Sirolimus is effective and safe in childhood relapsed-refractory autoimmune cytopenias: A multicentre study.

Autoimmune cytopenias are a heterogeneous group of disorders characterized by immune-mediated destruction of haematopoietic cell lines. Effective and well-tolerated treatment options for relapsed-refractory immune cytopenias are limited. In this study, the aim was to evaluate the efficacy and safety of sirolimus in this disease group within the paediatric age group. The study enrolled patients in the paediatric age group who used sirolimus with a diagnosis of immune cytopenia between December 2010 and December 2020, followed at six centres in Turkey. Of the 17 patients, five (29.4%) were treated for autoimmune haemolytic anaemia (AIHA), six (35.2%) for immune thrombocytopenic purpura (ITP) and six (35.2%) for Evans syndrome (ES). The mean response time was 2.7 months (range, 0-9 months). Complete response (CR) and partial response (PR) were obtained in 13 of 17 patients (76.4%) and nonresponse (NR) in four patients (23.5%). Among the 13 patients who achieved CR, three of them were NR in the follow-up and two of them had remission with low-dose steroid and sirolimus. Thus, overall response rate (ORR) was achieved in 12 of 17 patients (70.5%). In conclusion, sirolimus may be an effective and safe option in paediatric patients with relapsed-refractory immune cytopenia.

The impact of Treosulfan-based conditioning for inborn errors of immunity: Is dose monitoring crucial?

INTRODUCTION: In children with inborn errors of immunity (IEI) who will receive a hematopoietic stem cell transplant (HSCT) treosulfan-based conditioning is currently preferred. The aim of this study was to investigate early and late outcomes in pediatric IEI patients receiving pre-HSCT treosulfan and to examine the effect of treosulfan dose monitoring on outcomes. METHODS: Seventy-three pediatric patients receiving this management between 2015 and 2022 were included. RESULTS: Overall survival rate was 80%, and event-free survival was 67.8%. A larger treosulfan dose AUC after first application increased the rate of early toxicity (p = .034) and slowed lymphocyte engraftment (r = .290; p = .030). Underlying disease, treosulfan AUC, donor type, stem cell type, number of immunosuppressive agents, the dose of anti-thymocyte globulin, and post-transplantation cyclophosphamide did not to increase risk of acute graft-versus-host disease. The risk of mixed chimerism (MC) in patients with autoimmune lymphoproliferative syndrome and leukocyte adhesion deficiency were higher than those with severe combined immunodeficiency (p = .021 and p = .014, respectively). The risk of MC was lower in those receiving peripheral blood stem cells (SC) compared with bone marrow derived SC (OR = .204, p = .022). CONCLUSION: The AUC of the treosulfan dose was not associated with poorer late outcomes. Treosulfan is an agent that can be used safely in the IEI patient group,  level measurement appears essential to identify early toxicities. Prospective studies with more extended follow-up periods are needed.

A Retrospective Analysis of Clinical Characteristics, Treatment Modalities and Outcome of the Patients With Infantile Hepatic Hemangiomas: Single-center Experience From Turkey.

OBJECTIVE: Hepatic hemangiomas (HH) are the most common vascular tumors of the liver. It is important to distinguish hemangiomas from malignant liver tumors. MATERIALS AND METHODS: The patients 0 to 1 years old, were diagnosed with HH and followed up in the oncology outpatient clinic between 2009 and 2020 were included in the study. RESULTS: A total of 127 patients with the diagnosis of HH were included in the study. Of the patients, 99 (78%) had focal, 20 (15.7%) had multifocal, and 8 (6.3%) had diffuse HHs. Surgery was performed and the diagnosis was confirmed histopathologically in 6 patients (4.7%). During the follow-up, 16 (12.5%) patients received medical treatment. Thirteen (10.2%) were treated with propranolol, 2 (1.5%) with corticosteroids, and 1 (0.8%) with propranolol and corticosteroids. Complete response was obtained in 9 (9/16) patients and partial response was obtained in 6 (6/16) patients with medical treatment. CONCLUSION: Although HH is a benign tumor, it is important to make its differential diagnosis with malignant tumors of the liver. Over the years, the need for histopathologic examination for diagnosis has decreased. The success rate of propranolol is high, and the need for other treatment options with a high side-effect profile has decreased significantly since 2008.

