Incidence, severity, and temporal development of oral complications in pediatric allogeneic hematopoietic stem cell transplant patients - a multicenter study.

PURPOSE: Oral mucositis is a common complication for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) and causes pain and difficulties in functions like eating and swallowing, resulting in lower quality of life and greater need of treatment with opioids and parenteral nutrition. This prospective multicenter study focused on pediatric recipients of HSCT in the neutropenic phase concerning oral complications, timing, severity, and patient experience. METHODS: The cohort comprised 68 patients, median age 11.1 years (IQR 6.3) receiving allogeneic HSCT at three clinical sites. Medical records were retrieved for therapy regimens, concomitant medications, oral and dental history, and subjective oral complaints. Calibrated dentists conducted an oral and dental investigation before HSCT. After HSCT graft infusion, study personnel made bedside assessments and patients filled out a questionnaire once or twice a week until neutrophil engraftment. RESULTS: We followed 63 patients through the neutropenic phase until engraftment. 50% developed oral mucositis of grades 2-4. Peak severity occurred at 8-11 days after stem cell infusion. Altogether, 87% had subjective oral complaints. The temporal distribution of adverse events is similar to the development of oral mucositis. The most bothersome symptoms were blisters and oral ulcerations, including mucositis; 40% reported severe pain and major impact on activities of daily living despite continuous use of opioids. CONCLUSION: This study highlights the burden of oral complications and their negative effect on the health and quality of life of HSCT recipients.

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.

Risk Factors for Mortality in Asian Children Admitted to the Paediatric Intensive Care Unit after Haematopoietic Stem Cell Transplantation.

INTRODUCTION: This study aimed to investigate the risk factors associated with mortality in haematopoietic stem cell transplant (HSCT) patients admitted to our paediatric intensive care unit (PICU) over an 8-year period. MATERIALS AND METHODS: A retrospective chart review was conducted of all HSCT patients requiring PICU admission at our centre (a tertiary care university hospital in Singapore) from January 2002 to December 2010. Chief outcome measures were survival at the time of PICU discharge and survival at 6 months after initial PICU admission. RESULTS: Ninety-eight patients underwent HSCT during this period; 18 patients (18%) required 24 PICU admissions post-HSCT. The overall survival to PICU discharge was 62.5%. Of those who survived discharge from the PICU, 33% died within 6 months of discharge. Non-survivors to PICU discharge had a higher incidence of sepsis (89% vs 33%, P = 0.013) and organ failure as compared to survivors (cardiovascular failure 100% vs 20%, P = 0.0003; respiratory failure 89% vs 20%, P = 0.002; and renal failure 44% vs 7%, P = 0.047). Mortality rates were higher in patients requiring mechanical ventilation (70% vs 14%, P = 0.010) and inotropic support (70% vs 14%, P = 0.010). Mortality in all patients with renal failure requiring haemodialysis (n = 4) was 100%. Presence of 3 or more organ failures was associated with 80% mortality (P = 0.003). CONCLUSION: Sepsis, multiple organ failure and the need for mechanical ventilation, inotropes and especially haemodialysis were associated with increased risk of mortality in our cohort of HSCT patients.

Second Malignant Neoplasms in Childhood Cancer Survivors Treated in a Tertiary Paediatric Oncology Centre.

Introduction: One of the most feared complications of childhood cancer treatment is second malignant neoplasms (SMNs). This study evaluates the incidence, risk factors and outcomes of SMNs in a tertiary paediatric oncology centre in Singapore. Materials and Methods: A retrospective review was conducted on patients diagnosed with childhood cancer under age 21 and treated at the National University Hospital, Singapore, from January 1990 to 15 April 2012. Case records of patients with SMNs were reviewed. Results: We identified 1124 cases of childhood cancers with a median follow-up of 3.49 (0 to 24.06) years. The most common primary malignancies were leukaemia (47.1%), central nervous system tumours (11.7%) and lymphoma (9.8%). Fifteen cases developed SMNs, most commonly acute myeloid leukaemia/myelodysplastic syndrome (n = 7). Median interval between the first and second malignancy was 3.41 (0.24 to 18.30) years. Overall 20-year cumulative incidence of SMNs was 5.3% (95% CI, 0.2% to 10.4%). The 15-year cumulative incidence of SMNs following acute lymphoblastic leukaemia was 4.4% (95% CI, 0% to 8.9%), significantly lower than the risk after osteosarcoma of 14.2% (95% CI, 0.7% to 27.7%) within 5 years (P <0.0005). Overall 5-year survival for SMNs was lower than that of primary malignancies. Conclusion: This study identified factors explaining the epidemiology of SMNs described, and found topoisomerase II inhibitor use to be a likely risk factor in our cohort. Modifications have already been made to our existing therapeutic protocols in osteosarcoma treatment. We also recognised the importance of other risk management strategies, including regular long-term surveillance and early intervention for detected SMNs, to improve outcomes of high risk patients.

