Pusat Pengajian Sains Perubatan - Tesis

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Role of genetic variations of parp1 polymorphisms on triple negative breast cancer (TNBC) susceptibility risk
(2022)
Zamri, Durar Aqilah
Background: Breast cancer is the most common cancer in females worldwide and the second most common cause of cancer deaths. Triple negative breast cancer (TNBC) has the most aggressive phenotype and worst prognosis compared to other breast cancer subtypes. Poly(ADP-Ribose)Polymerase1 (PARP1) is a nuclear protein, that plays a role in deoxyribonucleic acid (DNA) damage repair by acting as sensor for DNA strand breaks. Inter-individual genetic variations such as single nucleotide polymorphisms (SNPs) of PARP1 Val762Ala (rs1136410 T>C) and Ala284Ala (rs1805414 T>C) may reduce the PARP1 activity in repairing DNA damage and thus may increase the cancer risk predisposition. Since there is paucity of information on the frequency of PARP1 rs1136410 T>C and rs1805414 T>C polymorphisms in TNBC patients, and limited reports available on these polymorphisms on TNBC susceptibility risk, the present study is designed to investigate the impact of PARP1 rs1136410 T>C and rs1805414 T>C polymorphisms in modulating TNBC susceptibility risk. Methods: Blood sample of 70 histopathologically confirmed TNBC patients and 70 healthy control individuals were collected, and DNA was extracted. The genotyping of PARP1 rs1136410 T>C and rs1805414 polymorphisms was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific-polymerase chain reaction (AS-PCR) technique, respectively. Next, the genotype patterns were categorized into homozygous wild-type, heterozygous and homozygous variant. The genotype and allele frequencies of both PARP1 polymorphisms were calculated and compared between TNBC patients and healthy individual group using chi-square test. Next, logistic regression analysis deriving Odds Ratio (OR) with 95% confidence interval (CI) was performed to evaluate the TNBC patients’ susceptibility risk. Results: The homozygous variant (CC) genotype of PARP1 rs1136410 polymorphism and heterozygous (TC) genotype of PARP1 rs1805414 showed a higher TNBC susceptibility risk with OR: 1.190, 95% CI: 0.300-4.721 and OR: 1.103, 95% CI: 0.402-3.031. In addition, heterozygous (TC) genotype of PARP1 rs1136410 was found to be significantly associated with lower risk of recurrence among TNBC patients with OR: 0.105, 95% CI: 0.029-0.374, p=0.001. Conclusion: Our results showed the lack of association of PARP1 rs1136410 T>C and rs1805414 T>C polymorphisms in modulating TNBC susceptibility risk. However, the present study observed that PARP1 rs1136410 (TC) genotype was found to be significantly associated with lower risk of disease recurrence among TNBC patients. The lack of association could be due to low sample size of study subjects which interfered the power of the study and influence the low frequency of variant allele in TNBC patients. The study needs to be extended to larger number of sample size which can increase the power of the study and needs to explore the polymorphic genotype combinations of PARP1
Association between routine preoperative electrocardiogram (ECG) findings with perioperative ecg changes in noncardiac surgeries among low cardiac risk patients: A cross-sectional study
(2020)
Sharizal, Zulhilm
Background Preoperative ECG plays a big role in detecting any underlying myocardial pathology. Recent evidence also suggests for pre-operative ECG in patients with symptoms and at increased cardiac risk undergoing non-cardiac surgeries. However, to screen all patients especially those without symptoms with low cardiac risk might add burden to the burgeoning healthcare cost. Objective To determine the proportion of abnormal preoperative ECG in low cardiac risk patients aged 40 years and above and factors associated with it and its association with actual development of perioperative ECG abnormalities in patient undergoing non-cardiac surgery under general or regional anaesthesia. Method A cross-sectional study design was adopted in this research. A total of 406 subjects were recruited in this study. They were aged 40 years old and above, ASA 2 and below, NYHA class 2 and below as well as patient who had low Revised Cardiac Risk Index (RCRI) that were admitted for non-cardiac surgeries in HUSM. Study sample were selected by convenient sampling. Preoperative ECG was done during routine preoperative anaesthetic assessment. Subsequent ECG assessments were done at 1) after induction of anaesthesia, 2) any changes in the cardiac monitoring, 3) one hour post-extubation period. ECG abnormalities include axis deviation, atrial fibrillation, bundle branch block, left ventricular hypertrophy, premature ventricular complexes more than 6 beats per minutes, Q wave, S-T segment changes, sinus tachycardia or bradycardia,supraventricular tachycardia, ventricular tachycardia and ventricular fibrillations. All ECG diagnoses were done by cardiologist following the recommendation by AHA/ACCF/HRS. Multiple logistic regression was used to determine the association between preoperative ECG findings and new or worsening perioperative ECG changes. Result A total of 132 patients (32.5%) had abnormal preoperative ECG and of this abnormal preoperative ECG, 53 patients (40.2%) experienced new or worsening ECG perioperatively. Factors associated with abnormal preoperative ECG were 1) Age (RR=1.02, 95%CI 