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  1. Oh L, Ab Rahman S, Dubinsky K, Azanan MS, Ariffin H
    Technol Cancer Res Treat, 2023;22:15330338221149799.
    PMID: 36624625 DOI: 10.1177/15330338221149799
    Recent studies have identified causal links between altered gut microbiome, chronic inflammation, and inflammation-driven conditions such as diabetes and cardiovascular disease. Childhood cancer survivors (CCS) show late effects of therapy in the form of inflammaging-related disorders as well as microbial dysbiosis, supporting a hypothesis that the conditions are interconnected. Given the susceptibility of the gut microbiome to alteration, a number of therapeutic interventions have been investigated for the treatment of inflammatory conditions, though not within the context of cancer survivorship in children and adolescents. Here, we evaluate the potential for these interventions, which include probiotic supplementation, prebiotics/fiber-rich diet, exercise, and fecal microbiota transplantation for prevention and treatment of cancer treatment-related microbial dysbiosis in survivors. We also make recommendations to improve adherence and encourage long-term lifestyle changes for maintenance of healthy gut microbiome in CCS as a potential strategy to mitigate treatment-related late effects.
  2. Chua LL, Azanan MS, Oh L, Ariffin H
    J Pediatr Hematol Oncol, 2023 Jul 01;45(5):e560-e566.
    PMID: 36730635 DOI: 10.1097/MPH.0000000000002586
    Young adult survivors of childhood leukemia have been reported with increased likelihood of age-related comorbidities compared with the general population. We compared the prevalence of frailty in young adult survivors of childhood acute lymphoblastic leukemia (n=58, median age=23 y, median survival time=18 y) with age-matched and sex-matched controls without history of cancer. Frailty phenotypes were determined using Fried frailty model. Association between frailty status and cardiometabolic conditions, systemic inflammation, and T-cell immunophenotype changes were also examined. Frailty and prefrailty were more common among survivors compared with controls (58.6% vs. 34.5%, P =0.019). Physical inactivity (39.7%) was the most frequently observed frailty criterion among the survivors. Prevalence of cardiometabolic conditions was comparable between the robust and frail/prefrail survivors. Robust survivors had a higher level of T-cell activation than the prefrail/frail survivors ( P <0.05), but no significant difference was observed for systemic inflammatory markers (IL-6 and C-reactive protein) and percentage of terminally differentiated T cells. Signs of frailty, especially physical inactivity, was detected in childhood acute lymphoblastic leukemia survivors early in their third decade of life. Survivors who were prefrail/frail also had altered T-cell activation; however, the role of such changes in T-cell phenotype in the etiology of frailty warrant further investigation.
  3. Lai CD, Marret MJ, Jayanath S, Azanan MS
    Child Abuse Negl, 2023 Nov;145:106434.
    PMID: 37657172 DOI: 10.1016/j.chiabu.2023.106434
    BACKGROUND: Abusive head trauma (AHT) is a major cause of traumatic brain injury in infancy. This exploratory study compared standardized developmental assessment versus functional outcome assessment between 18 months and 5 years of age following AHT in infancy.

    METHODS: Observational cross-sectional study after surviving AHT in infancy. Seventeen children between 18 months and 5 years of age underwent clinical examination, developmental assessment using the Schedule of Growing Skills II (SGS II) and functional assessment using the Glasgow Outcome Scale-Extended Pediatric Revision (GOS-E Peds). Additional clinical information was extracted from medical records.

