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Background This study aims to determine the predictors of acquired exon 20 T790M mutation in advanced non-small cell lung cancer (NSCLC) patients harbouring sensitizing epidermal growth factor receptor (EGFR) mutation following the failure of first- or second-generation EGFR-tyrosine kinase inhibitor (TKI). Methods This is a retrospective observational study of NSCLC patients with sensitising EGFR mutation experiencing disease progression (PD) whilst on first- or second-generation EGFR-TKIs with subsequent investigations to detect acquired T790M mutation at the University of Malaya Medical Centre from 1st January 2015 to 31st December 2017. Results A total of 87 patients were included. Upon PD, acquired T790M mutation was found in 55 (63.2%) patients and was significantly more common in patients who achieved partial response (PR) whilst on the EGFR-TKIs (p = 0.008) or had new lung metastasis upon PD (p = 0.048). It was less frequent in patients who developed new symptomatic brain lesions (p = 0.021). Patients with exon 19 deletion were more likely to acquire T790M mutation compared to those with exon 21 L858R point mutation (p = 0.077). Multivariate analysis revealed PR whilst on EGFR-TKI treatment was an independent predictor of acquiring T790M mutation (p = 0.021), whereas development of new symptomatic brain lesions (p = 0.034) or new lymph node metastases (p = 0.038) upon PD was independently against acquiring T790M mutation. Patients with exon 19 deletion were more likely to acquire T790M mutation compared to those with exon 21 L858R point mutation (odds ratio: 2.3, 95% confidence interval: 0.84-6.25, p = 0.104). Conclusion The best tumour response of PR to first- or second-generation EGFR-TKI treatment independently predicts acquired T790M mutation. Patients with exon 19 deletion are likely to acquire T790M mutation. This would prove useful for clinicians to prognosticate and plan subsequent treatments for patients with advanced NSCLC harbouring EGFR mutations.

In the recent years, increased understanding of the molecular profiles of non-small cell lung cancer (NSCLC) has allowed for targeted treatment of actionable genetic mutations. The management of NSCLC now requires multiple molecular tests to guide the treatment strategy. In the light of this, there is a need to establish a molecular testing consensus statement for advanced NSCLC patients in Malaysia. This Malaysian consensus statement was developed by a panel of experts, chaired by a pathologist and composed of three other pathologists, four respiratory physicians and three oncologists. It reflects currently available scientific data and adaptations of recommendations from international guidelines to the local landscape. Expert recommendations on different aspects of molecular testing agreed upon by the panel are provided as structured discussions. These recommendations address the appropriate patients and samples to be tested, as well as when and how these tests should be performed. The algorithms for molecular testing in metastatic NSCLC, in the first line setting and upon disease progression beyond first line therapy, were developed.

Alzheimer's Disease (AD) is a neurodegenerative disease that affects cognition and is the most common cause of dementia in the elderly. As the number of elderly individuals increases globally, the incidence and prevalence of AD are expected to increase. At present, AD is diagnosed clinically, according to accepted criteria. The essential elements in the diagnosis of AD include a patients history, a physical examination and neuropsychological testing, in addition to appropriate investigations such as neuroimaging. The omics-based approach is an emerging field of study that may not only aid in the diagnosis of AD but also facilitate the exploration of factors that influence the development of the disease. Omics techniques, including genomics, transcriptomics, proteomics and metabolomics, may reveal the pathways that lead to neuronal death and identify biomolecular markers associated with AD. This will further facilitate an understanding of AD neuropathology. In this review, omics-based approaches that were implemented in studies on AD were assessed from a bioinformatics perspective. Current state-of-the-art statistical and machine learning approaches used in the single omics analysis of AD were compared based on correlations of variants, differential expression, functional analysis and network analysis. This was followed by a review of the approaches used in the integration and analysis of multi-omics of AD. The strengths and limitations of multi-omics analysis methods were explored and the issues and challenges associated with omics studies of AD were highlighted. Lastly, future studies in this area of research were justified.

Objective With an age-standardized incidence rate of 2 per 100 000, esophageal cancer is not common among Malaysians, but they are nevertheless important due to its poor prognosis. The study is to clarify whether the human papillomavirus (HPV) is associated with esophageal cancer in Malaysians as there has been no report to date on this in Malaysians and other South East Asians. Methods Altogether 67 esophageal squamous cell carcinomas histologically diagnosed between 1 January 2004 and 31 December 2014 at the Department of Pathology, University of Malaya Medical Center, Malaysia were considered for HPV analysis using two commercially available methods, polymerase chain reaction with flow-through hybridization (21 HPV GenoArray Diagnostic Kit) and multiplex real-time polymerase chain reaction (Anyplex II HPV28 Detection). The DNA amplifiability of the formalin-fixed, paraffin-embedded tumor was checked by amplification of a 268 bp segment of the human β-globin gene (GH20/PC04) prior to HPV detection. Results HPV detection was finally carried out in 51 patients. HPV16 was detected in the moderately differentiated, stage IV lower esophageal tumor of a 32-year-old Malaysian-born Chinese woman by both methods. Except for a predilection for Indians, the clinical characteristics of esophageal squamous cell carcinomas in this Malaysian cohort were generally similar to those of other populations. Conclusion It appears that HPV is rare and an unlikely oncovirus in esophageal squamous cell carcinomas of Malaysians.

