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1.
Artigo em Inglês | MEDLINE | ID: mdl-31212740

RESUMO

There has been a paradigm shift in health service delivery to a more holistic approach, which considers Quality of Life (QoL) and overall functioning. Health-Related Quality of Life (HRQoL) is a multidimensional construct that encompasses physical functioning as well as psychosocial aspects of emotional and social functioning. This study explored factors related to HRQoL in Asian pediatric patients with leukemia in Singapore. The available variables included: age, treatment duration, household income, gender, ethnicity, religion, diagnosis, and phase of treatment. It is hypothesized that the relationships will be significant. In the current study, there were 60 patients (60% males) with leukemia; their ages ranged from 1 to 21 years (Mean = 8.03, Standard Deviation = 4.55). The hypothesis was partially supported. Age had a significant positive relationship with physical functioning, r(60) = 0.28, p < 0.05, physical health, r(60) = 0.28, p < 0.05, and the total HRQoL score, r(60) = 0.29, p < 0.05. Treatment duration had a positive relationship with school functioning, r(60) = 0.28, p < 0.05. All other correlations were statistically non-significant. The effects of the available psychosocial variables of gender, ethnicity, and religion were examined on scores from the Pediatric Quality of Life Inventory (PedsQL). Ethnicity had a significant effect on social functioning, U = 292.00, p < 0.05, r = 0.3 (medium effect size). Specifically, Chinese (Median = 85.00, n = 33) had significantly higher scores on social functioning than others (Median = 70.00, n = 27). The remaining comparisons were statistically non-significant. The current findings added to QoL research, and provided an impetus for more research in the area of HRQoL for children with leukemia in Singapore.

2.
J Clin Oncol ; 36(26): 2726-2735, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30044693

RESUMO

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.

3.
Blood ; 132(12): 1318-1331, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-29914977

RESUMO

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

4.
Br J Haematol ; 181(5): 653-663, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29808917

RESUMO

Accurate risk assignment in childhood acute lymphoblastic leukaemia is essential to avoid under- or over-treatment. We hypothesized that time-series gene expression profiles (GEPs) of bone marrow samples during remission-induction therapy can measure the response and be used for relapse prediction. We computed the time-series changes from diagnosis to Day 8 of remission-induction, termed Effective Response Metric (ERM-D8) and tested its ability to predict relapse against contemporary risk assignment methods, including National Cancer Institutes (NCI) criteria, genetics and minimal residual disease (MRD). ERM-D8 was trained on a set of 131 patients and validated on an independent set of 79 patients. In the independent blinded test set, unfavourable ERM-D8 patients had >3-fold increased risk of relapse compared to favourable ERM-D8 (5-year cumulative incidence of relapse 38·1% vs. 10·6%; P = 2·5 × 10-3 ). ERM-D8 remained predictive of relapse [P = 0·05; Hazard ratio 4·09, 95% confidence interval (CI) 1·03-16·23] after adjusting for NCI criteria, genetics, Day 8 peripheral response and Day 33 MRD. ERM-D8 improved risk stratification in favourable genetics subgroups (P = 0·01) and Day 33 MRD positive patients (P = 1·7 × 10-3 ). We conclude that our novel metric - ERM-D8 - based on time-series GEP after 8 days of remission-induction therapy can independently predict relapse even after adjusting for NCI risk, genetics, Day 8 peripheral blood response and MRD.

5.
PLoS One ; 12(6): e0178776, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28575107

RESUMO

Retinoblastoma (RB) is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA) assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59) while only 42.4% (25/59) of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9%) of tumors screened. There were 3 cases (5.1%) in which no mutations could be detected and germline mutations were detected in 19.5% (8/41) of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59) of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variant-c.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and asymptomatic family members carrying low-penetrance, germline mosaicism or heritable unilateral mutational phenotypes.


Assuntos
Aconselhamento Genético , Mutação Puntual , Proteína do Retinoblastoma/genética , Retinoblastoma/genética , Pré-Escolar , Metilação de DNA , Feminino , Humanos , Lactente , Masculino , Linhagem , Retinoblastoma/terapia , Singapura
7.
Ann Acad Med Singapore ; 46(1): 11-19, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28182813

RESUMO

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.