    RESULTS: Age at assessment ranged from 19 to 53 months (median 26 months). Most (n = 14) were delayed in at least 1 domain, even without neurological or visual impairment or visible cortical injury on neuroimaging, including 8 children with favourable GOS-E Peds scores. The most affected domain was hearing and language. Delay in the manipulative domain (n = 6) was associated with visual and/or neurological impairment and greater severity of delay across multiple domains. Eleven (64.7 %) had GOS-E Peds scores indicating good recovery, with positive correlation between GOS-Peds scores and number of domains delayed (r = 0.805, p 

  4. Al-Haroni H, Nik Farid ND, Azanan MS
    PLoS One, 2024;19(1):e0289937.
    PMID: 38232100 DOI: 10.1371/journal.pone.0289937
    BACKGROUND: Among the most urgent public health challenges, of the twenty-first century, is obesity. This can be attributed to its relationship with several non-communicable diseases (NCDs), as well as premature mortality. Being overweight or obese is a major concern not only in high-income countries, but also in low-income and middle-income countries, particularly in urban areas. Several studies have highlighted the prevalence of obesity, among Middle Eastern-descent adolescents, studying in Arabic secondary schools, located in Malaysia. Intervention studies, directed at Middle Eastern adolescents in Malaysia, are limited. This paper, describes the protocol, for an integrated health education intervention process. Titled 'Healthy lifestyle', it is a primary prevention process, aimed at curbing obesity and disordered eating, among Middle Eastern secondary school adolescents, aged 13-14 years old, residing in Malaysia.

    METHODS AND ANTICIPATED RESULTS: A cluster randomized controlled study will be conducted, involving 250 Middle Eastern adolescents, in Arabic schools in Malaysia. The participants will be randomly assigned to the intervention and control groups. While the intervention group participates in six weeks of fortnightly six sessions (45 minutes per session), the control group will carry on with their regular curriculums, and normal physical activity routines. The variables which will be evaluated include anthropometric measurements, knowledge, attitude, daily routines, physical activity, sedentary behaviour, food assessment, eating attitudes test-26, and a structured questionnaire based on the HBM. Data will be collected from the intervention and control groups at baseline, post-intervention, and two months following the intervention. Data analysis will be performed by way of the SPSS Statistics software version 26. The generalized estimating equation (GEE) will be used, to test the effect of the intervention program, with regards to the selected variables (outcomes), between and within-group at baseline, as well as six weeks and two months following intervention, after adjusting for clustering. Outcomes will be assessed at each time point, along with a derived average over all three-time points; thus, ensuring that both the cumulative and overall effects are determined.

    CONCLUSIONS: This trial will provide useful information for improving the knowledge, attitude, and practices of Middle Eastern adolescents, with regards to body weight status, physical activity level, nutrition status (BMI and dietary intake), and disordered eating. This will go a long way, towards ensuring their adherence to appropriate physical activities, and a healthy diet, to keep non-communicable diseases at bay.

    TRIAL REGISTRATION: This study is registered at NCT: NCT05694143.

  5. Chew N, Noor Azhar AM, Bustam A, Azanan MS, Wang C, Lum LCS
    PLoS Negl Trop Dis, 2020 09;14(9):e0008562.
    PMID: 32881914 DOI: 10.1371/journal.pntd.0008562
    BACKGROUND: Dengue is a systemic and dynamic disease with symptoms ranging from undifferentiated fever to dengue shock syndrome. Assessment of patients' severity of dehydration is integral to appropriate care and management. Urine colour has been shown to have a high correlation with overall assessment of hydration status. This study tests the feasibility of measuring dehydration severity in dengue fever patients by comparing urine colour captured by mobile phone cameras to established laboratory parameters.

    METHODOLOGY/PRINCIPAL FINDINGS: Photos of urine samples were taken in a customized photo booth, then processed using Adobe Photoshop to index urine colour into the red, green, and blue (RGB) colour space and assigned a unique RGB value. The RGB values were then correlated with patients' clinical and laboratory hydration indices using Pearson's correlation and multiple linear regression. There were strong correlations between urine osmolality and the RGB of urine colour, with r = -0.701 (red), r = -0.741 (green), and r = -0.761 (blue) (all p-value <0.05). There were strong correlations between urine specific gravity and the RGB of urine colour, with r = -0.759 (red), r = -0.785 (green), and r = -0.820 (blue) (all p-value <0.05). The blue component had the highest correlations with urine specific gravity and urine osmolality. There were moderate correlations between RGB components and serum urea, at r = -0.338 (red), -0.329 (green), -0.360 (blue). In terms of urine biochemical parameters linked to dehydration, multiple linear regression studies showed that the green colourimetry code was predictive of urine osmolality (β coefficient -0.082, p-value <0.001) while the blue colourimetry code was predictive of urine specific gravity (β coefficient -2,946.255, p-value 0.007).

