Publications by authors named "Azlan Husin"

25 Publications

  • Page 1 of 1

Impact of Fas/Fasl Gene Polymorphisms on Susceptibility Risk and Imatinib Mesylate Treatment Response in Chronic Myeloid Leukaemia Patients.

Asian Pac J Cancer Prev 2021 Feb 1;22(2):565-571. Epub 2021 Feb 1.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.

Background: The FAS mediated apoptosis pathway involving the FAS and FASL genes plays a crucial role in the regulation of apoptotic cell death and imatinib mesylate (IM) mechanism of action. Promoter polymorphisms FAS-670 A>G and FAS-844 T>C which alter the transcriptional activity of these genes may grant a risk to develop cancer and revamp the drug activities towards the cancer cell. We investigated the association of these two polymorphisms with the susceptibility risk and IM treatment response in Malaysian chronic myeloid leukaemia (CML) patients.

Methods: This is a retrospective study, which included 93 CML patients and 98 controls. The polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method was used to genotype the FAS and FASL polymorphisms. Data nanlysis was done using SPSS Version 22. The associations of the genotypes with susceptibility risk and IM response in CML patients were assessed by means of logistic regression analysis and deriving odds ratio with 95% CI.

Results: We observed a significant association between FASL-844T>C polymorphism and CML susceptibility risk and IM response. Variant C allele and FASL-844 CC variant genotype carriers had significantly higher risk for CML susceptibility (OR 1.756, CI 1.163-2.652, p=0.007 and OR 2.261, CI 1.013-5.047, p=0.047 respectively). Conversely, the heterozygous genotype FASL-844 TC conferred lower risk for CML susceptibility (OR 0.379, CI 0.176-0.816, p=0.013). The heterozygous and homozygous variant genotypes and variant C alleles were found to confer a lower risk for the development of IM resistance with OR 0.129 (95% CI: 0.034-0.489 p=0.003), OR 0.257 (95% CI: 0.081-0.818, p=0.021), and OR 0.486 (95% CI: 0.262-0.899, p=0.021) respectively. We also found that FAS-670 A>G polymorphism was not associated with CML susceptibility risk or IM response.

Conclusion: The genetic polymorphism FASL-844 T>C may contribute to the CML susceptibility risk and also IM treatment response in CML patients. Accodringly, it may be useful as a biomarker for predicting CML susceptibility risk and IM resistance.
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http://dx.doi.org/10.31557/APJCP.2021.22.2.565DOI Listing
February 2021

Aberrant Methylation of Tumour Suppressor Gene ADAM12 in Chronic Lympocytic Leukemia Patients: Application of Methylation Specific-PCR Technique.

Asian Pac J Cancer Prev 2021 Jan 1;22(1):85-91. Epub 2021 Jan 1.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Objective: Chronic Lymphocytic Leukemia (CLL) is a common leukemia among Caucasians but rare in Asians population. We postulated that aberrant methylation either hypermethylation or partial methylation might be one of the silencing mechanisms that inactivates the tumour suppressor genes in CLL. This study aimed to compare the methylation status of tumour suppressor gene, ADAM12, among CLL patients and normal individuals. We also evaluated the association between methylation of ADAM12 and clinical and demographic characteristics of the participants.

Methods: A total of 25 CLL patients and 25 normal individuals were recruited in this study. The methylation status of ADAM12 was determined using Methylation-Specific PCR (MSP); whereas, DNA sequencing method was applied for validation of the MSP results.

Results: Among CLL patients, 12 (48%) were partially methylated and 13 (52%) were unmethylated. Meanwhile, 5 (20%) and 20 (80.6%) of healthy individuals were partially methylated and unmethylated, respectively. There was a statistically significant association between the status of methylation at ADAM12 and the presence of CLL (p=0.037).

Conclusion: The aberrant methylation of ADAM12 found in this study using MSP assay may provide new exposure to CLL that may improve the gaps involved in genetic epigenetic study in CLL.
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http://dx.doi.org/10.31557/APJCP.2021.22.1.85DOI Listing
January 2021

Neuroretinitis: A Rare Coinfection in POEMS Syndrome.

Turk J Ophthalmol 2020 12;50(6):371-376

University Sains Malaysia School of Medical Sciences, Department of Internal Medicine, Kelantan, Malaysia.

is a recognized cause of neuroretinitis in cat scratch disease. Meanwhile, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome with Castleman disease (evidence of lymph node hyperplasia), is a chronic debilitating condition that predisposes to various superimposed infections. neuroretinitis implicated in POEMS syndrome has not been reported previously. A 34-year-old asymptomatic man was referred for an eye assessment. Examination showed visual acuity of 6/18 in the right eye and 6/24 in the left eye. On fundus examination, both eyes exhibited typical features of neuroretinitis (optic disc swelling and incomplete macular star). There was otherwise no vitritis or chorioretinitis. Serology for revealed high immunoglobulin M (IgM) titer (1:96) indicative of acute disease, and positive immunoglobulin G (IgG) (1:156). He was treated with oral azithromycin for 6 weeks and a short course of oral prednisolone. Subsequently, the visual acuity in both eyes improved with resolution of macular star. However, both optic discs remained swollen.
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http://dx.doi.org/10.4274/tjo.galenos.2020.83873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802104PMC
December 2020

Relapsed/Progressive Disease and Its Prognostic Factors among Multiple Myeloma Patients Receiving Novel Agent Treatment in North East Peninsular Malaysia: A Single Centre Experience.

