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Purpose: Hematopoietic stem cell (HSC) transplant is one of the curative methods for some patients with hematological malignancies. Granulocyte colony-stimulating factor (G-CSF) is the most common drug used to mobilize CD34 + cells, generally found in small numbers. Recent evidence showed that exercise causes transient mobilization in HSC. However, the type and intensity of exercise have not been fully revealed. We aimed to detect a significant increase in stem cell levels following 60 ​min of running at a personalized running pace., Materials/methods: Eighteen runners, 48.2 ​± ​1.9 years with peak oxygen consumption of 46.2 ​± ​1.4 ​ml/kg/min, were enrolled in the study. The cardiopulmonary exercise test was performed to determine the individual running pace, and the participants ran 60-min on a treadmill at an intensity close to their ventilatory threshold (VT). The blood sampling for HSC count was performed before, immediately after, at the 1st, 4th and 24th hour after the 60-min running., Results: The CD34 + HSCs were 13.9 ​± ​2.3 ​cells/μl before and significantly increased immediately after to 19.5 ​± ​3.6 ​cells/μl (p ​< ​0.05). The consecutive HSC counts were 15.3 ​± ​2.2, 19.5 ​± ​4.8 and 15.1 ​± ​3.4 ​cells/μl at the 1st, 4th, and 24th hour, respectively., Conclusion: The individual data showed that some runners had higher HSC levels than the transplantation limit before and after the 60-min running trail, which was maintained for 24 ​h. Pre-running high CD34 + HSCs may reflect an adaptive response to regular exercise, with a 60-min run near the VT further elevating HSCs. Individualized exercise may be a valuable tool to mobilize the CD34 + HSCs in peripheral blood for donors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Background: Chronic graft-versus-host disease (GVHD) is a debilitating, and sometimes life threatening, complication of allogeneic haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the activity, pharmacokinetics, and safety of ruxolitinib added to corticosteroids in paediatric patients (ie, <18 years) with moderate-to-severe chronic GVHD., Methods: In this single-arm, phase 2 study, patients were recruited at 21 hospitals or clinics across 14 countries in Asia, Europe, and Canada. Eligible patients were aged 28 days to younger than 18 years, had undergone allogenic HSCT, and had been diagnosed with treatment-naive or corticosteroid-refractory moderate-to-severe chronic GVHD, per 2014 National Institutes of Health consensus criteria. Patients received oral ruxolitinib dosing on the basis of their age at the start of treatment: those aged 12 years to younger than 18 years received 10 mg twice daily (age ≥12 to <18 years group), those aged 6 years to younger than 12 years (age ≥6 to <12 years group) received 5 mg twice daily, and those aged 2 years to younger than 6 years received 4 mg/m 2 twice daily (age ≥2 to <6 years group). Treatment was to be administered in 28-day cycles for approximately 36 months, alongside supportive treatment per institutional guidelines. The primary activity endpoint was overall response rate at cycle 7 day 1. Activity and safety analyses are reported in the full analysis set, which included all patients who received at least one dose of ruxolitinib. Here we report the prespecified interim analysis, scheduled to occur after all patients had completed 1 year of treatment or discontinued treatment, and the results for the primary endpoint evaluation reported here is to be considered final. This study is registered with ClinicalTrials.gov, NCT03774082, enrolment is complete, and the study is ongoing., Findings: Between May 20, 2020, and Sept 17, 2021, 48 patients were screened, of whom 45 were enrolled and received at least one dose of study drug (median age was 11·0 years [IQR 7·2-14·3], 16 [36%] were female, 29 [64%] were male, 21 [47%] were White, one [2%] was Black or African American, 23 [51%] were Asian, 17 [38%] were treatment-naive, 28 [62%] were corticosteroid-refractory). As of data cutoff (Oct 19, 2022), after a median ruxolitinib exposure of 55·1 weeks (IQR 13·1-75·3), the overall response rate at cycle 7 day 1 was 40·0% (18 of 45; 90% CI 27·7-53·3), with responses seen in seven (41%) of 17 treatment-naive patients and 11 (39%) of 28 corticosteroid-refractory patients. The most common treatment-related adverse events of grade 3 or worse were neutropenia (eight [18%] of 45) and thrombocytopenia (six [13%]). Seven (16%) patients had grade 3 or worse serious treatment-related adverse events; the most common was hyponatraemia (two [4%] of 45). Three (7%) patients died while on-treatment (within 30 days