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Background: Methotrexate-induced toxicities often occur in pediatric ALL undergoing chemotherapy. Methotrexate is inhibiting folate metabolism so no DNA synthesis occurs. Folate deficiency can occur before and after administration of methotrexate high dose (MTX-HD). This also may affect the outcome of chemotherapy. However, there has been limited research on folate levels in blood during MTX-HD therapy and its correlation to toxicity. Objective: To analyze the correlation between folate levels and toxicity following high-dose methotrexate (MTX-HD) administration in pediatric patients with acute lymphoblastic leukemia (ALL). Methods: This prospective observational study included 31 pediatric ALL patients aged 1-18 years undergoing consolidation phase chemotherapy. Serum folate levels were measured before and after MTX-HD using CalSet Folate, and MTX-induced toxicities were observed within 48 hours postadministration. Data were analyzed using the Wilcoxon Signed Rank test and Spearman Correlation Test, with p<0.05 considered significant. Results: Thirty-one subjects were included, with a median age of 4 years. Median folate levels increased significantly from 23.5 ng/mL before to 40 ng/mL after MTX-HD (p<0.05). Common toxicities included mucositis (100%), neutropenia (45.2%), DILI (35.5%), and AKI (6.4%). No significant correlation was found between folate levels and these toxicities (p>0.05). Conclusion: Significant differences in folate levels were observed before and after MTX-HD. Despite high folate levels, MTX-induced toxicities still occurred, suggesting other factors may contribute to toxicity. [ABSTRACT FROM AUTHOR]

Children with transfusion-dependent thalassemia experience stressful conditions related to chronic anemia, repeated blood transfusions, and iron chelation adherence. They are vulnerable to emotional and behavioral problems and psychosocial disturbances. An observational evaluation of psychosocial issues in children with TDTs aged 4–18 using Strengths and Difficulties Questionnaires (SDQ). Psychosocial part in children with TDTs often experiences difficulties in childhood under 10 years old, compared to adolescents (11–18 years) for emotional symptoms and conduct problems. Boys and girls had similar psychosocial problems regarding emotional symptoms, conduct problems, hyperactivity-inatttention, peer relationship problems, and prosocial behavior. In a quarter of cases, they had emotional symptoms, conduct, and hyperactivity-inattention issues, especially in younger children. Interestingly, younger children have more problems than adolescence in peer relations even though they are still under strict parental supervision. Difficulties in emotion, conduct, and hyperactivity would affect their relationship life. Children may try to be accepted by their social environment (prosocial) even though they realize that there are problems in their emotional life and peer relationships. Regular screening of the psychosocial aspects should be followed by counseling because regular transfusion and iron chelation are necessary for long-term management. [ABSTRACT FROM AUTHOR]

A gastric ulcer arises due to an imbalance between the stomach's aggressive and defensive factors, one of which can be induced by ketorolac. The gastric mucosa serves as a protective layer against gastric damage. Probiotics may enhance mucosal secretion, reinforcing their barrier function. This study evaluated the effect of Lactiplantibacillus plantarum IS-10506 on repairing gastric mucosal injury expressed by Mucin 5AC (MUC5AC) induction from ketorolac in rodent model. In the experiment, 48 male Wistar rats were randomly assigned and segregated into four groups: the control group (K1), the group with ketorolac administration (K2), the group given L. plantarum IS-10506 after ketorolac administration (K3), and the group given L. plantarum IS-10506 before and after ketorolac administration (K4). Gastric tissue was examined for cells producing MUC5AC via immunohistochemistry. MUC5AC differences between groups were compared using Kruskal-Wallis and Mann-Whitney U tests. Significant differences were observed between each group on Days 5, 7, and 10 of necropsy (p=0.043; p=0.030; p=0.022). The ketorolac group (K2) consistently exhibited the lowest values during all examination days. Group K4 manifested a higher expression of MUC5AC relative to group K3. However, group K3 demonstrated a significantly increased from Day 1 to 10 of necropsy (p=0.030). Administering probiotic L. plantarum IS-10506 prior to ketorolac proved beneficial by significantly accelerate (p=0.030) the MUC5AC expression cells and gene expression. [ABSTRACT FROM AUTHOR]

