Prognosis of Second Primary Malignancies in Pediatric Acute Lymphoblastic Leukemia Survivors: A Multicenter Study by the Turkish Pediatric Hematology Society.

The improved survival rates of childhood cancers raise the long-term risk of second primary malignancy (SPM) in childhood and adolescent cancer survivors. The intensity of the treatment protocol used, the use of some groups of chemotherapeutics, and radiotherapy were found to be risk factors for the development of second primary malignancies (SPMs). Forty-one patients who developed acute myelocytic leukemia or any solid organ cancer within 25 years of follow-up, after completion of pediatric acute lymphoblastic leukemia (ALL) treatment, were included in the study. The mean duration of initial ALL diagnosis to SPM was 9.3 ± 6.1 years. The 3 most common SPMs were acute myelocytic leukemia, glial tumors, and thyroid cancer. Thirteen (81%) of 16 patients exposed to cranial irradiation had cancer related to the radiation field. In total 13/41 (32%) patients died, and the 5-year overall survival rate was 70 ± 8%. Patients older than 5 years old at ALL diagnosis had significantly worse overall survival than cases younger than 5 years old. In conclusion, children and adolescents who survive ALL have an increased risk of developing SPM compared with healthy populations, and physicians following these patients should screen for SPMs at regular intervals.

Myeloid sarcoma with RBM15::MRTFA (MKL1) mimicking vascular neoplasm.

Extramedullary involvement of acute myeloid leukemia (AML), aka myeloid sarcoma, is a rare phenomenon in acute megakaryoblastic leukemia with RBM15:: MRTFA(MKL1) fusion, which might mimic non-hematologic malignancies. A 7-month-old infant presented with leukocytosis, hepatosplenomegaly, multiple lymphadenopathies, and a solid mass in the right thigh. Initially, the patient was diagnosed with a malignant vascular tumor regarding the expression of vascular markers from the biopsy of the right thigh lesion that was performed after the inconclusive bone marrow biopsy. The second bone marrow biopsy, which was performed due to the partial response to sarcoma treatment, showed hypercellular bone marrow with CD34 and CD61-positive spindle cell infiltration and > 20% basophilic blasts with cytoplasmic blebs. RNA sequencing of soft tissue biopsy revealed the presence of RBM15::MRTFA(MKL1) fusion. Based on these findings, myeloid sarcoma/AML with RBM15::MRTFA(MKL1) fusion diagnosis was made. AML with RBM15::MRTFA(MKL1) fusion can initially present as extramedullary lesions and might cause misdiagnosis of non-hematologic malignancies.

Clinical and Osteopetrosis-Like Radiological Findings in Patients with Leukocyte Adhesion Deficiency Type III.

BACKGROUND: Leukocyte and platelet integrin function defects are present in leukocyte adhesion deficiency type III (LAD-III) due to mutations in FERMT3. Additionally, osteoclast/osteoblast dysfunction develops in LAD-III. AIM: To discuss the distinguishing clinical, radiological, and laboratory features of LAD-III. METHODS: This study included the clinical, radiological, and laboratory characteristics of twelve LAD-III patients. RESULTS: The male/female ratio was 8/4. The parental consanguinity ratio was 100%. Half of the patients had a family history of patients with similar findings. The median age at presentation and diagnosis was 18 (1-60) days and 6 (1-20) months, respectively. The median leukocyte count on admission was 43,150 (30,900-75,700)/µL. The absolute eosinophil count was tested in 8/12 patients, and eosinophilia was found in 6/8 (75%). All patients had a history of sepsis. Other severe infections were pneumonia (66.6%), omphalitis (25%), osteomyelitis (16.6%), gingivitis/periodontitis (16%), chorioretinitis (8.3%), otitis media (8.3%), diarrhea (8.3%), and palpebral conjunctiva infection (8.3%). Four patients (33.3%) received hematopoietic stem cell transplantation (HSCT) from HLA-matched-related donors, and one deceased after HSCT. At initial presentation, 4 (33.3%) patients were diagnosed with other hematologic disorders, three patients (P5, P7, and P8) with juvenile myelomonocytic leukemia (JMML), and one (P2) with myelodysplastic syndrome (MDS). CONCLUSION: In LAD-III, leukocytosis, eosinophilia, and bone marrow findings may mimic pathologies such as JMML and MDS. In addition to non-purulent infection susceptibility, patients with LAD-III exhibit Glanzmann-type bleeding disorder. In LAD-III, absent integrin activation due to kindlin-3 deficiency disrupts osteoclast actin cytoskeleton organization. This results in defective bone resorption and osteopetrosis-like radiological changes. These are distinctive features compared to other LAD types.