Assuntos
Leucemia Mieloide Aguda/epidemiologia , Síndromes Mielodisplásicas/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Neoplasias/terapia , Sobreviventes/estatística & dados numéricos , Inibidores da Topoisomerase II/uso terapêutico , Neoplasias Ósseas/terapia , Institutos de Câncer , Neoplasias do Sistema Nervoso Central/terapia , Seguimentos , Humanos , Incidência , Leucemia/terapia , Linfoma/terapia , Osteossarcoma/terapia , Pediatria , Estudos Retrospectivos , Fatores de Risco , Singapura/epidemiologia , Centros de Atenção Terciária , Fatores de Tempo
8.
Genome Res ; 27(2): 185-195, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27903646

RESUMO

Chromosomal translocations are a genomic hallmark of many hematologic malignancies. Often as initiating events, these structural abnormalities result in fusion proteins involving transcription factors important for hematopoietic differentiation and/or signaling molecules regulating cell proliferation and cell cycle. In contrast, epigenetic regulator genes are more frequently targeted by somatic sequence mutations, possibly as secondary events to further potentiate leukemogenesis. Through comprehensive whole-transcriptome sequencing of 231 children with acute lymphoblastic leukemia (ALL), we identified 58 putative functional and predominant fusion genes in 54.1% of patients (n = 125), 31 of which have not been reported previously. In particular, we described a distinct ALL subtype with a characteristic gene expression signature predominantly driven by chromosomal rearrangements of the ZNF384 gene with histone acetyltransferases EP300 and CREBBP ZNF384-rearranged ALL showed significant up-regulation of CLCF1 and BTLA expression, and ZNF384 fusion proteins consistently showed higher activity to promote transcription of these target genes relative to wild-type ZNF384 in vitro. Ectopic expression of EP300-ZNF384 and CREBBP-ZNF384 fusion altered differentiation of mouse hematopoietic stem and progenitor cells and also potentiated oncogenic transformation in vitro. EP300- and CREBBP-ZNF384 fusions resulted in loss of histone lysine acetyltransferase activity in a dominant-negative fashion, with concomitant global reduction of histone acetylation and increased sensitivity of leukemia cells to histone deacetylase inhibitors. In conclusion, our results indicate that gene fusion is a common class of genomic abnormalities in childhood ALL and that recurrent translocations involving EP300 and CREBBP may cause epigenetic deregulation with potential for therapeutic targeting.


Assuntos
Proteína de Ligação a CREB/genética , Proteína p300 Associada a E1A/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transativadores/genética , Animais , Feminino , Regulação Leucêmica da Expressão Gênica , Genômica , Humanos , Masculino , Camundongos , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Regiões Promotoras Genéticas , Transcriptoma/genética , Translocação Genética/genética , Sequenciamento Completo do Genoma
9.
J Clin Oncol ; 33(27): 3065-73, 2015 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-26304881

RESUMO

Advances in the treatment of childhood cancers have resulted in part from the development of national and international collaborative initiatives that have defined biologic determinants and generated risk-adapted therapies that maximize cure while minimizing acute and long-term effects. Currently, more than 80% of children with cancer who are treated with modern multidisciplinary treatments in developed countries are cured; however, of the approximately 160,000 children and adolescents who are diagnosed with cancer every year worldwide, 80% live in low- and middle-income countries (LMICs), where access to quality care is limited and chances of cure are low. In addition, the disease burden is not fully known because of the lack of population-based cancer registries in low-resource countries. Regional and ethnic variations in the incidence of the different childhood cancers suggest unique interactions between genetic and environmental factors that could provide opportunities for etiologic research. Regional collaborative initiatives have been developed in Central and South America and the Caribbean, Africa, the Middle East, Asia, and Oceania. These initiatives integrate regional capacity building, education of health care providers, implementation of intensity-graduated treatments, and establishment of research programs that are adjusted to local capacity and local needs. Together, the existing consortia and regional networks operating in LMICs have the potential to reach out to almost 60% of all children with cancer worldwide. In summary, childhood cancer burden has been shifted toward LMICs and, for that reason, global initiatives directed at pediatric cancer care and control are needed. Regional networks aiming to build capacity while incorporating research on epidemiology, health services, and outcomes should be supported.


