cumulative distribution functions of the qPET values from all patients were nearly superimposable. Conclusion: The findings support that first- and second-line treatments in HL do not require different response criteria.

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.

Linkage between clinical databases and population-based cancer registries may serve to evaluate European Reference Networks' (ERNs) activity, by monitoring the proportion of patients benefiting from these and their impact on survival at a population level. To test this, a study targeting neuroblastoma (Nb) was conducted in Spain by the European Joint Action on Rare Cancers.Subjects: Nb cases, incident 1999-2017, aged 15 years. Linkage included: Spanish Neuroblastoma Clinical Database (NbCDB) (1217 cases); Spanish Registry of Childhood Tumours (RETI) (1514 cases); and 10 regional population-based registries (RPBCRs) which cover 33% of the childhood population (332 cases). Linkage was semiautomatic. We estimated completeness, incidence, contribution, deficit, and 5-year survival in the databases and specific subsets.National completeness estimates for RETI and NbCDB were 91% and 72% respectively, using the Spanish RPBCRs on International Incidence of Childhood Cancer (https://iicc.iarc.fr/) as reference. RPBCRs' specific contribution was 1.6%. Linkage required manual crossover in 54% of the semiautomatic matches. Five-year survival was 74% (0-14 years) and 90% (0-18 months).All three databases were incomplete as regards Spain as a whole and should therefore be combined to achieve full childhood cancer registration. A unique personal patient identifier could facilitate such linkage. Most children have access to Nb clinical trials. Consolidated interconnections between the national registry and clinical registries (including ERNs and paediatric oncology clinical groups) should be established to evaluate outcomes.

INTRODUCTION: Ependymomas remain a major cause of cancer-related death in childhood and adolescence, with recurrence occurring in up to 50% of patients. Despite exciting molecular advances in understanding ependymoma tumorigenesis and recurrence, MRI remains the mainstay for assessing objective response to therapy and duration of disease stability. Standardized response assessment criteria for clinical trials studying pediatric intracranial ependymoma are critically needed in order to accurately compare results between studies. METHODS: To generate these standardized response criteria in pediatric intracranial ependymoma, a multidisciplinary team of pediatric neuro-oncologists, neuroradiologists, neurosurgeons, radiation oncologists, and molecular biologists formed the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group. The expert members reviewed relevant published literature, assessed current clinical practices, and engaged in iterative discussions to provide consensus recommendations for objective response assessment in pediatric intracranial ependymoma for use in prospective clinical trials. RECOMMENDATIONS AND CONCLUSIONS: The primary sequences for detecting and measuring disease and assessing radiologic response to therapy should be the contrast-enhanced T1-weighted sequence or T2-weighted sequence (T2 or T2-FLAIR) depending on which sequence the tumor is best visualized. When metastatic disease is present, only the three largest lesions will be followed in addition to any residual disease at the primary tumor focus. Importantly, the RAPNO working group notes that radiologic response to therapy is of limited value in clinical trials of patients with ependymoma, since most patients enroll on clinical trials with either no evidence of disease or only minimal disease. In recurrent or progressive disease that cannot be resected, true radiologic disease response to therapy is less clinically meaningful as a study endpoint than event-free and/or overall survival (representing prolonged stable disease) but may provide a signal of efficacy worthy of future exploration in patients with complete to near complete resections.

BACKGROUND: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging. PATIENTS, MATERIALS, AND METHODS: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from 18 F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment. RESULTS: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient. CONCLUSIONS: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future. ispartof: PEDIATRIC BLOOD & CANCER vol:68 issue:4 ispartof: location:United States status: published

Background: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. Methods: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m2 etoposide taken intravenously on days 1–5; 60 mg/m2 prednisone taken orally on days 1–15; and 40 mg/m2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m2 prednisone taken orally on days 1 to 15; and 100 mg/m2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment. Findings: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7–71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5–92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1–92·8) for COPP (n=444) versus 86·1% (82·9–89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was −3·7% (−8·0 to 0·6). The most common grade 3–4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. Interpretation: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. Funding: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