Malays J Med Sci 2020 Oct 27;27(5):62-77. Epub 2020 Oct 27.

Haematopoietic Stem Cell Transplant Unit, Hospital Universiti Sains Malaysia, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Background: Some multiple myeloma (MM) patients still relapse/progress despite novel agent therapy and relapse/progression in MM is therefore a vital area of ongoing research in the novel treatment era. This retrospective cohort study aimed to evaluate the time to relapse/progression (TTP) among MM patients who received novel agents and to determine the associated prognostic factors.

Methods: This study included 89 MM patients treated at Hospital Universiti Sains Malaysia. We analysed the TTP and the type of relapse/progression (biochemical versus clinical), and a Cox proportional hazard model was used to identify the significant prognostic factors.

Results: Sixty-four percent of patients had biochemical relapse/progression. The overall median TTP among MM patients who received the novel agent(s) was 29.33 months (95% CI: 21.36-37.29). The type of paraprotein at diagnosis ( = 0.026, 0.228), International Staging System (ISS) score ( = 0.036, = 0.067) and autologous stem cell transplant (ASCT) ( 0.002) were prognostic factors for relapse/progression by simple Cox regression, but ASCT was the only significant predictor detected by multiple Cox regression ( = 0.003).

Conclusion: Our study reflects the importance of paraprotein monitoring to detect early features of relapse/progression. ASCT is the most prognostic factor that may lengthen the TTP.
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http://dx.doi.org/10.21315/mjms2020.27.5.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605841PMC
October 2020

Left atrial appendage and atrial septal occlusion in elderly patients with atrial septal defect and atrial fibrillation.

Pacing Clin Electrophysiol 2020 11 7;43(11):1252-1257. Epub 2020 Sep 7.

Electrophysiology Unit, Department of Cardiology, Institut Jantung Negara (National Heart Institute), Kuala Lumpur, Malaysia.

Background: Elderly patients with atrial septal defect (ASD) often present with chronic atrial fibrillation and large left to right shunt. This study reports the experience of left atrial appendage (LAA) and ASD closure in patients with significant ASD and chronic atrial fibrillation.

Methods: We report six consecutive elderly patients with chronic atrial fibrillation and significant ASD who underwent LAA and fenestrated ASD closure from January 1, 2014 until December 31, 2019. All periprocedural and long-term (>1 year) outcomes were reported.

Results: Six patients (male: 33.3%; mean age: 66.8 ± 3.3 years) were included. Mean CHADS , CHA DS -VAS , and HAS-BLED scores were 2.33 ± 0.82, 3.83 ± 0.75, and 1.83 ± 0.75. Four patients underwent simultaneous procedure, while two patients underwent a staged procedure. Procedural success was achieved in all patients. Total occlusion was achieved during LAA occlusion without device embolization prior to ASD closure. Patients who underwent simultaneous procedure had a shorter total hospital stay and lower total hospital stay. During a follow-up period of 32.8 ± 19.4 months, both the devices were well seated. No device-related thrombosis or erosion reported. All patients remained in atrial fibrillation. No patients experienced any thromboembolic stroke or transient ischemic attack.

Conclusions: LAA and ASD closure is feasible and can be safely performed in the same seating in elderly patients with a significant ASD.
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http://dx.doi.org/10.1111/pace.14049DOI Listing
November 2020

Autologous Peripheral Blood Stem Cell Transplantation Among Lymphoproliferative Disease Patients: Factors Influencing Engraftment.

Oman Med J 2019 Jan;34(1):34-43

Department of Hematology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia.

Objectives: Autologous peripheral blood stem cells transplantation (APBSCT) is a therapeutic option which can be used in various hematological, neoplastic disorders including lymphoproliferative disease (LPD). Differences in patient populations and treatment modalities in different transplant centers mean it is important to improve the knowledge of the different factors affecting engraftment after APBSCT for the success of this procedure. We sought to determine the factors influencing neutrophil and platelet engraftment after APBSCT in patients with LPD.

Methods: We conducted a retrospective review of 70 patients with LPD (35 with lymphoma and 35 with multiple myeloma) who had undergone APBSCT between January 2008 and December 2016. Data obtained included disease type, treatment, and stem cell characteristics. Kaplan-Meier analysis was performed for probabilities of neutrophil and platelet engraftment occurred and was compared by the log-rank test. The multivariate Cox proportional hazards regression model was used for the analysis of potential independent factors influencing engraftment. A -value < 0.050 was considered statistically significant.