Cutaneous Emboli of Invasive Basidiomycosis in a Child With Aplastic Anemia.

Invasive fungal diseases are a significant cause of mortality among the immunocompromised. This report documents an unusual case of disseminated fungal infection in a child with severe aplastic anemia. The offending fungus, a Basidiomycete, is rarely known to cause human infections. The patient presented acutely with multiple purpuric skin lesions in various parts of the body. The skin biopsy revealed septated fungal hyphae embolized within small dermal blood vessels. Molecular sequencing indicated Earliella scabrosa as the likely organism. The clinical course of the infection was inexorable despite systemic antifungal treatment, resulting in mortality. The literature of human infections due to Basidiomycetes, the usefulness of histopathology in the early diagnosis of the infection, and possible treatment options are discussed.

Case report: An unusual presentation of oral acute graft-versus-host-disease in a haploidentical hematopoietic stem cell transplant recipient.

Oral acute graft-versus-host disease (aGVHD) is a significant sequelae of allogeneic hematopoietic stem cell transplantation (HSCT). Presently, transplant physicians have to diagnose GVHD based on clinical judgment by interpreting available clinical and relevant laboratory findings. As such, characterization of diagnostic and distinctive clinical signs and symptoms of GVHD is essential for diagnosis and grading. The oral features of aGVHD have been reported infrequently and remain ill defined, unlike in oral chronic GVHD. The report describes an atypical and painful presentation of oral aGVHD in a 15-year-old boy, 16 days after haploidentical HSCT, who presented with swollen lips, herpetiform ulcerations, and erythematous fungiform papilla.

Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorder in children and young adults has similar molecular signature to extranodal nasal natural killer/T-cell lymphoma but shows distinctive stem cell-like phenotype.

We performed gene expression profiling in Epstein-Barr virus (EBV)-associated T/natural killer (NK)-cell lymphoproliferative disorder in children and young adults (TNKLPDC) in order to understand the molecular pathways deregulated in this disease and compared it with nasal-type NK/T-cell lymphoma (NKTL). The molecular and phenotypic signature of TNKLPDC is similar to NKTL, with overexpression of p53, survivin and EZH2. Down-regulation of EZH2 in TNKLPDC cell lines led to an increase in apoptosis and decrease in tumor viability, suggesting that EZH2 may be important for the survival of TNKLPDC cells and hence potentially a useful therapeutic target. Notably, our gene expression profiling revealed a distinctive enrichment of stem cell related genes in TNKLPDC compared to NKTL. This was validated by a significantly higher expression of aldehyde dehydrogenase 1 (ALDH1) in TNKLPDC cell lines compared to NKTL cell lines. The novel discovery of cancer stem cell properties in TNKLPDC has potential therapeutic implications in this group of disorders.

Prognostic implication of morphology, cyclinE2 and proliferation in EBV-associated T/NK lymphoproliferative disease in non-immunocompromised hosts.

