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Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9-10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide., Competing Interests: Declaration of interests AK declares honoraria from chiesi and Novartis and a research grant from Novaris. AK is on the advisory board of Chiesi and Novartis. FML declares honoraria from Chiesi and is on the advisory board of Chiesi. LK is on the advisory board of Agios, Amgen, Bayer, and Novartis. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Natural killer (NK) cells are important for early tumor immune surveillance. In patients with hematological cancers, NK cells are generally functional deficient and display dysregulations in their receptor repertoires. Acute leukemia is the most common cancer in children, and we here performed a comparative phenotypic profiling of NK cells from B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients to identify aberrant NK cell phenotypes. NK cell phenotypes, maturation, and function were analyzed in matched bone marrow and blood NK cells from BCP-ALL patients at diagnosis, during treatment, and at end of treatment and compared with age-matched pediatric control subjects. Expression of several markers were skewed in patients, but with large interindividual variations. Undertaking a multiparameter approach, we found that high expression levels of NKG2A was the single predominant marker distinguishing NK cells in BCP-ALL patients compared with healthy control subjects. Moreover, naïve CD57-NKG2A NK cells dominated in BCP-ALL patients at diagnosis. Further, we found dysregulated expression of the activating receptor DNAM-1 in resident bone marrow CXCR6+ NK cells. CXCR6+ NK cells lacking DNAM-1 expressed NKG2A and had a tendency for lower degranulation activity. In conclusion, high expression of NKG2A dominates NK cell phenotypes from pediatric BCP-ALL patients, indicating that NKG2A could be targeted in therapies for this patient group., Competing Interests: Conflict of interest statement. The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Objectives: This study aimed to describe the impact of allogeneic/haploidentical hematopoietic stem cell transplantation on nutritional status and intake in a group of children aged 2 to 18 years., Methods: In an observational study, data were collected prospectively. Patients were prescribed individual nutritional support by hospital routines. Anthropometrics were measured pre-transplant at hospital admission and weekly from the day of transplant (day 0) until day +28. z scores for weight, height, and BMI were calculated using Norwegian growth references to assess nutritional status. Pre-transplant diet was assessed on the day of hospitalization. Nutrient provision from enteral nutrition (EN = oral and tube) and parenteral nutrition (PN) was assessed by daily records from day +1 until day +28, or previous discharge, and compared with recommendations (RI) from the Nordic Nutrition Recommendations and ESPGHAN guidelines. Total energy intake was presented as the percentage (%) of basal metabolic rate (BMR) calculated by the Schofield equation. Macro- and micronutrient provisions were presented as medians (interquartile range) and the % of RI., Results: Twenty-eight patients, mean age 10.3 years (range 3.5-16.6), were included. Two-thirds (n = 18) had malignant diseases. At admission, mean weight Z-score was -0.3, height z scores -0.7, and BMI Z-score 0.1. Eighteen percent (n = 5) were stunted and 25% (n = 7) had overweight. At admission, 25% (n = 7) had established tube feeding, and 7% (n = 2) also had PN. No significant changes in weight z scores were detected during the studied weeks ( P = 0.454). The median daily energy provision was 115% (110-123) of BMR and proteins 1.5 (1.3-1.8) g/kg. EN was provided during a median of 93% of the studied days and provided 21% of the energy. PN was given on a median of 96% of the studied days and provided 79% of energy. RI for vitamins, magnesium, and zinc was met. Provision of copper, iodine, selenium, calcium, and phosphate was below RI., Conclusions: Combined EN and PN providing 115% of BMR and 1.5 g/kg protein ensured stable weight by day +28 and covered RI, except for trace elements and minerals., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background and Aims: Childhood cancer survivors are at risk of unwanted late effects. The primary aim of this study was to assess bone mineral density Z-scores (BMDz) in long-term survivors of childhood medulloblastoma (MB) or central nervous system supratentorial primitive neuroectodermal tumor (CNS-PNET). Secondary aims were to describe nutrient intake, vitamin D status, physical activity and explore potential risk factors for decreased BMDz., Methods: All MB and CNS-PNET survivors treated at Oslo University Hospital from 1974 to 2013 were invited to participate in a cross-sectional study. Dual-energy x-ray absorptiometry (Lunar Prodigy) assessed BMDz lumbar spine, BMDz total body, and lean body mass. Decreased BMDz was defined as a combination of low BMDz -1 to -1.99 and very low BMDz ≤-2. Lean body mass index (LMI) was calculated by dividing lean body mass by the squared height. Nutrient intake was assessed by a 3-day food record. Serum 25(OH)D was analyzed. Physical activity was reported by a questionnaire. Descriptive statistics and multivariable Cox regression analyses were applied., Results: Fifty survivors with a median age of 25.5 years (5.5-51.9) and a median follow-up time of 19.5 years (3.2-40.5) were included. Mean BMDz lumbar spine was -0.8 (SD 1.1, 95% CI: -1.1 to -0.4), and BMDz total body was -0.6 (SD 1.1, 95% CI: -0.9 to -0.3). Decreased BMDz was detected in 48% of the lumbar spine and 34% of the total body measurements. In all, 62% had low calcium, and 69% had low vitamin D intake. 26% of participants had serum 25(OH)D < 50 nmol/L, and 62% reported an inactive lifestyle. Male sex, higher age at diagnosis, and lower LMI were potential risk factors for decreased BMDz., Conclusions: Long-term survivors of childhood MB and CNS-PNET had decreased BMDz, and risk factors were male sex, higher age at diagnosis, and lower LMI. Inadequate calcium and vitamin D intake, an inactive lifestyle, and a high prevalence of 25(OH)D ≤ 50 nmol/L were detected., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective To investigate the long-term cognitive consequences of malignant pediatric brain tumor and its treatment, and factors explaining variability in cognitive functioning among survivors. Method: A geographical cohort of survivors of pediatric medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor (CNS-PNET), treated between 1974 and 2013, was invited to participate. Of the 63 surviving patients, 50 (79%) consented to participation. The participants were tested with a battery of neuropsychological tests covering a wide age range. Verbal cognition, nonverbal cognition, processing speed, attention, memory, executive functioning, and manual dexterity were assessed. The participants were between 5:5 and 51:11 years of age at time of assessment. Assessments took place on average 19 years after primary tumor resective surgery. Results: One participant had a severe intellectual disability. For the rest, IQ varied from 52 to 125, with a mean score of 88.0 ( SD 19.7). Twenty-eight (56%) of the participants had full-scale IQ scores in the age-average range or above. Gender, age at operation, time since operation, the presence of secondary medical complications, and treatment variables explained 46% of the variability in IQ scores, F (4,44) =  9.5, p <.001. The presence of endocrine insufficiency in combination with either epilepsy and/or hydrocephalus was associated with lowered IQ, lowered processing speed, and memory impairments. Conclusion: Patients treated for childhood MB and CNS-PNET have a lifelong risk of medical sequelae, including impaired cognitive functioning. This study adds to the literature by demonstrating the importance of following neuropsychological functioning closely, especially processing speed, learning, and memory, in survivors who have multiple secondary medical complications.

