Anthracycline-Free Protocol for Favorable-Risk Childhood ALL: A Noninferiority Comparison Between Malaysia-Singapore ALL 2003 and ALL 2010 Studies.

PURPOSE: To investigate whether, for children with favorable-risk B-cell precursor ALL (BCP-ALL), an anthracycline-free protocol is noninferior to a modified Berlin-Frankfurt-Muenster ALL-IC2002 protocol, which includes 120 mg/m2 of anthracyclines. PATIENTS AND METHODS: Three hundred sixty-nine children with favorable-risk BCP-ALL (age 1-9 years, no extramedullary disease, and no high-risk genetics) who cleared minimal residual disease (≤0.01%) at the end of remission induction were enrolled into Ma-Spore (MS) ALL trials. One hundred sixty-seven standard-risk (SR) patients (34% of Malaysia-Singapore ALL 2003 study [MS2003]) were treated with the MS2003-SR protocol and received 120 mg/m2 of anthracyclines during delayed intensification while 202 patients (42% of MS2010) received an anthracycline-free successor protocol. The primary outcome was a noninferiority margin of 1.15 in 6-year event-free survival (EFS) between the MS2003-SR and MS2010-SR cohorts. RESULTS: The 6-year EFS of MS2003-SR and MS2010-SR (anthracycline-free) cohorts was 95.2% ± 1.7% and 96.5% ± 1.5%, respectively (P = .46). The corresponding 6-year overall survival was 97.6% and 99.0% ± 0.7% (P = .81), respectively. The cumulative incidence of relapse was 3.6% and 2.6%, respectively (P = .42). After adjustment for race, sex, age, presenting WBC, day 8 prednisolone response, and favorable genetic subgroups, the hazard ratio for MS2010-SR EFS was 0.98 (95% CI, 0.84 to 1.14; P = .79), confirming noninferiority. Compared with MS2003-SR, MS2010-SR had significantly lower episodes of bacteremia (30% v 45.6%; P = .04) and intensive care unit admissions (1.5% v 9.5%; P = .004). CONCLUSION: In comparison with MS2003-SR, the anthracycline-free MS2010-SR protocol is not inferior and was less toxic as treatment for favorable-risk childhood BCP-ALL.

Expression and alteration of p16 in diffuse large B cell lymphoma.

OBJECTIVES: This study aimed to examine (1) the expression of P16 protein relative to sites of presentation, immunophenotypic subgroups and proliferative indices of tumour cells, and (2) the relationship between p16 gene alterations and P16 protein overexpression in 70 cases of diffuse large B cell lymphoma (DLBCL). METHODS: Expression of P16, CD10, BCL-6, MUM-1 and proliferation marker (Ki-67) was demonstrated by immunohistochemistry. Fluorescence in situ hybridization (FISH) was employed to detect p16 alterations. RESULTS: P16 overexpression was shown in 45.7% (32/70) of the DLBCL cases, and was significantly correlated with CD10 (p = 0.022) and germinal centre B-cell-like (GCB) phenotype (p = 0.022). High expression of P16 was inversely associated with high proliferative activity (Ki-67 index greater than 75%) (p = 0.020). Of the 47 cases that yielded interpretable FISH results, 57.4% (27/47) showed deletions of p16 and 27.7% (13/47) showed gains of p16. P16 overexpression and p16 deletions were mutually exclusive (p = 0.019). There was no correlation between P16 overexpression and p16 gains (p = 0.621). CONCLUSIONS: The GCB and non-GCB subgroups of DLBCLs show different patterns of P16 expression. High levels of P16 may mitigate tumour cell proliferation. Gains of p16 do not necessarily increase P16 protein expression.

Intensifying Treatment of Childhood B-Lymphoblastic Leukemia With IKZF1 Deletion Reduces Relapse and Improves Overall Survival: Results of Malaysia-Singapore ALL 2010 Study.