BACKGROUND: EBV-associated T/NK-cell lymphoproliferative diseases (TNKLPD) is a rare spectrum of disease that occurs more commonly in Asia, and Central and South America. It commonly affects children and young adults and is an aggressive disease that is poorly understood with no known biologic markers that can predict prognosis. The systemic form of TNKLPD includes chronic active EBV infection of T/NK type, aggressive NK cell leukemia and systemic EBV + T-cell lymphoproliferative disease of childhood. METHODS: In this study, we analyse the clinicopathologic and genetic features of 22 cases of systemic TNKLPD in non-immunocompromised patients, including chronic active EBV infection of T/NK cell type and systemic EBV + T-cell lymphoproliferative disease of childhood. We also performed gene expression profiling in a subset of cases to identify markers that may be of prognostic relevance and validated our results using immunohistochemistry. RESULTS: The median age is 14.9 years and two of our 22 cases occurring in patients older than 30 years. Fifteen of 17 cases (88%) with adequate data were of T-cell origin. Eleven of 22 cases revealed polymorphic cellular infiltrate (P-group) while the rest showed monomorphic lymphoid infiltrate (M-group). We found a significant difference in survival between P-group vs M-group patients with median survival not yet reached in P-group, and 1 month in M-group (p = 0.0001), suggesting a role for morphology in predicting patient outcome. We also performed gene expression profiling in a subset of patients and compared the genes differentially expressed between P-group and M-group cases to identify markers of prognostic value. We identified cyclin E2 gene and protein to be differentially expressed between patients with good outcome (P-group, median expression 8%) and poor outcome (M-group, median expression 42%) (p = 0.0005). In addition, the upregulation of cyclin E2 protein in M-group cases correlated with a higher Ki67 proliferation rate (Pearson correlation r = 0.73, p = 0.0006) detected by immunohistochemistry. High cyclin E2 expression was also significantly associated with shorter survival (p = 0.0002). CONCLUSION: Our data suggests the potential role of monomorphic morphology, high cyclin E2 and Ki67 expression as adverse prognostic factors for TNKLPD.

Allogeneic stem cell transplantation for children with acquired severe aplastic anaemia: a retrospective study by the Viva-Asia Blood and Marrow Transplantation Group.

We retrospectively analysed the outcomes of 127 children with acquired severe aplastic anaemia (SAA) who had received haematopoietic stem cell transplantation (HSCT) between 2000 and 2011 in one of the 10 Asia Pacific institutions. Fifty-three were matched sibling donor (MSD) and 74 were alternative donor (AD), including 22 matched unrelated donor, 32 mismatched unrelated donor and 20 mismatched related donor. With a median follow up 45.5 months (13-139) and when compared to the MSD group, AD recipients had more grade II-IV acute graft-versus-host disease (aGVHD; 14.3% vs. 32.8%, P = 0.029), but similar grade III-IV aGVHD (10.2% vs. 12.5%, P = 0.774), graft failure (GF) (15.1% vs. 15.5%, P = 0.658) and 5-year overall survival (90.6% vs. 83.7%, P = 0.251). As a source of stem cell, peripheral blood stem cells (PBSC) resulted in less GF (18% vs. 9.1% P = 0.013), similar grade II-IV aGVHD (28.1% vs. 17.4%, P = 0.258), chronic GVHD (25.8% vs. 29.3%, P = 0.822) and similar outcomes (89.7% vs. 82.4%, P =0.665) when compared to bone marrow (BM). In univariate analysis, GF (P < 0.001) and grade II-IV aGVHD (P = 0.009) were predictors of poor survival. In multivariate analysis, only GF was associated with poor survival (P = 0.012). The outcome of AD and PBSC HSCT were comparable to that of MSD and BM HSCT in the Asia Pacific region.

Stem cell transplantation for primary immunodeficiency disease: experience of a singapore hospital.

We retrospectively analyzed the outcomes of hematopoietic stem cell transplantation in 7 patients with primary immunodeficiency diseases treated at the National University Hospital, Singapore, over the period from December 1996 to January 2010. The primary immunodeficiency diseases managed were X-linked hyperimmunoglobulin M syndrome (n = 3), severe combined immunodeficiency (n = 1), leukocyte adhesion deficiency type 1 (n = 1), chronic granulomatous disease (n = 1), and Wiskott-Aldrich syndrome (n = 1). The age of the patients ranged from 5 months to 17 years. Conditioning regimen depended on the type of immunodeficiency, whereas supportive treatment was tailored for differing pretransplant conditions. Eight stem cell transplantations were performed for 7 patients. Donors were HLA-matched sibling donors for 2 patients and unrelated donors for the rest. At the median follow-up of 8.6 years (range 2.2-15.0 years) as of December 2011, 6 patients were alive and cured of their primary diseases.