X-ray repair cross-complementing group 1 (XRCC1) is one of the key components in the base excision repair pathway that repairs erroneous DNA lesions and removes nonbulky base adducts for the maintenance of genome integrity. Studies have revealed that differences in individual DNA repair capacity can impact the interindividual variation in cancer susceptibility, tumour aggressiveness and treatment response. The relationship between XRCC1 and sporadic colorectal cancer (CRC) susceptibility, which is hitherto inconclusive, has been explored in many association studies of different populations. In view of the conflicting findings generated, we aimed to investigate the association between XRCC1 and genetic predisposition to CRC among Malaysians. The present case-control association study was conducted on 130 CRC patients and 212 age-matched healthy controls. The genotyping of XRCC1 Arg194Trp, Arg280His and Arg399Gln single nucleotide polymorphisms was performed with allele-specific real-time PCR approach. This was followed by basic statistical analysis on the single nucleotide polymorphisms and haplotype data obtained. No significant difference in the allele and genotype frequencies was observed between CRC patients and healthy controls (P>0.05). There was also no association observed between XRCC1 haplotypes and CRC (P>0.05). In conclusion, a positive association between XRCC1 gene polymorphisms and CRC risk was not established in our Malaysian population.

Background This study aims to determine the predictors of acquired exon 20 T790M mutation in advanced non-small cell lung cancer (NSCLC) patients harbouring sensitizing epidermal growth factor receptor (EGFR) mutation following the failure of first- or second-generation EGFR-tyrosine kinase inhibitor (TKI). Methods This is a retrospective observational study of NSCLC patients with sensitising EGFR mutation experiencing disease progression (PD) whilst on first- or second-generation EGFR-TKIs with subsequent investigations to detect acquired T790M mutation at the University of Malaya Medical Centre from 1st January 2015 to 31st December 2017. Results A total of 87 patients were included. Upon PD, acquired T790M mutation was found in 55 (63.2%) patients and was significantly more common in patients who achieved partial response (PR) whilst on the EGFR-TKIs (p = 0.008) or had new lung metastasis upon PD (p = 0.048). It was less frequent in patients who developed new symptomatic brain lesions (p = 0.021). Patients with exon 19 deletion were more likely to acquire T790M mutation compared to those with exon 21 L858R point mutation (p = 0.077). Multivariate analysis revealed PR whilst on EGFR-TKI treatment was an independent predictor of acquiring T790M mutation (p = 0.021), whereas development of new symptomatic brain lesions (p = 0.034) or new lymph node metastases (p = 0.038) upon PD was independently against acquiring T790M mutation. Patients with exon 19 deletion were more likely to acquire T790M mutation compared to those with exon 21 L858R point mutation (odds ratio: 2.3, 95% confidence interval: 0.84–6.25, p = 0.104). Conclusion The best tumour response of PR to first- or second-generation EGFR-TKI treatment independently predicts acquired T790M mutation. Patients with exon 19 deletion are likely to acquire T790M mutation. This would prove useful for clinicians to prognosticate and plan subsequent treatments for patients with advanced NSCLC harbouring EGFR mutations.

Background The genus Onchocerca Diesing, 1841 includes species of medical importance, such as O. volvulus (Leuckart, 1893), which causes river blindness in the tropics. Recently, zoonotic onchocercosis has been reported in humans worldwide. In Japan, O. dewittei japonica Uni, Bain & Takaoka, 2001 from wild boars is a causative agent for this zoonosis. Many filarioid nematodes are infected with Wolbachia endosymbionts which exhibit various evolutionary relationships with their hosts. While investigating the filarial fauna of Borneo, we discovered an undescribed Onchocerca species in the bearded pig Sus barbatus Müller (Cetartiodactyla: Suidae). Methods We isolated Onchocerca specimens from bearded pigs and examined their morphology. For comparative material, we collected fresh specimens of O. d. dewittei Bain, Ramachandran, Petter & Mak, 1977 from banded pigs (S. scrofa vittatus Boie) in Peninsular Malaysia. Partial sequences of three different genes (two mitochondrial genes, cox1 and 12S rRNA, and one nuclear ITS region) of these filarioids were analysed. By multi-locus sequence analyses based on six genes (16S rDNA, ftsZ, dnaA, coxA, fbpA and gatB) of Wolbachia, we determined the supergroups in the specimens from bearded pigs and those of O. d. dewittei. Results Onchocerca borneensis Uni, Mat Udin & Takaoka n. sp. is described on the basis of morphological characteristics and its genetic divergence from congeners. Molecular characteristics of the new species revealed its close evolutionary relationship with O. d. dewittei. Calculated p-distance for the cox1 gene sequences between O. borneensis n. sp. and O. d. dewittei was 5.9%, while that between O. d. dewittei and O. d. japonica was 7.6%. No intraspecific genetic variation was found for the new species. Wolbachia strains identified in the new species and O. d. dewittei belonged to supergroup C and are closely related. Conclusions Our molecular analyses of filarioids from Asian suids indicate that the new species is sister to O. d. dewittei. On the basis of its morphological and molecular characteristics, we propose to elevate O. d. japonica to species level as O. japonica Uni, Bain & Takaoka, 2001. Coevolutionary relationships exist between the Wolbachia strains and their filarial hosts in Borneo and Peninsular Malaysia.

