Serum Adipokines as Biomarkers for Surveillance of Metabolic Syndrome in Childhood Acute Lymphoblastic Leukemia Survivors in Low Middle-Income Countries.

BACKGROUND: Serum adipokines (leptin and adiponectin) are dysregulated before the onset of metabolic syndrome and hence may be useful biomarkers for screening of cardiometabolic late effects in childhood Acute Lymphoblastic Leukemia (cALL) survivors. METHODS: We compared serum adipokine levels between 40 cALL survivors (aged 10-18 years, >2 years from treatment completion) with similar controls. A multivariable logistic regression analysis was then done to assess the association of metabolic syndrome in cALL survivors with variables including adipokines and other metabolic parameters, demographic and treatment details, and Dual-energy X-ray absorptiometry scan-derived variables. RESULTS: Compared to controls, cALL survivors had a higher prevalence of metabolic syndrome (8/40 vs. 2/40, P = .044) and central obesity (11/40 vs. 4/40, P = 0.042). Median Serum Leptin (7.39 vs. 4.23 ng/ml, P = 0.207) levels and derived Leptin-Adiponectin Ratio (1.44 vs. 0.80, P = 0.598), were higher but not statistically different in our survivors compared to controls; Adiponectin levels were similar (6.07 vs. 5.01 µg/ml, P = 0.283). In the cALL survivors, overweight/obesity (odds ratio [OR] 21.9, P = 0.020) or higher Leptin levels (OR 1.11, P = 0.047), were independently associated with metabolic syndrome. CONCLUSIONS: Serum Leptin, independently predictive of metabolic syndrome in our cALL survivors, may be tested in larger studies to assess its utility in surveillance and initiation of early preventive measures.

Safety of Procalcitonin Guided Early Discontinuation of Antibiotic Therapy among Children Receiving Cancer Chemotherapy and Having Low-Risk Febrile Neutropenia: A Randomized Feasibility Trial (ProFenC Study).

In low-risk febrile neutropenia (LR-FN), the safety of early discontinuation of empiric antibiotics without marrow recovery is not well established. This study aimed to evaluate the safety of procalcitonin (PCT) guided early discontinuation of antibiotics in LR-FN. In this trial, children with LR-FN with an afebrile period of at least 24 h, sterile blood culture, and negative/normalized PCT were randomized at 72 h of starting antibiotics into two groups: intervention arm and standard arm. The antibiotics were stopped in the intervention arm regardless of absolute neutrophil count (ANC), while in the standard arm, antibiotics were continued for at least 7 days or until recovery of ANC (>500/mm3). The primary objective was to determine the treatment failure rates, and the secondary objective was to compare the duration of antibiotics and all-cause mortality between the two arms. A total of 46 children with LR-FN were randomized to either the intervention arm (n = 23) or the standard arm (n = 23). Treatment failure was observed in 2/23 (8.7%) of patients in the intervention arm compared to 1/23 (4.3%) in the standard arm [RR: 2 (95% CI: 0.19-20.6); p = 0.55]. The median duration of antibiotics in the intervention arm and standard arm were 3 days vs 7 days (P= <0.001). There was no mortality in this study. PCT-guided early discontinuation of empirical antibiotics in LR-FN is feasible. There was no significant difference observed in treatment failure between the early discontinuation of antibiotics vs standard therapy. The total duration of antibiotic exposure was significantly lesser in the discontinuation arm. Further, larger multicenter studies are needed to confirm the finding of this study.

Efficacy and safety of zinc in the prevention of oral mucositis in children with cancer receiving intensified chemotherapy: A randomized double-blind placebo-controlled trial.

BACKGROUND AND AIMS: A limited number of safe and effective preventive options for oral mucositis (OM) are available. This randomized, double-blind, placebo-controlled trial aimed to evaluate the efficacy and safety of zinc in preventing OM in children with cancer receiving intensified chemotherapy. METHODS: Children aged 3-18 years were randomized to receive oral zinc at 1 mg/kg/dose daily for 14 days or a placebo at the same doses and schedule. The primary outcome of this study was to determine the effect of oral zinc in the prevention of OM, and secondary outcomes included any adverse effect of oral zinc, the severity and duration of OM, and the need for hospitalizations. RESULTS: A total of 90 children were randomized to either the oral zinc (n = 44) or placebo group (n = 46). The incidence of OM in the zinc group was 20.5%, while that in the placebo group was 19.6% (p = .91; risk ratio: 1.04, 95% CI 0.45-2.30). There were no significant adverse events of the drug observed. There were no significant differences between the two groups in the severity (p = .79), the mean time of onset (p = .09), the mean duration of OM (p = .18), and the need for hospitalizations (p = 1.0). CONCLUSIONS: Among children on cancer chemotherapy, there was no decrease in the incidence of OM observed with oral zinc at a dose of 1 mg/kg/day. No significant adverse events were observed with administering oral zinc. Further research is warranted to test higher doses of oral zinc with longer duration for a clinically significant effect.

