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.

Evaluation of childhood malignancies presenting with musculoskeletal manifestations from two different divisions: a multicenter study.

BACKGROUND: The aim of the study was to evaluate the approaches of pediatric rheumatologists and pediatric hematologists to patients with similar musculoskeletal (MSK) complaints and to highlight the differences that general pediatricians should consider when referring patients to these specialties. METHODS: This is a cross-sectional study involving the patients who applied to pediatric rheumatology centers with MSK complaints and were diagnosed with malignancy, as well as patients who were followed up in pediatric hematology centers with a malignancy diagnosis, and had MSK complaints at the time of admission. RESULTS: A total of 142 patients were enrolled in the study. Of these patients, 83 (58.4%) applied to pediatric rheumatology centers, and 59 (41.6%) applied to pediatric hematology centers. Acute lymphoblastic leukemia (ALL) was the most common diagnosis among the patients who applied to both centers, with 80 cases (56.3%). The median age of diagnosis was 87 (interquartile range, IQR: 48-140) months. The most common preliminary diagnosis in pediatric rheumatology centers was juvenile idiopathic arthritis (JIA), with 37 cases (44.5%). MSK involvement was mainly seen as arthralgia, and bone pain. While arthralgia (92.7%) was the most common complaint in rheumatology centers, bone pain (88.1%) was more common in hematology centers. The most frequently involved joints were the knee (62.9%), ankle (25.9%), hip (25%), and wrist (14%). The most common laboratory abnormalities were high lactate dehydrogenase (LDH), high C-reactive protein (CRP), anemia, and high erythrocyte sedimentation rate (ESR). Thrombocytopenia, neutropenia, and high LDH were statistically significantly more frequent in patients admitted to hematology centers than in patients admitted to rheumatology centers (p < 0.001, p=0.014, p=0.028, respectively). Patients who applied to rheumatology clinics were found to have statistically significantly higher CRP levels (p=0.032). CONCLUSIONS: Malignancies may present with only MSK system complaints in childhood. Therefore, malignancies should be included in the differential diagnosis of patients presenting with MSK complaints.

The First Definition of Pulmonary Component of Hypereosinophilic Syndrome: Bronchial Casts.

Hypereosinophilic syndrome is a heterogeneous disease characterized by eosinophilic tissue inflammation and eosinophilia. Pulmonary involvement could be seen in up to 55% among children with hypereosinophilic syndrome. A 3-year-old boy with chronic hypereosinophilia and respiratory complaints was diagnosed with idiopathic hypereosinophilic syndrome. Atelectasis was detected in the radiological evaluation, and bronchial casts with eosinophilic structures were removed by bronchoscopy. Steroid, inhaled hypertonic saline, inhaled bronchodilator, inhaled corticosteroid, and leukotriene receptor antagonist were used for 1 year in the management of hypereosinophilic syndrome, and related eosinophilic casts and repetitive bronchoscopies were administered for removal of the casts. The patient was successfully managed with an inhaled N-acetyl cysteine treatment. In children, the long-term prognosis of hypereosinophilic syndrome is uncertain. Comprehensive diagnostic tests are required for the early diagnosis and management of pediatric hypereosinophilic syndrome. In the presented case, the rare occurrence of pulmonary involvement of hypereosinophilic syndrome in a 3 year-old-boy with recurrent hypereosinophilic casts and its management were discussed.

Central nervous system thrombosis in pediatric acute lymphoblastic leukemia in Turkey: A multicenter study.