Background: Transfusion-dependent thalassemia (TDT) necessitates regular transfusions, resulting in complications such as iron overload, hemolytic anemia, and the emergence of alloantibodies/autoantibodies. This situation poses challenges in obtaining compatible transfusions. Excessive iron and chronic hemolysis impact the elevation of Interleukin-6 (IL-6), initiating an inflammatory process that triggers hepcidin formation and influences antibody development. This study aims to analyze disparities in IL-6 and hepcidin levels and establish the correlation between IL-6 and hepcidin in TDT patients with and without alloimmunization/autoimmunization. Methods: Forty whole blood samples were collected from TDT patients with and without alloimmunization/autoimmunization, centrifuged, and the serum extracted, then stored in a refrigerator at -80°C. IL-6 and hepcidin levels were assessed using the ELISA method. The Mann-Whitney U test was employed to evaluate differences in hepcidin and IL-6 levels between the two groups. In contrast, the Spearman Correlation test was utilized to analyze the correlation between hepcidin and IL-6 levels. Results: IL-6 levels in the TDT group with alloimmunization/autoimmunization (3.64 pg/mL) were significantly higher compared to the TDT group without alloimmunization/autoimmunization (1.41 pg/mL; p < 0.05). Hepcidin levels in the TDT group with alloimmunization/autoimmunization (2,950.6 pg/mL) were significantly higher compared to the TDT group without alloimmunization/autoimmunization (1,599.6 pg/mL; p < 0.05). The Spearman correlation test revealed a significant positive correlation between hepcidin and IL-6 levels in TDT patients with alloimmunization/autoimmunization (r = 0.764; p = 0.000). Additionally, a significant positive correlation was observed between hepcidin and IL-6 levels in TDT patients without alloimmunization/autoimmunization (r = 0.559; p = 0.010). Conclusion: IL-6 and hepcidin levels were elevated in TDT patients with alloimmunization/autoimmunization compared to those without. Interleukin-6 and hepcidin exhibited a positive correlation in both transfusion-dependent thalassemia groups. [ABSTRACT FROM AUTHOR]

Background Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Emergency complications such as hyperleukocytosis can arise as the disease develops. Exchange transfusion is one of many cytoreductive modalities to resolve the condition. Objective To analyze the clinical and laboratory effects of exchange transfusion in childhood acute lymphoblastic leukemia patients with hyperleukocytosis. Methods This analytical retrospective cohort study with a preand post-test design used secondary medical record data. The obtained characteristics were the incidences of dyspnea, tachypnea, headache, intracranial bleeding, hepatomegaly, splenomegaly, lymphadenopathy, abdominal pain, fever, pallor, nausea/vomiting, and skin or mucosal bleeding; hemoglobin, white blood cell, and platelet counts; and serum potassium, sodium, calcium, phosphate, blood urea nitrogen, and creatinine levels. Results A total of 16 patients underwent exchange transfusion; they had significant reductions of the incidence of dyspnea, tachypnea, hepatomegaly, and pallor and significant improvement in the form of elevation of hemoglobin level and decrease in white blood cell counts (P<0.05 for all) compared to pre-treatment. The remainder of the variables were not significantly different between pre- and post-treatment, but a general decrease in all clinical manifestations except intracranial bleeding was observed. Conclusion Exchange transfusion has the beneficial effect of resolving hyperleukocytosis and its manifestations, although correction in laboratory outcomes that remained abnormal are still needed. [ABSTRACT FROM AUTHOR]