of treatment discontinuation), one due to Aspergillus infection, one due to septic shock, and one due to acute respiratory distress syndrome; none were considered to be related to study drug., Interpretation: Pending final analysis, this study suggests that ruxolitinib is active and well tolerated in both treatment-naive and corticosteroid-refractory patients aged 2 years to younger than 18 years with chronic GVHD, thereby supporting its use in this patient population. The safety profile of ruxolitinib in this patient population is consistent with that of adults. Final analysis of this study will provide further information on the long-term benefits of ruxolitinib in children with chronic GVHD., Funding: Novartis., Competing Interests: Declaration of interests FL has participated in speaker bureaus for Amgen, Bluebird Bio, BMS, Medac Pharma, Miltenyi Biotec, Neovii, Novartis, and SOBI. HJK has received consulting fees from Structure Therapeutics (GPCR) and is on Data Safety Monitoring Boards or advisory boards with Jazz Pharmaceuticals, Novartis, Sanofi, Recordati, and Takeda. CD-d-H has received royalties from Jazz Pharmaceuticals and Vertex; received honoraria from Novartis; received meeting and travel support from Jazz Pharmaceuticals and Novartis; and has participated on a data safety monitoring board for Novartis. TS, CR, ASP, KB, YS, and KS are employees of Novartis. TS, KB, ASP, YS, and KS hold shares in Novartis. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Oral mucositis is one of the side effects developed post-hematopoietic stem cell transplant. This retrospective study aimed to assess the efficacy of a mouthwash mixture (lidocaine, sodium alginate, sucralfate, pheniramine) versus hyaluronic acid and a solution of sodium bicarbonate in terms of healing time and weight gain in the treatment of oral mucositis in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation with hemato-oncological malignancies., Methods: A total of 171 patients that received chemotherapy for the hematopoietic stem cell transplant were divided into three groups; group 1, treated with a mixed mouthwash of lidocaine, sodium alginate, sucralfate, and pheniramine; group 2, treated with hyaluronic acid; and group 3, treated with an aqueous solution of 5% sodium bicarbonate. Weight and mucositis scale scores derived from medical records of patients., Results: There was a statistically significant difference in the mucositis scale scores between the groups on the transplant day and days 5, 10, 15 and 20 after the transplantation. At these measurement points, Group 2 (receiving hyaluronic acid) had a lower score, and Group 3 (who received sodium bicarbonate) had a higher score, especially on days 5 and 10 after the transplantation., Conclusion: The results suggest that hyaluronic acid is a more effective treatment option than the other oral care solutions that are frequently used for prophylaxis and treatment of oral mucositis., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Data on the risk factors and outcomes for pediatric patients with SARS-CoV-2 infection (COVID-19) following hematopoietic stem cell transplantation (HSCT) are limited., Objectives: The study aimed to analyze the clinical signs, risk factors, and outcomes for ICU admission and mortality in a large pediatric cohort who underwent allogeneic HSCT prior to COVID-19 infection., Method: In this nationwide study, we retrospectively reviewed the data of 184 pediatric HSCT recipients who had COVID-19 between March 2020 and August 2022., Results: The median time from HSCT to COVID-19 infection was 209.0 days (IQR, 111.7-340.8; range, 0-3845 days). The most common clinical manifestation was fever (58.7%). While most patients (78.8%) had asymptomatic/mild disease, the disease severity was moderate in 9.2% and severe and critical in 4.4% and 7.6%, respectively. The overall mortality was 10.9% (n: 20). Deaths were attributable to COVID-19 in nine (4.9%) patients. Multivariate analysis revealed that lower respiratory tract disease (LRTD) (OR, 23.20, p: .001) and lymphopenia at diagnosis (OR, 5.21, p: .006) were risk factors for ICU admission and that HSCT from a mismatched donor (OR, 54.04, p: .028), multisystem inflammatory syndrome in children (MIS-C) (OR, 31.07, p: .003), and LRTD (OR, 10.11, p: .035) were associated with a higher risk for COVID-19-related mortality., Conclusion: While COVID-19 is mostly asymptomatic or mild in pediatric transplant recipients, it can cause ICU admission in those with LRTD or lymphopenia at diagnosis and may be more fatal in those who are transplanted from a mismatched donor and those who develop MIS-C or LRTD., (© 2024 Wiley Periodicals LLC.)