    CONCLUSIONS/SIGNIFICANCE: Urine colourimetry using mobile phones was highly correlated with the hydration status of dengue patients, making it a potentially useful hydration status tool.

  6. Chin TF, Ibrahim K, Thirunavakarasu T, Azanan MS, Oh L, Lum SH, et al.
    Fetal Pediatr Pathol, 2018 Aug;37(4):243-253.
    PMID: 30273079 DOI: 10.1080/15513815.2018.1492054
    BACKGROUND: Survivors of childhood cancer are at risk of developing a second malignancy. One possible mechanism for neoplastic transformation of cells is through induction of persistent genomic instability. This study aims to seek evidence of chromosomal instability in long-term childhood leukemia survivors (CLS) in one of the largest pediatric academic oncology centers in South East Asia.

    METHODS: 50 asymptomatic (subjects have remained leukemia-free since treatment cessation) CLS and 50 healthy controls were recruited in this cross-sectional study. Of 50 CLS, 44 had acute lymphoblastic leukemia and 6 had acute myeloid leukemia. G-banded karyotyping was performed on unstimulated peripheral blood leukocytes of all subjects.

    RESULTS: CLS had significantly higher occurrence of karyotypic abnormalities compared to controls. Five CLS harbored six nonclonal abnormalities (mostly aneuploidy) while none were found in controls.

    CONCLUSION: Subpopulations with nonclonal chromosomal aberrations were present in peripheral blood leukocytes of our cohort of childhood leukemia long-term survivors.

  7. Fong CY, Kangatharan PASS, Lim WK, Ong LC, Li L, Azanan MS, et al.
    Brain Dev, 2025 Apr;47(2):104339.
    PMID: 39999621 DOI: 10.1016/j.braindev.2025.104339
    AIM: Describe the neurological and functional outcomes, and health-related quality of life (HRQL) of Malaysian children with stroke; and explore factors associated with poor outcomes and lower HRQL.

    METHOD: Cross-sectional study of Malaysian stroke children who were followed-up for at least 2 years. Paediatric Stroke Outcome Measure (PSOM) and modified Rankin scale (mRS) were utilised to assess neurological and functional outcomes. HRQL was assessed using PedsQL (Paediatric Quality of Life inventory) 4.0. Multiple regression analysis was used to determine factors associated with poor PSOM, poor mRS, and lower HRQL.

    RESULTS: Seventy-six children were recruited. Majority have good mRS (72.4 %) and good PSOM (75 %). PedsQL total, physical health summary and psychosocial health summary mean scores were 74.2(SD 21.57), 74.2(SD 28.16) and 76.13(SD 18.66) respectively, which were significantly lower compared with healthy Malaysian children (p ≤ 0.001). Learning disability post-stroke was associated with poor PSOM and poor mRS; while cardiac surgery was associated with poor mRS. Learning disability post-stroke was associated with lower total, physical health summary and psychosocial health summary PedsQL scores. Poor mRS was associated with lower total PedsQL scores while poor PSOM was associated with lower total and physical health summary PedsQL.

    CONCLUSION: Although majority of Malaysian children with stroke had good long-term neurological and functional outcomes, they had lower HRQL compared to healthy Malaysian children. Optimizing care for cardiac surgery to reduce the risk of perioperative stroke may lead to improved neurological outcome. There is a need to address the issues of learning disability post-stroke and poor neurological outcome to reduce their impact on HRQL.

  8. Azanan MS, Chandrasekaran S, Rosli ES, Chua LL, Oh L, Chin TF, et al.
    J Pediatr Hematol Oncol, 2020 08;42(6):e394-e400.
    PMID: 32118813 DOI: 10.1097/MPH.0000000000001766
    BACKGROUND: Microvascular endothelial dysfunction is central to the pathogenesis of cardiovascular disease (CVD). The eye offers direct access for endothelial health assessment via the retinal microvasculature. The aim of the study was to investigate whether image-based retinal vessel analysis is a feasible method of assessing endothelial health in survivors of childhood acute lymphoblastic leukemia (cALL).