BACKGROUND: In patients with acute lymphoblastic leukemia (ALL), the risk of thromboembolism increases due to hemostatic changes secondary to the primary disease and due to treatment-related factors. In this multicenter study, we aimed to research the frequency of central nervous system (CNS) thrombosis occurring during treatment, hereditary and acquired risk factors, clinical and laboratory features of patients with thrombosis, treatment approaches, and thrombosis-related mortality and morbidity rates in pediatric ALL patients. PROCEDURE: Pediatric patients who developed CNS thrombosis during ALL treatment from 2010 to 2021 were analyzed retrospectively in 25 different Pediatric Hematology Oncology centers in Türkiye. The demographic characteristics of the patients, symptoms associated with thrombosis, the stage of the leukemia treatment during thrombosis, the anticoagulant therapy applied for thrombosis, and the final status of the patients recorded through electronic medical records were determined. RESULTS: Data from 70 patients with CNS thrombosis during treatment, out of 3968 pediatric patients with ALL, were reviewed. The incidence of CNS thrombosis was 1.8% (venous: 1.5 %; arterial: 0.03%). Among patients with CNS thrombosis, 47 had the event in the first 2 months. Low molecular weight heparin (LMWH) was the most commonly used treatment with a median of 6 months (min-max: 3-28 months). No treatment-related complications occurred. Chronic thrombosis findings occurred in four patients (6%). In five (7%) patients who developed cerebral vein thrombosis, neurological sequelae (epilepsy and neurological deficit) remained. One patient died related to thrombosis, and the mortality rate was 1.4%. CONCLUSION: Cerebral venous thrombosis and, less frequently, cerebral arterial thrombosis may develop in patients with ALL. The incidence of CNS thrombosis is higher during induction therapy than during other courses of treatment. Therefore, patients receiving induction therapy should be monitored carefully for clinical findings suggestive of CNS thrombosis.

Central Nervous System Fungal Infections in Children With Leukemia and Undergoing Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study.

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.

Assessment of the Nutritional Status, Bone Mineralization, and Anthropometrics of Children with Thalassemia Major.

OBJECTIVE: Children with thalassemia major (TM) are prone to growth failure and micronutrient deficiency. Thus, this study aimed to evaluate nutritional status, anthropometrics, and bone mineralization defects in patients with regular blood transfusion. METHODS: Data obtained were analyzed by evaluating laboratory tests, anthropometric measures, and bone mineral density. RESULTS: This study included 29 patients (62% male and 38% female) with a mean age of 12.26±4.74 years, mean pre-transfusion hemoglobin of 8.64±1.01 g/dL, and mean serum ferritin of 1158.6±556.8 ng/ mL. Vitamin D (72.4%), selenium (72.4%), and folate (37.9%) deficiencies were most frequent. Hypocalcemia was observed in 17.2%, hypomagnesemia in 3.5%, and decreased ceruloplasmin in 10.3% of patients. Folate was higher between 2 and 6 years old (p=0.028). Ceruloplasmin was higher between 6 and 10 years old (p=0.018). Selenium was significantly higher in patients with a ferritin of ≥1,500 (p=0.008). No significant ferritin-related differences were found in other micronutrients (p>0.05). Body mass index (BMI) were <5 percentile (p) in 31% of patient, whereas none was >95 p. Height in 24.5% and weight in 20.7% of patients were <3 p, whereas none with >97 p. BMI of patients aged 10-18 years was significantly higher (p=0.001). Anthropometric percentiles did not significantly differ in the mean serum ferritin and micronutrient levels. Hypoparathyroidism was observed in 13.8% and hypothyroidism in 3.5% of patients. Low bone density was detected in 14.8% (2 osteopenic and 2 osteoporotic) of patients. Bone mineral density did not significantly differ in the ferritin and micronutrient levels. CONCLUSIONS: Nutritional support and deficiency prevention are important to minimize the burden of complications and increase the life expectancy and quality in patients with TM.

Deferasirox in children with transfusion-dependent thalassemia or sickle cell anemia: A large cohort real-life experience from Turkey (REACH-THEM).

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.

Chylous ascites after lymphadenectomy in a Wilms` tumor patient.