Assuntos
Saúde Global/tendências , Comunicação Interdisciplinar , Cooperação Internacional , Oncologia/tendências , Neoplasias/terapia , Pediatria/tendências , Adolescente , Idade de Início , Criança , Comportamento Cooperativo , Difusão de Inovações , Disparidades nos Níveis de Saúde , Disparidades em Assistência à Saúde/tendências , Humanos , Neoplasias/diagnóstico , Neoplasias/etnologia , Neoplasias/mortalidade , Indução de Remissão , Sobreviventes , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Leuk Lymphoma ; 56(8): 2408-15, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25382618

RESUMO

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.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Linfoma Extranodal de Células T-NK/genética , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/patologia , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Transcriptoma , Adulto , Apoptose/genética , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células , Criança , Análise por Conglomerados , Proteína Potenciadora do Homólogo 2 de Zeste , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Células-Tronco Neoplásicas/patologia , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Survivina , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Adulto Jovem
11.
Orphanet J Rare Dis ; 9: 165, 2014 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-25475054

RESUMO

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.


Assuntos
Ciclinas/genética , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/isolamento & purificação , Células Matadoras Naturais/patologia , Transtornos Linfoproliferativos/patologia , Linfócitos T/patologia , Adolescente , Adulto , Proliferação de Células , Criança , Pré-Escolar , Ciclinas/metabolismo , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Feminino , Perfilação da Expressão Gênica , Humanos , Hospedeiro Imunocomprometido , Imuno-Histoquímica , Lactente , Japão , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Singapura , Taxa de Sobrevida , Adulto Jovem
12.
Ann Acad Med Singapore ; 43(6): 305-13, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25028139

RESUMO

INTRODUCTION: More than 80% of children with osteogenic sarcoma (OS) relapse and 35% to 40% of them die within the first 2 years after diagnosis due to relapse. We investigated the incidence, treatment modalities used and the outcome of patients with OS treated in Singapore. MATERIALS AND METHODS: Patients with OS treated in Department of Paediatrics KK Women's and Children's Hospital (KKH) and National University Hospital (NUH) between January 1994 and June 2011 were reviewed. Chemotherapy was as per the European Osteosarcoma Intergroup (EOI) and as per the Memorial Sloan-Kettering Cancer Centre's (MSKCC) T12 protocols. Overall and event-free (EFS) 5-year survivals were calculated using Kaplan-Meier analysis and Cox proportional hazards regression analysis. RESULTS: Of 66 patients with OS, 19 (29%) of them presented with metastatic OS. The median age of diagnosis was 12.1 years with 5-year overall survival of 61.7% (95% CI, 48.1 to 75.3). The 5-year overall survival for those with non-metastatic and metastatic OS was 73.1% (95% CI, 58.1 to 88.1) and 34.7% (95% CI, 8.7 to 60.7, P=0.007) respectively. The 5-year overall survival for those treated as per the MSKCC T12 and EOI was 72.4% (95% CI, 52.6 to 92.2) and 54.3% (95% CI, 36.3 to 72.3, P=0.087) respectively. After controlling for confounding factors, patients with non-metastatic OS had higher 5-year EFS (HR, 0.228, 95% CI, 0.096 to 0.541, P=0.001) and overall survival (HR, 0.294, 95% CI, 0.121 to 0.713, P=0.007) compared to those with metastatic OS. Non-metastatic OS patients treated as per EOI regimen had lower 5-year EFS (HR, 2.397, 95% CI, 1.012 to 6.678, P=0.047) compared to those treated per MSKCC T12 regimen. CONCLUSION: Multidrug combination chemotherapy including high-dose methotrexate (HD-MTX) and a multidisciplinary team approach introduced in 2003 in Singapore is well tolerated and can be safely delivered. The survival benefit between the 2 regimens still needs to be explored.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Adolescente , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Osteossarcoma/tratamento farmacológico , Osteossarcoma/mortalidade , Taxa de Sobrevida , Adulto Jovem
13.
BMJ Case Rep ; 20142014 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-24706711