    MATERIALS AND METHODS: Cardiovascular risk factors (CRFs) were estimated using the 30-year Framingham Risk Score in 73 childhood leukemia survivors (median age: 25; median years from diagnosis: 19) and 78 healthy controls (median age: 23). Radial arterial stiffness was measured using pulse wave analyzer, while endothelial activation markers were measured by soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). Retinal fundus images were analyzed for central retinal artery/vein equivalents (CRAE/CRVE) and arteriolar-venular ratio (AVR).

    RESULTS: cALL survivors had higher CRF (P<0.0001), arterial stiffness (P=0.001), and sVCAM-1 (P=0.007) compared with controls. Survivors also had significantly higher CRVE (P=0.021) while AVR was significantly lower (P=0.026) in survivors compared with controls, compatible with endothelial dysfunction. In cALL survivors with intermediate risk for CVD, CRAE, and AVR are significantly lower, while sVCAM-1 and sICAM-1 are significantly higher when compared with survivors with low CVD risk after adjusting with covariates (age, sex, and smoking status).

    CONCLUSIONS: cALL survivors have an increased risk of CVD compared with age-matched peers. The survivors demonstrated microvasculopathy, as measured by retinal vascular analysis, in addition to physical and biochemical evidence of endothelial dysfunction. These changes predate other measures of CVD. Retinal vessel analysis may be utilized as a robust screening tool for identifying survivors at increased risk for developing CVD.

  9. Azanan MS, Abdullah NK, Chua LL, Lum SH, Ghafar SS, Kamarulzaman A, et al.
    Eur J Immunol, 2016 Apr 30.
    PMID: 27129782 DOI: 10.1002/eji.201646356
    Many treatment complications which occur late in childhood cancer survivors resemble age-related co-morbidities observed in the elderly. An immune phenotype characterized by increased immune activation, systemic inflammation and accumulation of late-differentiated memory CD57(+) CD28(-) T cells has been associated with co-morbidities in the elderly. Here we explored if this phenotype was present in young adult leukemia survivors following an average of 19 years from chemotherapy and/or radiotherapy completion, and compared this with that in age-matched controls. We found that markers of systemic inflammation - IL-6 and human C-reactive protein (hCRP) and immune activation - CD38 and HLA-DR on T cells, sCD163 from monocytes and macrophages - were increased in survivors compared to controls. T-cell responses specific to cytomegalovirus (CMV) were also increased in survivors compared to controls while CMV IgG levels in survivors were comparable to levels measured in the elderly (>50years) and correlated with IL-6, hCRP, sCD163 and CD57(+) CD28(-) memory T cells. Immune activation and inflammation markers correlated poorly with prior chemotherapy and radiotherapy exposure. These data suggest that CMV infection/reactivation is strongly correlated with the immunological phenotype seen in young childhood leukemia survivors and these changes may be associated with the early onset of age-related co-morbidities in this group. This article is protected by copyright. All rights reserved.
  10. Chua LL, Rajasuriar R, Azanan MS, Abdullah NK, Tang MS, Lee SC, et al.
    Microbiome, 2017 03 20;5(1):35.
    PMID: 28320465 DOI: 10.1186/s40168-017-0250-1
    BACKGROUND: Adult survivors of childhood cancers such as acute lymphoblastic leukemia (ALL) have health problems that persist or develop years after cessation of therapy. These late effects include chronic inflammation-related comorbidities such as obesity and type 2 diabetes, but the underlying cause is poorly understood.

    RESULTS: We compared the anal microbiota composition of adult survivors of childhood ALL (N = 73) with healthy control subjects (N = 61). We identified an altered community with reduced microbial diversity in cancer survivors, who also exhibit signs of immune dysregulation including increased T cell activation and chronic inflammation. The bacterial community among cancer survivors was enriched for Actinobacteria (e.g. genus Corynebacterium) and depleted of Faecalibacterium, correlating with plasma concentrations of IL-6 and CRP and HLA-DR+CD4+ and HLA-DR+CD8+ T cells, which are established markers of inflammation and immune activation.