Results: Most patients were ethnic Malay, the median age at transplantation was 49.5 years. Neutrophil and platelet engraftment occurred in a median time of 18 (range 4-65) and 17 (range 6-66) days, respectively. The majority of patients showed engraftment with 65 (92.9%) and 63 (90.0%) showing neutrophil and platelet engraftment, respectively. We observed significant differences between neutrophil engraftment and patient's weight (< 60/≥ 60 kg), stage of disease at diagnosis, number of previous chemotherapy cycles (< 8/≥ 8), and pre-transplant radiotherapy. While for platelet engraftment, we found significant differences with gender, patient's weight (< 60/≥ 60 kg), pre-transplant radiotherapy, and CD34+ dosage (< 5.0/≥ 5.0 × 10/kg and < 7.0/≥ 7.0 × 10/kg). The stage of disease at diagnosis ( 0.012) and pre-transplant radiotherapy ( 0.025) were found to be independent factors for neutrophil engraftment whereas patient's weight (< 60/≥ 60 kg, 0.017), age at transplantation (< 50/≥ 50 years, 0.038), and CD34+ dosage (< 7.0/≥ 7.0 × 10/kg, 0.002) were found to be independent factors for platelet engraftment.

Conclusions: Patients with LPD who presented at an early stage and with no history of radiotherapy had faster neutrophil engraftment after APBSCT, while a younger age at transplantation with a higher dose of CD34+ cells may predict faster platelet engraftment. However, additional studies are necessary for better understanding of engraftment kinetics to improve the success of APBSCT.
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http://dx.doi.org/10.5001/omj.2019.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330180PMC
January 2019

The epidemiology and clinical characteristics of myeloproliferative neoplasms in Malaysia.

Exp Hematol Oncol 2018 17;7:31. Epub 2018 Dec 17.

Department of Haematology, Sunway Medical Centre, Kuala Lumpur, Malaysia.

Background: The evolution of molecular studies in myeloproliferative neoplasms (MPN) has enlightened us the understanding of this complex disease consisting of polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The epidemiology is well described in the western world but not in Asian countries like Malaysia.

Materials And Methods: This retrospective national registry of MPN was conducted from year 2009 to 2015 in Malaysia.

Results: A total of 1010 patients were registered over a period of 5 years. The mean age was 54 years with male predominance. The ethnic distribution revealed that Chinese had a relatively high weighted incidence proportion (43.2%), followed by Indian (23.8%), Malay (15.8%) and other ethnic groups (17.2%). The types of MPN reported were 40.4% of ET (n = 408), 38.1% of PV (n = 385), 9.2% of PMF (n = 93), 3.1% of hypereosinophilic syndrome (HES) (n = 31) and 7.9% of unclassifiable MPN (MPN-U) (n = 80). Splenomegaly was only palpable clinically in 32.2% of patients. The positive JAK2 V617F mutation was present in 644 patients with 46.6% in PV, 36.0% in ET, 9.0% in PMF, and 7.4% in MPN-U, and had significantly lower haemoglobin (p < 0.001), haematocrit (p < 0.001) and white blood cells (WBC) (p < 0.001) than those with negative mutation. Significant differences in platelet and WBC count were detected in ethnic groups and MPN sub-types. There were more arterial thrombosis events seen in those with JAK2 V617F mutation as compared to venous thrombosis events (23.1% vs 4.4%). The bleeding rate was only 6.6%. Among the risk factors, previous thrombosis, old age (≥ 60 years) and hypertension were significantly correlated to positive JAK2 V617F mutation. The arterial thrombosis event is associated with higher presenting HB, HCT and PLT while the bleeding event is associated with lower presenting HB, HCT but higher PLT. The presence of JAK2 V617F mutation is associated with higher risk of arterial thrombosis.

Conclusion: Chinese ethnicity is associated with higher rates of MPN. The history of thrombosis, age ≥ 60 years and hypertension are risk factors that can be correlated to JAK2 V617F mutation. This study is instrumental for policy makers to ensure preventive strategies can be implemented in future.
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http://dx.doi.org/10.1186/s40164-018-0124-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296047PMC
December 2018

Genetic variations in influx transporter gene are associated with clinical responses to imatinib mesylate among Malaysian chronic myeloid leukaemia patients.

J Genet 2018 Sep;97(4):835-842

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Imatinib mesylate (IM), a well-established gold standard drug in the treatment of chronic myeloid leukaemia (CML), is a synthetic tyrosine kinase inhibitor. Despite excellent efficacy, a significant number of patients on IM therapy develop resistance to IM. Currently, great focus has been laid on the effect of interindividual pharmacogenetic variability on IM treatment responses. IM uptake is mediated by the hOCT1 protein encoded by the solute carrier 22 gene (). The current study investigated the impact of few single-nucleotide polymorphisms (SNPs) of on mediating resistance and/or good response to IM among 278 Malaysian CML patients (146 IM-resistant group and 132 IM good response group) undergoing IM therapy on 400 mg daily. Our results showed that the allelic frequencies of heterozygous (CG) and homozygous variant (GG) genotypes of C480G were significantly higher in the IM-resistant group compared with the IM good response group (41.8% versus 30.3% and 10.9% versus 4.5% with values of 0.047 and 0.048, respectively). On evaluating the association of genotypes with risk of IM resistance development, heterozygous (CG) and homozygous (GG) variant genotypes showed significantly higher risk for developing resistance to IM treatment with odds ratio (OR): 1.901 (95% confidence interval (CI): 1.142-3.163, = 0.013) and 3.324 (95% CI: 1.235-8.947, = 0.017), respectively. Two SNPs and two insertions/deletions were detected in exon 7 of . For exon 7, 1222AA carriers together with the presence of both the 8-bp insertion and 3-bp deletion, and M420del alleles showed higher possibility of developing resistance towards IMtreatment. Our results warrant the need of genotyping this SNP in terms of modulating IM treatment in CML patients.
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September 2018

Homonymous Hemianopia: A Rare Presentation of Secondary Central Nervous System Neurolymphomatosis.

