CYP2D6 genetic polymorphisms and phenotypes in different ethnicities of Malaysian breast cancer patients

The cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) is an enzyme that is predominantly involved in the metabolism of tamoxifen. Genetic polymorphisms of the CYP2D6 gene may contribute to inter-individual variability in tamoxifen metabolism, which leads to the differences in clinical response to tamoxifen among breast cancer patients. In Malaysia, the knowledge on CYP2D6 genetic polymorphisms as well as metabolizer status in Malaysian breast cancer patients remains unknown. Hence, this study aimed to comprehensively identify CYP2D6 genetic polymorphisms among 80 Malaysian breast cancer patients. The genetic polymorphisms of all the 9 exons of CYP2D6 gene were identified using high-resolution melting analysis and confirmed by DNA sequencing. Seven CYP2D6 alleles consisting of CYP2D6*1, CYP2D6*2, CYP2D6*4, CYP2D6*10, CYP2D6*39, CYP2D6*49, and CYP2D6*75 were identified in this study. Among these alleles, CYP2D6*10 is the most common allele in both Malaysian Malay (54.8%) and Chinese (71.4%) breast cancer patients, whereas CYP2D6*4 in Malaysian Indian (28.6%) breast cancer patients. In relation to CYP2D6 genotype, CYP2D6*10/*10 is more frequently observed in both Malaysian Malay (28.9%) and Chinese (57.1%) breast cancer patients, whereas CYP2D6*4/*10 is more frequently observed in Malaysian Indian (42.8%) breast cancer patients. In terms of CYP2D6 phenotype, 61.5% of Malaysian Malay breast cancer patients are predicted as extensive metabolizers in which they are most likely to respond well to tamoxifen therapy. However, 57.1% of Chinese as well as Indian breast cancer patients are predicted as intermediate metabolizers and they are less likely to gain optimal benefit from the tamoxifen therapy. This is the first report of CYP2D6 genetic polymorphisms and phenotypes in Malaysian breast cancer patients for different ethnicities. These data may aid clinicians in selecting an optimal drug therapy for Malaysian breast cancer patients, hence improve the clinical outcome of the patients

A cross-sectional study on Sinonasal inverted Papilloma: does human Papilloma virus play a role in its etiology?

Aims: To correlate the HPV genotypes with recurrence of disease and malignant transformation. Methods: A prevalence cross-sectional study. The tumour tissue was isolated from the paraffin-embedded tissue (PET). The DNA was extracted from the tissue using the QiAamp DNA Mini Kit (Qiagen, Germany). Gel electrophoresis was performed to determine the presence of genomic DNA. HPV detection and genotyping were carried out using SACACE HPV High Risk and Low Risk Typing Real-TM kit (SACACE, Italy). Two different types of kits were used, that is HPV 6,11 Real-TM and HPV 16,18 Real-TM kits. Results: A total of 44 patients, 36 were male and 8 were female with a ratio of 5:1. 61.4% was Malay, 22.7% was Chinese, 11.4% Indian 4.5% other races. 15 out of 44 patients had HPV positive (34%). The recurrence rate of positive HPV infection compared to negative HPV was not statistically significant (p>0.05). There was a significant correlation of HPV 16 and 18 infection with malignant transformation (p<0.05). A high detection rate of a high-risk HPV type (67%) was observed in patients with inverted papilloma with malignant transformation. Conclusion: The prevalence of HPV in inverted papilloma is 34%. Our result supports that HPV infection is an aetiological factor in sinonasal inverted papilloma. A high-risk HPV plays a role in the oncogenesis of sinonasal inverted papilloma. Further studies should be conducted to further elaborate this relationship

Alveolar rhabdomyosarcoma of the left hand with bilateral breast metastases in an adolescent female

Rhabdomyosarcoma is a common extramammary malignancy in pediatric age groups, but it rarely metastasizes to the breast. Breast rhabdomyosarcomas are commonly metastatic, with possible primary locations at the head and neck, trunk, extremities, retroperitoneum and perianal region. We report a case of primary alveolar rhabdomyosarcoma of the upper extremities in a 17-year-old adolescent female who presented with bilateral lower limb weakness and bilateral breast lumps

Exploring the Legal and Contractual Impediments in BIM-based Application: A Systematic Literature Review