Background and Objectives: The status of red blood cell alloimmunization in patients with constitutional anemias including hemoglobinopathies is not known in Norway. The study objective was to investigate the impact of a strategy based on phenotype-matching for C, c, E, e, K, Jka, Jkb, Fya, Fyb, S and s on alloimmunization., Materials and Methods: We reviewed transfusions of 40 patients retrospectively using the computerized blood bank management system and medical records; including diagnosis, age at start of transfusion therapy, gender, number and age of packed red blood cell units transfused, follow-up time, phenotypes of the donors and patients, antigen-negative patients exposed to antigen-positive packed red blood cell units, transfusion reactions and alloantibody specificities., Results: Forty patients received 5402 packed red blood cell units. Alloimmunization frequency was 20 % for the whole group, being 7%, 25 % and 30 % in patients with sickle cell disease (n = 14), thalassemia (n = 16) and other conditions (n = 10), respectively. The alloantibodies detected were anti-E, -c, -C, -Cw, -K, -Jka and -Lua., Conclusion: Good communication between the clinicians and the transfusion services is essential for successful management of patients with constitutional anemias. Providing full phenotype-matched units was not always possible. Extended pheno-/genotyping before the first transfusion and providing antigen-negative units for antigen-negative patients for at least C, c, E and K in every red cell transfusion would probably have reduced the alloimmunization rate. Non-phenotype-matched transfusions seem to be the main reason for alloimmunization. Finding markers for identifying responders prone to alloimmunization will ensure targeted transfusion strategies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We describe two unrelated patients, both heterozygous for an unstable hemoglobin (Hb) variant named Hb Calgary ( HBB : c.194G>T) that causes severe hemolytic anemia and dyserythorpoietic, resulting in transfusion dependence and iron overload. The molecular pathogenesis is a missense variation on the β-globin gene, presumed to lead to an unstable Hb. The phenotype of Hb Calgary is particularly severe presenting as transfusion-dependent anemia in early infancy, precluding phenotypic diagnosis and highlighting the importance of early genetic testing in order to make an accurate diagnosis.

