Browsing by Author "Lokuhetty, M.D.S."

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Clinical exome gene panel analysis of a cohort of urothelial bladder cancer patients from Sri Lanka
(Asian Pacific Organization for Cancer Prevention, 2023) Malalasekera, A.; Neththikumara, N.; Somasundaram, P.; Pathirana, S.; Ediriweera, C.; Ediriweera, D.; Goonewardena, S.A.; Perera, N.D.; Abeygunasekara, A.; Jayasekara, R.W.; Wettasinghe, K.; Lokuhetty, M.D.S.; Dissanayeke, V.H.W.
BACKGROUND: Bladder cancer has a high rate of recurrence and high mortality rates in those who progress to muscle invasive disease. Biomarkers and molecular sub classification of tumours beyond standard histopathology has been proposed to address therapeutic dilemmas. The Cancer Genome Atlas project and other studies have contributed to the enhanced knowledge base of the mutational landscape of urothelial bladder cancer. Once again, these are mostly from Caucasian and Chinese patients, with data from the rest of Asia and Sri Lanka being sparse. The objective of this study was to assess the genomic variations of a cohort of urothelial bladder cancer patients in Sri Lanka. METHODS: The molecular genetic study was conducted on formalin fixed paraffin embedded tumour samples of 24 patients, prospectively enrolled from 2013 to 2017. The samples were sequenced and variant distribution performed based on a 70-gene panel. RESULTS: Total number of filtered mutations in the 24 patients was 10453. Median mutations per patient were 450 (range 22-987). The predominant mutational change was C>T and G>A. The top 5 mutated genes in our cohort were SYNE1, SYNE2, KMT2C, LRP2, and ANK2. The genes were clustered into 3 groups dependent on the number of mutations per patient per gene. The genes of cluster 1 and 2 mapped to Chromatin modifying enzymes and Generic Transcription Pathway. The chromatin remodelling pathway accounted for the largest proportion (22%) of mutations. CONCLUSIONS: Clinical exome sequencing utilising a gene panel yielded a high mutation rate in our patients. The predominant mutational change was C>T and G>A. Three clusters of genes were identified. SYNE1 was the gene with the most mutations. The mutations comprised predominantly of genes of the chromatin remodelling pathway.
Could quantitative real-time polymerase chain reaction assay serve as an alternative test method to evaluate human epidermal growth factor receptor 2 status of gastric carcinoma in the South Asian setting?
(Indian Society of Gastroenterology/Springer India, 2019) Kannangara, D.K.S.; Lokuhetty, M.D.S.; Subasinghe, D.; Gunawardene, Y.I.N.S.; Dassanayake, R.S.
BACKGROUND:Human epidermal growth factor receptor 2 (HER2) protein overexpression and/or HER2 gene amplification are/is linked to a dismal outcome of gastric carcinoma (GCa). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are key methods to identify patients for HER2 targeted therapy. Drawbacks of both the methods warrant novel tests. Hence, we evaluated the value of quantitative real-time polymerase chain reaction (qPCR) as an alternative test method, relative to IHC to detect HER2 status of GCa and to find relationship between these results with demographic/clinicopathological data.METHOD:Twenty GCa patients with known IHC HER2 scores were evaluated. qPCR was performed for the HER2 gene and amyloid precursor protein (reference gene) in formalin-fixed paraffin-embedded GCa tissue. Cycle threshold values (Ct) were analyzed using the Pfaffl method to detect HER2 gene amplification.RESULTS:HER2 positivity rates by IHC and qPCR were 20% and 35%, respectively. The sensitivity and specificity of qPCR were 67% and 76%, respectively, relative to IHC. qPCR results were reproducible. The diagnostic consistency between IHC and qPCR (κ = 0.146) was slightly agreeable (0.01 < k < 0.20), with a 65% concordance. Based on McNemar's test, there was no significant difference between the results of the two tests. IHC HER2 protein expression had relationship with the tumor (TNM) stage and Lauren histological type (p < 0.05). Positive HER2 gene expression by qPCR showed relationship with depth of invasion, lymph node involvement, and degree of differentiation (p < 0.05).CONCLUSION:Cost-effective qPCR could serve as an alternative test method for detection of HER2 status of GCa. Both HER2 overexpression by IHC and gene amplification by qPCR are associated with adverse clinicopathological features
Demographics, pathological characteristics and survival in urothelial bladder cancer in a cohort of Sri Lankan patients.