Objectives: Allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with transfusion-dependent thalassemia major. In recent years, a number of novel approaches have improved patient outcomes and quality of life by minimizing the toxicity of conditioning regimens. The objective of this study was to compare the role of treosulfan- and busulfan-based conditioning in transfusion-dependent thalassemia., Materials and Methods: Data were collected retrospectively on 121 children with beta thalassemia major who underwent hematopoietic stem cell transplant using treosulfan-based (n = 37) or busulfan-based (n = 84) conditioning regimens between 2012 and 2022., Results: Two-year overall survival was 87.5% in the busulfan-based conditioning group and 91.1% in the treosulfan-based conditioning group.The group given the busulfan regimen compared with treosulfan regimen had significantly increased number of side effects (58.3% vs 21.6%, respectively; P < .001). When the busulfan-based regimen by level was evaluated, we observed no significant differences between the frequency of side effects according to drug serum levels. In addition, no significant differences were shown between the 2 regimen groups for cumulative incidence of acute and chronic graft-versus-host disease., Conclusions: The safety and effectiveness of a treosulfan-based myeloablative conditioning regimen has been confirmed by ourretrospective investigation of pediatric patients with beta thalassemia.

Background: Central nervous system fungal infections (CNSFI) are seen in patients with hematologic malignancies and have high morbidity and mortality. Because of their rarity, there is limited data on CNSFI in children with no established treatment protocols or guidelines., Materials and Methods: In this multicenter retrospective study, 51 pediatric patients with leukemia, 6 of whom had undergone bone marrow transplantation, with proven or probable CNSFI were evaluated. Fungal infections were defined as proven or probable based on European Organisation for Research and Treatment of Cancer criteria. Proven CNSFI was diagnosed by appropriate central nervous system (CNS) imaging or tissue sample findings in combination with positive microbiological results of cerebrospinal fluid. A positive culture, microscopic evidence of hyphae, a positive result of the galactomannan assays are defined as positive microbiological evidence. Probable CNSFI was defined as appropriate CNS imaging findings together with proven or probable invasive fungal infections at another focus without CNS when there is no other explanatory condition. Data was collected by using the questionnaire form (Supplemental Digital Content 1, http://links.lww.com/JPHO/A541 )., Results: Seventeen patients had proven, 34 patients had probable CNSFI. Headaches and seizures were the most common clinical findings. The median time between the onset of fever and diagnosis was 5 days. The most common fungal agent identified was Aspergillus . Sixteen patients received single-agent, 35 received combination antifungal therapy. Surgery was performed in 23 patients. Twenty-two patients (43%) died, 29 of the CNSFI episodes recovered with a 20% neurological sequelae., Conclusion: CNSFIs should be considered in the differential diagnosis in patients with leukemia and refractory/recurrent fever, headache, neurologicalocular symptoms, and a radiologic-serological evaluation should be performed immediately. Early diagnosis and prompt management, both medical and surgical, are essential for improving clinical outcomes., Competing Interests: The authors declare no conflict of interest.

Haemophilia is an X-linked lifelong congenital bleeding disorder that is caused by insufficient levels of factor VIII (FVIII; haemophilia A) or factor IX (FIX; haemophilia B) and characterized by spontaneous and trauma-related bleeding episodes. The cornerstone of the treatment, factor replacement, constitutes several difficulties, including frequent injections due to the short half-life of recombinant factors, intravenous administration and the risk of inhibitor development. While extended half-life factors and subcutaneous novel molecules enhanced the quality of life, initial successes with gene therapy offer a significant hope for cure. Although adeno-associated viral (AAV)-based gene therapy is one of the most emerging approaches for treatment of haemophilia, there are still challenges in vector immunogenicity, potency and efficacy, genotoxicity and persistence. As the approval for the first gene therapy product is coming closer, eligibility criteria for patient selection, multidisciplinary approach for optimal delivery and follow-up and development of new pricing policies and reimbursement models should be concerned. Therefore, this review addresses the unmet needs of current haemophilia treatment and explains the rationale and principles of gene therapy. Limitations and challenges are discussed from a global and national perspective and recommendations are provided to adopt the gene therapies faster and more sufficient for the haemophilia patients in developing countries like Turkey., Competing Interests: Competing interests: The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Project and authors’ coordination was provided by Dr Ayse Ozlem Yilmaz and Feride Uçar at Remedium Consulting Group and was funded by Pfizer., (© The Author(s), 2022.)

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is one of the most severe and life-threatening complications after hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is approved for adult and pediatric patients with VOD/SOS with renal or pulmonary dysfunction after HSCT in the United States, and for severe VOD/SOS post-HSCT in patients above 1 month of age in the European Union. Several studies have examined whether DF prophylaxis can reduce the incidence of VOD/SOS in high-risk patients. A total of 334 pediatric allogeneic HSCT were included in this study. All patients received DF at the dose of 25 mg/kg/d, from the first day of the conditioning regimen to the 30th day after transplantation for VOD/SOS prophylaxis. Seventeen patients (5.08%) developed VOD/SOS; 4 of these had moderate, while 13 had mild VOD/SOS. None of the patients were developed severe or very severe VOD/SOS. In conclusion, we showed that prophylactic intervention with DF lowered the incidence of VOD/SOS in high-risk pediatric patients., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most frequent cause of post-transplantation mortality. Isolated extramedullary (EM) relapse (iEMR) after HSCT is relatively rare and not well characterized, particularly in pediatric patients. We retrospectively analyzed 1527 consecutive pediatric patients with acute leukemia after allo-HSCT to study the incidence, risk factors, and outcome of iEMR compared with systemic relapse. The 5-year cumulative incidence of systemic relapse (either bone marrow [BM] only or BM combined with EMR) was 24.8%, and that of iEMR was 5.5%. The onset of relapse after allo-HSCT was significantly longer in EM sites than in BM sites (7.19 and 5.58 months, respectively; P = .013). Complete response (CR) 2+/active disease at transplantation (hazard ratio [HR], 3.1; P < .001) and prior EM disease (HR, 2.3; P = .007) were independent risk factors for iEMR. Chronic graft-versus-host disease reduced the risk of systemic relapse (HR, 0.5; P = .043) but did not protect against iEMR. The prognosis of patients who developed iEMR remained poor but was slightly better than that of patients who developed systemic relapse (3-year overall survival, 16.5% versus 15.3%; P = .089). Patients experiencing their first systemic relapse continued to have further systemic relapse, but only a minority progressed to iEMR, whereas those experiencing their iEMR at first relapse developed further systemic relapse and iEMR at approximately similar frequencies. A second iEMR was more common after a first iEMR than after a first systemic relapse (58.8% versus 13.0%; P = .001) and was associated with poor outcome. iEMR has a poor prognosis, particularly after a second relapse, and effective strategies are needed to improve outcomes., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: BK virus-associated hemorrhagic cystitis is a common complication of allogeneic hematopoietic stem cell transplant. It is known to be associated with cyclophosphamide therapy and the intensity of the conditioning regimen as well as infection with the BK virus. Data are limited for BK virus-associated hemorrhagic cystitis in pediatric recipients of allogeneic hematopoietic stem cell transplant. Therefore, we aimed to identify the risk factors and etiology of BK virus-associated hemorrhagic cystitis and determine the factors that may improve the treatment efficacy., Materials and Methods: Data from recipients of allogeneic hematopoietic stem cell transplant were retrospectively analyzed. These data included information about age, sex, underlying disease, the details of ablative conditioning, graft-versus-host disease prophylaxis, donor type, stem cell source, history of acute graft-versus-host disease, and cytomegalovirus reactivation., Results: A total of 50 patients developed BK virusassociated hemorrhagic cystitis among 334 patients. Symptoms associated with BK virus-associated hemorrhagic cystitis manifested an average of 45.3 days after transplant. Most of the patients had grade 2 and grade 3 hemorrhagic cystitis. Risk factor analysis revealed that haploidentical donor type, treatment with busulfan and cyclophosphamide as part of conditioning regimen, and history of total body irradiation increased the risk of BK virus-associated hemorrhagic cystitis in the pediatric recipient population., Conclusions: We found that, despite current conditioning regimens, BK virus-associated infection still leads to a considerable incidence rate of hemorrhagic cystitis in pediatric recipients of allogeneic hematopoietic stem cell transplant. Patients with a haploidentical donor and a history of busulfan and cyclophosphamide treatment or total body irradiation had a higher risk of BK virus-associated hemorrhagic cystitis. Thus, we suggest that patients with these factors should be followed closely after allogeneic hematopoietic stem cell transplant.