Cureus 2018 May 29;10(5):e2708. Epub 2018 May 29.

Medicine, Universiti Sains Malaysia, Kubang Kerian, MYS.

Neurolymphomatosis is an atypical complication of non-Hodgkin lymphoma and leukaemia involving infiltration of neurotropic neoplastic cells in the central or peripheral nervous system. A 28-year-old Malay lady with background diffuse large B-cell lymphoma stage IV presented with left homonymous hemianopia associated with cognitive function deterioration. Her best corrected visual acuity was 6/9 in both eyes. Magnetic resonance imaging (MRI) of the brain showed a lesion suggestive of secondary lymphomatous infiltration of the splenium of corpus callosum. The patient underwent chemotherapy, after which repeated MRI showed a reduction in the lesion size. Homonymous hemianopia is a rare presentation of secondary central nervous system neurolymphomatosis. A comprehensive history, physical examination, and radiological imaging are essential to establish the diagnosis in patients presenting with visual field defects.
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http://dx.doi.org/10.7759/cureus.2708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063381PMC
May 2018

Aberrant DNA methylation at HOXA4 and HOXA5 genes are associated with resistance to imatinib mesylate among chronic myeloid leukemia patients.

Cancer Rep (Hoboken) 2018 08 27;1(2):e1111. Epub 2018 Jul 27.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.

Background: Imatinib mesylate is a molecularly targeted tyrosine kinase inhibitor drug. It is effectively used in the treatment of chronic myeloid leukemia (CML) patients. However, development of resistance to imatinib mesylate as a result of BCR-ABL dependent and BCR-ABL independent mechanisms has emerged as a daunting problem in the management of CML patients. Between these mechanisms, BCR-ABL independent mechanisms are still not robustly understood.

Aim: To investigate the correlation of HOXA4 and HOXA5 promoter DNA hypermethylation with imatinib resistance among CML patients.

Methods And Results: Samples from 175 Philadelphia positive CML patients (83 good response and 92 BCR-ABL non-mutated imatinib resistant patients) were subjected to Methylation Specific High Resolution Melt Analysis for methylation levels quantification of the HOXA4 and HOXA5 promoter regions. Receiver operating characteristic curve analysis was done to elucidate the optimal methylation cut-off point followed by multiple logistic regression analysis. Log-Rank analysis was done to measure the overall survival difference between CML groups. The optimal methylation cut-off point was found to be at 62.5% for both HOXA4 and HOXA5. Chronic myeloid leukemia patients with ≥63% HOXA4 and HOXA5 methylation level were shown to have 3.78 and 3.95 times the odds, respectively, to acquire resistance to imatinib. However, overall survival of CML patients that have ≤62% and ≥ 63% methylation levels of HOXA4 and HOXA5 genes were found to be not significant (P-value = 0.126 for HOXA4; P-value = 0.217 for HOXA5).

Conclusion: Hypermethylation of the HOXA4 and HOXA5 promoter is correlated with imatinib resistance and with further investigation, it could be a potential epigenetic biomarker in supplement to the BCR-ABL gene mutation in predicting imatinib treatment response among CML patients but could not be considered as a prognostic marker.
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http://dx.doi.org/10.1002/cnr2.1111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941502PMC
August 2018

Aberrant DNA Methylation of SOCS1 Gene is Not Associated with Resistance to Imatinib Mesylate among Chronic Myeloid Leukemia Patients.

Cardiovasc Hematol Disord Drug Targets 2018 ;18(3):234-238

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, USM Pinang, Malaysia.

Background: In exploring the cause of Imatinib Mesylate (IM) resistance among Chronic Myeloid Leukemia (CML) patients who do not harbor BCR-ABL dependent mechanism, BCR-ABL independent pathways are the most probable pathways that should be explored. In BCR-ABL independent pathway, SOCS1 plays an important role as it helps in regulating optimal JAK/STAT activity.

Objective: To identify the association of SOCS1 gene hypermethylation in mediating IM Resistance.

Method: The SOCS1 promoter methylation level of 92 BCR-ABL non mutated IM resistant CML patients, 83 IM good response CML patients and 5 normal samples from healthy individuals were measured using Methylation Specific-High Resolution Melt (MS-HRM) analysis.

Results: Both primers used to amplify promoter region from -333 to -223 and from -332 to -188 showed less than 10% methylation in all CML and normal samples. Consequently, there was no significant difference in SOCS1 promoter methylation level between IM resistant and IM good response patients.

Conclusion: SOCS1 promoter methylation level is not suitable to be used as one of the biomarkers for predicting the possibility of acquiring resistance among CML patients treated with IM.
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http://dx.doi.org/10.2174/1871529X18666180419101416DOI Listing
June 2019

Pharmacogenetics and the treatment of chronic myeloid leukemia: how relevant clinically? An update.

Pharmacogenomics 2018 04 23;19(5):475-393. Epub 2018 Mar 23.