Effect of Imatinib Mesylate on Growth in Pediatric Chronic Myeloid Leukemia: A Systematic Review and Meta-analysis.

The outcomes of pediatric chronic myeloid leukemia (CML) have improved with the use of imatinib mesylate (IM). Multiple reports of growth deceleration with IM have raised concerns, necessitating careful monitoring and evaluation in children with CML. We systematically searched the databases of PubMed, EMBASE, Scopus, CENTRAL, and conferences-abstracts, reporting the effect of IM on growth among children with CML, and published in the English language from inception till March 2022. For observational studies, the modified Newcastle Ottawa Scale was used to assess the risk of bias. Pooled estimates were derived using a random-effects meta-analysis, and heterogeneity was assessed using Cochrane Q statistic test of heterogeneity and I2 statistic. Of the 757 studies identified through electronic search, 15 (n=265) were included in the final analysis. Six studies (n=178) were included in the meta-analysis of the primary outcome. There was a significant deleterious effect of IM on height-standardized mean difference (SMD): -0.52 (95% CI: -0.76; -0.28) ( I2 =13%). The adverse effect of IM on height was significant among studies with a follow-up period <3 years [SMD: -0.66 (95% CI: -0.93, -0.40), I2 =0%, P =0.59] but not in studies with follow-up period ≥3 years [SMD: -0.26 (95% CI: -0.63, 0.11), I2 =0, P =0.44], indicating that the effect of IM on height is a short-term effect. The effect of IM on height was not dependent upon pubertal status at the initiation of therapy. Prospective studies with adequate sample size are required to confirm the findings of the effect of IM on height in children with CML.

Efficacy and Safety of Olanzapine for the Prevention of Chemotherapy-induced Nausea and Vomiting in Children: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Chemotherapy-induced nausea and vomiting (CINV) remain the most distressing event in patients receiving highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC). This meta-analysis was conducted to evaluate the efficacy and safety of olanzapine containing regimen in preventing CINV in children on HEC and MEC. We searched PubMed, Embase, and Cochrane central register of controlled trials electronic databases to identify randomized clinical trials that compared 2 groups who either got olanzapine (olanzapine group) or placebo/no olanzapine (control group) for the prevention of CINV in children. The primary outcome was to determine the efficacy of olanzapine (complete response). The secondary outcomes were nausea control, the need for rescue medications, and adverse events of olanzapine. Three randomized clinical trials (n=394 patients) were included in this meta-analysis (olanzapine group, n=194, and placebo/control group, n=200). The pooled analysis of this meta-analysis found that olanzapine had a higher complete response in all phases of emesis in the HEC group and only in the acute phase in HEC/MEC groups compared with the control group. Olanzapine had higher nausea control in all phases of HEC but no nausea control in HEC/MEC. Olanzapine also reduced the need for rescue medications. A significant number of patients in the olanzapine group experienced somnolence (grades 1 and 2), but none of the participants discontinued the study due to side effects. In conclusion, this meta-analysis showed that olanzapine significantly prevented CINV in HEC. There was also a lesser need for rescue medications in the olanzapine group. Somnolence was higher in the olanzapine group, but it was clinically insignificant.

Efficacy and safety of vemurafenib in Langerhans cell histiocytosis (LCH): A systematic review and meta-analysis.

Almost half of the patients with Langerhans cell histiocytosis (LCH) are refractory to primary induction chemotherapy or undergo reactivation. The ideal treatment modality for refractory/relapsed LCH is yet not evidenced. This review aimed to determine the efficacy and safety of vemurafenib (a BRAF pathway inhibitor) in LCH, particularly the refractory/relapsed cases. The literature search was conducted using PubMed, Embase, CENTRAL, and abstracts published in the SIOP meetings. Studies that described the outcome of patients of LCH being treated with vemurafenib, alone or in combination, were included. A total of 416 studies were screened, and after applying exclusion criteria, 22 studies (n = 107) were included in the final analysis. The first-line therapy was prednisolone plus vinblastine for most patients (n = 92, 86%), and vemurafenib was started upfront in 3 patients (3%). The median time to first clinical response with vemurafenib was one week. The median time to best response was 5.25 months. Out of 107 patients, 62 patients (58%) had ultimately no active disease (NAD) while 39 (36%) had active disease better (ADB), making the overall response rate (ORR) of 101/107, ie, 94.4% (CI 0.88; 0.98). The main adverse effects of vemurafenib were rash or photosensitivity (47%) and other cutaneous adverse events (15%). Vemurafenib is highly efficacious and safe in the treatment of refractory LCH; however, the timing of its commencement and duration of therapy is yet to be established. Larger prospective collaborative trials are needed to answer the appropriate treatment duration and effective maintenance therapy approach.