Evaluation for Metastatic Candida Focus and Mortality at Candida-associated Catheter-related Bloodstream Infections at the Pediatric Hematology-oncology Patients.

BACKGROUND: Candidemia and Candida-associated catheter-related bloodstream infections (CRBSIs) are the significant cause of mortality and morbidity in patients with malignancy. METHODS: A retrospective analysis including all pediatric hematologic/oncologic malignancies patients with CRBSIs treated in Dr. Behçet Uz Children Diseases and Surgery Training and Research Hospital between the period of 2009 and 2020. RESULTS: During the study period, 53 children with CRBSIs associated with Candida species were included. The most common malignancy was acute lymphoblastic leukemia (45.3%) and acute myeloid leukemia (15.1%). A total of 56 Candida isolates were present including non-albicans Candida species (80.4%) and Candida albicans (19.6%). The most common isolated Candida species was Candida parapsilosis (42.9%) and followed by C. albicans (19.6%). The ratio of azole prophylaxis was significantly higher in patients with the non-albicans Candida group (P=0.031). Candida-related endocarditis (vegetation) was present in 2 (3.8%) patients, and the overall rate of hepatosplenic candidiasis was 3.8%. Seven days Candida attributable mortality was 7.5% (4 patients) and 30 days Candida attributable mortality was 11.3% (6 patients). The Candida species responsible for the Candida-related deaths were as following: Candida tropicalis (n=3), C. parapsilosis (n=2), and C. lusitanae (n=1). CONCLUSION: In pediatric cancer patients with Candida-associated CRBSIs, evaluation of the patient for organ involvement including liver and spleen ultrasonography and cardiac involvement with echocardiography are essential regardless of the patients' clinical picture.

Long-Term Follow-Up of a Case with Dyskeratosis Congenita Caused by NHP2-V126M/X154R Mutation: Genotype-Phenotype Association.

Dyskeratosis congenita (DC) is a rare inherited syndrome characterized by classical mucocutaneous features and the presence of other clinical features including bone marrow failure, pulmonary fibrosis, liver cirrhosis, and a predisposition to cancer. The symptoms develop at various ages and may manifest over time. Gene mutations associated with DC, such as DC1, TERC, TERT, TINF2, NHP2, NOP10, ACD, CTC1, NAF1, PARN, POT1, RTEL1, STN1, and WRAP53, have been identified in about 70% of patients. Since the number of patients with DC is small and the effect of genetic pathogenic variant may affect the phenotype, we wanted to present the clinical features and course of illness in a patient with NHP2 gene mutation (compound heterozygote for the NHP2 mutations c.376G>A/c.460T>A; amino acid substitutions: p.Val126Met and p.X154Arg) that occurred as a compound heterozygous state.

Cup-like Blasts in 2 Pediatric Patients With NPM-1-Positive Acute Myeloid Leukemia.

Cup-like phenotype is defined in some subtypes of acute myeloid leukemia (AML) and have been associated with NPM-1 and/or FLT3-ITD positivity in the presence of normal karyotype in >60% of patients. Herein we present two pediatric AML-M1 patients with cuplike nuclear morphology and NPM-1 positivity. Both patients were negative for FLT3-ITD mutation. NPM-1 mutation and FLT3-ITD mutation should be kept in mind in AML patients with cup-like blast morphology as these two mutations are important molecular markers for prognosis, risk group classification and also for response to treatment.

Induction Failure in Acute Leukemia or Parvovirus B19 Infection?

Parvovirus B19 infection may be seen in acute leukemia patients and clinical findings and cytopenia caused by the viral infection may complicate the evaluation of the remission status. Herein we present a standard risk pediatric acute lymphobiastic leukemia patient who developed myalgia, bone pain, bone marrow aplasia and sinusoidal obstruction syndrome at the end of the induction treatment and was diagnosed as having parvovirus B19 infection.