Department of Medicine, International Medical University, Kuala Lumpur, Malaysia.

Despite the excellent efficacy and improved clinical responses obtained with imatinib mesylate (IM), development of resistance in a significant proportion of chronic myeloid leukemia (CML) patients on IM therapy have emerged as a challenging problem in clinical practice. Resistance to imatinib can be due to heterogeneous array of factors involving BCR/ABL-dependent and BCR/ABL-independent pathways. Although BCR/ABL mutation is the major contributory factor for IM resistance, reduced bio-availability of IM in leukemic cells is also an important pharmacokinetic factor that contributes to development of resistance to IM in CML patients. The contribution of polymorphisms of the pharmacogenes in relation to IM disposition and treatment outcomes have been studied by various research groups in numerous population cohorts. However, the conclusions arising from these studies have been highly inconsistent. This review encompasses an updated insight into the impact of pharmacogenetic variability on treatment response of IM in CML patients.
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http://dx.doi.org/10.2217/pgs-2017-0193DOI Listing
April 2018

DNMT1 is predictive of survival and associated with Ki-67 expression in R-CHOP-treated diffuse large B-cell lymphomas.

Pathology 2017 Dec 23;49(7):731-739. Epub 2017 Oct 23.

Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia. Electronic address:

DNMT1 is a target of approved anti-cancer drugs including decitabine. However, the prognostic value of DNMT1 protein expression in R-CHOP-treated diffuse large B-cell lymphomas (DLBCLs) remains unexplored. Here we showed that DNMT1 was expressed in the majority of DLBCL cases (n = 209/230, 90.9%) with higher expression in germinal centre B-cell-like (GCB)-DLBCL subtype. Low and negative DNMT1 expression (20% cut-off, n = 33/230, 14.3%) was predictive of worse overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001). Nonetheless, of the 209 DNMT1 positive patients, 33% and 42% did not achieve 5-year OS and PFS, respectively, indicating that DNMT1 positive patients showed considerably heterogeneous outcomes. Moreover, DNMT1 was frequently expressed in mitotic cells and significantly correlated with Ki-67 or BCL6 expression (r = 0.60 or 0.44, respectively; p < 0.001). We demonstrate that DNMT1 is predictive of DLBCL patients' survival, and suggest that DNMT1 could be a DLBCL therapeutic target due to its significant association with Ki-67.
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http://dx.doi.org/10.1016/j.pathol.2017.08.009DOI Listing
December 2017

Placebo Controlled Trials: Interests of Subjects versus Interests of Drug Regulators.

Malays J Med Sci 2017 Aug 18;24(4):1-4. Epub 2017 Aug 18.

Human Research Ethics Committee, Universiti Sains Malaysia, Department of Paediatrics, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

The use of placebo-controlled trials in situations where established therapies are available is considered ethically problematic since the patients randomised to the placebo group are deprived of the beneficial treatment. The pharmaceutical industry and drug regulators seem to argue that placebo-controlled trials with extensive precautions and control measures in place should still be allowed since they provide necessary scientific evidence for the efficacy and safety of new drugs. On the other hand, the scientific value and usefulness for clinical decision-making may be much higher if the new drug is compared directly to existing therapies. As such, it may still be unethical to impose the burden and risk of placebo-controlled trials on patients even if extensive precautions are taken. A few exceptions do exist. The use of placebo-controlled trials in situations where an established, effective and safe therapy exists remains largely controversial.
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http://dx.doi.org/10.21315/mjms2017.24.4.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609684PMC
August 2017

Association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with clinical response to imatinib mesylate treatment among Malaysian chronic myeloid leukaemia patients.

J Genet 2017 Sep;96(4):633-639

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

The detoxifying activity of glutathione S-transferases (GST) enzymes not only protect cells from the adverse effects of xenobiotics, but also alters the effectiveness of drugs in cancer cells, resulting in toxicity or drug resistance. In this study, we aimed to evaluate the association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with treatment response among Malaysian chronic myeloid leukaemia (CML) patients who everyday undergo 400 mg of imatinib mesylate (IM) therapy. Multiplex polymerase chain reaction (multiplex-PCR) was performed to detect GSTM1 and GSTT1 polymorphisms simultaneously and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was conducted to detect the GSTP1 Ile195Val polymorphism. On evaluating the association of the variant genotype with treatment outcome, heterozygous variant (AG) and homozygous variant (GG) of GSTP1 Ile105Val showed significantly a higher risk for the development of resistance to IM with OR: 1.951 (95% CI: 1.186-3.209, P = 0.009) and OR: 3.540 (95% CI: 1.305-9.606, P = 0.013), respectively. Likewise, GSTT1 null genotype was also associated with a significantly higher risk for the development of resistance to IM with OR = 1.664 (95% CI: 1.011-2.739, P = 0.045). Our results indicate the potential usefulness of GST polymorphism genotyping in predicting the IM treatment response among CML patients.
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http://dx.doi.org/10.1007/s12041-017-0819-2DOI Listing
September 2017

Impact of and Polymorphisms on Imatinib Mesylate Response Among Chronic Myeloid Leukemia Patients in Malaysia.