Claude Syndrome in Childhood Associated with Probable Neuro-Behcet Disease.

Claude syndrome is a rare midbrain stroke syndrome characterized by ipsilateral third cranial nerve palsy and contralateral hemiataxia. So far, only a few cases have been reported in childhood. We present two children with Claude syndrome at 9 and 15 years of age. The typical clinical picture was consistent with brain magnetic resonance imaging findings. A thorough investigation regarding the underlying etiology revealed no definite diagnosis but clues suggestive of probable neuro-Behcet disease. Awareness of pediatric neurologists on arterial ischemic stroke has been increasing over the past decades, enabling timely diagnosis and appropriate management of rare childhood cases with midbrain stroke.

Gene therapy in haemophilia: literature review and regional perspectives for Turkey.

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.

Adenosine Deaminase Type II Deficiency: Severe Chronic Neutropenia, Lymphoid Infiltration in Bone Marrow, and Inflammatory Features.

Deficiency of adenosine deaminase type 2 (DADA2) is an autoinflammatory disease characterized with immunologic, hematologic, and neurological features. Here, we presented two patients with severe persistent chronic neutropenia, which required differential diagnosis of congenital and autoimmune neutropenia, myelodysplastic syndrome (MDS), and primary immunodeficiency diseases, including autoimmune lymphoproliferative disease. The therapy of the disease except hematopoietic stem cell transplantation is a challenging experience.

Increased endoglin levels correlated with angiogenesis-associated angiopoietin-2 in haemophilia patients.

INTRODUCTION: Haemophilia is a bleeding disorder that occurs due to the deficiency of coagulation factors, and the angiogenesis process is an important process underlying the pathophysiology of haemophilic arthropathy. The role of the new adipocytokine endoglin (ENG) in patients with haemophilia is not yet known. AIM: The aim of this study is to evaluate the association between ENG protein and angiogenesis-related cytokines in patients with haemophilia for the first time. METHODS: Plasma protein levels and mRNA expressions of ENG and various angiogenesis-associated cytokines were compared in blood samples collected from 28 patients with haemophilia A or B and 29 healthy volunteers. The relationship between the cytokines and ENG were determined by correlation analysis. RESULTS: Plasma ENG levels and angiogenic markers were found to be significantly higher in patients with haemophilia compared to controls. Real-time PCR studies showed that mRNA expressions of ENG, vascular endothelial growth factor A, hypoxia-inducible factor A, and prostaglandin E2 increased in patients with haemophilia. Correlation analysis showed a significant positive correlation between ENG and angiopoietin-2 levels in the haemophilia group. Besides, a significant decrease in annexin-V binding to platelets in haemophilia patients compared to control was found to be related to the bleeding profiles in the patients. CONCLUSIONS: This study determined that ENG protein may be involved in the formation of angiogenesis in haemophilia patients and its effects may be related to angiogenetic marker angiopoietin-2 in this process. Our findings contribute to the literature during the determination of target proteins in haemophilia treatment.

The use of serum endothelial adhesion molecules in pediatric patients with leukemia with febrile neutropenia to predict bacteremia.

OBJECTIVE: Febrile neutropenia (FN) represents a life-threatening complication in hematological malignancies. We aimed to analyze the utility of soluble vascular cell adhesion molecule 1 (sVCAM-1), intercellular adhesion molecule 1 (sICAM-1), vascular endothelial growth factor (VEGF) levels compared with C-reactive protein (CRP) and procalcitonin (PCT) during febrile neutropenia episodes of pediatric patients with leukemia. METHODS: Two plasma samples, on day 0 (initial of episode) and day 3 (48-72 h after episode), for VCAM-1, ICAM-1 and VEGF, CRP and PCT were prospectively collected concomitantly during each febrile neutropenic episode between December 2016 and December 2017. The primary outcome was bacteremia and the secondary outcome was intensive care unit (ICU) admission. RESULTS: Twenty-two (28.6%) acute lymphoblastic lymphoma (ALL), seventeen (22.1%) acute myeloblastic lymphoma (AML) patients and thirty-eight (49.3%) control patients with no known underlying disease or fever were included in this study. Of the 39 patients; 16 (41%) had bacteremia. Mean serum sVCAM1 and sICAM1 levels were significantly higher in control group, compared to FN patients (p < 0.001). Mean serum sVCAM2 level was significantly higher in FN patients with bacteremia compared to FN patients without bacteremia (144.97 ± 70.35 pg/mL vs 85.45 ± 53.76 pg/mL, p = 0.022). Mean sVCAM1 and 2 levels were higher in FN patients with ICU admission. In this study, we found that sVCAM-1 and VEGF, when combined to CRP and PCT, could predict gram-negative bacteremia in FN episodes of pediatric hematological malignancy. CONCLUSION: Serum endothelial adhesion molecules, excluding sVCAM-1, cannot predict bacteremia and ICU admission alone in FN patients; but may be associated with clinical outcome when used with PCT and CRP.