A Pilot Randomised Controlled Trial Examining the Benefit of a Neutropenic Diet for Children Undergoing Cancer Treatment.

Neutropenic diet(ND) has been hypothesized to decrease the rate of febrile neutropenia(FN) occurring post-chemotherapy for pediatric cancers. Despite widespread use, it has not shown to be of benefit by randomized controlled trials(RCT) in western countries. No RCT has been conducted in India/LMIC to evaluate its efficacy against the standard Indian diet. Forty-two(42) children, aged 3-14 y, with cancer, scheduled to receive strongly myelosuppressive chemotherapy were randomized to receive either neutropenic diet(n = 21) or standard Indian diet(n = 21) for one chemotherapeutic cycle. FN rate was recorded as the primary outcome while the focus of infection, antibiotic length, the requirement for hospital admission, adherence to diet were the secondary outcomes. The groups were similar in baseline characteristics. Twelve patients (57%) in the neutropenic diet and nine patients(43%) in the standard diet arm developed FN. Patients in ND-arm had significantly higher chance of getting neutropenic enterocolitis(NEC) (33.33% vs 4.76% p = 0.044). Mortality (14.29%vs 0%, p = 0.23) and requirement for admission (47.6%vs 19.05%, p = 0.06), was more in the ND-arm but statistically non-significant. There was no significant difference in antibiotic length. Adherence was similar in both groups (95% vs 98%). Neutropenic diet was not effective in reducing FN rate and was associated with higher rate of NEC when compared to the standard diet.

Neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia: Experience from a tertiary care center in India.

BACKGROUND: Data of neurocognitive deficits in survivors of acute lymphoblastic leukemia (ALL) is scarce from low middle-income countries (LMICs), and is influenced by biological and cultural variations. The objective of this study was to assess the prevalence and spectrum of neurocognitive deficits in a cohort of survivors from India. PROCEDURE: Seventy survivors of childhood ALL were evaluated for neurocognitive deficits by the Indian adaptation of Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IVINDIA ). The prevalence of neurocognitive deficits was calculated based on the full-scale intelligence quotient (FSIQ), and scores in discrete domains like verbal comprehension, perceptual reasoning, working memory, and processing speed were calculated and compared to demographics, treatment, and sociocultural factors. RESULTS: The mean (SD) current age and time since diagnosis was 10.5 (±3.2) years and 5 (±2.8) years, respectively. The mean FSIQ was 86.1 ± 20.5, with significant neurocognitive deficit (FSIQ <90) being prevalent in 50% (95% CI: 38%-62%) of the cohort. The proportion of survivors with deficits in individual domains of verbal comprehension, perceptual reasoning, working memory, and processing speed were 49%, 50%, 47%, and 44%, respectively. The odds of having neurocognitive deficits were higher when a child belonged to lower socioeconomic strata (OR 5.7, p = .004), parents with lower education attainment (OR 4.3, p = .041), and whose birth order was higher (OR 20.1, p = .005). Age at diagnosis/assessment, chemotherapy received, or dose of radiotherapy did not have a direct impact on neurocognition. CONCLUSIONS AND RELEVANCE: Rates of neurocognitive deficits are higher in survivors in LMICs, with socioeconomic variables contributing more than the direct neurotoxic effects of treatment.

Outcome and prognostic factors in childhood B non-Hodgkin lymphoma from India: Report by the Indian Pediatric Oncology Group (InPOG-NHL-16-01 study).