Aim: To study incidence, types and degrees of late effects in a geographical cohort of paediatric medulloblastoma and central nervous system primitive neuroectodermal tumour (CNS-PNET) survivors, and identify the need for rehabilitation., Methods: Between 1974 and 2013, 63 patients survived treatment for paediatric medulloblastoma and CNS-PNET at Oslo University Hospital, Norway. Of these, 50 accepted invitation and were included in this study., Results: Median follow-up was 20 years (range 3.2-41), and 96% of participants had developed late effects. Cognitive impairment was found in 72%, reduced hearing in 68%, endocrine deficits in 66%, epilepsy in 32% and another 30% had been diagnosed with one or more second primary neoplasms. Radiotherapy significantly increased risk of secondary primary neoplasms and endocrinological deficits, chemotherapy risk of ototoxicity and endocrinological deficits, and epilepsy was found significantly more often in CNS-PNET than medulloblastoma patients. Epilepsy was the main cause of cognitive impairments (full-scale IQ) in our study. 86% of participants had an unmet rehabilitation need., Conclusion: Significant late effects and unmet rehabilitation needs were documented in the large majority of survivors after treatment for paediatric medulloblastoma and CNS-PNET., (© 2020 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Purpose: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors., Patients and Methods: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries., Results: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A , were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02)., Conclusion: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Vijay RamaswamyHonoraria: AstraZenecaMiriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmuneDaniel R. BoueStock and Other Ownership Interests: Vertex Pharmaceuticals, Intuitive Surgical, IlluminaAdela CaneteConsulting or Advisory Role: EUSA Pharma, Bayer Speakers’ Bureau: EUSA PHarma Research Funding: EUSA Pharma (Inst) Travel, Accommodations, Expenses: EUSA PharmaIra J. DunkelConsulting or Advisory Role: Bayer, Apexigen, Celgene, Roche/Genentech, AstraZeneca Research Funding: Bristol-Myers Squibb (Inst), Genentech (Inst), Novartis (Inst)Karen GauvainEmployment: Iqvia Biotech Consulting or Advisory Role: Bayer, Axiom Health Care SciencesJordan R. HansfordConsulting or Advisory Role: BayerSarah G. InjacResearch Funding: TakedaMatthias KarajannisConsulting or Advisory Role: Bayer, Recursion Pharma Research Funding: Novartis Travel, Accommodations, Expenses: Bayer Uncompensated Relationships: Debiopharm (Inst) Open Payments Link: https://openpaymentsdata.cms.gov/physician/710370/summaryNormand LaperriereHonoraria: Merck/Schering Plough Consulting or Advisory Role: AbbVieAlvaro LassalettaConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche Travel, Accommodations, Expenses: Shire, Gilead SciencesRoger PackerHonoraria: Novartis Consulting or Advisory Role: Novartis, AstraZenecaJaroslav SterbaResearch Funding: Roche/Genentech (Inst) Travel, Accommodations, Expenses: Bristol-Myers SquibbDerek S. TsangOther Relationship: Varian Medical Systems (Inst), Mevion Medical Systems (Inst), Hitachi (Inst), RaySearch Laboratories (Inst), IBA (Inst), ProTom (Inst)Cornelis M. van TilburgConsulting or Advisory Role: Novartis, BayerOlaf WittConsulting or Advisory Role: Novartis, AstraZeneca, Janssen Research & Development, Bristol-Myers Squibb, Roche, BayerEric BouffetResearch Funding: Roche (Inst), Bristol-Myers Squibb (Inst)Cynthia HawkinsConsulting or Advisory Role: Bayer Patents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Background: A previous study based on Norwegian Cancer Registry data suggested regional differences in overall survival (OS) after treatment for medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor (CNS-PNET) in Norway. The purpose of the present study was to confirm in an extended cohort whether there were regional differences in outcome or not, and if so try to identify possible explanations., Material and Methods: Data from patients aged 0-20 years diagnosed with and treated for MB/CNS-PNET at all four university hospitals in Norway from 1974 to 2013 were collected and compared., Results: Of 266 identified patients, 251 fulfilled inclusion criteria. MB was diagnosed in 200 and CNS-PNET in 51 patients. Five-year OS and event-free survival (EFS) were 59% and 52%, respectively. There was a significant difference in five-year OS and EFS between MB and CNS-PNET patients; 62% versus 47% (P =  0.007) and 57% versus 35% (P < 0.001). In multivariable analysis, two factors were found to significantly contribute to improved five-year OS and EFS, whereas one factor contributed to improved five-year OS only. Gross total resection (GTR) versus non-GTR (hazard ratio [HR] 0.53, P =  0.003; HR 0.46, P < 0.001) and cerebrospinal irradiation (CSI) versus non-CSI (HR 0.24, P < 0.001; HR 0.28, P < 0.001) for both, and treatment outside Oslo University Hospital for OS only (HR 0.64, P =  0.048)., Conclusion: Survival was comparable with data from other population-based studies, and the importance of GTR and CSI was confirmed. The cause for regional survival differences could not be identified., (© 2019 The Authors Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Unstable hemoglobin (Hb) variants are the result of sequence variants in the globin genes causing precipitation of Hb molecules in red blood cells (RBCs). Intracellular inclusions derived from the unstable Hb reduce the life-span of the red cells and may cause hemolytic anemia. Here we describe a patient with a history of hemolytic anemia and low oxygen saturation. She was found to be carrier of a novel unstable Hb variant, Hb Oslo [β42(CD1)Phe→Ile (TTT>ATT), HBB: c.127T>A] located in the heme pocket of the β-globin chain. Three-dimensional modeling suggested that isoleucine at position 42 creates weaker interactions with distal histidine and with the heme itself, which may lead to altered stability and decreased oxygen affinity. At steady state, the patient was in good clinical condition with a Hb concentration of 8.0-9.0 g/dL. During virus infections, the Hb concentration fell and on six occasions during 4 years, the patient needed a blood transfusion.

Background: Medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor of the central nervous system (CNS-PNET) are among the most common pediatric brain tumors. The diagnosis, treatment, and outcome of MB/CNS-PNET patients treated during the last four decades at Oslo University Hospital (OUH) are described., Material and Methods: All patients younger than 20 years of age diagnosed and treated for MB/CNS-PNET at OUH between 1 January 1974 and 31 December 2013 were identified., Results: We found 175 patients. In 13 of them, the diagnosis was changed upon histopathological review and in 4 patients part of the treatment was administered at other hospitals. Thus, 158 patients were included for further analysis. Eight patients did not receive adjuvant therapy because of a dismal clinical condition. The overall 5-year survival rate for MB and CNS-PNET was 54%, for MB 57%, and for CNS-PNET 41%. Gross total resection (GTR) was achieved in 118 patients and 5-year overall survival for patients with GTR versus those with non-GTR differed significantly with 64% versus 22%. Cytological examination of the cerebrospinal fluid was performed in 52 patients. A total of 126 patients received radiotherapy as part of the primary treatment and 24 did not due to young age. Median time from surgery to start of radiotherapy was 33 days. Duration of radiotherapy was more than 48 days in 22% of patients. At the time of analysis, 63 patients were alive and disease-free, one alive with disease, and 94 patients were deceased; 84 of these due to MB/CNS-PNET and 10 due to supposed late effects from the treatment., Conclusions: Survival was comparable to data from other population-based studies. The importance of GTR for survival was corroborated. Reporting real-world data remains crucial to know the true outcome of patients treated outside clinical trials.

Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions., Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs., Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping., Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays., Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMT(IA)) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT., Methods: Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy., Results: The degree of myelosuppression following HD-MTX was similar for patients with TPMT(IA) and patients with high TPMT activity (TPMT(HA)), when HD-MTX started with same blood counts and 6MP doses. However, since TPMT(IA) had lower blood counts at initiation of HD-MTX compared with TPMT(HA) patients (median WBC 2.8 vs. 3.3 × 10⁹/L, P = 0.01; median ANC 1.4 vs. 1.7 × 10⁹/L, P = 0.02), TPMT(IA) continued to have lower WBC and ANC levels compared with TPMT(HA) during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMT(IA) and TPMT(HA) patients (P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P < 0.001 for all analyses)., Conclusion: For both TPMT(IA) and TPMT(HA) patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.

Background: Previous studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMT(LA)) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMT(WT)) when treated with 6 MP maintenance therapy starting doses of 75 mg/m(2)/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m(2)/day for patients with TPMT heterozygosity in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2000 protocol., Procedure: We explored the pattern of SMN and relapse in the NOPHO ALL2000 protocol (n = 674) and NOPHO ALL92 protocol (n = 601) in relation to TPMT pheno- and/or genotype., Results: The overall risk of any event did not differ significantly between the two protocols. However, in event pattern analyses considering only the patients with TPMT(LA) who experienced relapse or SMN, the risk of SMN versus leukemia relapse was significantly lower in the ALL2000 cohort for patients with a 6MP starting dose <75 mg/m(2)/day when compared to the patients in ALL92 (relapse (n = 11) and SMN (n = 0) in ALL2000 versus relapse (n = 5) and SMN (n = 4) in ALL92, P = 0.03). Furthermore, the 8-year cumulative incidence of relapse for patients with TPMT(LA) was significantly higher in the ALL2000 compared to the ALL92 cohort (19.7% (11.6-33.3%) vs. 6.7% (2.9-15.5%), P = 0.03)., Conclusion: This study indicates that reducing 6MP starting dose for patients with TPMT(LA) may reduce SMN risk but lead to a relapse risk similar to that of patients with TPMT(WT)., (© 2014 Wiley Periodicals, Inc.)

Background: Non-operative management for blunt splenic injuries was introduced to reduce the risk of overwhelming post splenectomy infection in children. To increase splenic preservation rates, splenic artery embolization (SAE) was added to our institutional treatment protocol in 2002. In the presence of clinical signs of ongoing bleeding, SAE was considered also in children. To our knowledge, the long term splenic function after SAE performed in the paediatric population has not been evaluated and constitutes the aim of the present study., Methods: A total of 11 SAE patients less than 17 years of age at the time of injury were included with 11 healthy volunteers serving as matched controls. Clinical examination, medical history, general blood counts, immunoglobulin quantifications and flowcytometric analysis of lymphocyte phenotypes were performed. Peripheral blood smears were examined for Howell-Jolly bodies (H-J bodies) and abdominal ultrasound was performed in order to assess the size and perfusion of the spleen., Results: On average 4.6 years after SAE (range 1-8 years), no significant differences could be detected between the SAE patients and their controls. Total and Pneumococcus serospecific immunoglobulins and H-J bodies did not differ between the study groups, nor did general blood counts and lymphocyte numbers, including memory B cell proportions. The ultrasound examinations revealed normal sized and well perfused spleens in the SAE patients when compared to their controls., Conclusion: This case control study indicates preserved splenic function after SAE for splenic injury in children. Mandatory immunization to prevent severe infections does not seem warranted., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: After introducing splenic artery embolisation (SAE) in the institutional treatment protocol for splenic injury, we wanted to evaluate the effects of SAE on splenic function and assess the need for immunisation in SAE treated patients., Methods: 15 SAE patients and 14 splenectomised (SPL) patients were included and 29 healthy blood donors volunteered as controls. Clinical examination, medical history, general blood counts, immunoglobulin quantifications and flowcytometric analysis of lymphocyte phenotypes were performed. Peripheral blood smears from all patients and controls were examined for Howell-Jolly (H-J) bodies. Abdominal doppler, gray scale and contrast enhanced ultrasound (CEUS) were performed on all the SAE patients., Results: Leukocyte and platelet counts were elevated in both SAE and SPL individuals compared to controls. The proportion of memory B-lymphocytes did not differ significantly from controls in either group. In the SAE group total IgA, IgM and IgG levels as well as pneumococcal serotype specific IgG and IgM antibody levels did not differ from the control group. In the SPL group total IgA and IgG Pneumovax(®) (PPV23) antibody levels were significantly increased, and 5 of 12 pneumococcal serotype specific IgGs and IgMs were significantly elevated. H-J bodies were only detected in the SPL group. CEUS confirmed normal sized and well perfused spleens in all SAE patients., Conclusion: In our study non-operative management (NOM) of high grade splenic injuries including SAE, was followed by an increase in total leukocyte and platelet counts. Normal levels of immunoglobulins and memory B cells, absence of H-J bodies and preserved splenic size and intraparenchymal blood flow suggest that SAE has only minor impact on splenic function and that immunisation probably is unnecessary., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The number of circulating B-cells in peripheral blood plateaus between 2 and 24 months of age, and thereafter declines gradually. How this reflects the kinetics of the precursor B-cell pool in the bone marrow is of clinical interest, but has not been studied thoroughly in humans. The authors analyzed bone marrow (n = 37) from healthy children and adults (flow cytometry) searching for age-related changes in the total precursor B-cell compartment. In an age-matched cohort (n = 25) they examined age-related global gene expression changes (Affymetrix) in unsorted bone marrow with special reference to the recombination activating gene 1, RAG1. Subsequently, they searched the entire gene set for transcripts correlating to the RAG1 profile to discover other known and possibly new precursor B-cell related transcripts. Both methods disclosed a marked, transient increase of total precursor B-cells at 6-20 months, followed by a rapid decrease confined to the first 2 years. The decline thereafter was considerably slower, but continued until adulthood. The relative composition of total precursor B-cells, however, did not change significantly with age. The authors identified 54 genes that were highly correlated to the RAG1 profile (r >or= .9, p < 1 x 10(-8)). Of these 54 genes, 15 were characteristically B-lineage associated like CD19, CD79, VPREB, EBF1, and PAX5; the remaining 39 previously not described as distinctively B-lineage related. The marked, transient increase in precursor B-cells and RAG1 transcriptional activity is not reflected by a similar peak in B-cells in peripheral blood, whereas the sustained plateau concurs in time.