Yörük MA, Erat-Nergiz M, Timur Ç, Canbolat-Ayhan A, Ergüven M. Chylous ascites after lymphadenectomy in a Wilms` tumor patient. Turk J Pediatr 2018; 60: 436-438. Wilms` tumor is the most common renal malignancy in children and the fourth most common childhood cancer. It accounts 6-7% of all childhood malignancies. Surgical resection is an important therapy option and transabdominal or transperitoneal resection with lymph node sampling is preferred. Development of chylous ascites following intraabdominal or retroperitoneal resection in pediatric age group generally results from extensive lymph node dissection, accidental ligation or interruption of lymphatic ducts. Diseases or conditions affecting abdominal and/or retroperitoneal lymph nodes may cause chylous ascites. Postoperative chylous ascites is associated with significant morbidity and may cause mechanic, nutritional and immunological complications. In the present study, a 16-month-old infant with Stage IV Wilms` tumor who developed chylous ascites after left nephrectomy and lymphadenectomy will be presented; chylous ascites treatment with enteral nutrition and surgical treatment approach for Wilms` tumor will be reviewed.

A retrospective analysis of complications observed in children with acute lymphoblastic leukemia during chemotherapy.

BACKGROUND: We aimed to evaluate the complications that we observed in children with acute lymphoblastic leukemia (ALL) during the remission induction, consolidation, and reinduction phases of chemotherapy retrospectively. METHODS: We analysed the clinical records of 128 patients with ALL who were diagnosed and treated in the Department of Pediatric Hematology of Istanbul Medeniyet University Goztepe Training Hospital between August 2009 and April 2014 to document the acute complication other than febrile neutropenia episodes, which developed during the induction, consolidation and reinduction phases of chemotherapy. RESULTS: We documented 279 complications. Of these, 53.05% were in males, 46.95% in females; 32.26% were in standard-risk, 45.52% in medium-risk, 22.22% in high-risk group of patients. Common documented events were pneumonia (25%), therapy-induced hyperglycemia (16.40%) therapy-related hepatitis (15.6%), generalized tonic-clonic seizures (14.8%), anaphylaxis to asparaginase (14.1%), hypertension (13.3%) varicella zoster virus (VZV) infection (13.3%), renal tubulopathy (12.5%). Time of complications was induction phase in 32.62%, consolidation in 19.35%, HR blocks in 18.28%, reinduction 29.75% during the phases. Mortality rate due to complications was 13.28%. CONCLUSIONS: Therapy-related complications can limit the survival rates in children with ALL. To minimize the treatment burden, even very rare complications must be considered and treated promptly with a multidisciplinary approach.

Changes in platelet indices in children with bicuspid aortic valve.

Mean platelet volume (MPV) and platelet distribution width (PDW) can help diagnose cardiovascular pathologies. In this study, we aimed to demonstrate the changes in platelet (PLT) indices in children diagnosed with bicuspid aortic valve (BAV) with mild stenosis and without stenosis to compare patients with mild stenosis with those without stenosis. A total of 73 children diagnosed with BAV (30 patients with mild stenosis and 43 without stenosis) with a mean age 9.73 ± 5.01 years and a control group were included in the study. Mean MPV value was significantly lower in the control group compared with patients with BAV with mild stenosis and patients without stenosis (p = 0.001, and p < 0.01, respectively). MPV was significantly greater in patients with mild stenosis than in patients without stenosis (p = 0.049 and p < 0.05, respectively). Patients with mild stenosis had a significantly greater mean PDW value compared with patients without stenosis and the control group (p = 0.024 and p < 0.05, respectively). There was no significant difference between patients without stenosis and the control group with respect to mean PDW value (p > 0.05). In conclusion, the results of this study demonsrate that children with BAV either with or without stenosis have increased MPV; the ones with mild stenosis have even greater values than the ones without stenosis. It emphasizes the risk of thrombosis in children with BAV.

Myeloid sarcoma presenting with leukemoid reaction in a child treated for acute lymphoblastic leukemia.