1.01,1.03, P<0.001), 2) Male (RR=1.41, 95%CI 1.13,1.77, P<0.05), 3) Smoker (RR=1.62, 95%CI 1.04,2.52, P<0.05), 4) Hypertension (RR=1.28, 95%CI 1.01,1.62, P<0.05). Patients who had abnormal preoperative ECG changes were associated with higher incidence of developing new or worsening ECG perioperatively than patients with normal preoperative ECG findings (40.2 % vs 14.2 %, χ2(df)= 34.15(1), p=<0.001). The most common ECG findings were Left axis deviation (Preoperative, n=69 (17%), Perioperative, n=71 (17.5%)) and T Wave inversion (Preoperative, n=44 (10.8%), Perioperative, n=53 (13.1%)). After adjusting for covariates, the odds of developing new or worsening perioperative ECG were found to be higher in patients who had abnormal preoperative ECG findings (OR:4.41, 95%CI 2.62,7.39, p<0.001) and lower intraoperative heart rate (OR:2.71, 95%CI 1.55,2.74, p<0.001). Among patients with abnormal preoperative ECG findings, the most common new ECG findings during intraoperative and postoperative was sinus bradycardia, 16 patients (13.5%) and 20 patients (16.8%) respectively Conclusion Proportion of abnormal ECG in low cardiac risk patient age 50 and above is considerably significant. Those with abnormal preoperative ECG were significantly associated with new or worsening perioperative ECG abnormalities
The practice, outcome and complications of tracheostomy for traumatic brain injury patients in neurosurgical intensive care unit
(2020)
Zahari, Yusrina
Background: The tracheostomy procedure is commonly required to wean severe traumatic brain injury (TBI) patients. This study aimed to determine the practice, techniques and outcomes in TBI patients in a neurosurgical intensive care unit (Neuro-ICU). Methods: This was a retrospective, cross-sectional study conducted from January 1st, 2013, until December 31st, 2017, involving 268 severe TBI patients who required tracheostomy during Neuro-ICU management. The data were obtained from their medical records. Results: When based on techniques, percutaneous tracheostomy (PT) displayed a significantly shorter day of tracheostomy plan [7.0(2.5) vs 8.3(2.6) days; p<0.001], day of execution [7.2 (2.6) vs 8.6(2.9) days; p<0.001], duration of mechanical ventilation [9.8(3.4) vs 11.3(3.1) days; p<0.001], and duration of ICU stay [12.3(3.7) vs 13.8(3.5) days; p<0.003] than surgical tracheostomy (ST). If based on timing, early tracheostomy (ET) showed a significantly shorter duration of mechanical ventilation [8.8(2.1) vs 12.9(2.9) days; p<0.001], length of ICU stay [11.4(2.4) vs 15.2(3.5) days; p<0.001], and length of hospital stay [17.1(3.2) vs 20.0(4.0) days; p<0.001] than late tracheostomy (LT). Conclusion: PT showed a shorter mechanical ventilation and ICU stay duration than ST. In comparison, ET showed shorter mechanical ventilation, ICU stay, and hospital stay duration than LT
The significance of capillary electrophoresis in the detection of haemoglobin constant spring and its relationship with high-performance liquid chromatography
(2021)
Rameli, Nabilah
Introduction: Haemoglobin Constant Spring (Hb CS) is one of the most common non-deletional types of alpha (α) thalassaemia in Southeast Asia region. The nature of this abnormal globin gene is that it is unstable, labile and is present in minute amount in the peripheral blood. Thus, this may lead to underdiagnosis of the disease. This study was conducted to determine the proportion of Hb CS among the Kelantan population and to compare range of peak value in Zone 2 CE findings for 3 groups of Hb CS (heterozygous, homozygous, and compound heterozygous) and their haematological parameters. The study aimed to look at the findings of HPLC in relation to CE results in detecting Hb CS. Study design and methods: This was a cross-sectional study involving secondary data collection from 378 samples which showed peak value on Zone 2 of CE. The samples were taken from the National Thalassemia screening of Form 4 students from all districts in Kelantan. The haematological parameters of red cells were analysed using Sysmex XN 3000 automated blood cell analyser, Hb analysis was performed using automated CE system (CAPILLARYS2 Flex-Piercing System Sebia), HPLC Biorad variant II, DNA analysed using multiplex polymerase chain reaction (PCR) and multiplex Amplification refractory mutation system (ARMS) to detect both deletional and non-deletional α-thalassaemia. Results: 376 samples (99.5%) with presence of peak value on Zone 2 of CE were confirmed to have termination codon CS mutation. Heterozygous Hb CS is the most common type of Hb CS detected in 344 samples (91.5%), followed by compound heterozygous Hb CS which was 31 samples (8.2%) and only 1 sample (0.3%) of homozygous Hb CS. The mean ± SD of peak value in Zone 2 of heterozygous Hb CS and compound heterozygous Hb CS were 0.61 ± 0.13 and 0.77 ± 0.34 respectively. The only sample of homozygous Hb CS showed the value of 4.9% of peak value in Zone 2 of CE. The significant differences of haematological parameters between heterozygous and compound heterozygous Hb CS were observed in haemoglobin level, MCV, MCH and MCHC. This study showed there was a good linear correlation between peak in C-window on HPLC and peak value in Zone 2 of CE in detecting Hb CS, r=0.73. Conclusion: Thus, by combining the haematological parameters and complementary tests of both CE and HPLC, the diagnosis of Hb CS can be detected prior to confirmation by DNA molecular study that is far more expensive.