The autosomal recessive immunodeficiencies Griscelli syndrome type 2 (GS2) and familial hemophagocytic lymphohistiocytosis type 3 (FHL3) are associated with loss-of-function mutations in RAB27A (encoding Rab27a) and UNC13D (encoding Munc13-4). Munc13-4 deficiency abrogates NK-cell release of perforin-containing lytic granules induced by signals for natural and antibody-dependent cellular cytotoxicity. We demonstrate here that these signals fail to induce degranulation in resting NK cells from Rab27a-deficient patients. In resting NK cells from healthy subjects, endogenous Rab27a and Munc13-4 do not colocalize extensively with perforin. However, phorbol 12-myristate 13-acetate and ionomycin stimulation or conjugation to susceptible target cells induced myosin-dependent colocalization of Rab27a and Munc13-4 with perforin. Unexpectedly, individual engagement of receptors leukocyte functional antigen-1, NKG2D, or 2B4 induced colocalization of Rab27a, but not Munc13-4, with perforin. Conversely, engagement of antibody-dependent cellular cytotoxicity receptor CD16 induced colocalization of Munc13-4, but not Rab27a, with perforin. Furthermore, colocalization of Munc13-4 with perforin was Rab27a-dependent. In conclusion, Rab27a or Munc13-4 recruitment to lytic granules is preferentially regulated by different receptor signals, demonstrating that individual target cell ligands regulate discrete molecular events for lytic granule maturation. The data suggest Rab27a facilitates degranulation at an early step yet highlight a reciprocal relationship between Munc13-4 and Rab27a for degranulation.

Objective: Familial haemophagocytic lymphohistiocytosis (FHL) is a fatal disorder of immune dysregulation with defective cytotoxic lymphocyte function. Disease-causing mutations have been identified in the genes encoding perforin (PRF1), syntaxin-11 (STX11), and Munc13-4 (UNC13D). We screened for UNC13D mutations and studied clinical and functional implications of such mutations in a well defined patient cohort., Methods: Sequencing of UNC13D was performed in 38 FHL patients from 34 FHL families in which PRF1 and STX11 mutations had been excluded., Results: We identified six different mutations affecting altogether 9/38 individuals (24%) in 6/34 (18%) unrelated PRF1/STX11-negative families. Four novel mutations were revealed; two homozygous nonsense mutations (R83X and W382X), one splice mutation (exon 28), and one missense mutation (R928P). In addition, two known mutations were identified (R214X and a deletion resulting in a frame-shift starting at codon 782). There was considerable variation in the age at diagnosis, ranging from time of birth to 14 years (median 69 days). Three of nine patients (33%) developed central nervous system (CNS) symptoms. Natural killer (NK) cell activity was impaired in all four patients studied. Defective cytotoxic lymphocyte degranulation was evident in the two patients investigated, more pronounced in the patient with onset during infancy than in the patient with adolescent onset., Conclusions: Biallelic UNC13D mutations were found in 18% of the PRF1/STX11-negative FHL families. Impairment of NK cell degranulation was less pronounced in a patient with adolescent onset. FHL should be considered not only in infants but also in adolescents, and possibly young adults, presenting with fever, splenomegaly, cytopenia, hyperferritinaemia, and/or CNS symptoms.

Familial hemophagocytic lymphohistiocytosis (FHL) is typically an early onset, fatal disease characterized by a sepsislike illness with cytopenia, hepatosplenomegaly, and deficient lymphocyte cytotoxicity. Disease-causing mutations have been identified in genes encoding perforin (PRF1/FHL2), Munc13-4 (UNC13D/FHL3), and syntaxin-11 (STX11/FHL4). In contrast to mutations leading to loss of perforin and Munc13-4 function, it is unclear how syntaxin-11 loss-of-function mutations contribute to disease. We show here that freshly isolated, resting natural killer (NK) cells and CD8(+) T cells express syntaxin-11. In infants, NK cells are the predominant perforin-containing cell type. NK cells from FHL4 patients fail to degranulate when encountering susceptible target cells. Unexpectedly, IL-2 stimulation partially restores degranulation and cytotoxicity by NK cells, which could explain the less severe disease progression observed in FHL4 patients, compared with FHL2 and FHL3 patients. Since the effector T-cell compartment is still immature in infants, our data suggest that the observed defect in NK-cell degranulation may contribute to the pathophysiology of FHL, that evaluation of NK-cell degranulation in suspected FHL patients may facilitate diagnosis, and that these new insights may offer novel therapeutic possibilities.