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.

With an age-standardized incidence rate of 2 per 100 000, esophageal cancer is not common among Malaysians, but they are nevertheless important due to its poor prognosis. The study is to clarify whether the human papillomavirus (HPV) is associated with esophageal cancer in Malaysians as there has been no report to date on this in Malaysians and other South East Asians.Altogether 67 esophageal squamous cell carcinomas histologically diagnosed between 1 January 2004 and 31 December 2014 at the Department of Pathology, University of Malaya Medical Center, Malaysia were considered for HPV analysis using two commercially available methods, polymerase chain reaction with flow-through hybridization (21 HPV GenoArray Diagnostic Kit) and multiplex real-time polymerase chain reaction (Anyplex II HPV28 Detection). The DNA amplifiability of the formalin-fixed, paraffin-embedded tumor was checked by amplification of a 268 bp segment of the human β-globin gene (GH20/PC04) prior to HPV detection.HPV detection was finally carried out in 51 patients. HPV16 was detected in the moderately differentiated, stage IV lower esophageal tumor of a 32-year-old Malaysian-born Chinese woman by both methods. Except for a predilection for Indians, the clinical characteristics of esophageal squamous cell carcinomas in this Malaysian cohort were generally similar to those of other populations.It appears that HPV is rare and an unlikely oncovirus in esophageal squamous cell carcinomas of Malaysians.

Objective To examine the cost of operating an anatomic pathology laboratory in a teaching hospital in Malaysia. Once the cost is determined, compare it with the costs of operating other laboratories in the same hospital, and operating anatomic pathology laboratories in other countries. Methods Cost and workload data were obtained from hospital records for 2015. Time allocation of staff between laboratory testing and other activities was determined using assumptions from published workload studies. Results The laboratory received 20,093 cases for testing in 2015, and total expenditures were US $1.20 million, ie, $61.97 per case. The anatomic pathology laboratory accounted for 5.2% of the laboratory budget at the hospital, compared to 64.3% for the clinical laboratory and 30.5% for the microbiology laboratory. We provide comparisons to a similar laboratory in the United States. Conclusions Anatomic pathology is more costly than other hospital laboratories due to the labor-intensive work, but is essential, particularly for cancer diagnoses and treatment.

Endometrial cancer is the most common gynecologic cancer in developed countries and is rising in incidence globally. Although the 5-year survival rates are >80%, factors beyond conventional pathologic features that predict clinical outcomes are still being elucidated. The aims of this study were to define the prevalence and associations of deficient mismatch repair (dMMR) protein expression (MLH1, MSH2, MSH6, PMS2) by immunohistochemistry in a multiethnic Southeast Asian cohort with endometrioid endometrial cancer. A total of 77 patients with adequate formalin-fixed paraffin-embedded specimens were identified. The sections were stained in 2 centers for 4 MMR proteins and examined by 2 independent specialist histopathologists. The mean age for the cohort was 58.6 yr, with 19.4% (15/77) of patients’ cancers showing loss of 2 MMR proteins. All 13 cancers with absent MLH1 showed PMS2 loss (13/15), whereas absent MSH2 correlated with MHS6 loss (2/15). There were no significant differences for dMMR cases in age, body mass index, histopathologic characteristics, and clinical outcomes. In dMMR cases, an overrepresentation of patients of Indian ethnic origin was observed compared with Chinese and Malays. These findings suggest that dMMR protein expression in a Southeast Asian endometrial cancer cohort does not correlate with disease outcomes.

Objective To perform a follow-up study on non-alcoholic fatty liver disease (NAFLD) patients in our previous study using paired liver biopsy. Methods Patients who were included in our previous study on NAFLD and agreed to receive a repeat liver biopsy were included in the study. Their clinical characteristics, laboratory examination results and histological analysis on the repeat liver biopsied specimens were prospectively collected and compared with those in the previous study. Results Data from 35 patients (mean age 47.5 ± 10.9 years, male 40.0%) were analyzed. The mean interval between the liver biopsies was 6.4 ± 0.8 years. NAFLD activity score (NAS) worsened in 13, remained unchanged in 9 and ameliorated in 13. Fibrosis worsened in 18 and remained unchanged in 17. Two patients who were confirmed with cirrhosis at baseline developed decompensated cirrhosis. On multivariate analysis, elevated serum aspartate aminotransferase (AST) (odds ratio [OR] 10.74, 95% confidence interval [CI] 1.00–115.86, P = 0.050) and γ-glutamyl transpeptidase (γ-GT) (OR 16.10, 95% CI 1.30–198.90, P = 0.030) at follow-up were associated with worsened NAS. Patients with borderline NASH at baseline were more likely to have worsened NAS at follow-up than those with definite NASH (OR 12.67, 95% CI 2.29–70.02, P = 0.004). However, both groups had a similar likelihood of having worsened fibrosis at follow-up. No plausible factors were found to be associated with worsened fibrosis. Conclusions NAFLD patients with persistently elevated serum AST and γ-GT levels during follow-up should be suspected of having worsened NAS. NASH patients can have significant disease progression over a relatively short period of time and fibrosis might be irreversible without specific interventions.