Background. Myeloid sarcoma is an extramedullary neoplasm of immature myeloid cells. Our study reports a presentation of myeloid sarcoma which presented with severe leukemoid reaction as a secondary malignancy in a patient who was treated for acute lymphoblastic leukemia previously. The case emphasizes the difficulties in diagnosis of patients who do not have concomitant leukemia. Case Presentation. A 6-year-old girl who was treated for acute lymphoblastic leukemia previously presented with fatigue, paleness, and hepatosplenomegaly. Peripheral blood smear and bone marrow aspirate examination did not demonstrate any blasts in spite of severe leukemoid reaction with a white cell count 158000/mm(3). FDG/PET CT revealed slight uptake in cervical and supraclavicular lymph nodes. Excisional lymph node biopsy was performed from these lymph nodes and it showed myeloid sarcoma. Conclusion. Myeloid sarcoma can develop as a secondary malignancy in children who are treated for acute lymphoblastic leukemia. It can be associated with severe leukemoid reaction and diagnosis may be difficult if there is not concomitant leukemia. PET/CT is helpful in such cases.

Spontaneous intestinal perforation: an atypical presentation of neutropenic enterocolitis-a case report.

Background. Neutropenic enterocolitis is one of the most common gastrointestinal complications seen in patients who are receiving chemotherapy for leukemia. Severe neutropenia is the main underlying factor of this pathology. It is characterized by fever and abdominal pain. Case Presentation. Herein, we report a case of neutropenic enterocolitis which presented with intestinal perforation in an afebrile patient who was diagnosed with acute lymphoblastic leukemia and was receiving induction chemotherapy. Conclusion. We aimed to emphasize the importance of enterocolitis and increase awareness against such severe complications which could have unexpected presentations.

A trombosis story and PRES.

Trombosis is seen in children with acute lymphoblastic leukemia during or after L-asparaginase treatment. Posterior reversible encephalopathy syndrome (PRES) is a complex syndrome characterized with sudden hypertension, headache, nausea, vomiting, alteration in the state of consciousness, vision defect and seizures. The cases related to this syndrome have been reportedly seen after eclampsia, organ transplantation, immunsuppressive treatments, autoimmune diseases and chemotherapy. Vasogenic edema occuring in the brain parencyhma constitues the basic pathophysiology. We present a case who developed seizures during treatment for B-cell acute lymphoblastic leukemia and diagnosed as posterior reversible encephalopathy.

Chronic granulomatous Aspergillus synovitis: a case report.

Aspergillus can cause invasive disease of various organs especially in patients with weakened immune systems. Aspergillus synovitis and arthritis are uncommon types of involvement due to this infection. Approaches to fungal osteoarticular infections are based on only case reports. This paper presents a rare case of chronic granulomatous Aspergillus synovitis in an immunocompromised 5-year old girl who was treated for acute lymphoblastic leukemia.

Frequency of pericardial effusion in childhood acute lymphoblastic leukemia and clinical features of these patients.

In this study, we aimed to determine the frequency of pericardial effusion (PE) in children diagnosed with acute lymphoblastic leukemia (ALL). Clinical features of patients with effusion were evaluated. For this purpose, we reviewed the medical records of ALL patients who had pretherapy echocardiograms. A total of 90 patients aged between 1.8 and 16.3 years were analyzed retrospectively. In 23 of 90 (25.6%) patients, PE was detected at initial diagnosis. The age of patients with PE ranged between 1.8 and 14.8 years (mean 5.05 ± 3.77 years). The female/male ratio was 9/14. Six (26.1%) patients were T-lineage and 17 (73.9%) were B-lineage ALL. Nine (39%) patients were in standard risk group, 13 (57%) were in median risk group, 1 (4%) patient was in high-risk group. Mean initial white blood cell count was 40.756 ± 38.653/mm(3) (range 23.000-130.000/mm(3)). Mean initial hemoglobin count was 7.3 ± 1.39 gr/dL (range 5.5-10.1 gr/dL), mean initial platelet count was 35.200 ± 26.300/mm(3) (range 4.000-118.000 mm(3)). Size of effusions was between 2 and 6 mm (mean size 3.3 ± 1.8 mm). All patients had normal left ventricular systolic function. In 87% of patients, effusions disappeared in the first 7 days and, in 13%, disappeared between 8th and 15th days of chemotherapy. None of the patients required pericardiocentesis. Cardiac dysfunction did not occur among any of these patients during chemotherapy. In conclusion, PE is not frequent in childhood ALL. It usually does not cause cardiac impairment. It responds to treatment of leukemia.