Invasive Fungal Infections in Children with Leukemia: Clinical Features and Prognosis

Objective: The incidence of invasive fungal infections (IFIs) has increased due to intensive chemotherapy in childhood leukemia. The aim of this study was to evaluate the incidence, risk factors, causative pathogens, and impact on survival of IFIs among pediatric leukemia patients. Materials and Methods: The hospital records of 307 children with acute lymphoblastic leukemia (ALL, n=238), acute myeloid leukemia (AML, n=51), and relapsed leukemia (n=18) between January 2010 and December 2015 were retrospectively evaluated. Results: A total of 1213 febrile neutropenia episodes were recorded and 127 (10.4%) of them were related to an IFI. Of 307 children, 121 (39.4%) developed IFIs. The mean age was significantly older in the IFI group compared to children without IFIs (p<0.001). IFIs were defined as possible, probable, and proven in 73.2%, 11.9%, and 14.9% of the attacks, respectively. Invasive aspergillosis (81.9%) was the most frequent infection, followed by invasive candidiasis (13.4%) and rare fungal diseases (4.8%). The majority of IFI attacks in both ALL and AML occurred during the induction phase. In total, the death rate was 24% and the IFI-related mortality rate was 18%. The mortality rate among children with IFIs was found to be significantly higher than that of children without IFIs (p<0.001). Overall and event-free survival rates at 5 years were also found to be significantly lower in the IFI group (p<0.001). Relapse (odds ratio: 8.49) was the most effective risk factor for mortality, followed by developing an IFI episode (odds ratio: 3.2) and AML (odds ratio: 2.33) according to multivariate regression analysis. Conclusion: Our data showed that IFIs were more common in older children. Although proven and probable IFI episodes were more frequently diagnosed in cases of relapse and AML, children with ALL and AML had similar frequencies of experiencing at least one episode Conclusion: Our data showed that IFIs were more common in older children. Although proven and probable IFI episodes were more frequently diagnosed in cases of relapse and AML, children with ALL and AML had similar frequencies of experiencing at least one episode

Assessment of clinical characteristics and treatment outcomes of pediatric patients with intracardiac thrombosis: a single-center experience.

The prevalence of intracardiac thrombus (ICT) is gradually increasing, though it is rare among children. Data related to the occurrence of ICT among children are limited, and treatment recommendations have been made utilizing adult guidelines. The primary objective of this study is to determine associated factors, management, and outcomes of intracardiac thrombosis in children. Between January 2013 and January 2020, patients diagnosed with ICT at the Pediatric Hematology-Oncology and Pediatric Cardiology departments in our hospital were included in the study. Demographic characteristics, clinical and laboratory findings, treatment protocols, and outcomes were analyzed retrospectively. The median age at diagnosis was 10.5 months (2 days to 14.5 years), and the median follow-up period was 6.5 months (1 month to 3.1 years). The most common primary diagnoses of the patients, in order of frequency, were heart disease (n: 8), metabolic disease (n: 3), prematurity and RDS (n: 3), burns (n: 2), pneumonia (n: 2), and asphyxia (n: 2). CVC was present in 19/23 of the patients. The reasons for CVC insertion were the need for plasmapheresis in one patient with a diagnosis of HUS and the need for well tolerated vascular access because of long-term hospitalization in others. LMWH was administered to all patients as first-line therapy. Complete response was achieved in 19 (79%) of 24 patients and 4 patients (16.6%) were unresponsive to medical treatment. It was found out that the thrombus location, type, sepsis, and hemoculture positivity, as well as the presence of CVC, had no impact on treatment response (chi-square P = 0.16, 0.12, 0.3, 0.49, 0.56). Moreover, no correlation was determined between thrombus size and treatment response (Mann Whitney U test P = 0.47). The mortality rate was determined to be 12.5% (3/24). Spontaneous occurrence of ICT is rare in childhood, without any underlying primary disease or associated factor. The presence of CVC, sepsis, and heart disease are factors associated with ICT. The success rate is increased with medical treatment. There was no significant difference in treatment response between the newborn and 1 month to 18-year-old patient group. It has been demonstrated that thrombus size, type, localization; sepsis, and hemoculture positivity had no impact on the treatment response.

