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Background: Several disseminated intravascular coagulation (DIC) scoring systems are used for prognosticating the clinical outcomes of patients with DIC. However, research on children is scarce. Therefore, this study compared the clinical outcomes of overt and non-overt DIC using the International Society on Thrombosis and Hemostasis (ISTH) DIC scoring system. Methods: This retrospective study reviewed data on children aged one month to 15 years diagnosed with DIC between 2003 and 2014. Results: Of 244 patients, 179 (73.4%) had overt DIC, and 65 (26.6%) had non-overt DIC. The most common causes were infection (84.8%), tissue injury (7%), and malignancies (2.9%). The 28-day case fatality rate was significantly higher for overt than non-overt DIC (76% vs. 15.6%; P < 0.001). DIC scores were significantly associated with mortality (R² = 0.89). Each clinical parameter (platelet count, prothrombin time, and fibrin degradation products) was associated with mortality (P = 0.01). On multivariable analysis, the factors associated with death were platelet counts = 50 000 cells/mm³ (OR, 2.42; 95% CI, 1.08-5.42; P = 0.031); overt DIC score (OR, 7.62; 95% CI, 2.94-19.75; P < 0.001); renal dysfunction (OR, 2.92; 95% CI, 1.34-6.37; P = 0.007); shock (OR, 39.62; 95% CI, 4.99-314.84; P = 0.001); and acute respiratory distress syndrome (OR, 25.90; 95% CI, 3.12-214.80; P = 0.003). Conclusions: The 28-day case-fatality rate was significantly higher for patients with overt than non-overt DIC and concordant with ISTH scores. ISTH DIC scores can be used as a clinical predictor for DIC in children. [ABSTRACT FROM AUTHOR]

Background: 6‐Mercaptopurine (6‐MP) is considered the backbone of therapy in the maintenance phase of acute lymphoblastic leukemia (ALL). Gene polymorphisms involved in thiopurine degradation are predictors of toxicity in patients treated with 6‐MP. We investigated the effects of nucleoside diphosphate linked moiety X (nudix) type motif 15 (NUDT15) polymorphism NUDT15c.415C>T on neutropenia incidence, dose adjustment for 6‐MP, and survival rates in Thai children with ALL. Methods: Children diagnosed with ALL who received 6‐MP in the maintenance phase of treatment, in 2005–2016, were retrospectively enrolled. Results: The subjects consisted of 102 patients (median age, 5.2 years; 58 boys). On genetic testing 78, 22, and two patients were normal (CC), heterozygous (CT), and homozygous (TT), respectively. The incidence of neutropenia at 3 months was significantly higher in the CT/TT than CC polymorphism groups (OR, 12; 95%CI: 3.781–38.085, P < 0.001). The mean dose of 6‐MP at 3, 6, and 12 months was significantly lower in the CT/TT versus the CC group (P < 0.001). The 5 year overall survival (OS) rate for CC was 80.4%, and for CT/TT, 95.5% (P = 0.34). The 5 year event‐free survival (EFS) for CC and CT/TT was 75.1% and 85.7%, respectively (P = 0.17). After adjusted risk classification, no significant differences were observed for OS or EFS between the CC and CT/TT groups. Conclusion: Patients harboring the CT/TT polymorphism of NUDT15 had a significantly higher incidence of neutropenia during the first 3 months of maintenance, resulting in significantly lower doses of 6‐MP. [ABSTRACT FROM AUTHOR]

Retinoblastoma is the most common intraocular malignancy in children. The aim of this study was to investigate the efficacy and toxicity of combination ifosfamide, carboplatin, etoposide, and vincristine (ICEV) in advanced-stage pediatric retinoblastoma [International Classification of Retinoblastoma (ICRB) group D or E], and in ICRB group C in the second eye in simultaneously treated bilateral retinoblastoma. The medical records of retinoblastoma patients treated with concurrent ICEV regimen and focal therapy were retrospectively reviewed. The ICEV treatment protocol was, as follows: ifosfamide 1800 mg/m2 on Days 1–3; MESNA 600 mg/m2 on Days 1–3; carboplatin 560 mg/m2 on Day 1; etoposide 150 mg/m2 on Days 1–3; and vincristine 1.5 mg/m2 on Day 1. Of 16 retinoblastoma patients, 13 had bilateral disease. Seven first eyes in bilateral disease that were enucleated prior to ICEV therapy were excluded. Twenty-two eyes were finally included (six group C, six group D, and ten group E). Median follow-up was 3.4 years, and the median number of ICEV courses was 7. Fifteen globes could be salvaged, 12 responded to ICEV (six group C, five group D, and one group E), and three unresponsive eyes could be salvaged with external beam radiation therapy (EBRT). Enucleation-free and relapse-free survival was 68.2 and 54.5%, respectively. The results of this study suggest ICEV as an alternative therapeutic approach for globe salvage in pediatric retinoblastoma, especially in ICRB groups C and D with manageable acute toxicity. Further study in larger cohort is needed to confirm the effectiveness of treatment. [ABSTRACT FROM AUTHOR]