Objective: Hemophilia A is the second most common bleeding disorder causing patients to have lifelong follow-up and treatment. Despite being a rare disease, hemophilia A has a high economic burden on individuals and the public. The purpose of this study was to estimate the total disease cost of hemophilia A in Turkey., Materials and Methods: Data used in this analysis were collected through literature review, including studies conducted in Turkey in December 2018. A disease burden analysis was performed by modeling hemophilia A-related costs among patients, their relatives, and the social security system. Two expert panels were held to evaluate real-world data sources and to provide further information. All direct medical and non-medical costs were calculated annually from the Social Security Institution of the Republic of Turkey perspective, while indirect costs were estimated from the patient and community perspective., Results: For the calendar year of 2018, the number of hemophilia A patients in Turkey were estimated to be 5,055, with an average weight of 64.7 kg. The average annual direct medical, direct non-medical, and indirect costs of hemophilia A were calculated as €93,268 ($109,286; ₺502,717), €2,533 ($2,968; ₺13,655), and €7,957 ($9,323; ₺42,888) per patient, respectively, with a total annual cost of €103,759 ($121,578; ₺559,259). For the management of patients with inhibitors (4.9%), the average annual total cost was calculated to be €325,439 ($381,330; ₺1,754,117) per patient. The total annual disease burden of hemophilia A in 2018 was estimated to be about €524 million ($614 million; ₺2.82 billion), which corresponded to 1.6% of the total health expenditure in Turkey., Conclusion: The most important reason hemophilia A has a significant economic burden in Turkey is that replacement therapy is expensive. The major cost contributor was identified as factor replacement therapy. With inhibitor development, the average annual cost increased more than 3-fold.

Background and Objectives: We aimed to evaluate joint health in children with hemophilia (CwH) and to investigate the effects of hemarthrosis on the musculoskeletal system., Method: Forty-one CwH aged between 6-18 years participated in the study. Joint health status was evaluated according to Hemophilia Joint Health Score (HJHS). Pain intensity level was assessed in resting and in activity using Visual Analog Scale. Range of motion was measured with goniometer and muscle strength was assessed with digital dynamometer. Arthropathic joints were examined in three groups named knee, elbow and ankle., Results: Physical examination revealed arthropathy findings to be found in 29 knee, 19 elbow and 18 ankle joints. The median of flexion angle of the affected side were 120°, 122° and 12° for the knee, elbow and ankle and extension losses of these joints were 5°, 7° and 0, respectively. In CwH having knee and elbow arthropathy, index joint HJHS was found to be significantly higher than those with ankle arthropathy (p < 0.01). The flexor and extensor muscle strength significantly decreased in 11 CwH with unilateral elbow arthropathy compared to the non-arthropatic side (p < 0.05). In 15 CwH with unilateral ankle arthropathy decreased in the extensor muscle strength (plantarflexors) (p < 0.05). Extension loss showed a good correlation with index HJHS of elbow, knee and ankle joints, respectively. (rs= 0.599, 0.576, 0.606, p < 0.01). We observed that the muscle strength of elbow flexors/extensors and ankle extensors were significantly decreased compared to the non-arthropathic side. However this situation was not detected in knee joint despite having highest index HJHS., Conclusion: Our findings indicate that hemarthrosis may cause more muscle strength loss in the upper extremity than the lower extremity. Furthermore, extension loss was found to be an important parameter in physical examination of hemophilic arthropathy. Musculoskeletal system should be evaluated comprehensively at regular intervals and when necessary rehabilitative treatment should be planned.