Oncol Ther 2016 21;4(2):303-314. Epub 2016 Nov 21.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan Malaysia.

Introduction: Imatinib mesylate (IM), a selective inhibitor of the BCR-ABL tyrosine kinase, is a well-established first-line treatment for chronic myeloid leukemia (CML). IM is metabolized mainly by cytochrome P450 (CYP) in the liver, specifically the CYP3A4 and CYP3A5 enzymes. Polymorphisms in these genes can alter the enzyme activity of IM and may affect its response. In this study, the impact of two single-nucleotide polymorphisms (SNPs), (6986A>G) and (878T>C), on IM treatment response in CML patients ( = 270; 139 IM resistant and 131 IM good responders) was investigated.

Methods: Genotyping of and was performed using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The association between allelic variants and treatment response was assessed by means of odds ratio (OR) with 95% confidence intervals calculated by logistic regression.

Results: Our results indicated that CML patients carrying the heterozygous (AG) and homozygous variant (GG) genotype of *3 were associated with a significantly lower risk of acquiring resistance with OR 0.171; 95% CI: 0.090-0.324,  < 0.001 and OR 0.257; 95% CI: 0.126-0.525,  < 0.001, respectively. Although CML patients carrying the heterozygous (TC) genotype of showed a lower risk of acquiring resistance toward IM (OR 0.648; 95% CI: 0.277-1.515), the association was not statistically significant ( = 0.316). No homozygous variant (CC) genotype of was detected among the CML patients.

Conclusion: It is concluded that polymorphism of is associated with IM treatment response in Malaysian CML patients with carriers of and genotypes posing lower risk for development of resistance to IM.
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http://dx.doi.org/10.1007/s40487-016-0035-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315081PMC
November 2016

Low HIP1R mRNA and protein expression are associated with worse survival in diffuse large B-cell lymphoma patients treated with R-CHOP.

Exp Mol Pathol 2015 Dec 2;99(3):537-45. Epub 2015 Sep 2.

Oncology Department, Biodonostia Research Institute, San Sebastian 20014, Spain; Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.

Huntingtin-interacting protein 1-related (HIP1R) is an endocytic protein involved in receptor trafficking, including regulating cell surface expression of receptor tyrosine kinases. We have previously shown that low HIP1R protein expression was associated with poorer survival in diffuse large B-cell lymphoma (DLBCL) patients from Denmark treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). In this multicenter study, we extend these findings and validate the prognostic and subtyping utility of HIP1R expression at both transcript and protein level. Using data mining on three independent transcriptomic datasets of DLBCL, HIP1R transcript was preferentially expressed in germinal center B-cell (GCB)-like DLBCL subtype (P<0.01 in all three datasets), and lower expression was correlated with worse overall survival (OS; P<0.01) and progression-free survival (PFS; P<0.05) in a microarray-profiled DLBCL dataset. At the protein level examined by immunohistochemistry, HIP1R expression at 30% cut-off was associated with GCB-DLBCL molecular subtype (P=0.0004; n=42), and predictive of OS (P=0.0006) and PFS (P=0.0230) in de novo DLBCL patients treated with R-CHOP (n=73). Cases with high FOXP1 and low HIP1R expression frequency (FOXP1(hi)/HIP1R(lo) phenotype) exhibited poorer OS (P=0.0038) and PFS (P=0.0134). Multivariate analysis showed that HIP1R<30% or FOXP1(hi)/HIP1R(lo) subgroup of patients exhibited inferior OS and PFS (P<0.05) independently of the International Prognostic Index. We conclude that HIP1R expression is strongly indicative of survival when utilized on its own or in combination with FOXP1, and the molecule is potentially applicable for subtyping of DLBCL cases.
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http://dx.doi.org/10.1016/j.yexmp.2015.08.019DOI Listing
December 2015

Guidelines for nucleic acid detection and analysis in hematological disorders.

Malays J Pathol 2015 Aug;37(2):165-73

Universiti Sains Malaysia, School of Medical Sciences, Department of Haematology, 16150, Kubang Kerian, Kelantan, Malaysia.

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August 2015

Characterisation and Clinical Significance of FLT3-ITD and non-ITD in Acute Myeloid Leukaemia Patients in Kelantan, Northeast Peninsular Malaysia.

Asian Pac J Cancer Prev 2015 ;16(12):4869-72

Department of Hematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia E-mail :

Background: Mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor gene may promote proliferation via activation of multiple signaling pathways. FLT3-internal tandem duplication (FLT3-ITD) is the most common gene alteration found in patients diagnosed with acute myeloid leukaemia (AML) and has been associated with poor prognosis.

Materials And Methods: We performed mutational analysis of exons 14-15 and 20 of the FLT3 gene in 54 AML patients using PCR-CSGE (conformational sensitive gel electrophoresis) followed by sequencing analysis to characterise FLT3 mutations in adult patients diagnosed with AML at Hospital USM, Kelantan, Northeast Peninsular Malaysia.

Results: FLT3 exon 14-15 mutations were identified in 7 of 54 patients (13%) whereas no mutation was found in FLT3 exon 20. Six ITDs and one non-ITD mutation were found in exon 14 of the juxtamembrane (JM) domain of FLT3. FLT3-ITD mutations were associated with a significantly higher blast percentage (p-value=0.008) and white blood cell count (p-value=0.023) but there was no significant difference in median overall survival time for FLT3-ITD+/FLT3-ITD- within 2 years (p-value=0.374).