Background: The objective of this study was to evaluate the suitability of cord blood (CB) as a source of red blood cells (RBCs) for autologous transfusion., Study Design and Methods: CB was collected in 150-mL storage containers with citrate phosphate dextrose (CPD) as anticoagulant and stored in either saline, adenine, glucose, and mannitol (SAG-M; n = 18) or phosphate, adenine, glucose, guanosine, saline, and mannitol (PAGGS-M; n = 18) for 35 days at 4 degrees C. Hematologic status and hemolysis were studied. The lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 from CB monocytes was analyzed after incubation with addition of weekly sampled supernatants from the CB RBC units. Five additional units (PAGGS-M) were leukoreduced and thereafter analyzed as indicated above., Results: Hemolysis increased significantly over time, in SAG-M more than in PAGGS-M. During storage in both media, the number of white blood cells (WBCs) decreased, and the LPS-induced production of TNF-alpha and TGF-beta1 decreased and increased, respectively. There were no significant changes in the LPS-induced production of TNF-alpha and TGF-beta1 in the leukoreduced CB RBC units., Conclusion: Hemolysis in CB RBC units increased significantly over time, and PAGGS-M appears to be superior to SAG-M as a preservation solution for CB RBC. The changes in LPS-induced TNF-alpha and TGF-beta1 production over time were probably caused by substances released from apoptotic and/or necrotic WBCs. Further studies are needed to identify both which substances are responsible for the changes in LPS-induced cytokine release and the clinical significance hereof.

Objective: To evaluate whether our current practice of giving iron 18 mg daily to 6-week-old infants with very low birth weight (VLBW) was associated with increased oxidative stress markers or decreased antioxidant status., Study Design: The study was a prospective observational study of 21 healthy VLBW infants (born at gestational age <32 weeks, birth weight <1500 g). Blood and urine were sampled twice before starting iron supplementation at 6 weeks postnatal age and after 1 week of iron supplementation at age 7 weeks. Urine 8-isoprostane was analyzed by gas chromatography-mass spectrometry and plasma total hydroperoxides were measured. Antioxidant status was assessed by ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), ferric-reducing ability of plasma, and plasma glutathione., Results: After 1 week of iron supplementation, no significant changes in urine 8-isoprostane or plasma total hydroperoxides were seen, and plasma antioxidants were largely unchanged., Conclusions: Markers of oxidative stress in urine and plasma antioxidant status in healthy VLBW infants fed human milk remained unchanged after high-dose oral iron supplementation.

Background: A Hb balance model was used in very low birth weight (VLBW) infants to predict posttransfusion Hb levels from which we inferred allogeneic RBC recovery after transfusion of RBCs stored for varying periods of time., Study Design and Methods: Premature VLBW infants receiving RBC transfusions during the 1st month of life were evaluated retrospectively for RBC survival of stored donor blood. Actual Hb levels measured in infant blood 1 and 2 days after RBC transfusions were compared to those predicted using a Hb balance model based on factors affecting blood Hb loss and gain. Transfusions were subgrouped according to whether or not infants were clinically stable at the time of RBC transfusion. Model-predicted RBC recovery was also evaluated relative to duration of RBC storage., Results: Model-predicted mean (+/- SD) Hb levels 2 days after transfusion among the 30 VLBW infants receiving a total of 57 RBC transfusions were only 4 percent higher than actual values observed (15.2 +/- 1.2 g/dL vs. 14.7 +/- 1.4, respectively; p < 0.05). The infant's clinical status at the time of transfusion did not affect predicted 1- and 2-day posttransfusion RBC recovery. Model-predicted recovery of transfused RBCs was modestly, but significantly, decreased with increasing duration of donor RBC storage (i.e., 10% lower by 42 days-the maximal allowed storage period for donor blood [p < 0.01])., Conclusions: Our model-predicted RBC survival results are consistent with-but not direct evidence of-hemolysis of donor blood after RBC transfusion. Although observed post-RBC Hb levels 2 days after transfusion averaged only 4 percent less than predicted, model-predicted survival of donor RBCs at 42 days suggested a modest decrease (i.e., by 10%).

Unlabelled: Growth is a fundamental process of mammalian development. Several observations regarding regulation of erythropoiesis during growth are not easily explained by the hypoxia-erythropoietin (Epo) concept. This review focuses primarily on this aspect of the physiology of Epo. The question is raised of whether this regulation during growth is based on the hypoxia-Epo mechanism alone, or whether Epo acts in concert with general growth-promoting factors, particularly growth hormone (GH) and the insulin-like growth factors (IGF-I and -II). Supporting the latter hypothesis is the observation that the Epo and GH/IGF systems are activated by hypoxia and share similar receptors and pathways. Recent studies indicate that human fetal and infant growth is stimulated by GH, IGF-I and IGF-II. Epo, GH and IGFs are expressed early in fetal life. Although the rate of erythropoiesis in the fetus is high, serum Epo levels are low. The Epo response to hypoxia in the fetus and neonate is reduced compared with adults. Following delivery the Epo levels vary between species, probably related to the oxygen transport capacity of the hemoglobin (Hb) mass. IGF-I levels are low in the fetus and increase slowly following birth, except in preterm infants in whom the levels decline. In all mammals Hb declines following birth, giving rise to "early anemia". Except in the human, Epo levels increase proportionally with the fall in Hb, but there is a discrepancy between the curves for serum immunoreactive Epo (siEpo) and for erythropoiesis stimulating factors (ESF): the latter include other stimulatory factors in addition to Epo. Hypertransfusion of mice in the period of "early anemia" suppresses siEpo, but not ESF and erythropoiesis, as it does in adult mice. GH and IGF-I have direct effects on erythropoiesis in vitro and act particularly at the later stages of red cell differentiation. IGF-I acts synergistically with Epo, and its effects are most marked when Epo levels are low. Human recombinant (rhu) IGF-I stimulates erythropoiesis in neonatal rats, but not in newborn mice and lambs. In adult mice, in hypophysectomized rats and in mice with end-stage renal failure, however, a stimulatory effect of this growth factor was found on red cell production. RhuGH stimulates erythropoiesis in GH-deficient short children., Conclusion: Fetal and early postnatal erythropoiesis are dependent on factors in addition to Epo. The likely candidates are GH and IGF-I. The in vitro stimulating effects of these factors on erythropoiesis are convincing, but more data are needed on the in vivo effects.