Background: Since the beginning of SARS-CoV-2 pandemic, it has been widely recognized that children and adolescents seem to have milder clinical courses as compared to adult counterparts. However, there is concern that vulnerable collectives including pediatric patients treated for cancer or under immunosuppression may be at higher risk. Methods: We retrospectively collected Spanish COVID-19 cases in children and adolescents with solid and hematological malignancies, non-malignant chronic hematologic conditions, and post allogeneic-stem cell transplantation, from the beginning of the pandemic on January 31 to April 24, 2020. Results: We included 47 cases with RT-PCR positive COVID-19 from 41 centers in Spain, where 97.6% of pediatric patients are treated for cancer. In most cases (76.6%), infection was asymptomatic, or symptoms were mild. Severe illness was observed in 14.9% of cases with respiratory distress and/or hypoxemia, and 8.5% required admission to the PICU. Symptomatic patients received supportive care associated with antiviral and immunomodulatory agents depending upon severity. Anticancer therapy was withhold in the majority of cases during the infection course. Most patients recovered from COVID-19. Two deaths were reported. Conclusion: In our cohort, most children receiving anticancer chemotherapy presented a mild clinical course and had a good outcome. Highly immunosuppressed patients with major comorbidities were at higher risk of severe infections. Among this fragile collective, individualized expert discussion is critical for anti-infectious therapy and appropriate anticancer treatment.

BackgroundThe travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe.MethodsA cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries.ResultsCapture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI −12.4 to −5.4, pConclusionsFewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral.

Survival for childhood cancers has improved significantly over the last decades. However, patient outcomes have plateaued over the last decade for difficult-to-treat diseases. With high cure rates, decreasing long-term toxicities and sequelae remains crucial. Since many advances in childhood cancer research come from the adult oncology world, one of the key areas is improving the adaptation of tools that are essential for clinical trial conduct that were developed for adults into pediatrics. These include tools to evaluate toxicity, quality of life, radiological response, statistical methodology, or indicators of cancer care quality. In this review, we present ongoing international efforts to validate and adapt these tools for children and adolescents and discuss remaining challenges. These efforts will hopefully accelerate and improve the quality of pediatric oncology research in the upcoming years.

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.

Retinoblastoma (RB, MIM 180200) is the paradigm of hereditary cancer. Individuals harboring a constitutional mutation in one allele of the RB1 gene have a high predisposition to develop RB. Here, we present the first case of familial RB caused by a de novo insertion of a full-length long interspersed element-1 (LINE-1) into intron 14 of the RB1 gene that caused a highly heterogeneous splicing pattern of RB1 mRNA. LINE-1 insertion was inferred by mRNA studies and full-length sequenced by massive parallel sequencing. Some of the aberrant mRNAs were produced by noncanonical acceptor splice sites, a new finding that up to date has not been described to occur upon LINE-1 retrotransposition. Our results clearly show that RNA-based strategies have the potential to detect disease-causing transposon insertions. It also confirms that the incorporation of new genetic approaches, such as massive parallel sequencing, contributes to characterize at the sequence level these unique and exceptional genetic alterations.

Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor-specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0-21 years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2 weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7-9.3). 3-year PFS was 31.9% (95% CI 17-47%) and OS 35.1% (95% CI 20-50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients.

Background: Three substitutions at either Gly305 or Gly306 within the membrane attack/complex perforin domain (MACPF) of perforin have been previously identified in a number of patients with hemophagocytic lymphohistiocytosis (HLH). However, their pathogenic impact remains unclear since all the cases reported so far carried heterozygous genotypes and showed very heterogeneous clinical presentations. Here, we report a new substitution (p.Gly306Asp) and use in silico tools to elucidate the pathogenic mechanisms and severity associated with human Gly306 and Gly305 mutations.Methods: The immunological workup included perforin expression and perforin gene (PRF1) mutation analysis. Computer algorithms based on conservation, secondary, and tertiary protein structure analyses were applied to assess the role of the mutations in disease pathogenesis.Results: In our patient, we found a previously undescribed homozygous c. 917G>A (p.Gly306Asp) mutation in the PRF1 gene that was associated with null perforin expressio...