The tumour suppressor genes, p53 and pRb, are known to play important roles in neoplastic transformation. While molecular routes to the uncontrolled growth of hepatocytes, leading to primary liver cancer have generated considerable interest, the roles of p53 and pRb mutations in hepatocellular carcinoma (HCC) and hepatoblastoma (HB) remain to be clarified. We examined the immunohistochemical expression of p53 and pRb gene products in 26 HCC and 9 HB, sampled into tissue microarray blocks. 10 (38%) of 26 HCC showed > 10% tumour nuclear staining for p53 protein, 3 of these also being HbsAg positive. Conversely, none of 9 HB expressed nuclear p53 immunopositivity. Some 24 (92%) HCC and 8 (89%) HB showed loss of pRb nuclear expression. Two of the 26 HCC and one of the 9 HB showed >10% tumour nuclear staining for pRb protein. Our results suggest that p53 does not have an important role in the development of HB but may contribute in HCC. There is also loss of pRb expression in the majority of HCC and HB, supporting loss of pRb gene function in the hepatocarcinogenesis pathway. However, a comparison of the staining profiles of p53 and pRb proteins in HCC and HB did not reveal a consistent pattern to differentiate between the two types of tumours immunohistochemically. Hence the use of p53 and pRB protein expression has no contribution in the situation where there is a diagnostic difficulty in deciding between HCC and HB.

Background: The interesting preponderance of Chinese with colorectal carcinoma (CRC) amongst the three major ethnic groups in Malaysia prompted a study to determine DNA mismatch repair (MMR) status in our CRC and attempt correlation with patient age, gender and ethnicity as well as location, grade, histological type and stage of tumour. Histologically re-confirmed CRC, diagnosed between 1 st January 2005 and 31 st December 2007 at the Department of Pathology, University of Malaya Medical Centre, were immunohistochemically stained with monoclonal antibodies to MMR proteins, MLH1, MSH2, MSH6 and PMS2 on the Ventana Benchmark XT autostainer. Of the 142 CRC cases entered into the study, there were 82 males and 60 females (M:F=1.4:1). Ethnically, 81 (57.0%) were Chinese, 32 (22.5%) Malays and 29 (20.4%) Indians. The patient ages ranged between 15-87 years (mean=62.4 years) with 21 cases

Background: The majority of patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC) develop resistance to first- or second-generation EGFR-tyrosine kinase inhibitor (TKI) after a median treatment period of 12 months. This study aimed to determine the prevalence and predictors of acquired T790M mutation as a resistance mechanism among these patients. Method: This was a retrospective study of patients with sensitising EGFR-mutant advanced NSCLC who experienced disease progression (PD) while on first- or second-generation EGFR-TKI treatment and underwent investigations to determine the resistance mechanisms in University of Malaya Medical Centre from 1st January 2015 to 31st December 2017. Result: Of 87 patients, acquired T790M mutation was detected in 55 (63.2%) patients at PD. T790M mutation was significantly more frequent in patients who achieved partial response (PR) as the best response (p ¼ 0.008) or had new lung metastasis (p ¼ 0.048); and significantly less frequent in patients who developed new symptomatic brain metastases (p ¼ 0.021). Patients with exon 19 deletion were more likely to acquire T790M mutation compared to those with exon 21 L858R point mutation (p ¼ 0.077). In multivariate analysis, PR with EGFR-TKI treatment was a significant independent predictor of acquired T790M mutation (p ¼ 0.021) while having new symptomatic brain metastases (p ¼ 0.034) or new lymph node metastases (p ¼ 0.038) were significant independent predictors against acquired T790M mutation. Conclusion: Acquired T790M mutation was a common resistance mechanism leading to first- or second-generation EGFR-TKI treatment failure. Patients with tumours harbouring exon 19 deletion mutation were more likely to acquire T790M mutation. A best tumour response of PR to EGFR-TKI treatment was an independent predictor of acquiring this resistance. This information is helpful to clinicians in the early prognostication and management planning for patients with EGFR-mutant NSCLC.