(The Sri Lanka Medical Association, 2022) Malalasekera, A.P.; Ediriweera, D.; Goonewardena, S.A.S.; Perera, N.D.; Abeygunasekara, A.; Jayasekara, R.W.; Wettasinghe, K.; Dissanayake, V.H.W.; Lokuhetty, M.D.S.
INTRODUCTION: Bladder cancer has the 9th highest incidence among Sri Lankan males. This study describes the demographic profiles and survival in bladder cancer patients at two tertiary care centres in Sri Lanka. METHODS: A group of patients with urothelial bladder cancer, presenting for the first time for definitive treatment, were prospectively enrolled from 2013 to 2017. RESULTS: There were sixty-six patients, with median age of 65 years and male to female ratio of 7:1. Histopathologically pTa 24%, pT1 47% and pT2 29%. Of the pT1 tumours 61% were low grade (LG). The majority (71%) of non-muscle invasive bladder cancer (NMIBC) patients underwent transurethral resection of bladder tumour only. For the entire cohort the 5-year overall survival was 59% and cancer specific survival (CSS) was 65%. CSS in NMIBC was 75% and 30% in muscle invasive bladder cancer (MIBC). The 5-year female CSS (22%) was significantly lower than in males (71%). CONCLUSION: Our cohort has a high male to female ratio. The percentage of MIBC was lower than reported in previous Sri Lankan studies. Of the pT1 tumours there is a higher percentage of pT1 LG patients in comparison to Western reports. There is low utilisation of intravesical mitomycin / bacillus Calmette–Guérin (BCG) in the treatment of NMIBC. The 5-year CSS in the Sri Lankan (lower middle-income economy) cohort lies between the values of high-income economies and upper middle-income economies in Asia. The reasons for poor CSS among Sri Lankan women with bladder cancer needs to be further investigated.
Meta-analysis of global variations in grade of pT1 urothelial bladder cancer and supplementary evaluation of a Sri Lankan cohort
(The College of Surgeons of Sri Lanka, 2022) Malalasekera, A.P.; Ediriweera, D.; Goonewardena, S.; Perera, N.; Abeygunasekara, A.; Jayasekara, R.W.; Wettasinghe,T.K.; Dissanayake,V.H.W.D.; Lokuhetty, M.D.S.
Introduction Bladder cancer grading is fraught with ambiguity. We aimed to conduct a meta-analysis of grading of pT1 urothelial cancers and assess histopathology and outcomes in a Sri Lankan pT1 bladder cancer cohort. Patients and Method A meta-analysis of grading of pT1 urothelial cancers was conducted as per PRISMA guidelines. A second metaanalysis of the proportion of pTa/NMIBC at disease presentation was conducted to assess impact of delayed presentation on grading. Analysis was supplemented with data from a cohort of Sri Lankan patients. Results In the meta-analysis, the overall pooled pT1 HG prevalence was 75.3% [95% CI:68.3%-81.7%]. The pT1 HG prevalence was significantly higher (p=4.916878e-11) among the European, Japanese and Taiwanese studies at 90.1% [95% CI: 85.3%-94.0%] compared to the rest of the countries at 56.1% [95% CI:46.5%-65.4%]. The overall pooled pTa/NMIBC prevalence was 44.2% [95% CI:36.4%-52.1%]. The pTa/NMIBC percentage among Europe, China and Taiwan was 66.9%[95% CI:62.4%-71.2%] and it was 37.6% [95% CI:29.0%-46.6%] in Turkey and other Asian countries indicating a significant difference(P=1.08e-08). In the Sri Lankan cohort of 66 enrolled patients, 31(47%) had pT1, of which 61% were low-grade (LG). The 5-year progressionfree survival (PFS) of pT1 was 60.9%. In LG it was 85.7% and 22.2% in high-grade (HG) (P = 0.0006). Conclusion There is a global variation of percentages of pT1 LG versus HG disease in bladder cancer specimens at presentation which could be attributed to delay in treatment with stage migration, ethnic variations in tumour biology, and interobserver variability in assigning a grade of tumour, and needs further study.