The literature on B-non-Hodgkin lymphoma (NHL) in India is restricted to individual hospital data. The study aimed to evaluate the epidemiology and outcome of B-NHL in our country. One hundred and ninety-one patients of B-NHL from 10 centers diagnosed between 2013 and 2016 were analyzed retrospectively. B/T lymphoblastic lymphoma and patients with inadequate data were excluded. The median age was 88 months (IQR: 56, 144) with an M:F ratio of 5.6:1. Undernourishment and stunting were seen in 36.5% and 22%. Primary site was abdomen in 66.5%. Hypoalbuminemia was noted in 82/170 (48.2%). Histological subtypes: Burkitt lymphoma (BL): 69.6%, Burkitt-like: 10.4%, and diffuse large B cell lymphoma (DLBCL): 13.6%, unclassified and others (6.4%). Stage distribution: I/II, 33 (17.3%), III, 114 (59.7%), and IV, 44 (23%). One-eighty-six patients took treatment. Protocols used were LMB and BFM in 160/186 (86%). At a median follow-up of 21.34 (IQR: 4.34, 36.57) months, the disease-free-survival (DFS) was 74.4% and event-free-survival (EFS) was 60.7%. Treatment-related mortality (TRM), relapse/progression and abandonment were 14.3%, 14.5%, and 8.4%, respectively. Bone marrow positivity, stage IV disease, and lactate dehydrogenase (LDH) > 2,000 U/l predicted inferior EFS. Stage IV disease, LDH > 2,000 U/l, bone marrow positivity, tumor lysis syndrome and low albumin predicted TRM; LDH retained significance on multivariate analysis for EFS and TRM [OR: 4.54, 95% CI: 1.14-20, p 0.03; OR 20, 95%CI: 1.69-250, p 0.017]. BL was the main histological subtype. High TRM and relapse/progression are hampering survival. An LDH > 2,000 U/l was adversely prognostic. These data demonstrate a need to develop a national protocol that balances toxicity and potential for cure.

A review of the clinical applications of ketamine in pediatric oncology.

Ketamine is a dissociative anesthetic agent with excellent analgesic properties and a favorable safety profile. The feasibility and efficacy of various routes of administration have been established, including intravenous (IV), intramuscular (IM), oral, intranasal, rectal, and transdermal routes. The advent of newer anesthetic agents has led to a decline in the use of ketamine as an anesthetic, but its utility in short-term sedation and analgesia has expanded. Its value for chronic pain management in children with cancer is being increasingly recognized but requires more evidence. The use of topical ketamine is largely in investigational stages. Medical use of ketamine is, to a great extent, free from significant long-term neurological side effects. The objective of this review is to provide a brief account of the pharmacology of ketamine and primarily focus on the clinical applications of ketamine in pediatric oncology.

Clinical presentations and outcomes of children with cancer and COVID-19: A systematic review.

Information regarding the novel coronavirus disease (COVID-19) in pediatric oncology is limited. We conducted a systematic review of the available published literature on children with cancer affected by COVID-19. The last date of the study search was October 20, 2020, and 33 studies comprising 226 children were included for the final analysis. Data were extracted in a predefined data collection form, and the variables were extracted and analyzed. Patients with hematological malignancies were more in number. Males and children on intensive treatment were more frequently affected. Fever was the commonest symptom. The disease was asymptomatic/mild in 48% and severe in 9.6%. Consolidation, peribronchial cuffing, and consolidation with ground glass opacities were the common imaging findings. Hydroxychloroquine was the most frequently used drug for COVID-19. About 10% of children required intensive care, and about 32% had oxygen requirements. The percentage of children who died due to COVID-19 was 4.9%. The severity, morbidity, and mortality of COVID-19 in pediatric oncology were more compared to the general pediatric population. This information can help in risk stratification for the management of COVID-19.

Tumefactive demyelination in pediatrics: An unusual late neurological complication of hematopoietic stem cell transplant.

Immune-mediated demyelination is a rare posttransplant complication. Here, we report an 8.5-year-old boy who developed left hemiparesis, 18 months post matched sibling donor hematopoietic stem cell transplant (HSCT) for relapsed acute myeloid leukemia and was diagnosed to have tumefactive demyelination. The diagnosis was established based on clinical and radiological features. The complete resolution of the lesions with steroids further established the immune-mediated pathophysiology.

Ketamine mouthwash versus placebo in the treatment of severe oral mucositis pain in children with cancer: A randomized double-blind placebo-controlled trial.

BACKGROUND AND AIMS: Oral mucositis (OM) is a common and distressing toxicity in children on chemotherapy. There are a limited number of safe and effective therapeutic options available for OM. Ketamine oral rinse has shown promising results in a few studies in adults. This randomized, double-blind placebo-controlled trial aimed to test the efficacy of ketamine mouthwash in reducing chemotherapy-induced severe OM pain in children. METHODS: Children aged 8-18 years with severe OM were randomized to a single dose of ketamine mouthwash (4 mg/mL solution; dose 1 mg/kg) or a placebo. A sample size of 44 patients was determined. Pain score (6-point faces scale) was noted at baseline and 15, 30, 45, 60, 120, 180, and 240 min. The outcome variables were a reduction in pain score, need for rescue medications, and adverse events. RESULTS: The baseline characteristics were comparable in the two groups. The mean OM pain at 60 min decreased by 1.64 points (CI 1.13-2.14) in the ketamine group and 1.32 points (CI 0.76-1.87) in the placebo group (P = 0.425), with a group difference of 0.32 points. Rescue pain medication (at 60 min) was required in 13.6% in the ketamine group and 18.2% in the placebo group (P = 1.000). No significant adverse events were observed. CONCLUSIONS: Among children on cancer chemotherapy with severe OM, ketamine mouthwash at a dose of 1 mg/kg did not significantly reduce OM pain. It did not decrease the need for rescue pain medications. Further research is warranted to test higher doses of ketamine for a clinically significant effect.