Lipiodol accumulation pattern as imaging biomarker of tumoral response after conventional transarterial chemoembolization and survival outcome in hepatocellular carcinoma patients
(2021)
Azizi, Mohd Yadie Syazwan
Background: TACE is the locoregional treatment of choice for unresectable hepatocellular carcinoma, and a successful procedure would improve the survival rate of the patient. Good antitumoral coverage in the targeted liver tumor is necessary to produce good tumoral necrosis and results in a good therapeutic effect. TACE by using a mixture of anticancer and iodized oil (Lipiodol) may provide an overview of the degree of accumulation and retention within the targeted tumor on subsequent CT-scans follow up, thus predicting the outcome of the treatment. This study aimed to determine the correlation between the pattern of accumulation pattern of lipiodol and the targeted tumoral response toward the treatment given and the overall survival rate of HCC patients. Methods: This retrospective record review was done from 2013 until 2020 in patients who received TACE with anticancer and Lipiodol in Hospital Universiti Sains Malaysia, who are fulfilling inclusion and exclusion criteria. Lipiodol accumulation pattern is observed approximately after six weeks post-TACE on the follow-up CT scans and later is classified into 4 accumulation patterns; pattern 4, complete accumulation; pattern 3, intense (>75% of tumor volume); pattern 2, moderate (<75% of tumor volume); and pattern 1 – low accumulation. Evaluation of the tumoral response was done according to the mRECIST criteria. Chi-Square or Fischer Exact test and multiple logistic regression test analysis was used to determine the association between the lipiodol accumulation pattern and the tumor response towards the treatment. A survival analysis test (Kaplan-Meier analysis) was used to determine the association between the accumulation pattern and the overall survivability of the patient who received TACE. Simple and Multiple Cox Proportional Hazard Regression tests were used to study other associated factors affecting overall survivability. Results: A total of data from 38 subjects were obtained in both BCLC stage B (n=33) and BCLC stage C (n=10) groups. In BCLC stage B, 18% (n=7) were in complete accumulation, 26% (n=10) in intense accumulation, 16% (n=6) in moderate accumulation and 13% (n=5) in low accumulation pattern. Fisher’s exact test for BCLC stage B subjects showed significant association between lipiodol accumulation pattern and tumor response with Fisher’s Exact value of 27.025 (p<0.001). Spearman-rho test reports a significant association of lipiodol accumulation pattern and tumor response with a magnitude of 0.84 in this group. In BCLC stage C no complete accumulation pattern was observed, 5% (n=2) were in intense accumulation, 11% (n=4) were in moderate accumulation and 11% (n=4) were in low accumulation pattern. The Fisher’s exact test for subjects in BCLC Stage C showed no significant association between lipiodol accumulation pattern and tumor response with Fisher’s Exact value 2.281 (p>0.05). Survival analysis shows higher proportion of cases survived at 1- year and 3-year in complete (85.7% at 1-year and 17.1% at 3-year) and intense (88.9% at 1- year and 38.1% at 3-year) lipiodol accumulation group in BCLC stage B group as compared to other accumulation patterns. The median survival time in BCLC stage B for each group were 26 months (complete), 30 months (intense), 9 months (moderate) and 16 months (low). In BCLC stage C group where only moderate and low accumulation pattern were observed above one year, with 1-year survival rate was 50% (moderate) and 25% (low) with none survive at three and five years. The median survival time for BCLC stage C group were six months (intense), four months (moderate), and eight months (low). Simple and Multiple cox regression analysis revealed that the number of liver nodules group and number of TACE procedures done were among significant prognostic factor of death in HCC. Patients that have 5-9 liver nodules had a 12.1 times higher risk of death as compared to the group of patients with 1-4 liver nodules (HR: 12.1, 95% CI: 1.17 – 124.57). Patients that received one TACE procedure are expected to have a decrease in risk of death by 0.57 (HR: 0.565, 95% CI: 0.393 – 0.812). Though additional regression analysis did not report a significant influence of lipiodol accumulation pattern on disease progression, correlation analysis reported a moderate positive correlation between lipiodol accumulation pattern and disease progression (rs(36) = 0.796, p < 0.001). Conclusion: Lipiodol deposition in liver tumors can be evaluated using quantitative baseline imaging characteristics and it shows significant correlation with tumor response toward the treatment and influence the survival outcome of the patients. Our study confirms the findings of previous studies and validates the unique properties and function of Lipiodol as a tumorspecific, drug-carrying, and imaging biomarker agent to treat HCC patients.

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