RESUMO

A male fetus was noted to have an isolated pericardial effusion. At birth, he had dysmorphic features of Down syndrome and extensive petechiae. He was diagnosed to have transient myeloproliferative disorder. The large pericardial effusion and TMD spontaneously resolved. At 4 years of age, he was diagnosed with acute megakaryoblastic leukaemia, underwent chemotherapy and achieved complete remission.


Assuntos
Síndrome de Down/complicações , Feto , Leucemia Megacarioblástica Aguda/etiologia , Reação Leucemoide/complicações , Transtornos Mieloproliferativos/complicações , Derrame Pericárdico/etiologia , Pericárdio/patologia , Púrpura/etiologia , Pré-Escolar , Humanos , Recém-Nascido , Masculino
14.
Ann Acad Med Singapore ; 43(2): 86-95, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24652428

RESUMO

INTRODUCTION: Although rhabdomyosarcoma (RMS) constitutes nearly 4% of all children diagnosed with cancer in the ethnically diverse small island city of Singapore, it is unknown how children with RMS fare. MATERIALS AND METHODS: This study investigated 50 children with RMS from April 1993 to December 2010 from KK Women's and Children's Hospital (KKH) and National University Hospital (NUH). They were treated either as per Intergroup Rhabdomyosarcoma Study Group (IRSG) or Société Internationale Pediatrique D'Oncologie (SIOP) regimens. RESULTS: Median age of diagnosis was 5.1 years (range, 0.1 to 17.3 years) with a median follow-up of 3.3 years (range, 0.4 to 15.6 years). According to IRSG classifi cation, 18 (36%) were staged as low-risk (LR); 19 (38%) were intermediate-risk (IR), 12 (24%) were high-risk (HR) and it was unknown in 1 patient. Twenty-nine (58%) were of embryonal subtype, 17 (34%) were alveolar and subclassification was not available in 4. The primary sites of tumour were: head and neck region (n = 22); genitourinary (n = 19); extremity (n = 10); and abdomen/retroperitoneal (n = 5). At the time of analysis, 80% were alive with no evidence of disease, 9 were dead of disease, and 2 were alive with disease. By disease risk group, the 5-year event-free survival (EFS) for LR group disease was 81.3% (95% CI, 62.0 to 100.0), IR group was 61.4% (95% CI, 32.3 to 90.4) and HR group was 25.0% (95% CI, 0.0 to 49.5) respectively (P <0.001). The 5-year EFS for risk by chemotherapy received as per SIOP vs per IRSG revealed: LR 83.3% vs 75.0% (P = 0.787); IR 83.3% vs 43.8% (P = 0.351); HR 0.0% vs 42.9% (P = 0.336) respectively. Of 15 relapses (HR, n = 7), at median of 2 years, 4 of 6 patients treated as per SIOP regimen were dead of disease and 3 of 8 treated as per IRSG were alive. CONCLUSION: Radiation therapy (RT) can be avoided in LR classification although those in higher risk classification need RT to local and distant metastatic disease. The outcome of children with RMS in Singapore can be further improved by coming together as a cooperative group to provide the best total care. Improved communication, multidisciplinary team collaboration, standardisation of protocols and rigorous data collection are keys.


Assuntos
Rabdomiossarcoma/terapia , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Recidiva Local de Neoplasia/terapia , Padrões de Prática Médica , Estudos Retrospectivos , Singapura
15.
J Clin Oncol ; 30(19): 2384-92, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22614971

RESUMO

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.