Background: Growth retardation is a long-term complication in pediatric transfusiondependent thalassemias (TDTs), presented as short-stature and upper body segment shortening. The cause of this condition was chronic hypoxia, iron overload, endocrinopathy, inadequate transfusion, and iron chelation. We analyze the relationship between ferritin level and growth status of pediatric TDTs. Methods: This was a cross-sectional study on pediatric TDTs aged 2-18 years old at Dr. Soetomo General Academic Hospital Surabaya, Indonesia conducted in 2020. They required blood transfusion every 2-4 weeks. We evaluated the ratio of upper/lower body segments, weight for age Z-score (WAZ), height for age Z-score (HAZ), and body mass index (BMI) Z-score, based on CDC growth chart as growth status parameters. Serum ferritin was checked every three months to determine iron overload and iron chelation (deferiprone, deferasirox and deferoxamine). We used Spearman correlation and Mann-Whitney U test to analyze between variables (a=0.05). Results: We enrolled 15/29 males with median age 10.5 years. Serum Ferritin had negative correlation with the ratio of upper/lower body segments (rho=-0.552; P=0.002), but not for HAZ (rho=-0.078; P=0.694), WAZ (rho=-0.186; P=0.342), BMI Z-score (rho=-0.089; P=0.653) especially if serum ferritin was above 2500 µ/L. In deferiprone group (n=8), the WAZ (P=0.034) and BMI Z-score (P=0.031) were lower; but the ratio of upper/lower body segments was greater (P=0.039) than the deferasirox group. Conclusion: Growth retardation was more visible in pediatric TDTs with high ferritin and in deferiprone group. The height and the ratio of upper/lower body segments of the body were more affected. [ABSTRACT FROM AUTHOR]

Introduction: Caspase-3 is a crucial mediator of the extrinsic apoptosis pathway. The role of caspase-3 for extrinsic apoptosis signalling is still a challenge and should be exploited in childhood ALL. This study aimed to compare the caspase-3 expression in the patient's bone marrow before and after the induction phase of chemotherapy in childhood ALL. It will also to correlate the mean difference in caspase-3 expression between ALL standard-risk and ALL high-risk patients. Methods: Seventeen newly diagnosed ALL subjects were enrolled in this study. Caspase-3 expression in bone marrow was assessed using flow cytometry and monoclonal antibodies. A T-test and a paired T-test were used to compare between groups. The correlation coefficient between ALL groups was evaluated using Spearman's test and linear regression with a significant p-value of 0.05. Results: The caspase-3 expression is higher after induction therapy. However, it showed an insignificant difference (16.56+12.91% vs 27.71+12.33%; p = 0.08, p > 0.05). The mean difference of caspase-3 in ALL high-risk groups was significantly higher than in ALL standard-risk groups with a positive correlation (p = 0.007, r = 0.756). Conclusion: The caspase-3 expression after induction phase chemotherapy was increased in all standard-risk and high-risk patients; other lymphoblast apoptosis markers need to be confirmed alongside caspase-3. [ABSTRACT FROM AUTHOR]

Introduction: L-asparaginase chemotherapy often causes hepatotoxicity and affects complete remission in pediatric acute lymphoblastic leukemia (ALL). This study aims to investigate the risk factors that affect the incidence of hepatotoxicity caused by L-asparaginase chemotherapy in ALL children. Methods: An observational study with prospective sampling was conducted at Dr. Soetomo Hospital, Surabaya. The inclusion criteria included ALL children aged 1-18 years, undergoing ALL Induction phase chemotherapy based on the 2018 Indonesian Children's ALL protocol as evidenced by bone marrow aspiration, receiving L-asparaginase chemotherapy, and obtaining written consent from parents or guardians. Each child had 3 ml of blood drawn from a peripheral vein to assess their complete blood count, alanine transaminase (ALT) levels, and albumin level. Results: Thirty-two children with ALL were collected. Two of them were excluded due to allergic reaction and enable to continue the L-asparaginase chemotherapy. Thirty of them were eligible participants. Approximately 53.3% of ALL children aged ≤ seven years. Fourteen (47%) children with ALL were included in the standard-risk group and 16 (53%) of them included high-risk group. There were significant differences in ALT levels between the four stages of observation (p=<0.001). Twenty-two ALL children had hepatotoxicity (73.3%), while 8 had non-hepatotoxicity (26.7%). Two risk factors had a significant influence on the occurrence of hepatotoxicity due to L-asparaginase chemotherapy including age and hypoalbuminemia (p=0.045, p=0.028). Conclusion: Age and hypoalbuminemia were the risk factors that might affect the incidents of hepatotoxicity. Clinical monitoring before and after treatment needs to be done to prevent poor outcomes. [ABSTRACT FROM AUTHOR]