Purpose Although IKZF1 deletion ( IKZF1del) confers a higher risk of relapse in childhood B-cell acute lymphoblastic leukemia (B-ALL), it is uncertain whether treatment intensification will reverse this risk and improve outcomes. The Malaysia-Singapore ALL 2010 study (MS2010) prospectively upgraded the risk assignment of patients with IKZF1del to the next highest level and added imatinib to the treatment of all patients with BCR- ABL1 fusion. Patients and Methods In total, 823 patients with B-ALL treated in the Malyasia-Singapore ALL 2003 study (MS2003; n = 507) and MS2010 (n = 316) were screened for IKZF1del using the multiplex ligation-dependent probe amplification assay. The impact of IKZF1del on the 5-year cumulative incidence of relapse (CIR) was compared between the two studies. Results Patient characteristics were similar in both cohorts, including IKZF1del frequencies (59 of 410 [14.4%] v 50 of 275 [18.2%]; P = .2). In MS2003, where IKZF1del was not used in risk assignment, IKZF1del conferred a significantly higher 5-year CIR (30.4% v 8.1%; P = 8.7 × 10-7), particularly in the intermediate-risk group who lacked high-risk features (25.0% v 7.5%; P = .01). For patients with BCR-ABL1-negative disease, IKZF1del conferred a higher 5-year CIR (20.5% v 8.0%; P = .01). In MS2010, the 5-year CIR of patients with IKZF1del significantly decreased to 13.5% ( P = .05) and no longer showed a significant difference in patients with BCR-ABL1-negative disease (11.4% v 4.4%; P = .09). The 5-year overall survival for patients with IKZF1del improved from 69.6% in MS2003 to 91.6% in MS2010 ( P = .007). Conclusion Intensifying therapy for childhood B-ALL with IKZF1del significantly reduced the risk of relapse and improved overall survival. Incorporating IKZF1del screening significantly improved treatment outcomes in contemporary ALL therapy.

Challenges of Treating Childhood Medulloblastoma in a Country With Limited Resources: 20 Years of Experience at a Single Tertiary Center in Malaysia.

PURPOSE: Pediatric medulloblastoma (MB) treatment has evolved over the past few decades; however, treating children in countries with limited resources remains challenging. Until now, the literature regarding childhood MB in Malaysia has been nonexistent. Our objectives were to review the demographics and outcome of pediatric MB treated at the University Malaya Medical Center between January 1994 and December 2013 and describe the challenges encountered. METHODS: Fifty-one patients with childhood MB were seen at University Malaya Medical Center. Data from 43 patients were analyzed; eight patients were excluded because their families refused treatment after surgery. RESULTS: Headache and vomiting were the most common presenting symptoms, and the mean interval between symptom onset and diagnosis was 4 weeks. Fourteen patients presented with metastatic disease. Five-year progression-free survival (± SE) for patients ≥ 3 years old was 41.7% ± 14.2% (95% CI, 21.3% to 81.4%) in the high-risk group and 68.6% ± 18.6% (95% CI, 40.3% to 100%) in the average-risk group, and 5-year overall survival (± SE) in these two groups was 41.7% ± 14.2% (95% CI, 21.3% to 81.4%) and 58.3% ± 18.6% (95% CI, 31.3% to 100%), respectively. Children younger than 3 years old had 5-year progression-free and overall survival rates (± SE) of 47.6% ± 12.1% (95% CI, 28.9% to 78.4%) and 45.6% ± 11.7% (95% CI, 27.6% to 75.5%), respectively. Time to relapse ranged from 4 to 132 months. Most patients who experienced relapse died within 1 year. Febrile neutropenia, hearing loss, and endocrinopathy were the most common treatment-related complications. CONCLUSION: The survival rate of childhood MB in Malaysia is inferior to that usually reported in the literature. We postulate that the following factors contribute to this difference: lack of a multidisciplinary neuro-oncology team, limited health care facilities, inconsistent risk assessment, insufficient data in the National Cancer Registry and pathology reports, inadequate long-term follow-up, and cultural beliefs leading to treatment abandonment.

Does vitamin A supplementation protect schoolchildren from acquiring soil-transmitted helminthiasis? A randomized controlled trial.

BACKGROUND: Despite the intensive global efforts to control intestinal parasitic infections, the prevalence of soil-transmitted helminth (STH) infections is still very high in many developing countries particularly among children in rural areas. METHODS: A randomized, double-blind, placebo-controlled trial was conducted on 250 Aboriginal schoolchildren in Malaysia to investigate the effects of a single high-dose of vitamin A supplementation (200,000 IU) on STH reinfection. The effect of the supplement was assessed at 3 and 6 months after receiving interventions; after a complete 3-day deworming course of 400 mg/daily of albendazole tablets. RESULTS: Almost all children (98.6%) were infected with at least one STH species. The overall prevalence of ascariasis, trichuriasis and hookworm infection was 67.8%, 95.5% and 13.4%, respectively. Reinfection rates of Ascaris, Trichuris and hookworm were high; at 6 months, assessment reached 80% of the prevalence reported before treatment. There were no significant differences in the reinfection rates and intensities of STH between vitamin A supplemented-children and those who received placebo at 3 and 6 months (p > 0.05). CONCLUSIONS: Vitamin A supplementation showed no protective effect against STH reinfection and this could be due to the high endemicity of STH in this community. Long-term interventions to reduce poverty will help significantly in reducing this continuing problem and there is no doubt that reducing intestinal parasitic infection would have a positive impact on the health, nutrition and education of these children. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT00936091.

Effects of vitamin A supplementation on iron status indices and iron deficiency anaemia: a randomized controlled trial.