Purpose: Investigate antileukemic activity of artemisinins, artesunate (ART), and dihydroartemisinin (DHA), in combination with cytarabine, a key component of acute myeloid leukemia (AML) chemotherapy using in vitro and in vivo models.Methods: Using ten human AML cell lines, we conducted a high-throughput screen to identify antimalarial agents with antileukemic activity. We evaluated effects of ART and DHA on cell viability, cytotoxicity, apoptosis, lysosomal integrity, and combination effects with cytarabine in cell lines and primary patient blasts. In vivo pharmacokinetic studies and efficacy of single-agent ART or combination with cytarabine were evaluated in three xenograft models.Results: ART and DHA had the most potent activity in a panel of AML cell lines, with selectivity toward samples harboring MLL rearrangements and FLT3-ITD mutations. Combination of ART or DHA was synergistic with cytarabine. Single-dose ART (120 mg/kg) produced human equivalent exposures, but multiple dose daily administration required for in vivo efficacy was not tolerated. Combination treatment produced initial regression, but did not prolong survival in vivo.Conclusions: The pharmacology of artemisinins is problematic and should be considered in designing AML treatment strategies with currently available agents. Artemisinins with improved pharmacokinetic properties may offer therapeutic benefit in combination with conventional therapeutic strategies in AML. [ABSTRACT FROM AUTHOR]

The Thai Pediatric Oncology Group (ThaiPOG) has adapted treatment regimens from the Children's Oncology Group (COG) to enhance outcomes for childhood acute lymphoblastic leukemia (ALL). This study examined the risk factors and treatment results of pediatric ALL in Thailand. This multicenter study included newly diagnosed children (< 18 years) with ALL in 19 centers between January 1, 2015, and December 31, 2019. Most of the 1,157 patients (97.6%) were treated according to ThaiPOG protocols. The genetic testing was performed in 71% of patients. The patients were classified as standard (n = 539), high (n = 402), and very high (n = 130) risks. The 5-year event-free survival (EFS) and overall survival (OS) rates were 75% (95% confidence intervals (CI), 72%–77.8%) and 81.7% (95% CI, 78.9%–84.1%), respectively. The 5-year EFS rates of the standard-, high-, and very high-risk groups were 78.5% (95% CI, 74.1%–82.3%), 73.6% (95% CI, 68.5%–78%) (p = 0.761), and 65% (95% CI, 55.1%–73.3%) (p = 0.001), respectively, and the 5-year OS rates were 86.9% (95% CI, 83.1%–89.9%), 77.3% (95% CI, 72.5%–81.4%) (p = 0.001), and 73.1% (95% CI, 63.7%–80.4%) (p = 0.001), respectively. The independent risk factors for relapse and death were age ≥ 10 years, white blood cells (WBCs) ≥ 50,000/mm3, M2 or M3 marrow status at the end of induction, and high-risk group. The overall outcome of Thai pediatric ALL has improved after the implementation of new modified COG treatment protocols. High-risk characteristics of ALL increased adverse outcome risk. [ABSTRACT FROM AUTHOR]

Background: 6-Mercaptopurine (6-MP), a thiopurine agent, is a essential medication for treating pediatric acute lymphoblastic leukemia (ALL). However, its side effects of neutropenia and hepatotoxicity might interrupt treatment, resulting in poor outcomes. Inosine triphosphate pyrophosphatase (ITPA), an enzyme in the thiopurine pathway, may prevent the accumulation of toxic thiopurine metabolites. Studies on ITPA and thiopurine-associated toxicities are scarce. Methods: This study retrospectively investigated 1- to 15-year-old children with ALL who received 6-MP during the maintenance phase of treatment between 2000 and 2020. Toxicity during the first year of maintenance therapy and the mean dose of 6-MP were analyzed. Results: The 209 patients had a median age of 4.8 (0.3-14.8) years. Of these, 124 patients (59.3%) had wild-type ITPA, 73 patients (34.9%) had heterozygous ITPA 94C>A (hetITPA), and 12 patients (5.7%) had homozygous ITPA 94C>A (homITPA), with an allele frequency of 0.23. The incidence of neutropenia among ITPA polymorphisms did not significantly differ (P = 0.813). In patients harboring homITPA, transaminitis was more frequent than other polymorphisms but without a significant difference (P = 0.063). The mean dose of 6-MP for patients with homITPA was significantly lower than that for patients with hetITPA or wild-type ITPA (P = 0.016). Conclusions: HomITPA had a higher incidence of transaminitis and required a significantly larger dose reduction of 6-MP than wild-type ITPA. Further study is warranted to elucidate the effects of ITPA polymorphisms on toxicity in patients with ALL treated with 6-MP. [ABSTRACT FROM AUTHOR]