Background: Mortality due to Infection associated therapy in acute lymphoblastic leukemia (ALL) children remains high, although therapeutic success and survival rate are substantially improving. Methods: This study used a pre and post-test group design for children aged less than 18 years with ALL newly diagnosed and receiving chemotherapy in pediatric patient of Dr. Soetomo hospital Surabaya. Results: The study involved 25 subjects, 10 subjects were male, average age ranged from 3 to 9 years. The high risk-ALL subjects were 15 (60%), hyperleukocytosis 4 (16%) subjects and 7 (28%) subjects with leukopenia. Statistical analysis showed a significant difference in decreasing cortisol levels in week-4 compared to week-0 (p <0.001) and an increased in cortisol levels between week-12 compared to week-10. The incidence of infection during induction phase is higher than the consolidation phase (40vs15). The relationship between the mean cortisol levels and the incidence of infection in general showed a significant difference in the induction phase of week-0 (p=0.029), week-4 (p=0.041), and week-6 (p=0.005). Conclusion: In the induction phase, there is an association between mean cortisol levels and the risk of infection, but there is no such association in the consolidation phase. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze the diagnostic value of mid regional proadrenomedullin as a sepsis biomarker in pediatric patients with cancer-related chemotherapy. This cross-sectional observational study was located in General Hospital Dr. Soetomo Surabaya from September until December 2020. International Pediatric Sepsis Consensus Conference criteria was used to define sepsis term on 2 study groups. Serum mid regional proadrenomedullin has been drawn from 60 subjects (41 in-ward pediatric patients) and measured on sandwich enzyme-linked immunosorbent assay from Elabscience® Human Mid Regional Proadrenomedullin. Humareader Single Plus® was used to measure the optical density. ROC analysis was used to find out cut off value, sensitivity, specificity, positive predictive value, negative predictive value, negative likelihood ratio, positive likelihood ratio, and accuracy, respectively. Statistics declared significant if p<0.05 (95% CI). Between groups, temperature and heart rate were statistically different (p<0.001; 95% CI). The median difference of mid regional proadrenomedullin between groups was significant (p<0.05; 95% CI). Cut off value 2,88 nmol/L, sensitivity 60.0%, specificity 56.67%, positive predictive value 58.06%, negative predictive value 58.62%, positive likelihood ratio 1.38, negative likelihood ratio 0.71 and diagnostic accuracy 59.33% was obtained while area under curve was 0.707, respectively. Sepsis in children with cancer -related chemotherapy has not well diagnosed by serum mid regional proadrenomedullin. [ABSTRACT FROM AUTHOR]

Background: Hyperglycemia is a recognized side effect of the corticosteroids and asparaginase given during induction chemotherapy for pediatric acute lymphoblastic leukemia (ALL). The ALL is the malignant tumor with the highest incidence in the childhood. The aim of this study is to investigate the impact of hyperglycemia during induction chemoteraphy in childhood ALL. Methods: This prospective study was done in Dr. Soetomo hospital from January to April 2018. The subject was newly diagnosed as ALL under the age of 18 years, treated with Indonesian childhood ALL 2013 protocol (Standard Risk (SR) group and High Risk (HR) group). Hyperglycemia was defined as at least two separate random plasma glucose levels > 200 mg/dL, which was evaluated before and during induction chemotherapy. Statistical analysis using Paired T-test for parametric and Wilcoxon Test for nonparametric. Results: Thirty-three children were enrolled, 18/33 boys with mean age 5.8 (SD 3.78) years, compromised as ALL-L1 30/33. They were treated with ALL-HR 19/33 and ALL-SR 14/33. In overall groups, the mean random blood glucose level significantly increased from 108 (SD 21.3) mg/dL to 147 (SD 48.1) mg/dL, (mean difference 38.67 mg/dL; 95% CI 18.08 to 59.26 mg/dL, P=0.008). In SR group, there was a significant increased of mean random blood glucose level from 102 (SD 13.5) mg/dL to 133 (SD 37.3) mg/dL, (mean difference 31.8 mg/dL; 95% CI 8.78 to 54.8 mg/dL; P=0.01). In HR group, the mean random blood glucose level increased from 113 (SD 51.9) mg/dL to 165 (SD 25.4) mg/dL, (mean difference 51.9 mg/dL; 95% CI 18.6 to 85.2 mg/dL, P=0.004). Conclusion: Blood glucose level is significantly increase during induction chemotherapy in both SR and HR Indonesian childhood ALL 2013 protocol. [ABSTRACT FROM AUTHOR]