Outcomes of juvenile myelomonocytic leukemia patients after sequential therapy with cytarabine and 6-mercaptopurine.

Juvenile myelomonocytic leukemia(JMML) is a pediatric myeloproliferative disorder. Allogeneic hematopoietic stem cell transplant (HSCT) is the only curative treatment for JMML. Pre-transplant therapy is a matter of controversy, and there are no firm recommendations. Whether chemotherapy is effective in achieving durable remission is questionable. Patients diagnosed as JMML at our center from January-2014 to December-2019 were retrospectively analyzed. All patients treated with at least one cycle of sequential therapy with subcutaneous cytarabine and oral 6-mercaptopurine were further assessed. The total number of patients diagnosed during the study period was 33. Patients were divided into two groups: patients who did not get any chemotherapy (n = 13) and ones who received at least one cycle of chemotherapy(n = 20). Age, total leukocyte count (TLC), monocyte percent, platelet count and spleen size were comparable between the two groups. There was no difference in the overall survival between the two groups, but 6 out of 20 patients showed a response to chemotherapy (2 complete remission, 4 partial remission). Two patients out of 20 underwent hematopoietic stem cell transplant (HSCT). The patients who achieved complete remission received 12 cycles of chemotherapy and have been in follow up for 28 months and 50 months respectively. Our results showed that sequential therapy with 6-mercaptopurine and cytarabine may be offered to patients in whom HSCT is not feasible or as a bridge therapy in those awaiting HSCT. The advantages of this approach include low cost, out-patient management and decreased requirement of blood components. In a subset of patients it may achieve remission.

Prevalence and clinical outcome of respiratory viral infections among children with cancer and febrile neutropenia.

Background: The role of respiratory viruses (RV) in children with cancer having febrile neutropenic episodes has not been well studied. The objectives of our study were to investigate the prevalence and clinical outcomes of Respiratory viral infection (RVI). Methods: Children with cancer and febrile neutropenia (FN) having acute respiratory infections (ARI) were considered as cases and febrile neutropenic cancer patients without ARI were considered as controls. A throat swab sample was obtained for the detection of 21-respiratory pathogens. Results: A total of 81 episodes of FN in cases and 37 episodes of FN in controls were included. Prevalence of RVI (at least 1 RV) was seen in 76.5% of cases and 48.6% of controls (p = 0.005). The mixed-respiratory viruses (co-infections of ≥2 viruses) were seen only in cases (26%) (p = 0.00). Rhinovirus (36.8%) and respiratory syncytial virus (13.6%) were the most frequently detected viruses. Median duration of fever before presentation was more in cases with RVI compared to without RVI [2 (1-5) days vs 1 (1-5) day (p = 0.012)]. The median total duration of febrile period was 4 (IQR, 3-6) days in cases with RVI and 3 (IQR, 1-4) days in cases without RVI (p = 0.005). The median duration of antibiotic days were longer in cases with RVI as compared to patients without RVI [9 (IQR, 7-17) days vs 7 (IQR, 6-10) days (p = 0.046)] respectively. Conclusion: There was high prevalence of RVI in children with cancer and FN; more in association with ARI. The RVI were associated with prolonged febrile period and days of antibiotics therapy.

Hematopoietic Stem Cell Transplantation for Storage Disorders: Present Status.

Storage disorders are a group of inborn errors of metabolism caused by the defective activity of lysosomal enzymes or transporters. All of these disorders have multisystem involvement with variable degrees of neurological features. Neurological manifestations are one of the most difficult aspects of treatment concerning these diseases. The available treatment modalities for some of these disorders include enzyme replacement therapy, substrate reduction therapy, hematopoietic stem cell transplantation (HSCT) and the upcoming gene therapies. As a one-time intervention, the economic feasibility of HSCT makes it an attractive option for treating these disorders, especially in lower and middle-income countries. Further, improvements in peri-transplantation medical care, better conditioning regimens and better supportive care have improved the outcomes of patients undergoing HSCT. In this review, we discuss the current evidence for HSCT in various storage disorders and its suitability as a mode of therapy for the developing world.