Minimal residual disease-guided treatment deintensification for children with acute lymphoblastic leukemia: results from the Malaysia-Singapore acute lymphoblastic leukemia 2003 study.

PURPOSE: To improve treatment outcome for childhood acute lymphoblastic leukemia (ALL), we designed the Malaysia-Singapore ALL 2003 study with treatment stratification based on presenting clinical and genetic features and minimal residual disease (MRD) levels measured by polymerase chain reaction targeting a single antigen-receptor gene rearrangement. PATIENTS AND METHODS: Five hundred fifty-six patients received risk-adapted therapy with a modified Berlin-Frankfurt-Münster-ALL treatment. High-risk ALL was defined by MRD ≥ 1 × 10(-3) at week 12 and/or poor prednisolone response, BCR-ABL1, MLL gene rearrangements, hypodiploid less than 45 chromosomes, or induction failure; standard-risk ALL was defined by MRD ≤ 1 × 10(-4) at weeks 5 and 12 and no extramedullary involvement or high-risk features. Intermediate-risk ALL included all remaining patients. RESULTS: Patients who lacked high-risk presenting features (85.7%) received remission induction therapy with dexamethasone, vincristine, and asparaginase, without anthracyclines. Six-year event-free survival (EFS) was 80.6% ± 3.5%; overall survival was 88.4% ± 3.1%. Standard-risk patients (n = 172; 31%) received significantly deintensified subsequent therapy without compromising EFS (93.2% ± 4.1%). High-risk patients (n = 101; 18%) had the worst EFS (51.8% ± 10%); EFS was 83.6% ± 4.9% in intermediate-risk patients (n = 283; 51%). CONCLUSION: Our results demonstrate significant progress over previous trials in the region. Three-drug remission-induction therapy combined with MRD-based risk stratification to identify poor responders is an effective strategy for childhood ALL.

Reduced-intensity conditioning regimens for allogeneic transplantation in children with acute lymphoblastic leukemia.

Reduced-intensity conditioning regimens have been used extensively in adults with hematologic malignancies. To address whether this is a feasible approach for children with acute lymphoblastic leukemia, we evaluated transplant outcomes in 38 recipients transplanted from 1995-2005 for whom this was their first transplant. The median age at transplant was 12 years, and 47% had performance scores <90%. Disease status was first complete remission (CR) in 13%, > or =CR2 in 60% of patients, and 22% had active disease at transplantation. Matched related donors were available for a third of patients, about half of whom received bone marrow (BM) and the others, peripheral blood progenitor cells. Sixty percent of unrelated donor transplant recipients received peripheral blood progenitor cells. The day-100 probability of grade II-IV acute graft-versus-host disease was 37% and the 3-year probability of chronic graft-versus-host disease, 26%. At 3 years, the probability of treatment-related mortality was 40%, relapse 37%, and disease-free survival 30%. These data indicate long-term DFS can be achieved using reduced-intensity conditioning regimens in children with acute lymphoblastic leukemia. Given the relatively small cohort, these findings must be validated in a larger population.

Health-related quality of life in children with cancer undergoing treatment: a first look at the Singapore experience.

INTRODUCTION: With intensive chemotherapy and increased survival, quality of life in our paediatric population is of increasing concern. The aim of this study was to assess the children's quality of life during the treatment process. MATERIALS AND METHODS: Patients between the ages of 7 and 18 years old who are undergoing cancer treatment in the Division of Paediatric Haematology-Oncology, Department of Paediatrics, National University Health System, were identified. The child self-reported his/her health-related quality of life (HRQOL) using the PedsQL Paediatric Quality of Life Inventory and Cancer module as a validated assessment tool. RESULTS: Thirty-two patients were enrolled over a 3-week period in November 2007. The median age was 11 years (range, 7 to 17). There was 1 non-responder (3%). Fourteen (45%) boys and 17 (55%) girls were interviewed. There were 8 (26%) and 23 (74%) patients with solid and haematologic malignancies, respectively. For the Cognitive Problem Dimension score, 86% of patients with haematologic malignancy and 50% of those with solid malignancy scored below the 75th percentile (82), [OR 0.72 (0.01-0.8), P = 0.03]. For the Physical Health Summary score, patients with solid malignancy scored worse, 25% below the 10th percentile, as compared to 4.3% of patients with haematologic malignancy. This is reflected by a worse Pain and Hurt Dimension score for patients with solid malignancy. For the Perceived Appearance Dimension score, patients with solid malignancy (75%) scored lower than the median score (67) compared to those with haematologic malignancy (44%). CONCLUSIONS: The domains of HRQOL are affected to different extents for the patients with solid and those with haematologic malignancy. This is most likely to be due to the differences in treatment strategies and clinical course. Healthcare professionals should be aware of the effects of treatment on HRQOL and take practical steps to address these issues.