To evaluate the quantitative aspects of the shift in production from fetal hemoglobin (HbF) to adult hemoglobin (HbA), the HbF and HbA mass were estimated in a preterm infant (gestational age 29 weeks) for 22 weeks after an exchange transfusion the second day of life, leading to an initial HbA% of 100. Up until the estimated time of delivery, the HbA mass declined continuously, at a rate corresponding to a survival time of the transfused HbA erythrocytes of 100 days, and the rise in total hemoglobin mass could be ascribed solely to a rise in the HbF mass. HbF% maximum was reached 3 weeks before HbF mass maximum, and, thus, the HbF% and HbA% time courses gave no basis for evaluation of the production/destruction balance of HbF and HbA erythrocytes. The applied quantitative approach seems to be a useful additional procedure for evaluating the switch from HbF to HbA production and for estimating HbA erythrocyte survival time in preterm infants.

Ritscher-Schinzel syndrome (cranio-cerebello-cardiac syndrome, 3C syndrome) is a recently delineated disorder with Dandy-Walker malformation, congenital heart defects, and characteristic face. Various other defects, including eye and kidney malformations, have been described in the few patients reported. Here we describe 3 sibs born to consanguineous Pakistani parents with 3C syndrome. All 3 children had atrial septal defects II and ventricular septal defects and died within 3 months. Two of them had a Dandy-Walker malformation, whereas 1 had only slightly dilated ventricles. One sib had anal atresia, and another a ventrally displaced anus. The findings in the 3 sibs demonstrate the intrafamilial variation in the Ritscher-Schinzel syndrome, because the second sib did not have a Dandy-Walker malformation. Anal anomalies have not been previously reported as a component manifestation of the disorder. The occurrence of 3 affected sibs in a consanguineous family confirms autosomal recessive inheritance.

Unlabelled: There is no consensus regarding protein intake and the doses of recombinant human erythropoietin (r-HuEpo) and iron in the treatment of anaemia of prematurity (AOP). This open, randomized study has compared the effectiveness of 50 IU r-HuEpo/kg with that of 100 IU/kg, both given subcutaneously thrice weekly. In addition, two different protein supplements have been compared; lyophilized human milk protein and a commercial cow's milk product. Total protein intake was 3 g/kg per day. Daily iron dose was 18-36 mg. "Healthy" preterm infants (n = 32, birth weight: 800-1400 g, gestational age < or = 31 weeks) were studied from age 3 to 8 weeks. The two protein regimens yielded no differences in body growth, reticulocyte count or Hb concentration. In both r-HuEpo dose groups increased number of reticulocytes followed start of treatment; higher levels were, however, found in the group receiving 100 IU/kg. Mean Hb concentration plateaued at 12 g/dl for infants receiving 100 IU/kg, at 11 g/dl in the 50 IU/kg group. Even though serum levels of ferritin and transferrin saturation indicated no iron deficiency, soluble transferrin receptor increased in both groups, more rapidly and to higher levels in the 100 IU/kg group. In addition, the number of infants having more than 8% hypochromic red cells increased in both groups., Conclusions: Commercial cow's milk protein added to human milk was as good as human milk protein supplementation in supporting growth and erythropoiesis. Fifty IU/kg r-HuEpo thrice weekly during AOP stimulated erythropoiesis significantly, but less so than 100 IU/kg. Even when using high oral doses of iron to preterms receiving r-HuEpo, our data suggested a certain degree of iron deficient erythropoiesis.

Parenteral iron abolishes the "early anaemia' in all mammals tested and increases packed cell volume (PCV) and haemoglobin concentration (Hb) significantly above adult levels. In the present study we examined the effect of parenteral iron upon serum immunoreactive erythropoietin (siEpo) concentration in young mice (age 6-24d) and in adult iron-deficient mice. Young BALB/CJ mice, from 5 to 23 d of age, and adult (60-100 d old)mice, some of which were iron deficient due to a low iron diet from the time of weaning, were given iron subcutaneously (iron sorbitol, Fe+3, 1.2 mg iron/100g body weight/injection). Iron was given as one single dose and the animals killed 20-24 h later. Control mice were similarly treated with saline. In young mice, from the age 10 d to weaning at 20 d, the siEpo level, measured 20-24 h after a single subcutaneous dose of iron, was 5 times greater than that in control mice (P < 0.0001). In contrast, there was no change in siEpo 20-24 h after a single subcutaneous dose of iron in adult mice, whether iron-deficient anaemic or normal. Thus, during the "early anaemia' in young mice over 10 d old, iron increased siEpo levels, whereas it had no such effect in iron-deficient and normal adult mice. This suggests that between ages 10 and 20 d, iron has additional effects in the regulation of erythropoiesis, which may not occur in adult or in 6-d-old mice.