Usage of Plasma Presepsin, C-Reactive Protein, Procalcitonin and Proadrenomedullin to Predict Bacteremia in Febril Neutropenia of Pediatric Hematological Malignancy Patients.

OBJECTIVE: To investigate the value of presepsin and proadrenomedullin (proADM) as new markers for febrile neutropenia, by comparing them with conventional markers. METHODS: Plasma specimens for presepsin, proADM, C-reactive protein (CRP), and procalcitonin (PCT) were collected every 3 days during each episode of febrile neutropenia. RESULTS: A total of 39 patients experiencing a collective 47 episodes of febrile neutropenia with hematological malignant neoplasms, as well as 40 healthy control patients without infectious disease, were enrolled in this study. Levels of the studied analytes in the presepsin 1 group (with baseline values taken at admission), presepsin 2 group (values recorded on the 3rd day of febrile neutropenia), and presepsin 3 group (values recorded on the 6th day of hospitalization) were all higher in the subgroups with bacteremia. C-reactive protein 1 (baseline value taken at admission), procalcitonin 1 (as recorded at admission), and procalcitonin 2 (recorded on the 3rd day of febrile neutropenia) were higher in the subroups with bacteremia (P =.03, P = .04, and P = .04, respectively). In multivariate logistic regression analysis, presepsin 1 and/or PCT 1/CRP 1 combined analysis was superior in predicting bacteremia. CONCLUSION: Presepsin could be used in combination with other biomarkers to detect bacteremia.

Is Posaconazole Really Effective in Adolescent patients as a Prophylactic Agent: Experience of a Tertiary Care Center.

BACKGROUND: Invasive fungal infections (IFIs) are a leading cause of morbidity and death in immunocompromised patients. Data on efficacy and pharmacokinetics of posaconazole in pediatric patients are rare (1 to 5). Herein, we retrospectively analyzed adolescent patients who had received posaconazole as antifungal prophylaxis. METHODS: We retrospectively analyzed patients who received posaconazole as primary or secondary antifungal prophylaxis. RESULTS: A total of 34 adolescent patients, 19 men (55.9%) and 15 women (44.1%) with a mean age of 15.8±2.1 years were included. Twenty-five of 34 (73.5%) patients were on primary and nine of 34 (26.5%) patients were on secondary antifungal prophylaxis. Diagnosis of the patients receiving posaconazole as primary antifungal prophylaxis were acute myeloid leukemia (n=12, 48%), hematopoietic stem cell transplantation (n=7, 28%), acute lymphoblastic leukemia (n=5, 20%), and Fanconi aplastic anemia (n=1, 4%). Five patients (55.6%) with hematopoietic stem cell transplantation, 1 patient with acute myeloid leukemia (11.1%), 1 patient with Fanconi aplastic anemia (11.1%), and 2 (22.2%) patients with chronic granulomatous disease received posaconazole as secondary antifungal prophylaxis. Twelve of 25 (48%) patients receiving posaconazole as primary antifungal prophylaxis were complicated by IFI; 4 of them were proven, 6 probable, and 2 with possible IFI. Three of 9 patients (33.3%) receiving posaconazole as secondary antifungal prophylaxis was complicated by IFI (P=0.29), 2 of them were probable and 1 was possible IFI. Five of 25 patients (20%) receiving posaconazole as primary prophylaxis died because of IFI. CONCLUSION: Improvement of antifungal prophylaxis in patients with high risk of invasive infections seems clearly necessary, and analyzing serum posaconazole levels and individualizing dosing may be 1 approach to improve outcomes.

Colchicine and Leukopenia: Clinical Implications.

Colchicine is the mainstay of treatment for familial Mediterranean fever. We investigated the frequency of leukopenia in 213 patients with familial Mediterranean fever treated with standard doses of colchicine (0.5-2.0 mg/day). We found that 23 patients (10.8%) had reversible leukopenia, 3 moderate, and none severe and that their rate of infections was not increased.