Recent genome-wide association studies demonstrated an association between single nucleotide polymorphisms (SNPs) on the glucokinase regulatory gene (GCKR) with hepatic steatosis. This study attempted to investigate the association of GCKR rs780094 and rs1260326 with susceptibility to non-alcoholic fatty liver disease (NAFLD) and its severity. The genotypes were assessed on 144 histologically confirmed NAFLD patients and 198 controls using a Sequenom MassARRAY platform. The GCKR rs1260326 and rs780094 allele T were associated with susceptibility to NAFLD (OR 1.49, 95 % CI 1.09–2.05, p = 0.012; and OR 1.51, 95 % CI 1.09–2.09, p = 0.013, respectively), non-alcoholic steatohepatitis (NASH) (OR 1.55, 95 % CI 1.10–2.17, p = 0.013; and OR 1.56, 95 % CI 1.10–2.20, p = 0.012, respectively) and NASH with significant fibrosis (OR 1.50, 95 % CI 1.01–2.21, p = 0.044; and OR 1.52, 95 % CI 1.03–2.26, p = 0.038, respectively). Following stratification by ethnicity, significant association was seen in Indian patients between the two SNPs and susceptibility to NAFLD (OR 2.64, 95 % CI 1.28–5.43, p = 0.009; and OR 4.35, 95 % CI 1.93–9.81, p

Background and Aim Genetic polymorphism has been implicated as a factor for the occurrence of non-alcoholic fatty liver disease (NAFLD). This study attempted to assess whether polymorphisms in the leptin receptor (LEPR) gene and its combined effect with patatin-like phospholipase domain-containing protein 3 (PNPLA3/adiponutrin) are associated with risk of NAFLD. Methods A total of 144 biopsy-proven NAFLD and 198 controls were genotyped using the Sequenom MassARRAY platform. Results We observed a significant association between the LEPR rs1137100 and rs1137101 with susceptibility to NAFLD (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.18–2.28, P = 0.003; and OR 1.61, 95% CI 1.11–2.34, P = 0.013, respectively) and to non-alcoholic steatohepatitis (OR 1.49, 95% CI 1.05–2.12, P = 0.026; and OR 1.57, 95% CI 1.05–2.35, P = 0.029, respectively). The LEPR rs1137100 is also associated with simple steatosis (OR 2.27, 95% CI 1.27–4.08, P = 0.006). Analysis of gene–gene interaction revealed a strong interaction between the LEPR and PNPLA3 genes (empirical P = 0.001). The joint effect of LEPR and PNPLA3 greatly exacerbated the risk of NAFLD (OR 3.73, 95% CI 1.84–7.55, P

With a cervical carcinoma remaining the second leading cancer among Malaysian women, it is imperative to clarify the prevalence of human papillomavirus (HPV)in this respect, considering the death of local information.

Although most of the cervical cancer cases are reported to be closely related to the Human Papillomavirus (HPV) infection, there is a need to study genes that stand up differentially in the final actualization of cervical cancers following HPV infection. In this study, we proposed an integrative machine learning approach to analyse multiple gene expression profiles in cervical cancer in order to identify a set of genetic markers that are associated with and may eventually aid in the diagnosis or prognosis of cervical cancers. The proposed integrative analysis is composed of three steps: namely, (i) gene expression analysis of individual dataset; (ii) meta-analysis of multiple datasets; and (iii) feature selection and machine learning analysis. As a result, 21 gene expressions were identified through the integrative machine learning analysis which including seven supervised and one unsupervised methods. A functional analysis with GSEA (Gene Set Enrichment Analysis) was performed on the selected 21-gene expression set and showed significant enrichment in a nine-potential gene expression signature, namely PEG3, SPON1, BTD and RPLP2 (upregulated genes) and PRDX3, COPB2, LSM3, SLC5A3 and AS1B (downregulated genes).

OBJECTIVE: Although well established in the West, stool antigen tests (SAT) are not widely used in Asia. Data on the accuracy of this test in Asia is sparse and, to date, there have been no studies looking at the more refined monoclonal SAT. The aim of this study is to validate the diagnostic accuracy of a stool antigen test, Hp STAR, for the detection of Helicobacter pylori. METHODS: Consecutive new patients with dyspepsia, referred to the endoscopy unit were recruited. At endoscopy, biopsies were taken for rapid urease tests and histology. Stool specimens were collected before any therapy was given and were tested for H. pylori using the monoclonal SAT HpSTAR test. Samples were collected from 90 patients. The stool antigen results were compared with the results of rapid urease tests and histopathology, which were used together as the gold standard test in the diagnosis of H. pylori. RESULTS: Of the 90 patients tested, 45 were H. pylori positive and 45 were H. pylori negative. There was one false positive and one false negative test. The sensitivity, specificity, positive predictive value and negative predictive value for the Hp STAR were identical: 97.8% with a 95% confidence interval of 88.2–99.9%. The diagnostic accuracy was 97.8% with a 95% confidence interval of 92.2–99.7%. CONCLUSION: The monoclonal stool antigen test, HpSTAR is a highly accurate test for the diagnosis of H. pylori.

BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is increasing rapidly in the Asia–Pacific region. There has been a paucity of studies from the region. The aims of this study were to define the demographic, anthropometric, metabolic and histological characteristics of patients with NAFLD in our local population and to determine independent predictors of severe liver fibrosis. METHODS: Patients with persistently raised liver enzymes and/or fatty liver detected on ultrasonography with exclusion of other liver disorders were prospectively recruited. Their insulin resistance was assessed using the homeostasis model assessment of insulin resistance score. A liver biopsy was performed in all cases for grading (for steatohepatitis) and staging (for fibrosis) of NAFLD. Independent risk factors for fibrosis were determined using multiple logistic regression analysis. RESULTS: Seventy-five patients were recruited: 39 men (52%) and 36 women (48%). The mean age of the patients was 47.0 ± 12.2 years. Of these, 58 patients (77.3%) were centrally obese, 29 patients (38.7%) were diabetic and 15 patients (20.0%) had impaired glucose tolerance. Insulin resistance was diagnosed in 62 out of 64 (96.9%) patients. Benign steatosis, nonalcoholic steatohepatitis and cirrhosis were diagnosed in three (4.3%), 59 (84.3%) and eight (11.4%) of 70 patients, respectively. Significant independent predictors of liver fibrosis were; male sex (P = 0.019, OR = 5.55, CI = 1.33–23.18) and Indian race (P = 0.013, OR = 8.21, CI = 1.56–43.16). CONCLUSIONS: The full histological spectrum of NAFLD was seen in our patients. The majority of patients were insulin resistant, centrally obese and either diabetic or had impaired glucose tolerance. The predictors of severe liver fibrosis were male sex and Indian race.

In the past, lupus nephritis was histologically classified according to the 1995 WHO Classification. With the introduction of the 2003 ISN/RPS Classification, many nephropathology services converted to this new classification. This study was undertaken to compare both classification systems in a single centre practice.103 consecutive adequate renal biopsies initially reported as lupus nephritis in the Department of Pathology, Faculty of Medicine, University of Malaya were reassessed using the criteria of both the 1995 WHO Classification and the 2003 ISN/ RPS Classification.The relative prevalence for each class using the WHO Classification were: Class I (1%), Class II (8.7%), Class III (6.8%), Class IV (60.2%), Class V (20.4%), Class VI (2.9%) while the prevalence using the 2003 ISN/RPS Classification were: Class I (1%), Class II (8.7%), Class III (6.8%), Class IV (61.2%), Class V (21.3%), Class VI (1%). Both classifications were essentially comparable with regards to Classes I, II and III. The differences in Classes IV, V and VI were significant in potential to alter patient management. The identification of segmental lesions (Class IV-S) over and above a global nephritis (Class IV-G) deserves more focused clinicopathological studies to gauge whether these groups have different clinical manifestations and outcomes. With regards Class V, the ISN/RPS system, by requiring that all mixed classes be stipulated in the diagnostic line, minimizes the chances of patients missing out on additional treatment. The ISN/ RPS system has stricter criteria for Class VI, which again minimizes patients missing out on therapy. On the whole, the ISN/RPS system is more user-friendly as criteria are more clearly defined which translates to more benefits to patient care.

Loss of E-cadherin, a 120 kDA transmembrane glycoprotein responsible for cell-cell adhesion, is one of the hallmarks of epithelial-mesenchymal-transition (EMT). E-cadherin expression was immunohistochemically studied in 94 histopathologically re-confirmed colorectal carcinomas (CRC) using a monoclonal antibody to E-cadherin (Dako: Clone NCH-38) on a Ventana Benchmark XT automated system. Each case was assessed for E-cadherin immunopositivity at two separate locations viz the tumour centre (TC) as well as the infiltrating front (IF). Expression was semiquantitated for proportion of immunopositive malignant cells as 0 (negative), 1 (1-25% staining), 2 (26-50% staining), 3 (51-75% staining) and 4 (75% staining) and staining intensity: 0 (negative), 1 (weak), 2 (moderate) and 3 (strong). The final histoscore of E-cadherin immunopositivity was arbitrarily computed as proportion of immunopositivity multiplied by staining intensity of the malignant cells. E-cadherin histoscores were significantly lower at the IF (4.5±2.5) compared with TC (10.7±2.4). Furthermore, the histoscores were significantly reduced at the IF of 49 TNM III+IV tumours (3.6±2.5) compared with 45 II+III CRC (5.4±2.2). Reduction of E-cadherin expression was also noted in the 23 high grade (TC=8.6±3.2; IF=2.6±2.3) compared with 71 low grade tumours (TC=11.4±1.5; IF=5.1±2.3). E-cadherin is downregulated at the infiltrating front of CRC, possibly marking for EMT at this location. The downregulation is further enhanced amongst late stage and high grade tumours compared with earlier stage and low grade tumours; findings which are similar to that noted in CRC of other populations.