Background: Hemoglobin H disease (HbH), a hemoglobinopathy resulting from abnormal alpha globin genes, is classified into two categories: deletional HbH (DHbH) and nondeletional HbH (NDHbH). The alpha-mutation genotypes exhibit a range of clinical anemias, which differentially impact patient growth. Objectives: This retrospective study assessed the growth of HbH patients at Siriraj Hospital, Mahidol University. Methods: Patients diagnosed with HbH between January 2005 and April 2021 were analyzed using growth standard scores of the Thai Society for Pediatric Endocrinology (2022 version) and BMIfor- age Z scores of the World Health Organization. Growth failure was defined as a patient's height for age exceeding two standard deviations below the mean. Results: Of the 145 HbH patients, 75 (51.7%) had NDHbH, with --SEA/αCSα being the most common genotype (70 patients; 93.3%). The mean baseline hemoglobin level was significantly lower in NDHbH patients than in DHbH patients (8.16 ± 0.93 g/dL vs. 9.51 ± 0.68 g/dL; P < 0.001). Splenomegaly and growth failure prevalences were higher in NDHbH patients (37.3% vs. 0%, with P < 0.001, and 22.7% vs. 8.6%, with P = 0.020, respectively). Multivariable analysis revealed splenomegaly > 3 cm was associated with growth failure (OR = 4.28; 95% CI, 1.19-15.39; P = 0.026). Conclusions: NDHbH patients exhibited lower hemoglobin levels and more pronounced splenomegaly than DHbH patients. Growth failure can occur in both HbH types but appears more prevalent in NDHbH. Close monitoring of growth velocity is essential, and early treatment interventions may be required to prevent growth failure. [ABSTRACT FROM AUTHOR]

FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcomes. Although initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3-ITD-positive patients, subsequent relapse often occurs upon acquisition of secondary FLT3 kinase domain (KD) mutations, primarily at residues D835 and F691. Using biochemical assays, we determined that crenolanib, a novel TKI, demonstrates type I properties and is active against FLT3 containing ITD and/or D835- or F691 -activating mutations. Potent activity was observed in FLT3-ITD-positive AML cell lines. Crenolanib delayed the outgrowth of MV4-11 cells in a xenograft mouse model, whereas in combination with the type II TKI sorafenib, a significant decrease in leukemic burden (P < .001) and prolonged survival (P < .01) was observed compared with either type I or II TKI alone. Crenolanib was active against Ba/F3 cells harboring FLT3-ITD and secondary KD mutations and sorafenibresistant MOLM-13 cells containing FLT3-ITD/D835Y both in vitro and in vivo. In addition, crenolanib inhibited drug-resistant AML primary blasts with FLT3-ITD and D835H/Y mutations. These preclinical data demonstrate that crenolanib is effective against FLT3-ITD containing secondary KD mutations, suggesting that crenolanib may be a useful therapeutic agent for TKI-naive and drug-resistant FLT3-ITD-positive AML. [ABSTRACT FROM AUTHOR]

Background: Invasive fungal diseases (IFDs) are common and contribute to mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). The relative efficacies of posaconazole (POS) and fluconazole (FLU) as primary antifungal prophylaxes are uncertain. Methods: A retrospective study was performed on children treated with allogeneic HSCT who received POS or FLU during the early neutropenic period. The efficacies, safety, and tolerabilities of the prophylaxes were compared. Results: Data on 78 HSCT recipients were analyzed. Most had thalassemia (58%). Pre-engraftment, POS and FLU were administered to 41 and 37 cases, respectively. There were no proven cases of IFD. However, 2 POS cases and 1 FLU case had probable IFDs. The IFD incidences of the POS (5%) and FLU (3%) groups demonstrated no statistical difference (p = 0.620). Of the 75 surviving cases receiving FLU post-engraftment (including 39 cases previously given POS), 3 had proven IFDs whereas 3 had probable IFDs (total, 6 [8%]) within 1 year post-HSCT. No cases discontinued the prophylaxes due to drug intolerance. The common adverse events with POS and FLU were not significantly different. Only 19% of the patients achieved the therapeutic POS level, with a starting dose of 4 mg/kg thrice daily. Conclusion: POS and FLU demonstrate comparable levels of effectiveness, safety, and tolerability as IFD prophylaxes for neutropenic children treated with allogeneic HSCT. Determination of the optimum POS dose and duration requires larger studies. [ABSTRACT FROM AUTHOR]