Introduction: Among children with haemophilia and their caregivers; problems arising from the teeth and the surrounding tissues have an important role in the treatment of this disease and it affects the quality of life of children and their parents., Aim: Aim of this study is to evaluate the oral health-related quality of life of children with haemophilia from the perspective of their parents., Methods: Paediatric oral health-related quality of life (POQL) instrument was used in this cross-sectional study for quality of life measurement. The research data collected by the questionnaire form were coded for scale items and personal information questions and transferred to SPSS, a multivariate statistical analysis program for social sciences. SPSS 23.0 (IBM Corp, Armonk, NY) package program was used for statistical analysis of the data., Results: Primary dentition dmft scores of patients with haemophilia are higher than the control group; mean value of haemophilic group is 3.5 vs control group are 2.6, respectively (P = 0.034). In spite of higher dmft scores, the haemophilia and control groups have shown no significant difference in oral health-related quality of life scores; median scores were 63.9 in haemophilic group and 85.3 in control group (P = 0.336), respectively., Conclusion: In spite of lower oral health measures, children with haemophilia and their parents reported no difference in oral health-related quality of life from their healthy counterparts., (© 2019 John Wiley & Sons Ltd.)

Objectives: To evaluate the long-term efficacy and safety of deferasirox therapy in a large observational cohort of children with transfusion-dependent thalassemia (TDT) and sickle cell anemia (SCA) in Turkey., Methods: This was a multicenter, prospective cohort study including TDT and SCA patients aged 2-18 years with iron overload (≥100 mL/kg of pRBC or a serum ferritin [SF] level >1000 μg/L) receiving deferasirox. Patients were followed for up to 3 years according to standard practice., Results: A total of 439 patients were evaluated (415 [94.5%] TDT, 143 [32.6%] between 2 and 6 years). Serum ferritin levels consistently and significantly decreased across 3 years of deferasirox therapy from a median of 1775.5 to 1250.5 μg/L (P < 0.001). Serum ferritin decreases were noted in TDT (1804.9 to 1241 μg/L), SCA (1655.5 to 1260 μg/L), and across age groups of 2-6 years (1971.5 to 1499 μg/L), 7-12 years (1688.5 to 1159.8 μg/L), and 13-18 years (1496.5 to 1107 μg/L). Serum ferritin decreases were also noted for all deferasirox dose groups but only significant in patients with doses ≥30 mg/kg/d (n = 120, -579.6 median reduction, P < 0.001). Only 9 (2%) patients had adverse events suspected to be related to deferasirox. Serum creatinine slightly increased but remained within the normal range., Conclusions: Deferasirox has long-term efficacy and safety in children with TDT and SCA, although higher doses (≥30 mg/kg/d) may be required to achieve iron balance., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

FK506 (tacrolimus) is an immunosuppressive drug and more potent than cyclosporine. FK506 is widely used for immunosuppression in the prevention and treatment of graft-versus-host disease after allogeneic bone marrow transplantation and solid organ transplantation. Neurotoxicity is a recognized complication of FK506 therapy, but ptosis and weakness of eye abduction unilaterally has not been reported in association with FK506 administration to date. We discuss a 13-year-old male patient who developed ptosis and weakness of eye abduction unilaterally 90 days after transplantation with bone marrow from an unrelated donor, for acute lymphoblastic leukemia in this case report. FK506 therapy was administered for graft-versus-host disease prophylaxis and CMV infection was treated with ganciclovir. The physical examination findings completely resolved 72 to 96 hours after concomitant FK506 and ganciclovir treatment were terminated.

Background: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy., Methods: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites., Results: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00)., Conclusions: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Following joint hemorrhages, intramuscular hemorrhages are the second most prevalent bleeding pattern in hemophiliac patients. Hematomas of the iliopsoas muscle are a well-known complication of hemophilia; however, obturator muscle hematomas are rare. We herein report a case of spontaneous bleeding of the bilateral external obturator muscles, which occured three times within a period of 9 months in a hemophilia patient with factor VIII inhibitors. To the best of our knowledge, this is the first published case of an obturator externus muscle hematoma in hemophilia. In addition to hip hemarthrosis, iliopsoas hematomas and acute appendicitis, obturator muscle hematoma should be considered as one of the diagnostic alternatives for pelvic pain in hemophiliaψ patients. Magnetic resonance imaging enables rapid diagnosis of obturator muscle hematoma.

This study aimed to determine the effect of haemolysis on plasma oxidation and nitration in sickle cell disease (SCD) patients. Blood was collected from haemoglobin (Hb)A volunteers and homozygous HbSS patients who had not received blood transfusions in the last 3 months. Haemolysis was characterised by low levels of haemoglobin and haptoglobin and high levels of reticulocyte, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), plasma cell-free haemoglobin, bilirubin, total lactate dehydrogenase (LDH) and dominance of LDH-1 isoenzyme. Plasma 8-isoprostane, protein carbonyl and nitrotyrosine levels were measured to evaluate oxidised lipids, oxidised and nitrated proteins, respectively. Plasma nitrite-nitrate levels were also determined to assess nitric oxide (NO) production in both SCD patients and controls. Markers of haemolysis were significantly evident in SCD patients compared to controls. Plasma 8-isoprostane, protein carbonyl and nitrotyrosine levels were markedly elevated in SCD patients compared to controls. Linear regression analysis revealed a significant inverse correlation between haemoglobin and reticulocyte counts and a significant positive correlation of plasma cell-free haemoglobin with protein carbonyl and nitrotyrosine levels. The obtained data shows that increased haemolysis in SCD increases plasma protein oxidation and nitration.