Clinical predictors of pulmonary functions, respiratory/peripheral muscle strength and exercise capacity at discharge in adults with burn injury.

PURPOSE: To identify clinical predictors of pulmonary functions, respiratory and peripheral muscle strength and functional exercise capacity in burn injury patients, and to compare these parameters with healthy subjects. METHODS: The study included 47 burn injury patients aged 20-49 years, and 47 age and gender-matched healthy subjects. The patients were evaluated on the day of discharge from hospital. Pulmonary functions and respiratory muscle strength were assessed with a spirometer (Cosmed Pony FX). Hand grip and pain were evaluated with a Jamar dynamometer and visual analog scale, respectively. The six-minute walk test (6-MWT) was performed to determine the functional exercise capacity of the participants. RESULTS: With the exception of FEV1/FVC, all the parameters of pulmonary functions test, respiratory and peripheral muscle strength and 6-MWT distances were lower in the burn injury patients than in the healthy subjects (p < 0.05). Significant predictors for these parameters were age, gender, height, body mass index, total burn surface area, burn injury type, the presence of trunk burn, hand burn, lower limb burn, inhalation injury, and intubation in the burn group (p < 0.05). CONCLUSIONS: Burn injury and the demographic characteristics of the patients are important determinants of clinical parameters. These results are clinically important as they can be of guidance in creating a personalized rehabilitation program. CLINICAL TRIAL REGISTRATION NUMBER: NCT03780218.Implications for rehabilitationBurn patients have impaired pulmonary functions and exercise capacity at discharge. Assessment of respiratory muscle strength should be added into clinical practice in adults with burn injury.Lung functions and exercise capacity should be evaluated in burn patients at discharge.It is important to monitor lung functions of burn patients after discharge.

Comparison of upper limb burn injury versus simulated pathology in terms of gait and footprint parameters.

BACKGROUND: Little is known about whether a simulated upper limb condition reflects a real (burn-injury) upper limb pathology in terms of gait/footprint parameters. RESEARCH QUESTION: The main aim of this study was to investigate the differences in these parameters between two conditions (real-simulation). METHODS: The study included burn patients (n = 30) and a control group of 30 healthy subjects. Gait and footprint parameters were evaluated using the GAITRite electronic walkway. Kinesiophobia and pain were assessed with the Tampa Kinesiophobia Scale and Visual Analog Scale, respectively. Gait evaluation of the control group was performed randomly in two conditions:1. Normal arm swing (control group) 2.Elbow flexed at 90° with a bandage (simulated group). RESULTS: Step and stride length in the burn group were significantly shorter than in the other groups (p < 0.05). Stance phase was significantly higher while swing phase, velocity and cadence were lower in the burn group (p < 0.05). Peak time in the midfoot for both sides were significantly higher in the burn group (p < 0.05). Peak time in the hindfoot for the affected side was significantly lower while peak time in the hindfoot for the intact side was significantly higher in the burn group compared to the simulated group (p < 0.05). There were significant correlations between pain, kinesiophobia and velocity, and cadence in the burn group (p < 0.05). SIGNIFICANCE: Compared to the other groups, patients with burn injury have different gait/footprint parameters due to increased pain and kinesiophobia. To determine the effects of upper limb injury and arm swing on gait parameters, a real pathology should be considered rather than a simulated pathology.

Evaluation of spatio-temporal gait parameters and gait symmetry in diabetic polyneuropathic patients with burn injury: A pilot study.