    CONCLUSIONS: We demonstrated a relationship between microbial dysbiosis and immune dysregulation in adult ALL survivors. These observations suggest that interventions that could restore microbial diversity may ameliorate chronic inflammation and, consequently, development of late effects of childhood cancer survivors.

  11. Chandrasekaran S, Ramli N, Ahmad MJ, Effendi I, Amir NN, Chow RC, et al.
    J Adolesc Young Adult Oncol, 2021 08;10(4):425-431.
    PMID: 32996803 DOI: 10.1089/jayao.2020.0064
    Purpose: Childhood cancer survivors (CCS) demonstrate features of premature aging in a multitude of organ systems. The aim of this pilot study is to determine the presence of premature ocular aging features in CCS, specifically childhood acute lymphoblastic leukemia (ALL) survivors. Methods: This prospective case-control study was conducted over a period of 21 months, starting July 2015 till March 2017. A total of 59 childhood ALL survivors who attended the Paediatric Oncology Clinic of University Malaya Medical Centre (UMMC) and 48 age, race, and gender-matched controls went through a series of ocular examinations and tests. Inclusion criteria used to recruit survivors were age above 16 years, history of ALL in childhood, completion of treatment for ALL, and a remission period of at least 5 years. Patients with ocular disease and those who received hematopoietic stem cell transplantation were excluded. The parameters measured were visual acuity, amplitude of accommodation, pupil cycle time (PCT), and tear break-up time (TBUT). Results: Survivors of childhood ALL demonstrated significant differences in amplitude of accommodation, PCT, and TBUT compared to age-matched controls. Survivors had a lower median (interquartile range [IQR]) amplitude of accommodation compared to controls (11.0 D [9.0-13.0] vs. 12.0 D [10.5-15]; p = 0.045). Survivors also showed a longer median (IQR) PCT in comparison to controls (931.00 mseconds (857.00-1063.00) vs. 875.50 mseconds (825.75-966.00); p = 0.024). In addition, median (IQR) TBUT was worse in survivors in comparison to the control group (9 seconds [6-13] vs. 11 seconds [10-15]; p = 0.001). Conclusion: Survivors of childhood ALL demonstrate premature ocular aging features compared to age-matched controls. Thus, survivors may benefit from having ocular examinations as part of their routine late-effects screening to detect age-related ocular morbidities early in its course.
  12. Abdullah AH, Nathan AM, Jayanath S, Kwan Z, Azanan MS, Hng SY, et al.
    Pediatr Int, 2023 Jan;65(1):e15473.
    PMID: 36645391 DOI: 10.1111/ped.15473
    BACKGROUND: Sleep disturbance in children with atopic dermatitis (AD) frequently goes unnoticed and can be associated with behavioral challenges. The aims of this study were to determine (a) the prevalence and factors associated with sleep disturbance and behavioral problems and (b) the correlation between sleep disturbance and behavioral problems in children with AD.

    METHODS: This cross-sectional study involved children aged 4-12 years old with moderate to severe AD. Age and sex-matched healthy children were recruited as the comparison group. The Children's Sleep Habits Questionnaire (CSHQ) and the Strengths and Difficulties Questionnaire (SDQ) were used to assess sleep disturbance and behavioral problems, respectively. Higher scores in both questionnaires signify more disturbance.

    RESULTS: Seventy patients and 141 controls were recruited. Median (interquartile range) age of patients was 5 (4,8) years. Patients had later sleep time (p 

  13. Tan YT, Azanan MS, Hng SY, Eg KP, Jalaludin MY, Thong MK, et al.
    J Clin Sleep Med, 2024 Aug 01;20(8):1291-1299.
    PMID: 38557309 DOI: 10.5664/jcsm.11140
    STUDY OBJECTIVES: The effect of recombinant human growth hormone (rhGH) on sleep-disordered breathing (SDB) in Malaysian children with Prader-Willi syndrome (PWS) is under-investigated. We determined (1) the short- and long-term effects of rhGH and (2) factors associated with worsening SDB in children with PWS receiving rhGH.