Iron deficiency anaemia (IDA) is the most common nutritional deficiency in the world including developed and developing countries. Despite intensive efforts to improve the quality of life of rural and aboriginal communities in Malaysia, anaemia and IDA are still major public health problems in these communities particularly among children. A randomized, double-blind, placebo-controlled trial was conducted on 250 Orang Asli (aboriginal) schoolchildren in Malaysia to investigate the effects of a single high-dose of vitamin A supplementation (200,000 IU) on iron status indices, anaemia and IDA status. The effect of the supplement was assessed after 3 months of receiving the supplements; after a complete 3-day deworming course of 400 mg/day of albendazole tablets. The prevalence of anaemia was found to be high: 48.5% (95% CI=42.3, 54.8). Moreover, 34% (95% CI=28.3, 40.2) of the children had IDA, which accounted for 70.1% of the anaemic cases. The findings showed that the reduction in serum ferritin level and the increments in haemoglobin, serum iron and transferrin saturation were found to be significant among children allocated to the vitamin A group compared to those allocated to the placebo group (p<0.01). Moreover, a significant reduction in the prevalence of IDA by almost 22% than prevalence at baseline was reported among children in the vitamin A group compared with only 2.3% reduction among children in the placebo group. In conclusion, vitamin A supplementation showed a significant impact on iron status indices and IDA among Orang Asli children. Hence, providing vitamin A supplementation and imparting the knowledge related to nutritious food should be considered in the efforts to improve the nutritional and health status of these children as a part of efforts to improve the quality of life in rural and aboriginal communities.

Challenges in the Management of a Child with Yolk Sac Tumour of the Nasal Cavity Presenting with Epistaxis and Progressive Respiratory Distress

@#Yolk Sac tumour (YST) of the nasal cavity is extremely rare with only less than five previously reported cases in the English literature. Due to its rarity, the diagnosis is not one that is considered at initial presentation until tissue biopsies are sent for histopathological examination. Serum α-fetoprotein levels aid in diagnosis and in monitoring progression of the tumour. Being a very uncommon tumour of germ cell origin presenting as localized disease in the nasal cavity, prognosis and survival rates are difficult to determine. We are reporting a rare yolk sac tumour case in an infant and the challenges encountered in its management.

Cefepime monotherapy for treatment of febrile neutropenia in children.

AIM: Empirical therapy for children with febrile neutropenia has traditionally consisted of combination antibiotics, usually a beta-lactam and an aminoglycoside. However, recent trends and international guidelines have now made monotherapy a feasible option in the management of this group of patients. We prospectively evaluated the efficacy and safety of cefepime monotherapy in our population of paediatric cancer patients with febrile neutropenia. METHODS: An audit was performed on children aged 16 years and younger presenting with fever and neutropenia who were managed with empirical single-agent cefepime. The patients were analysed for clinical outcome, documented infections and side-effects of the study drug. Success was defined as clinical improvement without treatment modification. Death or any change to the empirical antibiotic was considered as failure. RESULTS: In this study 79 children (median age 5.2 years) with 133 episodes of febrile neutropenia were prospectively studied between August 2004 and August 2005. A microbiologically documented infection was seen in 26 episodes. The success rate of cefepime monotherapy was 60%. The rate of survival through neutropenia (with or without modification) was 98%. No significant adverse effects were seen. CONCLUSION: Cefepime monotherapy is a safe and feasible option for treatment of childhood cancer patients with febrile neutropenia.

Pattern of Epstein-Barr virus association in childhood non-Hodgkin's lymphoma: experience of university of malaya medical center.

The pattern of childhood non-Hodgkin's lymphoma (NHL) usually differs in adults. The most common subtypes are lymphoblastic, Burkitt's and anaplastic large cell lymphoma. Recent data indicate that a higher risk of developing lymphoma is associated in children of certain ethnic origins. The difference is probably related to the underlying etiological factors of these diseases, and Epstein-Barr virus (EBV) is a strong candidate. The present study aims to determine the disease pattern of childhood lymphomas in the University Hospital Kuala Lumpur, for a direct comparison to the reported data of adults from the same medical center. A total of 69 and 34 childhood NHL and Hodgkin's lymphomas, respectively, were retrieved. The most common subtypes were lymphoblastic (23 cases), Burkitt's (25 cases) and anaplastic large cell lymphomas (9 cases). Epstein-Barr virus association was more prevalent in B-cell (23%) than T-cell (12%) lymphomas. The most common EBV-associated tumor was Burkitt's lymphoma, and there was an increased risk of EBV association for Burkitt's lymphoma in Chinese patients. In conclusion, the pattern of childhood lymphoma in Malaysia is relatively similar to children elsewhere in the world. The EBV association of B- and T-NHL differs between children and adults from the same medical center because of differences in the subtype composition in these two age groups.