PNR-16. DIAGNOSIS, MANAGEMENT AND OUTCOME OF CHILDREN WITH CENTRAL NERVOUS SYSTEM (CNS) PRIMITIVE NEUROECTODERMAL TUMORS (PNET) IN SPAIN: A STUDY FROM THE SPANISH NATIONAL PEDIATRIC ONCOLOGY & HEMATOLOGY SOCIETY (SEHOP) Teresa de Rojas1, Francisco Jose Bautista1, Miguel Flores2, Victoria Fioravantti1, Lucia Igual3, Raquel Rubio4, Eduardo Bardon5, Lucia Navarro6, Laura Murillo7, Raquel Hladun8, Adela Canete3, Miguel Garcia4, Carmen Garrido5, Ana Fernandez-Teijeiro6, Eduardo Quiroga6, Carlota Calvo7, Anna Llort8, Luis Madero1, Ofelia Cruz2, and Lucas Moreno1; Hospital Infantil Universitario Nino Jesus, Madrid, Spain; Hospital Sant Joan deDeu,Barcelona, Spain; HospitalUniversitarioy Politecnico La Fe, Valencia, Spain; Hospital Universitario Cruces, Bilbao, Spain; Hospital General Universitario Gregorio Maranon, Madrid, Spain; Hospital Universitario Virgen del Rocio, Sevilla, Spain; Hospital Universitario Miguel Servet, Zaragoza, Spain; Hospital Universitario Vall d’Hebron, Barcelona, Spain BACKGROUND: CNS-PNET are aggressive embryonal tumors with poor outcome that have been historically treated in the context of medulloblastoma clinical trials. The purpose of this study is to present a tumor-specific, realworld data cohort of CNS-PNET. METHODS: Patients 0-21 years with CNS-PNET treated in 8 large institutions were included. Baseline characteristics, received treatment and outcomes [relapse-free and overall survival (RFS and OS respectively)] were analysed. RESULTS: From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (79%). Median duration of the main symptom was 2 weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Primary tumor location was hemispheres (67%), pineal (12%), infratentorial (16.5%) and spinal cord (4.5%). Frontline treatment: 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy with over 10 different strategies, and 33% autologous stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7-9.3). 5-year RFS was 27.9% (95%CI 13-43%) and OS 30.7% (95%CI 16-46%). 73% of survivors had severe long-term sequelae. Age, M stage, extent of resection, radiotherapy and aHSCT were prognostic of OS in univariate analyisis (p , 0.05). CONCLUSIONS: Real-world data continues to show a dismal outcome for CNS-PNET despite advances in the field. In the current era, CNS-PNET is a distinct biological and genomic entity and new therapeutic strategies should be developed in multinational clinical trials. Neuro-Oncology 18:iii7–iii15, 2016. doi:10.1093/neuonc/now067.13 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Philadelphia-chromosome acute lymphoblastic leukaemia (Ph+ ALL) is a subgroup of ALL with very high risk of treatment failure. We report here the results of the Sociedad Espanola de Hematologia y Oncologia Pediatricas (SEHOP/SHOP) in paediatric Ph+ ALL treated with intermediate-dose imatinib concurrent with intensive chemotherapy. The toxicities and outcome of these patients were compared with historical controls not receiving imatinib. Patients with Ph+ ALL aged 1-18 years were enrolled in three consecutive ALL/SHOP trials (SHOP-94/SHOP-99/SHOP-2005). In the SHOP-2005 trial, imatinib (260 mg/m(2) per day) was given on day-15 of induction. Allogeneic haematopoietic stem-cell transplantation (HSCT) from a matched related or unrelated donor was scheduled in first complete remission (CR1). Forty-three patients were evaluable (22 boys, median age 6.8 years, range, 1.2-15). Sixteen received imatinib whereas 27 received similar chemotherapy without imatinib. Seventeen of 27 and 15 of 16 patients in the non-imatinib and imatinib cohort, respectively, underwent HSCT in CRI. With a median follow-up of 109 and 39 months for the non-imatinib and imatinib cohorts, the 3-year event-free survival (EFS) was 29.6% and 78.7%, respectively (P = 0.01). These results show that, compared to historical controls, intermediate dose of imatinib given concomitantly with chemotherapy and followed by allogeneic HSCT markedly improved early EFS in paediatric Ph+ ALL.

