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  1. Abdul Aziz AA, Md Salleh MS, Ankathil R
    Int J Breast Cancer, 2020;2020:8424365.
    PMID: 32308997 DOI: 10.1155/2020/8424365
    Triple negative breast cancer (TNBC) is associated with aggressive tumour phenotype and early tumour relapse following diagnosis. Generally, clinicopathological features such as tumour size, patient's age at diagnosis, tumour histology subtypes, grade and stage, involvement of lymph nodes, and menopausal status are commonly used for predicting disease progression, prospects of recurrence, and treatment response. Prognostic value of clinicopathological features on Malaysian TNBC patients is limited. Thus, this study is aimed at investigating the association of clinicopathological features on disease-free survival (DFS) and overall survival (OS) of Malaysian TNBC patients undergoing TAC chemotherapy. Seventy-six (76) immunohistochemistry-confirmed TNBC patients were recruited. The clinicopathological features of TNBC patients were collected and recorded. Kaplan-Meier and log-rank followed by a Cox proportional hazard regression model were performed to evaluate the TNBC patients' survival. Out of 76 TNBC patients, 25 were chemoresistant and 51 were chemoresponders to the TAC chemotherapy regimen. The overall 5-year cumulative DFS and OS of TNBC patients were 63.5% and 76.3%, respectively. Multivariate Cox analysis demonstrated that medullary and metaplastic histology subtypes and positive axillary lymph node metastasis were significant prognostic factors associated with relapse with adjusted HR: 5.76, 95% CI: 2.35, 14.08 and adjusted HR: 3.55, 95% CI: 1.44, 8.74, respectively. Moreover, TNBC patients with medullary and metaplastic histology subtypes and positive axillary lymph node metastases had a higher risk to death than patients who had infiltrating ductal carcinoma and negative axillary lymph node metastasis (adjusted HR: 8.30, 95% CI: 2.38, 28.96 and adjusted HR: 6.12, 95% CI: 1.32, 28.42, respectively). Our results demonstrate the potential use of medullary and metaplastic histology subtype and positive axillary lymph node metastasis as a potential biomarker in predicting relapse and survival of the TNBC patients. This warrants further studies on intensification of chemotherapy and also identification and development of targeted therapy to reduce relapses and improve survival of TNBC patients.
  2. Ghani SA, Wan Ismail WF, Md Salleh MS, Yahaya S, Syahrul Fitri ZM
    Indian J Orthop, 2018 2 9;52(1):31-34.
    PMID: 29416167 DOI: 10.4103/ortho.IJOrtho_153_17
    Background: Giant cell tumor (GCT) of bone is a benign locally aggressive primary bone tumor which is risky for local recurrences and pulmonary metastasis. Till date, there are still many uncertainties in predicting the aggressiveness of GCT. We aim to investigate whether receptor activator nuclear kappa-B ligand (RANKL) expression may determine the prognosis of the lesion.

    Materials and Methods: We examined RANKL expression in 39 patients (21 males, 18 females) by immunohistochemistry. Four patients (10%) were presented with tumor recurrence, eight patients (20%) were complicated with lung metastasis, and two patients (5%) were presented with both recurrence and lung metastasis. Positive RANKL expression was assessed according to a scoring system evaluating the percentage of the immunostained epithelial area and the staining intensity. The cumulative score was calculated to determine the final score value. Data were analyzed using PASW version 18.0 and independent t-test between nonrecurrence/recurrence groups, and nonlung metastasis/lung metastasis groups. Significance was set at P < 0.05.

    Results: Thirty-two patients (82%) scored 3 in RANKL-staining percentage from whole stromal cell population (>75%), 6 patients scored 2, and 1 patient scored 1. Nine patients (23%) scored 3 in RANKL-staining intensity (most intense), 19 patients (48%) scored 2, and 11 patients (29%) scored 1. Twenty six patients (67%) had strong RANKL expression (total score of 5-6), 12 patients (31%) showed moderate score (3-4) whereas only 1 patient (2%) showed weak RANKL expression. Together, the mean value of RANKL-staining percentage was 2.79, intensity 1.95 and the total score 4.77. The mean RANKL-staining percentage between recurrence and nonrecurrence groups was statistically significant (P = 0.009). There was no significant difference in the mean staining intensity and total score between nonrecurrence and recurrence groups, and staining percentage staining intensity and a total cumulative score of RANKL expression between lung metastasis and nonlung metastasis groups.

    Conclusion: RANKL expression is generally high in Stage III GCT and is a reliable prognostic marker in predicting the risk of local recurrence however not in lung metastasis.