In the present study we assess the effect of recombinant human erythropoietin (r-HuEpo) upon levels of fetal Hb (HbF) and adult Hb (HbA) in preterm infants. Twenty-eight "healthy," appropriate for gestational age infants with birth weights 900-1400 g entered the study at 3 wk of age. Fourteen infants were randomized to receive r-HuEpo, and 14 infants served as controls. Four controls and six r-HuEpo treated infants had been transfused before study start, whereas four control infants were transfused in the course of the study. The untransfused infants showed a high HbF/Hb ratio during the study with only a weak tendency to decline toward the expected time of delivery. The total Hb mass increased (p < 0.05) more in the r-HuEpo-treated infants than in the untreated, whereas the rise in HbF mass was similar in the two groups. After each transfusion, the HbF/Hb ratio reverted gradually to the ratio expected at the infant's postconceptional age. There was no difference in the production rate of HbF between r-HuEpo-treated infants and controls. The present data indicate that the HbF/HbA ratio in preterm infants is subject to the same programmed mechanisms which govern intrauterine erythropoiesis until term and that exogenous r-HuEpo does not influence this pattern significantly.

The impact of chronic administration of the luteinizing hormone-releasing hormone agonist leuprolide depot on cardiovascular risk factors was investigated in a controlled double-blind study comprising 50 evaluable patients with benign prostatic hyperplasia. In the 26 patients receiving leuprolide the mean total cholesterol level increased by 10.6%, high density lipoprotein cholesterol by 8.2% and triglycerides by 26.9% (p = 0.003, 0.052 and 0.050, respectively). Low density lipoprotein cholesterol levels were unchanged. Apolipoprotein A1 increased by 13.2% (p = 0.001), while apolipoprotein B, fibrinogen, thrombocytes and plasminogen activator inhibitor were unchanged. Hemoglobin decreased by 1.2 gm./100 ml. without a concomitant decrease in serum erythropoietin concentration. These changes act in different directions with regard to cardiovascular risk and the overall effect is difficult to assess.

The in vivo effect of recombinant human insulin-like growth factor (rh-IGF-1) upon erythropoiesis was studied in inbred BALB/C mice. Unweaned, rapidly growing 20 days old mice and adult female mice received subcutaneous rh-IGF-1 or control injections every 6 h for 48 h. The mice were killed either 12 or 48 h after the last injection, i.e. a study time of 60 and 96 h, respectively. Bone marrow erythroid colony forming units (CFU-E), reticulocytes, haematocrit, serum immunoreactive erythropoietin (siEPO) and body and organ weight were measured. An additional group of young mice were given iron prior to the rh-IGF-1 injections to ensure sufficient available iron. No differences in overall body or organ weights were observed. In the young mice erythropoiesis as measured by bone marrow CFU-E, reticulocytes and haematocrit did not differ between rh-IGF-1 group and controls. When iron alone was given, reticulocytes (P < 0.05) and haematocrit (P < 0.0001) increased significantly, but no further stimulation was seen when rh-IGF-1 injections were given in addition to iron. The adult female mice responded with significantly increased erythropoiesis as judged by increased reticulocyte counts following rh-IGF-1 injections (P < 0.001). No significant effect upon CFU-E and haematocrit was detected. The reticulocyte response was more pronounced at 96 than at 60 h after the first rh-IGF-1 injection. SiEPO was significantly (P < 0.01) lower in the adult 96 h rh-IGF-1 group than in the appropriate control group. In conclusion parenteral iron significantly increased haematocrit in unweaned mice. Short time rh-IGF-1 treatment did not stimulate erythropoiesis in these rapidly growing mice, whether or not iron supplementation had been given.(ABSTRACT TRUNCATED AT 250 WORDS)

The effectiveness of recombinant human erythropoietin (r-HuEpo) in raising haemoglobin concentrations in very low birthweight infants was examined in a randomised multicentre study. Twenty nine 'healthy' appropriate for gestational age infants with birth weights 900-1400 g entered the study at 3 weeks of age. All infants received breast milk supplemented with 9 g/l human breast milk protein from 3 to 8 weeks of age. Eighteen mg iron was given daily from week 3 and was doubled if serum iron concentration fell below 16.0 mumol/l. Fourteen infants were randomised to receive 100 U/kg r-HuEpo subcutaneously three times a week from week 3 to week 7; 15 infants served as controls. After one week reticulocyte and haemoglobin concentrations were significantly higher in the r-HuEpo treated group and the haemoglobin values remained significantly higher throughout r-HuEpo treatment and at the concentrations observed in full term infants. No adverse effects were associated with the treatment. In stable very low birthweight infants with optimal iron and protein intakes, moderate dose r-HuEpo can produce significant gains in red cell production that may be clinically useful.

We report the finding of inappropriately high estimates of erythropoietin (Epo) in 11% of serum samples tested by one commercial assay kit. These estimates were not confirmed when the same samples were tested independently in four other systems for the immunoassay of Epo. As yet no explanation has been found to account for the anomalously high estimates.

In 1988 several reports described leukemia in former/present growth hormone (GH)-treated children, and a doubled incidence of leukemia in GH-treated children was concluded in a workshop in Bethesda. A mouse strain (AKR/O) with a high incidence of leukemia was used as a model. AKR/O-mice in the preleukemic adult age and younger mice during rapid growth were treated with recombinant human GH (rhGH) in human therapeutic doses to see whether this treatment would affect the time and presentation of malignant disease. The malignant development did not appear earlier or in a different way in the animals receiving rhGH from day 6 to 50 than in their appropriate controls. A borderline protective effect to the development of leukemia was seen in the adult group receiving rhGH; in this group antibodies to hGH also developed. We conclude that in this experimental model human therapeutic doses of rhGH do not influence the development of malignancy in the AKR/O mice.