Building information modelling (BIM) has been theoretically proven to enhance the integration of design, construction, and operation processes, hence improving the holistic delivery of a construction project. Despite the many initiatives provided by the government across various countries to increase the uptake of BIM in project implementation, previous studies have discovered the many barriers to successfully applying BIM, among which are legal and contractual issues. Hence, the present study explores and reviews the current legal and contractual impediments that have restricted BIM-based applications in the construction industry. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were employed as a standard protocol for reviewing the current research in the existing literature. The overall search process resulted in a total of 44 articles, which were then thematically analysed to disclose the findings. The review derived eight key aspects, namely procurement method, contract documentation, time and cost, quality, coordination, liability, security and law and regulation and their respective subcomponents as the basis of legal and contractual impediments that could challenge the success of BIM application in construction projects. The study extends the existing knowledge of BIM application and the implications arising from its utilisation and offers some practical insights for design and construction practitioners to improve their roles, obligations, and compliance with BIM contractual requirements. Several recommendations are also made for future research on BIM functionalities for contract administration

Fas promoter -670 polymorphism and the risk of cervical cancer: a case-control study in multi-ethnic Malaysia

Background/Objective: Single nucleotide polymorphism (SNP) is a commonly occurring DNA sequence variation within the human population. The prevalence of these sequence variations differs in various populations and may lead to the suboptimal regulation of genes, including those of the apoptosis pathway. The regulation of cellular death is partially controlled by the interaction between tumor necrosis factor receptor family gene, Fas and its ligand, FasL. A base substitution in Fas -670 A>G (rs1800682) has been found to alter the binding affinity of the Fas protein to its activators, potentially altering its apoptotic potential. The lack of proper apoptosis regulation can lead to a wide plethora of human conditions involving uncontrolled cellular growth such as cancer. The purpose of the study was to investigate whether there was any association between the Fas -670 polymorphism and risk of cervical cancer in multi-ethnic Malaysian women. Methods: Using restriction fragment length polymorphism (RFLP-PCR), Chi-square and logistic regression analysis, this study investigated the Fas -670 SNP and its associations with cervical cancer in the multi-ethnic population of Malaysia. Results: No significant associations were found between Fas -670 A>G SNP and risk of cervical cancer using the genotype model, dominant model and allele frequency model analysis, even after stratification into the Malay, Chinese and Indian ethnic subgroups; and cancer types. Conclusions: Our results showed that the A>G SNP of Fas -670 does not affect the risk of cervical carcinogenesis in Malaysian females

CYP1A1 MspI polymorphism and cervical carcinoma risk in the multi-ethnic population of Malaysia: a case-control study

Background: Tobacco smoking is considered a risk factor for cervical cancer development due to the presence of tobacco based carcinogenic metabolites in cervical cells of female smokers. In this study, we investigated the role of the T3801C (MspI) polymorphism of CYP1A1, a gene encoding an enzyme necessary for the initiation of tobacco based carcinogen metabolism, on cervical cancer risk. The T to C substitution may alter CYP1A1 activities, potentially elevating cervical cancer risk. Since results of gene-disease association studies vary according to the study population, the multi-ethnic population of Malaysia provides an excellent representative cohort for identifying and comparing the cervical cancer risk among the 3 major ethnics in Southeast Asia in relation to CYP1A1 MspI polymorphism. Materials and Methods: A total of 195 Thin Prep Pap smear samples from HPV negative and cancer free females were randomly selected as controls while 106 formalin fixed paraffin embedded samples from females with invasive cervical cancer were randomly selected for the cases group. The polymorphisms were identified using restriction fragment length polymorphism (RFLP) PCR. Results: We found no significant associations between CYP1A1 MspI polymorphism and cervical cancer in the general Malaysian female population. However, upon ethnic stratification, the variant C/C genotype was significantly associated with a 4.66-fold increase in cervical cancer risk in Malay females (95% CI= 1.21-17.9; p=0.03). No significant association was observed in the Chinese and Indian females. Additionally, there were no significant associations in the dominant model and allele frequency model analysis in both the general and ethnically stratified female population of Malaysia. Conclusions: Our findings suggest that the C/C genotype of CYP1A1 MspI polymorphism is associated with the development of cervical carcinoma in the Malay females of Malaysia

Immunohistochemical study of p16INK4A and survivin expressions in cervical squamous neoplasm.