The pattern of p53 expression was studied in pre-invasive and invasive cervical carcinoma in an attempt to clarify its role in cervical carcinogenesis.A total of 234 invasive cervical carcinomas (152 squamous cell carcinomas, 61 adenocarcinomas and 21 adenosquamous carcinomas) and 16 cervical intraepithelial neoplasia (CIN) I, six CIN II and 25 CIN III were immunohistochemically studied for p53.p53 was detected more frequently in CIN and invasive carcinoma (100% of CIN I, 74.2% CIN II + III and 70.1% invasive carcinoma) compared with benign cervices (P0.001); however, only three squamous cell carcinomas, 11 adenocarcinomas and two adenosquamous carcinomas exhibited p53 expression in75% of tumour nuclei. Six of the 11 adenocarcinomas and both adenosquamous carcinomas were poorly differentiated compared with one of the three squamous carcinomas. p53 immunoreactive cells were randomly distributed in invasive carcinoma, confined to the lower third of the epithelium in CIN I, reached the middle third in 20% of CIN II and upper third in 16.6% of CIN III.Assuming that p53 immunoreactivity indicates gene mutation when the majority (75%) of neoplastic cells express p53, p53 mutations would seem uncommon in cervical carcinogenesis. Nonetheless, glandular malignancies, in particular poorly differentiated variants, may show a higher frequency of mutation. p53 was detected more frequently in CIN I compared with CIN II/III and invasive carcinoma which may be due to p53 protein degradation following interaction with high risk human papillomavirus E6 protein in CIN II/III and invasive carcinoma.

Aim: Telomerase activity was studied in invasive uterine cervical carcinoma to assess whether it was activated during cervical malignant transformation and to look for a possible association with human papillomavirus (HPV) infection in a set of Malaysian patients. Methods: Histologically confirmed invasive cervical carcinoma and benign cervices were assayed for telomerase activity using a commercial telomerase polymerase chain reaction (PCR) enzyme linked immunosorbent assay kit. The same cases were subjected to PCR detection of HPV using type specific (HPV types 6b, 11, 16, and 18) followed by L1 open reading frame (ORF) consensus primers. Results: HPV was detected in 18 (13 HPV-16, one HPV-6b, four only L1 ORF) of 20 invasive cervical carcinoma and one (only L1 ORF) of 19 benign cervices. Raised telomerase activity (A450 nm > 0.215) was detected in 11 cervical carcinomas, with A450 nm ranging between 0.238 and 21.790 (mean, 3.952) in positive squamous carcinomas, whereas A450 nm was only 0.222 in the one positive adenosquamous carcinoma. Five of 11 cervical carcinomas in stage I, three of six in stage II, both in stage III, and the only case in stage IV showed telomerase activation. Increased telomerase activity was noted in five of the 12 lymph node negative, five of the seven lymph node status unknown cases, and the one case with presumed lymph node metastasis. Ten of 18 HPV positive and one of two HPV negative cervical carcinomas showed telomerase upregulation. Conclusions: Telomerase is activated in invasive cervical carcinoma. Although larger studies are needed, there seems to be no clear association between telomerase upregulation and HPV status, although there is a suggestion of increased telomerase activity in squamous carcinomas and late stage disease.

To perform a follow-up study on non-alcoholic fatty liver disease (NAFLD) patients in our previous study using paired liver biopsy.Patients who were included in our previous study on NAFLD and agreed to receive a repeat liver biopsy were included in the study. Their clinical characteristics, laboratory examination results and histological analysis on the repeat liver biopsied specimens were prospectively collected and compared with those in the previous study.Data from 35 patients (mean age 47.5 ± 10.9 years, male 40.0%) were analyzed. The mean interval between the liver biopsies was 6.4 ± 0.8 years. NAFLD activity score (NAS) worsened in 13, remained unchanged in 9 and ameliorated in 13. Fibrosis worsened in 18 and remained unchanged in 17. Two patients who were confirmed with cirrhosis at baseline developed decompensated cirrhosis. On multivariate analysis, elevated serum aspartate aminotransferase (AST) (odds ratio [OR] 10.74, 95% confidence interval [CI] 1.00-115.86, P = 0.050) and γ-glutamyl transpeptidase (γ-GT) (OR 16.10, 95% CI 1.30-198.90, P = 0.030) at follow-up were associated with worsened NAS. Patients with borderline NASH at baseline were more likely to have worsened NAS at follow-up than those with definite NASH (OR 12.67, 95% CI 2.29-70.02, P = 0.004). However, both groups had a similar likelihood of having worsened fibrosis at follow-up. No plausible factors were found to be associated with worsened fibrosis.NAFLD patients with persistently elevated serum AST and γ-GT levels during follow-up should be suspected of having worsened NAS. NASH patients can have significant disease progression over a relatively short period of time and fibrosis might be irreversible without specific interventions.

This investigation was carried out to gain insight into the prevalence of pS2 expression in invasive ductal breast carcinoma in the Malaysian population and its correlation with oestrogen receptor (ER) protein expression and tumour aggressiveness. Seventy consecutive infiltrating ductal breast carcinomas treated with mastectomy and axillary lymph node clearance were investigated, using the standard avidin biotin complex immunoperoxidase method with microwave antigen retrieval and commercial monoclonal antibodies (Dako), for expression of pS2 and human ER. This was correlated against histological grade (modified Bloom and Richardson) and the presence of axillary lymph node metastasis of these carcinomas. Four (5.7%) were grade 1, 40 (57.1%) grade 2 and 26 (37.1%) grade 3 tumours. A total of 45 (64%) showed histological evidence of axillary lymph node metastasis. Forty (57%) were ERpositive, while 31 (44%) were pS2-positive. There was a statistically significant correlation between pS2 and ER expressions ( ...