    METHODS: This retrospective study included children with PWS (with and without rhGH) who had undergone at least 1 polysomnography. Outcomes measured were the presence of SDB before and after starting rhGH and the progress of SDB with and without rhGH. Serial insulin-like growth factor 1 (IGF-1) measurements were recorded.

    RESULTS: One-hundred and thirteen polysomnograms were analyzed. The majority (92.3%) of initial polysomnograms showed SDB, with a median (interquartile range) apnea-hypopnea index of 5.0 (2.6, 16.3) events/h. The age for receiving rhGH was a median (IQR) of 1.9 (0.7, 3.4) years. One-third (36.8%) had worsening SDB after initiating rhGH, which was associated with higher IGF-1 levels post-rhGH (P = .007). After a median of 5 years of rhGH, 73.6% maintained or reduced their positive airway pressure settings. Without rhGH, 80% had increased their positive airway pressure settings. Worsening SDB while on rhGH was associated with higher body mass index, lower rhGH dose, higher IGF-1 levels, and non-15q deletion.

    CONCLUSIONS: The majority of Malaysian children with PWS had SDB. At initiation of rhGH, one-third of patients had worsening SDB, associated with increased IGF-1 levels. Stabilization of SDB was more frequently seen in those receiving long-term rhGH. Worsening SDB while on rhGH was associated with a higher body mass index, receiving a lower dose of rhGH, higher IGF-1 levels, and non-15q deletion.

    CITATION: Tan YT, Azanan MS, Hng SY, et al. Long-term effect of growth hormone on sleep-disordered breathing in Malaysian children with Prader-Willi syndrome: a retrospective study. J Clin Sleep Med. 2024;20(8):1291-1299.

  14. Ariffin H, Azanan MS, Abd Ghafar SS, Oh L, Lau KH, Thirunavakarasu T, et al.
    Cancer, 2017 Nov 01;123(21):4207-4214.
    PMID: 28654149 DOI: 10.1002/cncr.30857
    BACKGROUND: Large epidemiologic studies have reported the premature onset of age-related conditions, such as ischemic heart disease and diabetes mellitus, in childhood cancer survivors, decades earlier than in their peers. The authors investigated whether young adult survivors of childhood acute lymphoblastic leukemia (ALL) have a biologic phenotype of cellular ageing and chronic inflammation.

    METHODS: Plasma inflammatory cytokines were measured using a cytometric bead array in 87 asymptomatic young adult survivors of childhood ALL (median age, 25 years; age range, 18-35 years) who attended annual follow-up clinic and compared with healthy, age-matched and sex-matched controls. Leukocyte telomere length (LTL) was measured using Southern blot analysis.

    RESULTS: Survivors had significant elevation of plasma interleukin-2 (IL-2), IL-10, IL-17a, and high-sensitivity C-reactive protein levels (all P 0.8 mg/dL) was related to increased odds of having metabolic syndrome (odds ratio, 7.256; 95% confidence interval, 1.501-35.074). Survivors also had significantly shorter LTL compared with controls (median, 9866 vs 10,392 base pairs; P = .021). Compared with published data, LTL in survivors was similar to that in healthy individuals aged 20 years older. Survivors who received cranial irradiation had shorter LTL compared with those who had not (P = .013).

    CONCLUSIONS: Asymptomatic young adult survivors of childhood ALL demonstrate a biologic profile of chronic inflammation and telomere attrition, consistent with an early onset of cellular processes that drive accelerated aging. These processes may explain the premature development of age-related chronic conditions in childhood cancer survivors. Understanding their molecular basis may facilitate targeted interventions to disrupt the accelerated aging process and its long-term impact on overall health. Cancer 2017;123:4207-4214. © 2017 American Cancer Society.

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