Wan Ariffin Bin Abdullah

Ceftazidime-resistant Klebsiella pneumoniae bloodstream infection in children with febrile neutropenia

OBJECTIVES To evaluate prevalence of ceftazidime-resistant Klebsiella pneumoniae (CRKP) in the pediatric oncology unit of University Hospital, Kuala, Lumpur, and to identify differences between febrile neutropenic pediatric patients with CRKP and ceftazidime-sensitive K. pneumoniae (CSKP) bacteremia. MATERIALS AND METHODS Febrile neutropenic patients treated between January 1996 and December 1997 at the pediatric oncology unit of University Hospital, Kuala Lumpur, were prospectively studied. Empirical antibiotic therapy consisted of ceftazidime and amikacin. Those who developed K. pneumoniae bacteremia were identified, and clinical features analyzed. Ceftazidime-resistance was documented via disk-diffusion testing. Production of extended-spectrum beta-lactamase (ESBL) was inferred on the basis of synergy between ceftazidime and amoxicillin-clavulanic acid. The different features between the two groups and variables associated with the development of CRKP bacteremia were analyzed using chi-square and t-tests and calculation of odds ratios. A multivariate analysis was used to identify independent factors for CRKP development. RESULTS Ceftazidime-resistance was seen in 51.6% of all K. pneumoniae isolates, and all these isolates were inferred to be ESBL producers. All isolates were sensitive to imipenem. Susceptibility to gentamicin was 90.5%. The mean continuous hospital stay prior to the detection of bacteremia was 13.7 days overall, but significantly longer in the CRKP group (21.9 d) compared to the CSKP group (4.3 d) (P = 0.003). Children with CRKP were more likely to have received antibiotics in the 2 weeks prior to detection of bacteremia (87.5% of cases) than the CSKP group (20.0% of cases) (P = 0.0008). Sepsis-related mortality was higher in those with CRKP (50.0%) than in the CSKP group (13.3%) (P = 0.02). Patients who did not receive CRKP-directed antibiotics within 48 hours of admission were more likely to have a fatal outcome than those who did (P = 0.009). Logistic regression analysis identified use of third-generation cephalosporins 2 weeks prior to presentation and a hospital stay of 2 weeks or more as independent risk factors for development of CRKP. CONCLUSIONS More than half of total K. pneumoniae isolated from blood cultures in the unit were ceftazidime-resistant. Children with febrile neutropenia with prolonged hospital stay and recent prior antibiotic exposure are at high risk of developing CRKP bacteremia. Mortality was significantly higher in this group. Early commencement of appropriate antibiotics (e.g., imipenem with or without gentamicin), according to susceptibility study results, may be beneficial in such circumstances.

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.

Factor V inhibitor in neonatal intracranial hemorrhage secondary to severe congenital factor V deficiency

We report a newborn infant girl, born to consanguineous parents, with recurrent intracranial hemorrhage secondary to congenital factor V deficiency with factor V inhibitor. Repeated transfusions of fresh-frozen plasma (FFP) and platelet concentrates, administrations of immunosuppressive therapy (prednisolone and cyclophosphamide), and intravenous immunoglobulin failed to normalize the coagulation profiles. Exchange transfusion followed-up by administrations of activated prothrombin complex and transfusions of FFP and platelet concentrates caused a temporary normalization of coagulation profile, enabling an insertion of ventriculoperitoneal (VP) shunt for progressive hydrocephalus. The treatment was complicated by thrombosis of left brachial artery and ischemia of left middle finger. The child finally died from another episode of intracranial hemorrhage 10 days after insertion of the VP shunt.

Pattern of Epstein–Barr virus association in childhood non-Hodgkin's lymphoma: Experience of University of Malaya Medical Center

The pattern of childhood non‐Hodgkins lymphoma (NHL) usually differs in adults. The most common subtypes are lymphoblastic, Burkitts 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 Hodgkins lymphomas, respectively, were retrieved. The most common subtypes were lymphoblastic (23 cases), Burkitts (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 Burkitts lymphoma, and there was an increased risk of EBV association for Burkitts 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.

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.

Pediatric Vaginal Yolk Sac Tumor: Reappraisal of Treatment Strategy in a Rare Tumor at a Unique Location.

Review of the management of 6 young girls with vaginal yolk sac tumor over 25 years showed that the &agr;-fetoprotein levels normalized in 5/6 within 4 cycles of primary cisplatin, bleomycin, etoposide (PEB)/carboplatin, etoposide, bleomycin (JEB)/cisplatin, vinblastine, bleomycin (PVB) chemotherapy. Radioimaging revealed residual tissue but viable tumor was found in only 1 of 2 biopsied. Resection/biopsy is necessary to avoid giving additional primary chemotherapy or to identify patients who need different treatment. If markers do not decay appropriately, PEB/JEB/PVB chemotherapy should not be continued. Taxol-containing salvage chemotherapy regimens, adjuvant modern radiotherapeutic treatment, and fertility-saving curative surgery should then be considered. Despite having mostly advanced disease, 5/6 patients were cured, 2 with chemotherapy alone.

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.

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.

Connectionist architectures for triggering and track reconstruction

Abstract Connectionist methods of distributed parallel processing have the advantage of being fast and having a “global view of the problem at hand”. We consider several possibilities for using such methods for triggering in the complex events obtained at high energies, and in fast track-finding and -fitting with the complex detectors used at high energies.

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.