BACKGROUND Teratoma of the thyroid in adults is extremely rare, and most are malignant. Only nine cases have been adequately documented in the English-language literature, and there are no reports detailing the fine needle aspiration (FNA) cytologic characteristics. CASE A 32-year-old female presented with a left-sided nodular thyroid mass with left cervical lymphadenopathy. FNA cytology of the thyroid and lymph nodes was done. The cytologic and immunocytochemical features were that of a small round cell tumor with neuroepithelial (NE) differentiation, metastasizing to the cervical nodes. Microscopic study of the thyroidectomy specimen showed a tumor showing an NE pattern with occasional islands of squamous and cuboidal epithelium, leading to a diagnosis of malignant teratoma. CONCLUSION Knowledge of FNA cytologic features of rare but highly malignant lesions like thyroid teratomas allow early recognition so that suitable and possibly aggressive treatment protocols can be adopted in the hope of prolonging survival.

Between 10 and 25% of individuals with non-alcoholic fatty liver disease (NAFLD) develop hepatic fibrosis leading to cirrhosis and hepatocellular carcinoma (HCC). To investigate the molecular basis of disease progression, we performed a genome-wide analysis of copy number variation (CNV) in a total of 49 patients with NAFLD [10 simple steatosis and 39 non-alcoholic steatohepatitis (NASH)] and 49 matched controls using high-density comparative genomic hybridization (CGH) microarrays. A total of 11 CNVs were found to be unique to individuals with simple steatosis, whilst 22 were common between simple steatosis and NASH, and 224 were unique to NASH. We postulated that these CNVs could be involved in the pathogenesis of NAFLD progression. After stringent filtering, we identified four rare and/or novel CNVs that may influence the pathogenesis of NASH. Two of these CNVs, located at 13q12.11 and 12q13.2 respectively, harbour the exportin 4 (XPO4) and phosphodiesterase 1B (PDE1B) genes which are already known to be involved in the etiology of liver cirrhosis and HCC. Cross-comparison of the genes located at these four CNV loci with genes already known to be associated with NAFLD yielded a set of genes associated with shared biological processes including cell death, the key process involved in 'second hit' hepatic injury. To our knowledge, this pilot study is the first to provide CNV information of potential relevance to the NAFLD spectrum. These data could prove invaluable in predicting patients at risk of developing NAFLD and more importantly, those who will subsequently progress to NASH.

To determine the accuracy of transient elastography (TE) and factors associated with discordance between TE and liver histology in patients with non-alcoholic fatty liver disease (NAFLD).The accuracy of TE was assessed and compared with the aspartate aminotransferase-to-platelet ratio index (APRI) in patients with histologically proven NAFLD. Factors associated with discordance between liver histology and TE were analyzed.Altogether 131 patients with a mean age of 49.9 years, including 69 men and 62 women, with NAFLD underwent liver stiffness measurement (LSM) by TE. Among all patients, 120 (91.6%) had a successful LSM with an interquartile to median ratio of 0.15. The accuracy of TE in detecting ≥F3 and F4 fibrosis, assessed by the area under the receiver operating characteristic curve, were 0.77 and 0.95, respectively. The sensitivity and specificity of the optimal LSM cut-off values for detecting ≥F3 fibrosis (sensitivity 70.4% and specificity 66.6%) and F4 (sensitivity 87.5% and specificity 89.3%) were modest, but better than those of APRI. Discordance between TE and histology for fibrosis grading was observed in 22.5% of patients, but it could not be explained by body mass index, alanine aminotransferase level, the length of the biopsied specimens or the grade of steatosis.TE plays an important role in the detection of advanced fibrosis and cirrhosis in patients with NAFLD and its accuracy does not appear to be influenced by components of the disease.

Objective To determine the accuracy of transient elastography (TE) and factors associated with discordance between TE and liver histology in patients with non-alcoholic fatty liver disease (NAFLD). Methods The accuracy of TE was assessed and compared with the aspartate aminotransferase-to-platelet ratio index (APRI) in patients with histologically proven NAFLD. Factors associated with discordance between liver histology and TE were analyzed. Results Altogether 131 patients with a mean age of 49.9 years, including 69 men and 62 women, with NAFLD underwent liver stiffness measurement (LSM) by TE. Among all patients, 120 (91.6%) had a successful LSM with an interquartile to median ratio of 0.15. The accuracy of TE in detecting ≥F3 and F4 fibrosis, assessed by the area under the receiver operating characteristic curve, were 0.77 and 0.95, respectively. The sensitivity and specificity of the optimal LSM cut-off values for detecting ≥F3 fibrosis (sensitivity 70.4% and specificity 66.6%) and F4 (sensitivity 87.5% and specificity 89.3%) were modest, but better than those of APRI. Discordance between TE and histology for fibrosis grading was observed in 22.5% of patients, but it could not be explained by body mass index, alanine aminotransferase level, the length of the biopsied specimens or the grade of steatosis. Conclusion TE plays an important role in the detection of advanced fibrosis and cirrhosis in patients with NAFLD and its accuracy does not appear to be influenced by components of the disease.