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Background: The frequency of the beta-thalassemia (β-thalassemia) gene in Indonesia ranges from 3 to 10%. However, in the East Java province, there is still limited information on the prevalence of β-thalassemia mutations in clinically diagnosed beta-thalassemia patients of East Java. Therefore, this study aimed to characterize β-thalassemia mutations in selected patients in the East Java province of Indonesia., Methods: This is an analytical observational study. Diagnosis of β-thalassemia was based on clinical presentation, complete blood count (CBC), and hemoglobin (Hb) electrophoresis. Blood specimens taken from each patient in three ethylenediaminetetraacetic acid (EDTA) tubes were analyzed for CBC and Hb electrophoresis and processed for DNA extraction and subsequent polymerase chain reaction (PCR). Detection of mutations in Hemoglobin Subunit Beta (HBB) gene exons 1-3 of the β-thalassemia gene as the common mutation in Indonesia was done using PCR followed by Sanger sequencing., Results: In total, 33 ( n = 33) participants were involved in this study with ages ranging from 5 to 17 years comprising 19 women and 14 men. Their ethnic origins were Javanese ( n = 30) and Chinese ( n = 3). CBC results showed that mean ± standard deviation (SD) for Hb, red blood cell (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW)-CV were 81.2 ± 7.0 g/L; 3.40 ± 0.39 × 10 9 /L; 71.05 ± 5.72 fL; 24.12 ± 2.45 pg; 33.91 ± 1.47 g/dl; 24.38 ± 6.02%, respectively. Hb electrophoresis revealed that 5 out of 33 participants had beta-thalassemia and 28 out of 33 participants had hemoglobinopathy (Hb) E/beta-thalassemia. Results of Sanger sequencing showed the following genotype variations in the samples: 12 (36.4%) with β CD 26 / β IVS - I -5 ; 6 (18.2%) with β CD 26 / β CD 35 ; 3 (9.1%) with β CD 26 / β IVS - I -2 ; 2 (6.1%) with β CD 27/28 / β CD 40 ; 2 (6.1%) with β IVS - I -1 / β CAP +1 ; and β CD 26 / β IVS - I -1 ; β IVS - I -5 / β CAP +1 ; β IVS - I -5 / β CD 35 ; β CD 26 / β CD 37 ; β CD 26 / β CD 15 ; β CD 26 / β CD 40 ; and β IVS - I -5 / β CD 19 in 1 (3%) sample, respectively, and 1 (3%) had no abnormality detected in sequencing even though electrophoresis showed abnormality in the migration pattern. The β CD 26 / β IVS - I -5 mutation was found in samples that were noted to have Hb E/beta-thalassemia on Hb electrophoresis., Conclusion: The underlying genetic variations are heterogeneous in thalassemia patients in East Java, where 12 variants were found. The most common variant was β CD 26 / β IVS - I -5 , which all accounted for Hb E/beta-thalassemia on Hb electrophoresis. Furthermore, 28 out of 33 participants had hemoglobinopathy (Hb) E/beta-thalassemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor ZAL declared a past co-authorship with the author NY., (Copyright © 2022 Hernaningsih, Syafitri, Indrasari, Rahmawan, Andarsini, Lesmana, Moses, Abdul Rahim and Yusoff.)