Assuntos
Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Malásia , Masculino , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Singapura , Resultado do Tratamento
16.
Ann Acad Med Singapore ; 41(4): 170-5, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22635281

RESUMO

INTRODUCTION: The care of children with cancer creates emotional and financial hardships for their families. There is a lack of information on the impact of childhood cancer on the family as a whole in Singapore. Thus, we set out to assess the financial impact as well as its psychosocial impact in our local context. MATERIALS AND METHODS: All patients diagnosed and treated for cancer at the Departments of Paediatrics, KK Women's and Children's Hospital and National University Hospital, Singapore were eligible for this study. Families of these patients completed 2 self-administered questionnaires: (i) About-you and your-family and (ii) the Impact-On-Family scale. For the latter, the total score was obtained by the summation of all scores, where high scores correlated to high impact. RESULTS: Seventy-nine parents were enrolled during the study period from October 2008 to February 2009. Being of Malay/Indian origin was associated with a high overall family burden. On the other hand, being of Malay/Indian origin was also associated with most successful at mastery when a child was diagnosed with cancer (P = 0.001). In addition, when compared to caregivers who remained employed, those who were asked to quit their job, experienced a higher Financial Burden (P = 0.03), a high Familial/Social Burden (P = 0.05) and a high Personal Strain (P = 0.03). CONCLUSION: Childhood cancer impacted family life in Singapore at many levels. In particular, the factors involved are various cultural discourses; employment status of caregivers; and those whose leave/pay are affected.


Assuntos
Cuidadores/psicologia , Efeitos Psicossociais da Doença , Saúde da Família , Família/psicologia , Neoplasias/psicologia , Adulto , Emprego/economia , Feminino , Humanos , Masculino , Neoplasias/economia , Singapura , Inquéritos e Questionários
17.
Pediatr Blood Cancer ; 58(4): 561-5, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22052842

RESUMO

BACKGROUND: Despite socioeconomic and clinical progress, pediatric tumors continue to present in advanced stage, and may be due to delays in diagnosis. This study aimed to identify factors associated with diagnostic delay (time between symptom onset and diagnosis) in pediatric tumors in a population-based study, and to assess the impact of delay on subsequent outcome. PROCEDURE: Natural logarithm of delay was retrospectively described for 390 newly diagnosed tumors reported to the Singapore Childhood Cancer Registry from 1997 to 2007. Delay was correlated with socio-demographic, disease and healthcare-system factors using multivariate linear regression, and with event-free survival (EFS) using Cox regression analysis. RESULTS: Total median delay was 5.3 weeks (range 0.1-283.1). Shorter delay was independently associated with younger patient age (P = 0.006), abdominal and pelvic sites (P < 0.001 and P = 0.036, respectively), incidental diagnoses by healthcare staff (P = 0.002), and when pediatric emergency units were the first contacted healthcare facilities and the first to raise suspicion of malignancy (P = 0.034, and P = 0.018, respectively). These factors explained only a small percentage of variance in delay times (21%). Delay was not associated with EFS and disease stage, with 24% of tumors presenting in stage 4. CONCLUSIONS: Diagnostic delay was independently associated with age and site of presentation, and points of first symptom detection, first healthcare contact, and first suspicion of malignancy. The broad range of clinical variables analyzed could only account in a small way for differences in delay times observed. While overall delay times were short, they did not influence disease stage at presentation and eventual outcome.


Assuntos
Neoplasias , Sistema de Registros , Adolescente , Criança , Pré-Escolar , Assistência à Saúde/economia , Assistência à Saúde/organização & administração , Assistência à Saúde/normas , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/economia , Neoplasias/mortalidade , Neoplasias/terapia , Estudos Retrospectivos , Singapura/epidemiologia , Fatores Socioeconômicos
18.
J Pediatr Hematol Oncol ; 33(6): e239-44, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21646920