  3. Roslinah M, Wan Hitam WH, Md Salleh MS, Abdul Hamid SS, Shatriah I
    Cureus, 2019 Jan 25;11(1):e3954.
    PMID: 30956907 DOI: 10.7759/cureus.3954
    We aimed to compare clinical and pathological reactions towards locally synthesized bovine bone derived from hydroxyapatite (bone docosahexaenoic acid (dHA)) and commercially available porous polyethylene (Medpor®, Porex Surgical Incorporation, Georgia, USA) orbital implants in animal models. An experimental study was performed on 14 New Zealand white rabbits. Group A (n=7) was implanted with bovine bone dHA and group B (n=7) was implanted with Medpor®. Clinical examinations were performed on Days 1, 7, 14, 28, and 42 post-implantation. The implanted eyes were enucleated on Day 42 and were sent for pathological evaluation. Serial clinical examinations included urine color and odor; feeding and physical activity demonstrated normal wellbeing in all the subjects. Localized minimal infection was observed in both groups during the first two weeks following implantation, and the subjects responded well to topical moxifloxacin. Both groups exhibited evidence of wound breakdown. No signs of implant migration or extrusion were observed in either group. The histopathological examination revealed no statistically significant difference in inflammatory cell reactions and fibrovascular tissue maturation between both types of implants. However, all (100%) of the bovine bone dHA implants displayed complete fibrovascular ingrowth compared to Medpor® implants (57.1%) at six weeks post-implantation (p=0.001). In conclusion, bovine bone dHA and Medpor® orbital implants were well-tolerated clinically and displayed similar inflammatory reactions and fibrovascular tissue maturation. Locally synthesized bovine bone dHA orbital implants displayed significantly greater complete fibrovascular ingrowth in comparison with Medpor® implants.
  4. Mohd Isa SA, Md Salleh MS, Ismail MP, Hairon SM
    Asian Pac J Cancer Prev, 2019 Apr 29;20(4):1081-1087.
    PMID: 31030477
    Background: Cervical cancer is a preventable disease caused by human papillomaviruses. It is the third most
    common cancer to occur in women of reproductive age. The ADAM9 protein plays a role in basement membrane
    degradation and tumour metastasis in certain types of tumour. Thus, it has the potential to become a new targeted
    therapy. The objective of this study was to investigate ADAM9 expression in cervical cancer and to determine the
    factors associated with ADAM9-positive expression. Methods: This cross-sectional study was conducted in Hospital
    Universiti Sains Malaysia (HUSM) Kelantan, Malaysia from December 2010 to December 2012. Histological slides
    obtained from 95 cervical cancer cases diagnosed and/or treated in HUSM from 2000 to 2010 were analysed. The
    ADAM9 immunostain was then performed on the paraffin blocks. The statistical data entry and analysis were done
    using SPSS version 18.0. Multiple logistic regression analysis was performed to determine the factors associated with
    ADAM9-positive expression. Result: Of the 95 cervical cancer patients included in the study, 72 (75.8%) patients showed
    positive ADAM9 expression. The mean age of the patients was 53.89 (10.83) years old. Squamous cell carcinoma was
    the most common type of cervical cancer (n = 67, 70.5%). Factors that showed a statistically significant association
    with ADAM9-positive expression were tumour size (adjusted odds ratio [adj. OR]: 1.08; 95% confidence interval
    [CI]: 1.02, 1.13; p = 0.004), distant metastasis (adj. OR: 12.82; 95% CI: 1.91, 86.13; p = 0.009) and the histological
    type of cervical cancer (i.e. squamous cell carcinoma) (adj. OR: 7.39; 95% CI: 1.42, 38.51; p = 0.017). Conclusion:
    The ADAM9 immunostain was consistently positive in malignant cells. Thus, ADAM9 expression can be used as a
    prognostic/therapeutic indicator in aiding clinician decision-making regarding patient treatment (targeted therapy).
  5. Tang WJ, Adnan AS, Md Salleh MS, Mat Saad AZ
    J Vasc Access, 2018 Oct 01.
    PMID: 30269637 DOI: 10.1177/1129729818775359
    INTRODUCTION: A functioning and reliable arteriovenous fistula is a lifeline for individuals suffering from chronic kidney disease. The success and failure to arteriovenous fistula maturation have been frequently related to patient and surgeon factors.