Hb H Disease Diagnosed During Adolescent Pregnancy.

Hb H disease is a moderate to severe form of α-thalassemia (α-thal). Patients with Hb H disease may become symptomatic, especially during infections and pregnancy, and may require transfusions. Herein, we present a 16-year-old female with Hb H disease who was initially diagnosed during adolescent pregnancy and was found to carry the -α3.7/-(α)20.5 deletions. The relatively mild presentation of this case highlights the milder phenotypic consequences of deletional α mutations. The case describes the screening and management of pregnancy with Hb H disease. Additionally, this case demonstrates that screening of some undiagnosed inherited blood disorders is important during pregnancy.

Pharmacology, Efficacy and Safety of a Triple-Secured Fibrinogen Concentrate in Children Less than or Equal to 12 Years with Afibrinogenaemia.

OBJECTIVE: To date, the use of a fibrinogen concentrate (FC) administered in children with inherited fibrinogen deficiency is poorly documented. Treatment modalities may differ from those of adults. The aim of this study was to investigate the pharmacokinetics (PK), efficacy (bleeding/surgery) and safety of a triple-secured FC (FibCLOT, LFB, France) in young patients aged of 12 years or less. METHODS: This was a prospective, non-comparative, multicentre, phase 2-3 study. Estimated PK parameters were based on population PK modelling. Target fibrinogen levels were 1.2 and 1.0 g/L for major and minor events, respectively. In vivo recovery (IVR) was calculated at study entry to tailor the dose. RESULTS: Sixteen afibrinogenaemia patients were treated with FC: 12 included in the PK study (6 aged ≤ 6 years and 6 aged 7-12 years). IVR at 1 hour post-infusion (geometric mean [coefficient of variation]) was 1.91 [20%] mg/dL per mg/kg and results were similar between the two age groups (1.87 [14%]) and (1.96 [27%]) with no statistical differences. Estimated half-life (t 1/2) was 49.0 hours [12%] with no observed differences between groups (46.6 hours [10%] and 51.6 hours [12%]). Overall efficacy was rated as excellent/good in 96.9% of 32 bleeds and in 100% of 11 surgeries. Most of the events (39/43, 90.7%) were managed with one infusion. There was no serious adverse drug reaction. CONCLUSION: Individually tailored dosing was efficacious in children who exhibited a lower IVR and shorter t 1/2 than those previously reported in adolescent and adult patients emphasising the importance of individualised dose optimisation.

Autoinflammation in addition to combined immunodeficiency: SLC29A3 gene defect.

INTRODUCTION: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). AIM: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. PATIENT AND METHODS: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide. RESULTS: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1ß and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient. CONCLUSION: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.

Clinical and Molecular Spectrum of Glucose-6-Phosphate Isomerase Deficiency. Report of 12 New Cases.

Glucose-6-phosphate isomerase (GPI, EC 5.3.1.9) is a dimeric enzyme that catalyzes the reversible isomerization of glucose-6-phosphate to fructose-6-phosphate, the second reaction step of glycolysis. GPI deficiency, transmitted as an autosomal recessive trait, is considered the second most common erythro-enzymopathy of anaerobic glycolysis, after pyruvate kinase deficiency. Despite this, this defect may sometimes be misdiagnosed and only about 60 cases of GPI deficiency have been reported. GPI deficient patients are affected by chronic non-spherocytic hemolytic anemia of variable severity; in rare cases, intellectual disability or neuromuscular symptoms have also been reported. The gene locus encoding GPI is located on chromosome 19q13.1 and contains 18 exons. So far, about 40 causative mutations have been identified. We report the clinical, hematological and molecular characteristics of 12 GPI deficient cases (eight males, four females) from 11 families, with a median age at admission of 13 years (ranging from 1 to 51); eight of them were of Italian origin. Patients displayed moderate to severe anemia, that improves with aging. Splenectomy does not always result in the amelioration of anemia but may be considered in transfusion-dependent patients to reduce transfusion intervals. None of the patients described here displayed neurological impairment attributable to the enzyme defect. We identified 13 different mutations in the GPI gene, six of them have never been described before; the new mutations affect highly conserved residues and were not detected in 1000 Genomes and HGMD databases and were considered pathogenic by several mutation algorithms. This is the largest series of GPI deficient patients so far reported in a single study. The study confirms the great heterogeneity of the molecular defect and provides new insights on clinical and molecular aspects of this disease.