Angiogenesis has been associated with the growth, dissemination and metastasis and has been shown to be a prognostic. Although there are some data suggesting that angiogenesis may have a role in the pathophysiology of leukemia, its role in patient prognosis is yet to be defined. We analyzed the expression level of vascular endothelial growth factor (VEGF), an angiogenesis promoter and its possible- prognostic value in bone marrow samples at the time of diagnosis and remission of acute childhood leukemia patients. Besides 46 patients diagnosed as ALL or AML, 16 children were also included as a control group in the study. Our data have demonstrated that VEGF levels of AML patients were found higher than the control group statistically (P = 0.022). However we could not find any significant difference between VEGF levels of diagnosis and remission in both AML and ALL groups by blastic VEGF expression (P > 0.05). In this study the higher levels of VEGF in AML patients is one of the main findings although we were not able to assess any role of VEGF in predicting prognosis in pediatric leukemia patients by evaluating blastic cell VEGF expression. These results have demonstrated that the relationship between angiogenesis or angiogenesis promoters and hematological malignancies is not clear and simple as different methods or different cells beside different angiogenesis promotors are involved to these studies. So that not only tumor cells and their cytokines but also surrounding cells and their cytokines must be taken into consideration with the standardized study methods in the further studies to obtain a promising treatment approach.

Background: Patients with severe hemophilia A and factor VIII inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Effective strategies to prevent bleeding in such patients have not yet been established., Methods: We enrolled patients with hemophilia A who were older than 2 years of age, had high-titer inhibitors, and used concentrates known as bypassing agents for bleeding in a prospective, randomized, crossover study comparing 6 months of anti-inhibitor coagulant complex (AICC), infused prophylactically at a target dose of 85 U per kilogram of body weight (±15%) on 3 nonconsecutive days per week, with 6 months of on-demand therapy (AICC at a target dose of 85 U per kilogram [±15%] used for bleeding episodes). The two treatment periods were separated by a 3-month washout period, during which patients received on-demand therapy for bleeding. The primary outcome was the number of bleeding episodes during each 6-month treatment period., Results: Thirty-four patients underwent randomization; 26 patients completed both treatment periods and could be evaluated per protocol for the efficacy analysis. As compared with on-demand therapy, prophylaxis was associated with a 62% reduction in all bleeding episodes (P<0.001), a 61% reduction in hemarthroses (P<0.001), and a 72% reduction in target-joint bleeding (≥3 hemarthroses in a single joint during a 6-month treatment period) (P<0.001). Thirty-three randomly assigned patients received at least one infusion of the study drug and were evaluated for safety. One patient had an allergic reaction to the study drug., Conclusions: AICC prophylaxis at the dosage evaluated significantly and safely decreased the frequency of joint and other bleeding events in patients with severe hemophilia A and factor VIII inhibitors. (Funded by Baxter BioScience; Pro-FEIBA ClinicalTrials.gov number, NCT00221195.).

Hemophilia patients sometimes need careful treatment of urgent serious bleedings and management of some surgeries. Development of inhibitor has some impact on the management of these situations. Here a case of patient of hemophilia A is presented in whom urological surgery resulted in inhibitor development and a second operation with bypass agent.

The literature on the use of recombinant factor VIIa (rFVIIa), which was initially used in hemophiliac patients with inhibitors, for hemorrhages that cannot be managed with conventional methods or operations that cannot be performed safely is increasingly growing. This study presents a group of nonhemophiliac patients with hemorrhagic problems or hemorrhage risk for some interventions that were successfully resolved with the use of rFVIIa. The patient group was composed of 20 patients with different disorders resulting in similar results as hemorrhage or hemorrhage risk. Most of the patients were diagnosed with liver disorders primary or secondary to other diseases. The remaining cases were patients with leukemia, sepsis, intracranial hemorrhage, and burn. Some of the patients had multiple problems like a patient with liver disorder and intracranial hemorrhage or a leukemia patient with sepsis and disseminated intravascular coagulation. rFVIIa had been administered to the patients at dosages between 70 and 150 microg/kg up to 6 doses with 2-hour to 3-hour intervals. All the patients had benefited from the use of rFVIIa even though some of them died because of primary disease. This study shows that rFVIIa can be safely used in high-risk patients with a history of recurrent hemorrhage, for whom no improvement can be achieved in the hemostasis tests.