    METHOD: In total, 138 participants with stage IV and V chronic kidney disease were included in this prospective observational study. Preoperative vascular mapping using ultrasound was performed to evaluate the condition and size of the vessels to fulfil the inclusion criteria. Intraoperatively, the vessel size was measured prior to anastomosis under magnified view. A specimen from the arterial wall of 5 mm in diameter was obtained from the arterotomy for histopathology assessment. Arteriovenous maturation was assessed at 6 weeks with the guidance of the ultrasound criteria of rule of sixes.

    RESULTS: From the total of 138 participants, 110 participants (79.7%) had matured arteriovenous fistula in 6 weeks. The mean size of the artery measured intraoperatively was 3.82 ± 1.33 mm and the vein was 4.05 ± 1.20 mm. Microcalcification in the arterial media which was hypothesised to be the cause of the arteriovenous fistula failure was insignificant, with a p value of 0.115. Despite having atherosclerosis in the artery, 83.3% of the arteriovenous fistula matured.

    CONCLUSION: Microcalcification and atherosclerosis are frequently seen in the arteries of chronic kidney disease patients, but they do not explain arteriovenous fistula non-maturation.

  6. Abdul Aziz AA, Md Salleh MS, Yahya MM, Zakaria AD, Ankathil R
    Asian Pac J Cancer Prev, 2021 Apr 01;22(4):1319-1324.
    PMID: 33906328 DOI: 10.31557/APJCP.2021.22.4.1319
    BACKGROUND: Triple negative breast cancer (TNBC) which is treated with taxane, adriamycin and cyclophosphamide (TAC) chemotherapy regimen show variation in treatment response. CYP1B1 4326 C>G polymorphism has been implicated in contributing to the differences in treatment response in various types of cancers.

    AIM: The objective of the present study was to investigate whether this polymorphism modulate the risk of disease recurrence in TNBC patients undergoing TAC chemotherapy regimen.

    METHODS: Blood samples of 76 immunohistochemistry confirmed TNBC patients were recruited. The genotyping of CYP1B1 4326 C>G polymorphism was carried out using PCR-RFLP technique. The genotype patterns were categorized into homozygous wildtype, heterozygous and homozygous variant. Kaplan-Meier analysis followed by Cox proportional hazard regression model were performed to evaluate the TNBC patients' recurrence risk.

    RESULTS: Out of 76 TNBC patients, 25 (33.0%) showed disease recurrence after one-year evaluation. Kaplan Meier analysis showed that TNBC patients who are carriers of CYP1B1 4326 GG variant genotypes (37.0%) had a significantly lower probability of disease-free rates as compared to TNBC patients who are carriers of CYP1B1 4326 CC/CG genotypes (71.0%). Univariate and multivariate Cox analysis demonstrated that TNBC patients who carried CYP1B1 4326 GG variant genotype had a significantly higher risk of recurrence with HR: 2.50 and HR: 4.18 respectively, even after adjustment as compared to TNBC patients who were carriers of CYP1B1 4326 CC and CG genotypes.

    CONCLUSION: Our results demonstrate the potential use of CYP1B1 4325 GG variant genotype as a candidate biomarker in predicting risk of recurrence in TNBC patients undergoing TAC chemotherapy regimen.

  7. Hao Ing Y, Md Salleh MS, Yahya MM, Ankathil R, Abdul Aziz AA
    Asian Pac J Cancer Prev, 2023 Nov 01;24(11):3891-3897.
    PMID: 38019248 DOI: 10.31557/APJCP.2023.24.11.3891
    OBJECTIVE: The aim of this study was to elucidate the association of ATP-binding cassette super-family G member 2 (ABCG2) gene polymorphisms with individual susceptibility to Triple Negative Breast Cancer (TNBC) as well as clinicopathological variables in TNBC patients. Two common polymorphisms in Asian population, ABCG2 34 G>A and 421 C>A was selected in this study.

    METHODS: Blood samples were collected from 75 TNBC patients and 83 controls. Genomic DNA was extracted from blood samples and the SNP genotyping was performed by using PCR-RFLP technique. The genotypes were characterized and grouped into homozygous wildtype, heterozygote and homozygous variant based on the band size. The result was subjected to statistical analysis.

    RESULTS: The A allele and AA genotype of ABCG2 421 C>A had OR of 3.011 (p=0.003, 95% CI: 1.417-6.398) and 9.042 (p=0.011, 95% CI: 1.640-49.837), to develop advanced staging carcinoma respectively. The AA genotype of ABCG2 421 C>A polymorphism was also associated with metaplastic and medullary carcinoma with an OR of 6.429 (p=0.018, 95% CI: 1.373-30.109). A significant association was also found in haplotype 34G/421A of ABCG2 with advanced cancer staging as well as metaplastic and medullary carcinoma with OR of 2.347 (p=0.032, 95% CI: 1.010-5.560) and 2.546 (p=0.008, 95% CI: 1.005-6.447), respectively.  Conclusion: The present study suggests that ABCG2 421 C>A polymorphism was associated with metaplastic and medullary histology and advanced cancer staging in TNBC patients.