PURPOSE: The purpose of this study was to investigate the effects of burn injury on spatio-temporal gait parameters and gait symmetry in individuals with diabetic polyneuropathy (DPN)-related lower extremity burn injury. METHODS: Demographic information and the physical examinations of the lower extremities of 14 patients with unilateral lower extremity burn injury due to DPN (DPNB) and 14 uninjured patients with DPN (DPN0) were recorded. The GAITRite computerized gait analysis system was used to evaluate the spatio-temporal parameters of gait. Symmetry Index (SI) was calculated to determine gait symmetry. The Mann Whitney U test was used to determine the demographical and clinical differences between the groups, the Wilcoxon's test was used to compare both sides of all the participants for all gait parameters and linear regression analysis was used to find the variables that affect gait parameters. RESULTS: The groups were similar in terms of their demographic information except for age. Compared with the DPN0 group, DPNB group had increased extent of area with sensory loss and severity of DPN, decreased ankle joint range of motions and intrinsic foot muscles strength and they displayed lower gait speed, step length, stride length and swing percentage but their double support and stance percentage were increased. CONCLUSION: This study results have shown that, spatio-temporal gait parameters of DPNB patients are different. These differences in spatiotemporal parameters are found on both sides, probably owing to the symmetric and bilateral sensory loss is superior to unilateral burn injury due to symmetrical and bilateral sensory loss. Gait analysis should be considered in order to reveal the changes in gait parameters and to improve appropriate healing process of patients with DPN-related lower extremity burn injury.

The effects of enhanced abdominal activation on quadriceps muscle activity levels during selected unilateral lower extremity exercises.

The purpose of this study was to investigate the effect of Abdominal Enhancement (AE) on the muscle activation of vastus medialis obliquus (VMO), vastus lateralis (VL) and rectus femoris (RF) muscle activation levels during eccentric, isometric and concentric phases of single leg raise (SLR), single leg wall squat (SLWS) and forward lunge (FL) exercises. Sixteen healthy individuals (Age: 24.6 ± 1.7 years) were included in the study. Internal Obliques/Transversus Abdominis (IO/TA), VMO, RF and VL muscle activation levels were measured by surface EMG during the exercises in two conditions: with and without AE. The abdominal drawing-in technique was used for AE. Repeated-measures analysis of variance was performed for statistical analysis. With AE, the average of IO/TA muscle activation level was 28.9%. VMO and VL muscle activation levels were significantly greater with AE during SLR (p = .02), SLWS (p < .001) and FL (VMO, p = .008, VL, p = .04) exercises. The effect of AE on VMO muscle activation level ranged from 2.5% to 5% (Effect size range: 0.54 to 0.91) and VL muscle activation level ranged from 2.1% to 5.5% (Effect size range: 0.35-1.24). RF muscle activation level did not change with AE (p > .05). The results of this study showed that AE increased VMO and VL muscle activities during SLR, SLWS and FL exercises but the corresponding changes were small. Even if this is not enough for muscle strengthening, exercises with AE may be used to enhance knee joint stability while controlling lumbopelvic stability.

Analysis of apoptotic, platelet-derived, endothelial-derived, and tissue factor-positive microparticles of children with acute lymphoblastic leukemia during induction therapy.

OBJECTIVES: Thromboembolism is one of the most common complications during induction therapy of pediatric acute lymphoblastic leukemia (ALL). Procoagulant microparticles in the circulation may cause thromboembolic events. The aim of our study was to determine the levels of apoptotic, platelet-derived, endothelial-derived, and tissue factor-positive microparticles of children with ALL at diagnosis and during induction therapy. METHODS: Sixteen precursor B-cell ALL cases and 30 healthy children between 1 and 18 years of age were included. Microparticle levels were analyzed from peripheral blood samples at initial diagnosis, on days 12 and 13 (before and after the first L-asparaginase administration), and on day 33 of ALL-BFM 2000 treatment protocol. Microparticle levels were analyzed by using flow cytometry. RESULTS: At initial diagnosis, platelet, endothelial-derived, and tissue factor-positive microparticle levels were significantly high in children with ALL. They increased significantly after prednisone and L-asparaginase administration. Apoptotic microparticle levels were not elevated at diagnosis, but remained high during all induction therapy period. None of the patients had evidence of thromboembolism during induction therapy. CONCLUSION: Our study demonstrated that children with ALL have increased levels of apoptotic, platelet-derived, endothelial-derived, and tissue factor-positive microprticles during induction therapy. Further studies are needed in larger groups of patients in order to evaluate the risk of elevated microprticles for development of thromboembolism during induction therapy period in children with ALL.