Background: Overexpression of the antiapoptotic protein Bcl-2 causes apoptosis to stop and conversely the increased expression of the proapoptotic protein Bax makes lymphoblasts easy to destroy. The Bax/Bcl-2 ratio plays a role in the balance of apoptosis, immortality, resistance, and outcome of chemotherapy. We analyzed the relationship between the Bax/BCl-2 ratio and the outcome of induction phase chemotherapy in pediatric Acute Lymphoblastic Leukemia (ALL)., Methods: This research was conducted with a prospective observational study on pediatric ALL aged 1-18 years who were newly diagnosed based on bone marrow aspiration (morphology and immunophenotyping) at Dr. Soetomo General Hospital, Surabaya on October 2020 to March 2021. Expression of Bcl-2, Bax, and Bax/Bcl-2 protein ratio was measured by the flow cytometry method from lymphoblast on bone marrow aspirate samples before and after induction phase chemotherapy according to the 2018 Childhood ALL Indonesian Protocol. The outcomes evaluated were survival and remission rate (lymphoblasts in the bone marrow less than 5%). We used the Mann-Whitney U test and Wilcoxon Signed Rank test to analyze the differences between protein expression with p<0.05 for a two-tailed test., Results: We included 17/26 pediatric ALL, consisting of 88% male, 94% LLA-L1, 76% B cell ALL and 24% T cell ALL. Mean expression of Bax, Bcl-2, and Bax/Bcl-2 protein ratio before chemotherapy among pediatric ALL who alive (N=11) and dead (N=6) were not significantly different (p>0.05). All children who completed the induction phase of chemotherapy went into remission. Bax and Bcl-2 expression before and after chemotherapy showed no difference (p>0.05). The Bax/Bcl-2 ratio increased from 1.74(SD 1.846) to 6.17(4.139) with p=0.021., Conclusion: Expression of Bax, Bcl-2, and Bax/Bcl-2 protein ratio at the beginning of diagnosis did not affect the survival of pediatric ALL after the induction phase of chemotherapy. The Bax/Bcl-2 protein ratio increased 3.5 times in pediatric ALL with remission outcomes, indicating proapoptotic dominance.

Background: Daunorubicine, a type of anthracycline, is a drug commonly used in cancer chemotherapy that increases survival rate but consequently compromises with cardiovascular outcomes in some patients. Thus, preventing the early progression of cardiotoxicity is important to improve the treatment outcome in childhood acute lymhoblastic leukemia (ALL)., Objective: The present study aimed to identify the risk factors in anthracycline-induced early cardiotoxicity in childhood ALL., Methods: This retrospective study was conducted by observing ALL-diagnosed children from 2014 to 2019 in Dr. Soetomo General Hospital. There were 49 patients who met the inclusion criteria and were treated with chemotherapy using Indonesian Childhood ALL Protocol 2013. Echocardiography was performed by pediatric cardiologists to compare before and at any given time after anthracycline therapy. Early cardiotoxicity was defined as a decline of left ventricle ejection fraction (LVEF) greater than 10% with a final LVEF < 53% during the first year of anthracycline administration.  Risk factors such as sex, age, risk stratification group, and cumulative dose were identified by using multiple logistic regression. Diagnostic performance of cumulative anthracycline dose was evaluated by receiver operating characteristic (ROC) curve., Results: Early anthracycline-induced cardiotoxicity was observed in 5 out of 49 patients. The median cumulative dose of anthracycline was 143.69±72.68 mg/m2. Thirty-three patients experienced a decreasing LVEF. The factors associated with early cardiomyopathy were age of ≥ 4 years (PR= 1.128; 95% CI: 1.015-1.254; p= 0.001), high risk group (PR= 1.135; 95% CI: 1.016-1.269; p= 0.001), and cumulative dose of ≥120 mg / m2 (CI= 1.161; 95% CI:1.019-1.332)., Conclusion: Age of ≥ 4 years, risk group, and cumulative dose of ≥120 mg/m2 are significant risk factors for early cardiomyopathy in childhood ALL.