  8. Abdul Aziz AA, Md Salleh MS, Mohamad I, Krishna Bhavaraju VM, Mazuwin Yahya M, Zakaria AD, et al.
    J Genet, 2018 Dec;97(5):1185-1194.
    PMID: 30555068
    Triple negative breast cancer (TNBC) is typically associated with poor and interindividual variability in treatment response. Cytochrome P450 family 1 subfamily B1 (CYP1B1) is a metabolizing enzyme, involved in the biotransformation of xenobiotics and anticancer drugs. We hypothesized that, single-nucleotide polymorphisms (SNPs), CYP1B1 142 C>G, 4326 C>G and 4360 A>G, and CYP1B1 mRNA expression might be potential biomarkers for prediction of treatment response in TNBC patients. CYP1B1 SNPs genotyping (76 TNBC patients) was performed using allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism methods and mRNA expression of CYP1B1 (41 formalin-fixed paraffin embeddedblocks) was quantified using quantitative reverse transcription PCR. Homozygous variant genotype (GG) and variant allele (G) of CYP1B1 4326C>G polymorphism showed significantly higher risk for development of resistance to chemotherapy with adjusted odds ratio (OR): 6.802 and 3.010, respectively. Whereas, CYP1B1 142 CG heterozygous genotype showed significant association with goodtreatment response with adjusted OR: 0.199. CYP1B1 142C-4326G haplotype was associated with higher risk for chemoresistance with OR: 2.579. Expression analysis revealed that the relative expression of CYP1B1 was downregulated (0.592) in cancerous tissue compared with normal adjacent tissues. When analysed for association with chemotherapy response, CYP1B1 expression was found to be significantly upregulated (3.256) in cancerous tissues of patients who did not respond as opposed to those of patients who showed response to chemotherapy. Our findings suggest that SNPs together with mRNA expression of CYP1B1 may be useful biomarkers to predict chemotherapy response in TNBC patients.
  9. Loo SK, Ch'ng ES, Md Salleh MS, Banham AH, Pedersen LM, Møller MB, et al.
    Histopathology, 2017 Jul;71(1):98-111.
    PMID: 28248435 DOI: 10.1111/his.13204
    AIMS: Transient receptor potential channel melastatin 4 (TRPM4) is an ion channel that regulates influx of calcium cations (Ca2+ ). Recent studies suggest that TRPM4 is an oncoprotein, and its up-regulated transcript level has been reported in diffuse large B cell lymphoma (DLBCL). We aimed to investigate TRPM4 protein expression pattern in non-malignant tissues and DLBCL cases, and its association with clinico-demographic parameters and survival in DLBCL.

    METHODS AND RESULTS: Analysis of publicly available DLBCL microarray data sets showed that TRPM4 transcripts were up-regulated in DLBCL compared to normal germinal centre B (GCB) cells, were expressed more highly in the activated B cell-like DLBCL (ABC-DLBCL) subtype and higher TRPM4 transcripts conferred worse overall survival (OS) in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL cases (P < 0.05). Our immunohistochemical analysis showed that TRPM4 was expressed in various human tissues but not in normal B cells within lymphoid tissues (reactive tonsil, lymph node and appendix). TRPM4 protein was present in 26% (n = 49 of 189) of our cohort of R-CHOP-treated DLBCL cases and this was associated significantly with more aggressive clinical parameters, including higher lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) scores or stage (P < 0.01 for each of the parameters) and the ABC-DLBCL subtype (P = 0.016). TRPM4 positivity conferred significantly worse OS (P = 0.004) and progression-free survival (PFS) (P = 0.005). Worse OS remained associated significantly with TRPM4 positivity in multivariate analysis, including higher International Prognostic Index (IPI) or the non-GCB DLBCL phenotype (P < 0.05).

    CONCLUSIONS: TRPM4 protein expression is up-regulated in DLBCL cases compared to non-malignant B cells with preferential expression in ABC-DLBCL cases, and it confers significantly poorer DLBCL patient outcomes.

  10. Loo SK, Ch'ng ES, Lawrie CH, Muruzabal MA, Gaafar A, Pomposo MP, et al.
    Pathology, 2017 Dec;49(7):731-739.
    PMID: 29074044 DOI: 10.1016/j.pathol.2017.08.009
    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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