Background: Retinoblastoma (RB) outcomes in Thailand are unfavorable compared to those of developed countries. This study aims to determine whether the clinical outcomes of patients with RB significantly improved after the implementation of new therapeutic approaches and which clinical factors affect survival and globe‐saving outcomes. Methods: The medical records of patients newly diagnosed with RB and treated at Siriraj Hospital between January 2005 and December 2018 were reviewed retrospectively. Clinical data, treatments, and outcomes were collected and analyzed. Results: In 194 eyes (144 patients), leukocoria was the most common presenting feature (76.8%); 129 (66.5%) eyes were staged in group E of the International Classification of Intraocular Retinoblastoma. Of the 149 enucleated eyes, 35 had high‐risk histopathological features, mostly choroidal invasion; 45 eyes (23.2%) could be salvaged. The 5‐year overall survival rate was 90.3%, an improvement compared to the previous study. The 5‐year enucleation‐free survival rates of Groups A and B, C, D and E were 100%, 83.1%, 36.7% and 16.6% respectively. Factors associated with a lower survival rate were interval from symptom onset to diagnosis >3 months (hazard ratio (HR): 5.8: 95% confidence interval (CI): 1.637, 20.579) and buphthalmos (HR: 12.57: 95% CI: 3.936, 40.153). Factors associated with high‐risk features were secondary glaucoma (HR: 11.016: 95% CI: 1.24, 98.10) and pseudohypopyon (HR: 14.110: 95% CI: 2.16, 92.05). Conclusions: Survival rates and globe‐saving rates appear to have improved; however, advanced‐stage presentation remains the major hindrance. Further studies with a larger cohort and longer follow‐up are warranted. [ABSTRACT FROM AUTHOR]

Background: Iron overload is a major complication of transfusion‐dependent thalassemia (TDT) and requires iron chelation (IC) therapy. However, a combination therapy may be required for patients responding poorly to monotherapy. Methods: Nine TDT patients previously treated with IC were enrolled; five patients were previously treated with deferasirox (DFX) twice daily. The dose of DFX was 20–40 mg/kg/day, while the dose of deferoxamine (DFO) was 18–40 mg/kg/day for 3–6 days/week. Results: At the 6‐ and 12‐month time points, six and eight patients demonstrated decreased serum ferritin levels, with median reductions of 707 ng/mL (range, 1,653–5,444 ng/mL) and 1,129 ng/mL (range, 1,781–7,725 ng/mL) compared to the baseline, respectively. Eight patients also had a reduced liver iron concentration (LIC), with a median reduction of 3.9 mg/g dry wt (range, 8.3–11.1 mg/g dry wt). Of the five patients treated with DFX twice daily, four responded to combination therapy. All responsive patients could finally stop DFO after the decline in LIC. Moreover, there were no treatment‐related complications. Conclusion: The combination of DFX and DFO proved to be effective and without significant toxicities for TDT patients who had been unresponsive to standard IC therapy. Further studies with a larger cohort size and long‐term follow‐up are warranted to elucidate the efficacy of the combination. [ABSTRACT FROM AUTHOR]

BACKGROUND: The effect of body mass index (BMI) on the treatment outcomes of children with acute myeloid leukemia (AML) is unclear and needs further evaluation. METHODS: Children with AML (n = 314) who were enrolled in 4 consecutive St. Jude protocols were grouped according to BMI (underweight, <5th percentile; healthy weight, 5th to 85th percentile; and overweight/obese, ≥85th percentile). RESULTS: Twenty-five patients (8%) were underweight, 86 patients (27.4%) were overweight/obese, and 203 patients (64.6%) had healthy weight. The 5-year overall survival rate of overweight/obese patients (46.5% ± 7.3%) was lower than the rate of patients with healthy weight (67.1% ± 4.3%; P < .001); underweight patients also tended to have lower survival rates (50.6% ± 10.7%; P = .18). In a multivariable analysis that was adjusted for age, leukocyte count, French-American-British classification, and study protocols, patients with healthy weight had the best survival rate among the 3 groups ( P = .01). When BMI was considered as continuous variable, patients with lower or higher BMI percentiles had worse survival ( P = .03). There was no difference in the occurrence of induction failure or relapse among BMI groups, although underweight and overweight/obese patients had a significantly higher cumulative incidence of treatment-related mortality, especially because of infection ( P = .009). CONCLUSIONS: An unhealthy BMI was associated with worse survival and more treatment-related mortality in children with AML. Meticulous supportive care with nutritional support and education, infection prophylaxis, and detailed laboratory and physical examination is required for these patients. These measures, together with pharmacokinetics-guided chemotherapy dosing, may improve outcome. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]