Conclusions: The incidence of FLT3-ITD in AML patients in this particular region of Malaysia is low compared to the Western world and has a significant association with WBC and blast percentage.
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http://dx.doi.org/10.7314/apjcp.2015.16.12.4869DOI Listing
April 2016

Low level of TERC gene amplification between chronic myeloid leukaemia patients resistant and respond to imatinib mesylate treatment.

Asian Pac J Cancer Prev 2014 ;15(4):1863-9

Human Genome Center, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia E-mail :

The amplification of telomerase component (TERC) gene could play an important role in generation and treatment of haematological malignancies. This present study was aimed to investigate copy number amplification status of TERC gene in chronic myeloid leukaemia (CML) patients who were being treated with imatinib mesylate (IM). Genomic DNA was extracted from peripheral blood of CML-IM Resistant (n=63), CML-IM Respond (n=63) and healthy individuals (n=30). TERC gene copy number predicted (CNP) and copy number calculated (CNC) were determined based on Taqman® Copy Number Assay. Fluorescence in situ hybridization (FISH) analysis was performed to confirm the normal signal pattern in C4 (calibrator) for TERC gene. Nine of CML patients showed TERC gene amplification (CNP=3), others had 2 CNP. A total of 17 CML patients expressed CNC>2.31 and the rest had 2.31>CNC>1.5. TERC gene CNP value in healthy individuals was 2 and their CNC value showed in range 1.59-2.31. The average CNC TERC gene copy number was 2.07, 1.99 and 1.94 in CML- IM Resistant patients, CML-IM Respond and healthy groups, respectively. No significant difference of TERC gene amplification observed between CML-IM Resistant and CML-IM Respond patients. Low levels of TERC gene amplification might not have a huge impact in haematological disorders especially in terms of resistance towards IM treatment.
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http://dx.doi.org/10.7314/apjcp.2014.15.4.1863DOI Listing
November 2014

BCR-ABL kinase domain mutations, including 2 novel mutations in imatinib resistant Malaysian chronic myeloid leukemia patients-Frequency and clinical outcome.

Leuk Res 2014 Apr 6;38(4):454-9. Epub 2014 Jan 6.

Human Genome Centre, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Malaysia. Electronic address:

Discovery of imatinib mesylate (IM) as the targeted BCR-ABL protein tyrosine kinase inhibitor (TKI) has resulted in its use as the frontline therapy for chronic myeloid leukemia (CML) across the world. Although high response rates are observed in CML patients who receive IM treatment, a significant number of patients develop resistance to IM. Resistance to IM in patients has been associated with a heterogeneous array of mechanisms of which point mutations within the ABL tyrosine kinase domain (TKD) are the frequently documented. The types and frequencies of mutations reported in different population studies have shown wide variability. We screened 125 Malaysian CML patients on IM therapy who showed either TKI refractory or resistance to IM to investigate the frequency and pattern of BCR-ABL kinase domain mutations among Malaysian CML patients undergoing IM therapy and to determine the clinical significance. Mutational screening using denaturing high performance liquid chromatography (dHPLC) followed by DNA sequencing was performed on 125 IM resistant Malaysian CML patients. Mutations were detected in 28 patients (22.4%). Fifteen different types of mutations (T315I, E255K, G250E, M351T, F359C, G251E, Y253H, V289F, E355G, N368S, L387M, H369R, A397P, E355A, D276G), including 2 novel mutations were identified, with T315I as the predominant type of mutation. The data generated from clinical and molecular parameters studied were correlated with the survival of CML patients. Patients with Y253H, M351T and E355G TKD mutations showed poorer prognosis compared to those without mutation. Interestingly, when the prognostic impact of the observed mutations was compared inter-individually, E355G and Y253H mutations were associated with more adverse prognosis and shorter survival (P=0.025 and 0.005 respectively) than T315I mutation. Results suggest that apart from those mutations occurring in the three crucial regions (catalytic domain, P-loop and activation-loop), other rare mutations also may have high impact in the development of resistance and adverse prognosis. Presence of mutations in different regions of BCR-ABL TKD leads to different levels of resistance and early detection of emerging mutant clones may help in decision making for alternative treatment. Serial monitoring of BCR-ABL1 transcripts in CML patients allows appropriate selection of CML patients for BCR-ABL1 KD mutation analysis associated with acquired TKI resistance. Identification of these KD mutations is essential in order to direct alternative treatments in such CML patients.
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http://dx.doi.org/10.1016/j.leukres.2013.12.025DOI Listing
April 2014

Thrombotic thrombocytopenic purpura: three peripartum cases and diagnostic challenges.

Clin Med Insights Case Rep 2013 15;6:141-6. Epub 2013 Sep 15.

School of Dental Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.