RESUMO

The mitochondrial displacement loop (D-loop) controls mitochondrial expression, with mutations and mitochondrial DNA (mtDNA) content linked to oncogenesis. We investigated D-loop polymorphisms and mtDNA content in childhood acute lymphoblastic leukemia (ALL). The D-loop was sequenced in 251 children: precursor B ALL (n=114), with 76 paired remission/relapse samples; T-ALL (n=24); cord blood controls (n=113). The mtDNA copy number was analyzed using real-time quantitative polymerase chain reaction for 92 controls and 54 ALL patients at diagnosis and remission. Polymorphisms around H-strand replication origin (nucleotides 150 to 199) and conserved sequence block II (nucleotides 299 to 317) were associated with leukemia biology and treatment response. T-ALL patients were more likely to have longer nt303 poly-C tract. T199C polymorphism was associated with increased risk of ALL in Malays; T152C was more frequent in good responders. There was no difference in mtDNA content between diagnostic ALL samples and controls; however, there was significant decrease in mtDNA content after treatment, especially in samples with OH polymorphisms. Somatic mutations were found in 13% (9 of 76) of patients, suggesting a link to leukemogenesis. Our results suggest that polymorphisms impacting transcriptional control could affect mtDNA replication. Decrease in mtDNA content after treatment may confer susceptibility to chemotherapy and be a clue to the good prognosis of childhood ALL.


Assuntos
Aberrações Cromossômicas , DNA Mitocondrial/genética , Mitocôndrias/genética , Neoplasia Residual/genética , Polimorfismo Genético/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/administração & dosagem , Estudos de Casos e Controles , Criança , Pré-Escolar , Daunorrubicina/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Sangue Fetal , Humanos , Masculino , Neoplasia Residual/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Indução de Remissão , Vincristina/administração & dosagem
19.
Hematol Oncol ; 29(4): 211-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21387358

RESUMO

FMS-like tyrosine kinase 3 (FLT3) is critical for normal haematopoiesis and have been reported to be expressed in the majority of acute myeloid and lymphoid malignancies. We correlated the impact of FLT3 mutations and its expression with age, WHO 2008 classification and treatment outcome in 531 childhood acute leukaemias. Of 150 acute myeloid leukaemia (AMLs), 18 (12%) harboured FLT3-ITD while nine (6%) had FLT3-TKD. FLT3-ITD and -TKD were rare in acute megakaryoblastic leukaemia (AMKL; FLT3-ITD 0/26, FLT3-TKD 1/26) and children below 3 years (n = 2/48). Acute promyelocytic leukaemia (APL) with t(15;17);PML-RARα (n = 7/18; 39%) harboured the highest frequency of FLT3 mutations, followed by myelomonocytic (n = 4/18; 22%) and AML with t(8;21);RUNX1-RUNX1T1 (n = 2/21; 9%). FLT3 expression levels were also lowest in AMKL, both in Down's and non-Down's (p = 0.002) followed by patients <3 years (p = 0.001). The rarity of FLT3 mutations and expression levels in AMKL were independent of age. Conversely, only 2% of childhood acute lymphoblastic leukaemia (ALL) harboured FLT3 mutations (ITD = 1/381; TKD = 6/381). FLT3 was highly expressed in hyperdiploid ALL (p < 0.001). Of the 121 AMLs with clinical history, there were no significant differences in 4-year event-free survival (EFS) (46% vs. 38%; p = 0.46) and overall-survival (OS) (55% vs. 43%; p = 0.30) between FLT3-wildtype and ITD+ patients. Similarly, FLT3 expression levels did not influence survival in AML in both the good risk and non-good risk subgroups. FLT3 does not appear to be involved in the pathogenesis of AMKL, both in Down's and non-Down's. Therapeutic targets using FLT3 inhibitors may not be useful in AMKL and in young children with AML.


Assuntos
Leucemia/genética , Leucemia/mortalidade , Mutação , Tirosina Quinase 3 Semelhante a fms/genética , Doença Aguda , Adolescente , Grupo com Ancestrais do Continente Asiático , Criança , Pré-Escolar , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino
20.
Ann Acad Med Singapore ; 39(1): 43-8, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20126814

RESUMO

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.


Assuntos
Neoplasias/psicologia , Qualidade de Vida , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Neoplasias/terapia , Singapura
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