Erythrocyte membrane protein defects in hereditary spherocytosis patients in Turkish population.

Hereditary spherocytosis (HS) is a congenital hemolytic anemia which is characterized by spherocytes in peripheral blood and increased osmotic fragility test. The disease is caused by defects in red cell membrane cytoskeleton. In this study, we investigated erythrocyte membrane protein defects in 50 Turkish HS patients and 42 controls. We used sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) to identify the protein defects causing HS. The patients were from 27 families (39 kindred and 11 unrelated patients). They were aged between 6 months and 53 years and the mean age was 18.75 (±14.70) years. Protein deficiencies related to HS were demonstrated in 42% of study group. There was not any statistically significant relation between the protein deficiency and hemoglobin levels. Isolated or combined spectrin deficiency was the most common protein abnormality among our patients. Spectrin deficiency was detected in 22% of cases (11/50), ankyrin deficiency in 8% (4/50), protein 4.2 deficiency in 8% (4/50), combined spectrin and protein 4.2 deficiency in 2% (1/50), combined spectrin and ankyrin deficiency in 2% (1/50). Fifty-eight percent of cases (29/50) showed normal protein contents.

Seroconversion status after single dose and double doses of varicella vaccination in children with leukemia.

Although varicella is a benign self-limiting disease in healthy children, it can be fatal when it occurs in immunocompromised hosts. Despite that immunosuppressed children are suggested to require 2 doses of vaccine to achieve seroconversion, conflicting results are reported in the literature. The aim of this study was to investigate the seroconversion status and mean antibody titers at first year after single dose and double doses of varicella vaccination in acute lymphoblastic leukemia patients. Patients with leukemia in remission for at least 1 year who were seronegative for varicella-zoster virus immunoglobulin G (IgG) were vaccinated. Titers above the cutoff level (0.65) were accepted as seroconversion. Seventeen patients were vaccinated with single dose whereas 24 patients were vaccinated with double doses. Mean prevaccination antibody titers were 0.56 ± 0.05 in patients with single dose and 0.51 ± 0.08 in patients with double doses (P > .05, Student t test). The mean antibody titers at first year were 0.61 ± 0.05 in patients with single-dose vaccination (P > .05, Wilcoxon signed-rank test) and 1.48 ± 0.04 in patients with double doses (P < .001, Wilcoxon signed-rank test). Seroconversion after single-dose vaccination was achieved in 29% of patients (n = 5/17) and in 75% of patients with double doses (n = 18/24) at first year (P = .004, chi-square test). These results suggest that seroconversion after single-dose vaccination might not persist at first year in malignancy patients. Double doses should be applied in order to provide long-term seroconversion.

Does hypereosinophilic syndrome precede common B acute lymphoblastic leukaemia in childhood? A case report.

Hypereosinophilic syndrome (HES) and the association of hypereosinophilia with acute lymphoblastic leukaemia (ALL) are both rare in children. Some acute myelogenous leukaemias can present with eosinophilia, but the relationship between HES and ALL is not well known and is rarer than the relationship between HES and acute myelogenous leukaemia. Patients are diagnosed with HES when no cause is found to explain the eosinophilia leading to end organ damage. For this reason, it is recommended that patients presenting with hypereosinophilia be carefully assessed to exclude any malignant clonal proliferation. HES may present with severe clinical manifestations such as high leucocyte count, anaemia, thrombocytopaenia, hepatosplenomegaly or cardiac and neurological involvement, all of which are primarily features of myeloproliferative disorders. Some patients with HES can develop chronic eosinophilic leukaemia. Successful treatment of HES with agents used in chronic myeloid leukaemia supports the idea that HES can be a chronic myeloid disorder. There are few cases reporting an association between ALL and hypereosinophilia that precedes or is concomitant with ALL. Here we report the case of a 14-year-old girl who developed common B ALL 7 months after diagnosis and treatment of HES. Interestingly, eosinophilia was not concomitant with the diagnosis of ALL.