Objective: In systemic sclerosis (SSC), certain abnormalities can occur in fibroblasts, endothelial cells, and immune system cells. Severe pathological changes such as visceral fibrosis and obliteration of the lumen of arteries may develop due to functional alterations of these cells. Because the vascular abnormality is a central mechanism of sclerosis, the aim of this study was to further investigate the impaired vascularity in the gingival tissues of SSC patients by means of immunohistochemistry using vascular endothelial growth factor A (VEGF-A), VEGF-C, and CD34 staining., Study Design: Thirteen SSC patients and 11 systemically healthy controls who had moderate gingivitis were included in the study. Gingival biopsies were obtained from the interdental papilla, and VEGF-A, VEGF-C, and CD34 analyses were done by using immunohistochemical methods., Results: Patients with scleroderma had higher levels of inflammatory infiltrate (P = .041) and microvessel density (P = .003) in their gingival biopsy samples. In contrast, when compared with the controls, the expressions of VEGF-A and VEGF-C were significantly lower in scleroderma patients (P = .033 and P = .015, respectively)., Conclusion: These findings may reflect the defective vascularity and the pronounced histological inflammation of the gingival tissues in systemic scleroderma and may provide a novel target for treatment methods for the gingival involvement in these patients.

Mucormycosis is an uncommon, severe, life-threatening fungal infection in the immunocompromised host. Mucormycosis with aplastic anemia is seen rarely. Only a few cases of cardiac mucormycosis with aplastic anemia have been reported in the literature. The authors present a case with severe aplastic anemia that did not respond to classic and immunosuppressive treatment for disease and developing invasive cardiac mucormycosis despite empiric treatment for febrile neutropenia.

Background: Invasive procedures such as bone marrow aspiration in children may be painful and cause anxiety. We investigated the efficacy and safety of remifentanil (R) alfentanil (A), remifentanil-midazolam (RM), and alfentanil-midazolam (AM) combinations in providing analgesia and sedation for bone marrow aspiration., Methods: Eighty children undergoing a diagnostic bone marrow aspiration whose ages ranged from 5-16 years (mean 9.20 +/- 3.00 years) were enrolled in this study. The patients were randomly assigned to one of 4 treatment groups. Vital signs, sedation and pain scores, somatic responses (sweating and tears) were recorded before, during bone marrow aspiration and after 5 and 15 min of the procedure., Results: There were no statistical differences between sedation and the CHEOPS scores of the four groups during and after the procedures. The VAS scores were significantly higher for group A compared with groups R and RM during the procedure (P < 0.008). There were no differences between the VAS scores in group AM compared with groups R and RM (P > 0.008). There were also no statistical differences among the VAS scores of four groups after the procedure (P > 0.008). All patients had adequate sedation and analgesia. None of the patients in the study had deep sedation, hypotension, bradycardia, hypoxemia, or respiratory depression., Conclusions: Remifentanil, alfentanil, remifentanil-midazolam, and alfentanil-midazolam combinations are effective in children and can be used safely in bone marrow aspiration which is a brief but painful procedure performed in the pediatric patient group.

Purpose: The aim of this retrospective study was to assess the safety of dental treatment in pediatric patients with acute lymphoblastic leukema (ALL), and Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), and to report any complications related to dental treatment during a preventive dental program covering a 4-year period., Materials and Methods: In this study 74 preventive fissure sealants, 69 fillings and 81 extractions along with periodontal treatment that included prophylaxis and/or scaling were performed on 124 patients with a mean age of 7.00+/-2.3. The patients were monitored for at least three weeks after the treatment for bleeding, pain, local and/or systemic infection, fever, delayed wound healing or any other complication., Results: Two patients (one ALL and one HL) suffered delayed wound healing after extractions which resulted in the delay of chemotherapy. In three of the patients who were in remission-induction phase of ALL, oral mucositis occurred in the cheek mucosa adjacent to extraction sites and five patients had tooth staining due to the routine use of a chlorhexidine mouthrinse. The healing was uneventful in all other patients., Conclusions: The findings of this study suggest that with special precautions such as adequate hematological values, timing of the intervention and supportive medical care, dental treatment can be safely performed in pediatric patients with hematological malignancies.

Anthracycline and cytosine arabinoside are used in combination as the standard therapy for remission induction of acute nonlymphoblastic leukemia. Idarubicin, a synthetic daunorubicin analogue, shows an improved spectrum activity and diminishes acute or chronic toxicity when compared with the other anthracyclines. This study has been carried out in our clinic in order to evaluate the efficiency of the acute nonlymphoblastic leukemia protocol which includes idarubicin. Thirty-eight patients admitted to our Department between 1992-1999 and diagnosed as acute nonlymphoblastic leukemia (ANLL) were included in the study. Their median age was 7 years 6 months (range, 8 months to 14 years). Induction therapy consisted of idarubicin plus cytosine arabinoside and etoposide. Consolidation therapy consisted of two courses, followed by maintenance therapy with thioguanine, cytosine arabinoside, vincristine and cyclophoshamide. The complete remission rate was found to be 71%. The overall survival estimate was found to be 40% for one year and 23% for three years. We established that the protocol with idarubicin reached a higher remission ratio when compared with the other protocols with anthracycline. However, the degree of the hematologic toxicity ratios related to the therapy increased the complication ratios, which affected the long-term life analyses directly. Therefore this protocol may be revised according to socioeconomical conditions, especially in the developing countries.