Retinoblastoma: a recent experience at the National University Hospital, Singapore.

INTRODUCTION: Retinoblastoma is a very rare disease. There were 30 cases of retinoblastoma diagnosed and treated at National University Hospital (NUH). MATERIALS AND METHODS: A retrospective chart review was performed on the medical records of 30 patients who were diagnosed with retinoblastoma between 1995 and 2008 at the Department of Paediatrics, National University Hospital, Singapore. RESULTS: The median age at diagnosis was 1.6 years (range, 0-5.9) with a median follow-up of 1.8 years (range, 0.1 to 11.6). The median time from presenting signs to the time of diagnosis was 5.2 months (range, 0-25.2). Common presenting signs of retinoblastoma were identified; the most common of which were leukocoria (50.0%), squinting (13.3%), poor vision (10.0%), strabismus (6.6%) and unknown (33.3%). Of the 30 patients, 10 were from Singapore whilst the other 20 patients were from the surrounding countries. Twelve patients had bilateral disease at the time of diagnosis, while 18 had unilateral disease. Staging information was available in 27 patients. Enucleation was performed in 25 of 30 patients. Radiation therapy was given in 3 patients in 1995 (bilateral disease), 2001 (bilateral disease) and 2003 (unilateral disease). At the time of analysis, 19 patients were alive with no evidence of disease. Overall 5-year survival for the cohort was 88.1% [95% confidence interval (CI), 88.0-100] and event-free survival for the whole cohort was 74.2% (95% CI, 55.8-92.6). CONCLUSION: In our limited experience, the importance of collaboration and standardisation of the staging system, raising awareness and education of primary healthcare providers and parents are strongly stressed.

Thiopurine S-methyltransferase activity in three major Asian populations: a population-based study in Singapore.

OBJECTIVE: The distribution of thiopurine methyltransferase (TPMT) activity in Asian populations has not been well documented. We studied the TPMT phenotype in three major Asian ethnic groups in Singapore, namely the Chinese (Ch), Malays (Mal) and Indians (Ind), with the aim of carrying out a comprehensive survey of the distribution of TPMT activity in Asians. METHODS: A radiochemical assay was used to measure the enzymatic activity of TPMT in the red blood cells (RBCs) of 479 healthy adults (Ch=153, Mal=163 and Ind=163). Cut-off points for intermediate TPMT activity were validated using a receiver operating curve (ROC) analysis. PCR-based methods were used to screen for the TPMT*3C, TPMT*3A and TPMT*6 variants. RESULTS: The histogram of the combined population cohort showed a bimodal distribution of TPMT activity, with no subject having low TPMT activity (<5 units). In total, TPMT variants were detected in 14 subjects (*1/*3C in 13 subjects; *1/*3A in one subject). We observed significant inter-ethnic differences in terms of TPMT activity (p<0.001), with the Malays showing a higher median activity than the Chinese or Indians (17.8 units vs 16.4 units). The Malays also showed a higher methylation rate--with a cut-off point for intermediate TPMT activity of 11.3 units--than the Chinese (9.9 units) or Indians (9.4 units). A high phenotype-genotype correlation of >97% was observed in all three races. We also genotyped 418 childhood leukaemias. The combined analysis of subjects participating in this and a previous study--1585 subjects--showed that 4.7% of Chinese (n=30/644), 4.4% of Malays (n=24/540) and 2.7% of Indians (n=11/401) were heterozygous at the TPMT gene locus. CONCLUSION: This is the first comprehensive TPMT phenotype and genotype study in Asian populations, particularly in the Malays and Indians.