Introduction: Cervical cancer is the second most common cancer affecting Malaysian women. Despite the implementation of pap smear screening, many women are still diagnosed only in the advanced stage of cervical cancer. This could partly be due to failure of detection of its precursor lesions; hence the need to search for novel biomarkers to assist in the screening and diagnosis of cervical neoplasia. This study aims to determine the expression of p16 INK4A and survivin as possible predictive biomarkers in cervical squamous neoplasm. Material and Methods: This is a retrospective study on 201 cases of cervical neoplasm comprising of 129 cervical intraepithelial neoplasia (CIN) and 72 squamous cell carcinoma (SCC). All samples were evaluated by two independent observers using p16INK4A and survivin monoclonal antibodies. The p16INK4A expression was graded as negative, focal and diffuse positivity. The intensity for survivin expression was graded as weak, moderate and intense. Results: It is seen that p16INK4A expression in CIN 1, CIN 2 and CIN 3 were 25.4%, 42.9% and 95.9% respectively. Majority of SCC (98.6%) showed p16INK4A expression. Survivin expressions in CIN 1, CIN 2, CIN 3 and SCC were 56.7%, 33.4%, 87.5% and 98.6%. There was a linear relationship between increasing grade of CIN and p16INK4A expressions. Conclusion: Our study showed that p16INK4A expressions correlate well with the increasing grade of CIN. Although survivin does not correlate well to the increasing grade of CIN, it could be useful in differentiating CIN 3 from SCC

Epidermal growth factor receptor (EGFR) gene alteration and protein overexpression in Malaysian triple-negative breast cancer (TNBC) cohort

Background: Epidermal growth factor receptor (EGFR) is a member of the ErbB family of tyrosine kinase receptor proteins that plays important roles in tumour cell survival and proliferation. EGFR has been reported to be overexpressed in up to 78% of triple-negative breast cancer (TNBC) cases suggesting it as a potential therapeutic target. The clinical trials of anti-EGFR agents in breast cancer showed low response rates. However, a subgroup of patients demonstrated response to EGFR inhibitors highlighting the necessity to stratify patients, who might benefit from effective combination therapy that could include anti EGFR-agents. Population variability in EGFR expression warrants systematic evaluation in specific populations. Purpose: To study EGFR alterations and expressions in a multi ethnic Malaysian TNBC patient cohort to determine the possibility of using anti-EGFR combinatorial therapy for this population. Patients and methods: In this study, we evaluated 58 cases of Malaysian TNBC patient samples for EGFR gene copy number alteration and EGFR protein overexpression using fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) methods, respectively. Results: EGFR protein overexpression was observed in about 30% while 15.5% displayed high EGFR copy number including 5.17% gene amplification and over 10% high polysomy. There is a positive correlation between EGFR protein overexpression and gene copy number and over expression of EGFR is observed in ten out of the 48 low copy number cases (20.9%) without gene amplification. Conclusion: This study provides the first glimpse of EGFR alterations and expressions in a multi ethnic Malaysian TNBC patient cohort emphasising the need for the nationwide large scale EGFR expression evaluation in Malaysia

Utility of Ki-67 and p53 in distinguishing cervical intraepithelial neoplasia 3 from squamous cell carcinoma of the cervix

The differentiation between cervical intraepithelial neoplasia 3 (CIN 3) and early squamous cell carcinoma (SCC) of the cervix may be difficult in certain situations. Identification of invasion beyond the basement membrane is the gold standard for the diagnosis of the latter. The objective of this study was to determine whether the use of Ki-67 and p53 could help in solving the above dilemma. This was a retrospective study on 61 cases of cervical neoplasms comprising of 25 cases of CIN 3 and 36 SCC. All cases were evaluated by immunohistochemistry using Ki-67 and p53 monoclonal antibodies. Results showed that the differences of Ki-67 and p53 expression between CIN 3 and SCC were statistically significant. In conclusion, Ki-67 and p53 may serve as helpful adjuncts to routinely-stained histological sections in differentiating between CIN 3 and SCC

Fine needle aspiration cytology of metastatic renal cell carcinoma - a case report

Fine needle aspiration cytology under radiologic guidance for diagnosis of renal cell carcinoma is well established and is increasingly utilized. This is because renal cell carcinoma displays fairly characteristic cellular features permitting correct cytologic identification. We present a case of a 66-year-old man who had advanced renal cell carcinoma with spread to aortic and cervical lymph nodes, lungs and liver. Fine needle aspiration cytology of the para-aortic mass showed tight clusters of malignant cells with abundant and vacuolated cytoplasm consistent with renal cell carcinoma. Histology of the left cervical lymph nodes together with immunohistochemistry findings were consistent with the cytologic diagnosis of metastatic renal cell carcinoma. The patient succumb to his illness three years after the diagnosis was mad