Thrombotic thrombocytopenic purpura (TTP) is a medical emergency characterized by occlusive microangiopathy due to intravascular platelet aggregation. This event results in damage to the red blood cells (RBCs) known as microangiopathic hemolytic anemia (MAHA). Schistocytes are circulating fragments of damaged RBCs that have different morphological features including keratocytes, helmet cells, and spherocytes. It is critical to report even a small number of these abnormal RBCs in the peripheral blood and to be alert for the possible diagnosis of TTP, especially in unexplained anemia and thrombocytopenia. The application of pentad criteria in the diagnosis has been reviewed, and the challenges still remained on the hematologic evidence of this disorder. In the 3 cases discussed here, the red cell morphological diagnosis gave an impact on TTP diagnosis, but overdiagnosis might be encountered in obstetrical patients due to nonspecific diagnostic criteria.
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http://dx.doi.org/10.4137/CCRep.S12122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782395PMC
October 2013

Survival and prognostic factors in Malaysian acute myeloid leukemia patients after allogeneic haematopoietic stem cell transplantation.

Int J Hematol 2013 Aug 30;98(2):197-205. Epub 2013 May 30.

Regenerative Medicine Cluster, Advanced Medical & Dental Institute, Universiti Sains Malaysia, Bertam, 13200 Kepala Batas, Pulau Pinang, Malaysia.

Studies of survival outcomes in acute myeloid leukemia (AML) patients treated with allogeneic haematopoietic stem cell transplantation (HSCT) are essential for planning patient care. The objectives of the present study were to determine overall survival (OS) and disease-free survival (DFS) in AML patients treated with allogeneic HSCT, and to identify prognostic factors associated with poor outcome. This study was conducted retrospectively, using data from the Blood and Bone Marrow Transplant, National Transplant Registry, Malaysia. All cases of AML treated with allogeneic HSCT registered at the registry between 1st January 1987 and 31st December 2010 were included in the study. A total of 300 patients were included for final analysis. The Kaplan-Meier method and Cox proportional hazard regression were used for statistical analysis. The overall 10-year OS and DFS for Malaysian AML patients after allogeneic HSCT were 63 and 67 %, respectively. Donor gender, marrow status, and conditioning intensity were identified as important prognostic factors for overall survival, whereas the significant prognostic factors for disease-free survival were ethnic group, donor gender, marrow status, and conditioning intensity. In conclusion, the survival outcomes for Malaysian AML patients treated with allogeneic HSCT were good, and this treatment should be considered the standard therapeutic approach for suitable candidates.
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http://dx.doi.org/10.1007/s12185-013-1373-1DOI Listing
August 2013

HOXA4 gene promoter hypermethylation as an epigenetic mechanism mediating resistance to imatinib mesylate in chronic myeloid leukemia patients.

Biomed Res Int 2013 26;2013:129715. Epub 2012 Dec 26.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus 16150 Kubang Kerian, Kelantan, Malaysia.

Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients has emerged as a significant clinical problem. The observation that increased epigenetic silencing of potential tumor suppressor genes correlates with disease progression in some CML patients treated with IM suggests a relationship between epigenetic silencing and resistance development. We hypothesize that promoter hypermethylation of HOXA4 could be an epigenetic mechanism mediating IM resistance in CML patients. Thus a study was undertaken to investigate the promoter hypermethylation status of HOXA4 in CML patients on IM treatment and to determine its role in mediating resistance to IM. Genomic DNA was extracted from peripheral blood samples of 95 CML patients (38 good responders and 57 resistant) and 12 normal controls. All samples were bisulfite treated and analysed by methylation-specific high-resolution melt analysis. Compared to the good responders, the HOXA4 hypermethylation level was significantly higher (P = 0.002) in IM-resistant CML patients. On comparing the risk, HOXA4 hypermethylation was associated with a higher risk for IM resistance (OR 4.658; 95% CI, 1.673-12.971; P = 0.003). Thus, it is reasonable to suggest that promoter hypermethylation of HOXA4 gene could be an epigenetic mechanism mediating IM resistance in CML patients.
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http://dx.doi.org/10.1155/2013/129715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591123PMC
September 2013

Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients.

Hematol Rep 2012 Nov 23;4(4):e23. Epub 2012 Nov 23.

Human Genome Centre;

Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is mediated by different mechanisms that can be classified as BCR-ABL dependent or BCR-ABL independent pathways. BCR-ABL dependent mechanisms are most frequently associated with point mutations in tyrosine kinase domain (TKD) of BCR-ABL1 and also with BCR-ABL gene amplification. Many different types and frequencies of mutations have been reported in different studies, probably due to the different composition of study cohorts. Since no reports are available from Malaysia, this study was undertaken to investigate the frequency and pattern of BCR-ABL kinase domain mutations using dHPLC followed by sequencing, and also status of BCR-ABL gene amplification using fluorescence in situ hybridization (FISH) on 40 IM resistant Malaysian CML patients. Mutations were detected in 13 patients (32.5%). Five different types of mutations (T315I, E255K, Y253H, M351T, V289F) were identified in these patients. In the remaining 27 IM resistant CML patients, we investigated the contribution made by BCR-ABL gene amplification, but none of these patients showed amplification. It is presumed that the mechanisms of resistance in these 27 patients might be due to BCR-ABL independent pathways. Different mutations confer different levels of resistance and, therefore, detection and characterization of TKD mutations is highly important in order to guide therapy in CML patients.
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http://dx.doi.org/10.4081/hr.2012.e23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555211PMC
November 2012