BACKGROUND Structural hemoglobinopathies do not usually have a clinical impact, but they can interfere with the analytical determination of some parameters, such as the glycated hemoglobin in diabetic patients. Thalassemias represent a serious health problem in areas where their incidence is high. The defects in the post-translational modifications produce hyper-unstable hemoglobin that is not detected by most of electrophoretic or chromatographic methods that are available so far. METHODS We studied seven patients who belong to six unrelated families. The first two families were studied because they had peak abnormal hemoglobin (Hb) during routine analytical assays. The other four families were studied because they had microcytosis and hypochromia with normal HbA2 and HbF without iron deficiency. HbA2 and F quantification and abnormal Hb separation were performed by chromatographic and electrophoretic methods. The molecular characterization was performed using specific sequencing. RESULTS The Hb Puerta del Sol presents electrophoretic mobility and elution in HPLC that is different from HbA and similar to HbS. The electrophoretic and chromatographic profiles of the four other variants are normal and do not show any anomalies, and their identification was only possible with sequencing. CONCLUSIONS Some variants, such as Hb Valdecilla, Hb Gran Via, Hb Macarena and Hb El Retiro, have significant clinical impact when they are associated with other forms of α-thalassemia, which could lead to more serious forms of this group of pathologies as for HbH disease. Therefore, it is important to maintain an adequate program for screening these diseases in countries where the prevalence is high to prevent the occurrence of severe forms.

The Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary disorder associated with different tumor types in childhood and young adults. Approximately 70% of LFS cases contain germline mutations in the TP53 gene. We report a case of a family suspected of LFS.The proband and four members of the family affected were diagnosed with cancer at an early age and they all died except the proband. Exons 5-9 from TP53 gene were analysed by direct amplification and sequencing in 7 family members.The analysis revealed a germline nonsense mutation in exon 8 at codon 306 of the codified region of the TP53 gene, causing a change of CGA to TGA (Arg→Stop) in the proband, her mother, her cousin and her maternal uncle. Proband's maternal grandmother and aunt do not have the mutation.The members of this family that were studied meet the criteria of classic LFS and the described mutation increases their susceptibility to develop cancer. The proband's maternal grandfather died of lung cancer in 1993, and we believe that he was the carrier of the mutation in this family.

We describe a 3 year-old male who presented with fever and cerebellar dysfunction after varicella. He developed transient hepatosplenomegaly, cytopenias, and progressive central nervous system involvement (coma, status epilepticus, and hydrocephalus). Despite normal initial cranial computed tomographic scan, diffuse swelling of the cerebellum with downward tonsillar herniation ensued. Diagnosis of hemophagocytic lymphohistiocytosis was difficult and delayed because of the relapsing course, and complete diagnostic criteria were not fulfilled at initial presentation. Central nervous system disease preceded the typical clinical picture of this disease; it dominated the clinical course and caused life-threatening complications and sequelae. The patient improved after treatment, according to the hemophagocytic lymphohistiocytosis protocol (HLH-94) of the Histiocyte Society, with dexamethasone, etoposide, and cyclosporine and unrelated cord blood stem cell transplantation. A mutation in the perforin gene confirmed the diagnosis of familial hemophagocytic lymphohistiocytosis.