The Klippel-Trenaunay-Weber syndrome is a rare disorder characterized by congenital vascular hamartomas, limb hypertrophy, cutaneous manifestations, lymphangiomas and atresia of lymph vessels with non-pitting edema. A three-year-old boy was referred to our clinic for progressive hypertrophy of leg and feet with 32-month history. We diagnosed Klippel-Trenaunay-Weber syndrome, and determined vesicoureteral reflux in our patient. To our knowledge, hydronephrosis and vesicoureteral reflux have not been described previously in the KTWS.

Objectives: To determine both erythrocyte pyruvate kinase activity (ePKA) at the time of diagnosis of patients with acute leukemia or lymphoma and the differences in the ePKA profiles during the malignant disease and its chemotherapy., Methods: A prospective, longitudinal clinical study was performed involving 57 patients, 10 were the ones with relapse of acute lymphoblastic leukemia, 32 were the ones with acute lymphoblastic leukemia (ALL) and 15 were the ones with lymphoma. None of the subjects in this study group received treatment or blood transfusion before the study, except the ones diagnosed with relapse of ALL. Forty two healthy children were also selected to form the control group. In order to measure ePKA, blood samples were taken for five times, with 1.5 months apart between each other during the study. Statistical analysis were done by using Wilcoxon's signed rank test, Kruskall-Wallis with Mann-Whitney U Test and Spearman rank correlation coefficient test., Results: The ePKA of the patients with relapse of ALL, and ALL, but not the patients with lymphoma, at the time of diagnosis were found to be lower compared to the one's in the control group (respectively p = 0.001, p = 0.003). The comparison between the first ePKA samples and the third ePKA samples of the patients with both ALL and lymphoma showed a significant increase (respectively p = 0.006, and p = 0.047)., Conclusion: The measurement of ePKA can be considered for follow-up the neoplastic treatment due to the fact that it is detected to be low in leukemia and relapse of ALL and in normal values after chemotherapy. However, more long-term studies, including more number of cases, are required to be carried out in order to prove the accuracy of this hypothesis. (Tab. 2, Fig. 1, Ref. 28.)

We evaluated the oral health status of 85 acute lymphoblastic leukemia (ALL)/lymphoma pediatric patients who received remission-induction and maintenance chemotherapy and 85 age and sex-matched healthy children with the criteria of World Health Organization (WHO) and to determine the prevalence and distribution of dental problems in order to constitute preventive dentistry precautions in this study. The gingival tissues were scored with Community Index of Periodontal Treatment Necessity (CPITN) and dmf-t and DMF-T indices were used for caries evaluation. In the study group, malocclusion was found in 24 patients (28.2%). CPITN was scored as follows in the study group; 11% of the patients had healthy gingiva (Grade 0), the presence of plaque (Grade I) 79% of the patients, the presence of calculus (Grade II) 10% of patients were observed. Nevertheless, mucositis was found with various grades in 9 patients who received chemotherapy. Decayed teeth were found in the 76 patients and in 45 healthy children. 91.7% of patients and 52.9% of children needed dental treatment were determined. The DMF-T and dmf-t scores showed that ALL/lymphoma patients had more decayed and needed more dental treatment, missing or filled teeth both in their deciduous (p< 0.001) and permanent (p< 0.05) dentition when compared to systemically healthy children.

The aim of this study was to determine the prevalence of GB virus C (GBV-C) infection in pediatric patients receiving multiple blood transfusions in Turkey where HBV and HCV infections are common. Sera of a total of 148 children, of whom 85 had cancer and 63 hemoglobinopathies, were tested for GBV-C RNA and HCV RNA by RT-PCR and for antibodies to HBV and HCV. Demographic and clinical information as well as laboratory results were recorded for the patients (81 boys, 67 girls, aged 1-19 years). HBsAg positivity was found in 23 (15.5%) patients, HBV DNA positivity in 12 (8.1%), HCV RNA positivity in 9 (6.7%), and GBV-C RNA positivity in 4 (2.7%). There was no significant difference in the GBV-C RNA positivity between patients with cancer (3.2%) and patients with hemoglobinopathies (2.4%) (p > 0.05). GBV-C RNA was found in 4 (3.1%) out of 127 patients who had received transfusions, but it was not found in any of 21 patients who had not received transfusions. However, there was no relationship between GBV-C RNA positivity and the number of transfusions. Two of the patients with GBV-C RNA had high levels of ALT (ALT > 40 IU). In these two patients, neither HBV DNA nor HCV RNA were detected by PCR, and serological tests were also negative for these agents. We concluded that pediatric patients who had multiple transfusions in Turkey are at risk of being infected with GBV-C, in addition to HBV and HCV. Investigation of GBV-C RNA in patients with high ALT levels in the absence of other viral markers may be useful.

The effect of environmental tobacco smoke on serum total immunoglobulin E (IgE) of respiratory allergic patients was evaluated in this study. A total of 558 patients with respiratory allergies (311 boys and 248 girls) aged between 1 and 17 years (mean 6.92 +/- 3.81 years) were included. None of the subjects were active smokers. IgE levels were significantly higher in children with smoking parents compared with non-smokers (P < 0.05). Children with smoking mothers were found to have higher levels of IgE than children with smoking fathers. The highest level of IgE was found in children when both parents were smokers (P < 0.005).