Investigation of the Relationship Between Fok1 and Col1A1 Gene Polymorphisms and Development of Treatment-Related Bone Complications in Children with Acute Lymphoblastic Leukemia

Objective: In acute lymphoblastic leukemia (ALL), various clinical risk factors and genetic predispositions contribute to the development of bone complications during and after chemotherapy. In this study, we aimed to investigate whether vitamin D receptor (VDR) Fok1 and collagen protein Col1A1 Sp1-binding site gene polymorphisms, which are important in bone mineral and matrix formation, have effects on the development of bone abnormalities in childhood ALL survivors. Materials and Methods: Fifty children with ALL who were treated with the ALL Berlin-Frankfurt-Muenster-95 protocol between 1998 and 2008 and were followed for at least 7 years were enrolled. The control group consisted of 96 healthy children. VDR Fok1 and Col1A1 Sp1-binding site gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymorphism. Bone mineral density (BMD) and markers of bone metabolism were all noted. All patients who presented with pain in the joints were examined for bone pathologies while on chemotherapy or during long-term follow-up. Results: Low BMD (16%), osteoporosis (12%), and osteonecrosis (8%) were present in a total of 18 patients (36%). The frequency of osteonecrosis and total bone abnormalities was significantly higher in children aged ≥10 years (p=0.001). The risk of low BMD and osteonecrosis was higher in those with vitamin D deficiency. Only the Col1A1 Sp1-binding site gene polymorphism showed a significant association in ALL patients with osteonecrosis. Conclusion: The development of therapy-induced bone mineral loss and osteonecrosis in children with ALL is frequent and the risk is especially higher in children aged ≥10 years and with vitamin D deficiency. The association between Col1A1 Sp1-binding site gene polymorphisms and osteonecrosis has to be assessed in a larger group of ALL survivors.

FLAG Regimen with or without Idarubicin in Children with Relapsed/Refractory Acute Leukemia: Experience from a Turkish Pediatric Hematology Center.

INTRODUCTION: The optimal therapy to achieve higher rates of survival in pediatric relapsed/refractory acute leukemia (AL) is still unknown. In developing countries, it is difficult to obtain some of the recent drugs for optimal therapy and mostly well-known drugs proven to be effective are used. We assessed the efficacy of the combination of fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG regimen) with or without idarubicin (IDA) in children with relapsed/refractory acute lymphoblastic leukemia and acute myeloid leukemia. METHODS: Between September 2007 and May 2015, 18 children with refractory/relapsed AL attending our center, treated with a FLAG regimen with or without IDA, were included. The primary end point was the remission status of the bone marrow sampled after the first/second course of chemotherapy. The second end point was the duration of survival after hematopoietic stem cell transplantation (HSCT). RESULTS: Complete remission (CR) was achieved in 7 patients (38.8%) after the first cycle, and at the end of the second cycle the total number of patients in CR was 8 (42.1%). All patients in CR underwent HSCT. The CR rate in patients who had IDA in combination therapy was 28.6%, and it was 50% in patients treated without IDA (p=0.36). Mean survival duration in transplanted patients was 24.7±20.8 months (minimum-maximum: 2-70, median: 25 months), and it was 2.7±1.64 months (minimum-maximum: 0-5, median: 3 months) in nontransplanted patients. Five of them (27.7%) were still alive at the end of the study and in CR. The median time of follow-up for these patients was 33 months (minimum-maximum: 25-70 months). CONCLUSION: FLAG regimens with or without IDA produced a CR of >24 months in 27.7% of children with relapsed/refractory AL and can be recommended as therapeutic options prior to HSCT in developing countries.