Search PubMed⌕ Search

Biomedical subjects

H S Goh

Publications and source records attributed to H S Goh.

At least 19 recordsLinked to original sources
PubMed2001

Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study.

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.

Adolescent↗
PubMed2000

Prognostic significance of TP53 gene mutation in 995 cases of colorectal carcinoma. Influence of tumour site, stage, adjuvant chemotherapy and type of mutation.

Previous studies on the prognostic significance of TP53 gene alterations in colorectal cancer (CRC) have led to conflicting results. The present study investigated the prognostic significance of TP53 gene mutation in a very large series of 995 Dukes' B and C CRC patients, the majority of whom did not receive chemotherapy. Mutations were found in 385 (39%) cases and were not associated with tumour stage, histological grade, patient age or sex. Significantly more mutations were found in tumours from the left-sided colon compared with those from the right side (43% versus 34%, P=0.006). TP53 gene mutation had no prognostic value in the overall series or in different site or stage subgroups. None of the different types of TP53 gene mutation showed prognostic value. A trend for association with worse survival was observed in the patient subgroup that received adjuvant chemotherapy (Hazard Ratio (HR) 1.4, 95% confidence interval (CI) 0.89-2.21, P=0.15). These results indicate that mutation of the TP53 gene is not a useful prognostic marker for CRC patients who do not receive adjuvant chemotherapy. Further study is required to determine whether different types of TP53 mutation might be of value in predicting the response of CRC patients to chemotherapy.

Adult↗
PubMed2000

Prostate tumours from an Asian population: examination of bax, bcl-2, p53 and ras and identification of bax as a prognostic marker.

Molecular studies have suggested that ethnicity may play a significant role in prostate tumorigenesis, but no information exists for groups other than Caucasian or Japanese patients. We examined 62 archival samples of prostate tumours from Asians of non-Japanese origin for the over-expression of p53, for the possible presence of mutated ras genes, for the overexpression of the bcl-2 and bax proteins, as well as directly for the presence of apoptotic cells by the TUNEL methodology. Gene lesions of both ras (0%) and p53 (3%) were rare. While bcl-2 expression was not observed in any sample, bax expression was noted in 76% of samples and was associated with a significantly worse patient prognosis both overall (P< 0.005) and specifically in Chinese patients (P< 0.02). Apoptotic cells were found in 61% of samples, and were significantly associated with the presence of bax expression (P = 0.002), but not patient survival. These results suggest that prostate tumours from non-Japanese Asians are genetically distinct from prostate tumour found in both Japanese and Caucasian patients, and that treatment modalities may need to be tailored for specific population groups.

Aged↗
PubMed2000

Apoptosis and apoptosis related gene expression in normal conjunctiva and pterygium.

BACKGROUND: Pterygium is a relatively common eye disease in the tropics whose aetiology and pathogenesis remain uncertain. As such, interest has focused on understanding the underlying mechanism of pterygia development. METHODS: 15 specimens of pterygia from 15 eyes were examined, together with normal conjunctival tissue from the same eyes for the pattern of gene expression of genes associated with the induction or repression of apoptosis (p53, bcl-2, and bax). In addition, the samples directly for apoptotic cells were examined by the terminal deoxynucleotide transferase (TdT) mediated nick end labelling (TUNEL) methodology. RESULTS: In pterygia specimens apoptotic cells were found mainly confined to the basal layer of cells of the epithelial layer, situated immediately adjacent to the fibrovascular support layer. These cells were shown to express significant levels of p53 and bax, as well as the apoptosis inhibiting protein bcl-2. In contrast, normal conjunctival specimens displayed no bcl-2 expression and apoptotic cells were seen throughout the entire width of the epithelial layer, coupled with high levels of bax expression. CONCLUSION: These results support a model whereby pterygia development is a result of disruption of the normal process of apoptosis occurring in the conjunctiva.

Apoptosis↗
PubMed1999

c-Ki-ras mutations in colorectal adenocarcinomas from a country with a rapidly changing colorectal cancer incidence.

We have examined the incidence of mutation of the c-Ki-ras proto-oncogene in colorectal adenocarcinomas from two different time periods, namely 1962-1966 and 1994-1996. The first cohort of samples consisted of formalin-fixed, archival paraffin block and represent the oldest colorectal cancer samples for which ras mutation has been examined, while the second cohort of tumours were fresh, flash-frozen samples representative of genetic events occurring in contemporary times. Analysis of mutation status was undertaken by a mismatch-specific oligonucleotide hybridization analysis of exon 1 of the c-Ki-ras proto-oncogene after amplification by the polymerase chain reaction. Mutations in codon 12 or 13 of c-Ki-ras were detected in 28% (14/50) of contemporary samples, a figure consistent with locally established mutation rates. In contrast no mutation was detected in any of the 18 samples from the earlier period, a result that is statistically significant (P = 0.007). Age-standardized rates of colorectal cancer in Singapore have seen a marked increase over the last 30 years, and for the first time we have shown that such an increase in colorectal cancer is associated, at least in part with an increase in incidence of a specific mutagenic change.

Adenocarcinoma↗
PubMed1999

HIT family genes: FHIT but not PKCI-1/HINT produces altered transcripts in colorectal cancer.

Forty-five colorectal adenocarcinomas were examined for alterations in the HIT family genes FHIT and PKCI-1/HINT by a combination of reverse transcriptase polymerase chain reaction and DNA sequencing. In all cases a single transcript corresponding to the reported sequence was detected using primers specific for the PKCI-1/HINT gene. In contrast multiple transcripts were detected using primers specific for the FHIT gene transcript. 6% (3/45) of tumours evinced no detectable expression of any FHIT transcript and a further 12% (6/45) produced only the normal full length transcripts. Ninety-six aberrant transcripts were characterized from the remaining tumours. Deviations from the normal full length sequence characterized included deletions, insertions of novel sequences, a point mutation as well as the usage of a putative alternate splice site in exon 10. Message variants were detected with approximately equal frequency in all tumour stages with the exception that templates with insertions were found solely in Dukes' stage B tumours (P < 0.001). With the exception of the putative alternate splice site, aberrant transcripts were not detected in matched normal mucosa. These results suggest that members of the HIT family of genes are only selectively involved in tumorigenesis and that perturbation of FHIT gene expression is an early event in colorectal tumorigenesis.

Acid Anhydride Hydrolases↗
PubMed1999

p53 point mutation and survival in colorectal cancer patients: effect of disease dissemination and tumour location.

The relationship between p53 point mutation and patient survival was examined in 328 colorectal cancer patients. Point mutation was detected in 51% (166/328) of cases and was associated with a poorer prognosis in univariate and multivariate analysis. However, subcohort analysis showed that this relationship was restricted to patients with lymphatic dissemination, patients without evident distant metastatic lesions at the time of presentation and in tumours confined to the distal colorectum. These results suggest that the utility of p53 point mutation as a specific, patient based prognostic marker may be restricted to certain classes of patients.

Adenocarcinoma↗
PubMed1999

Young Investigator's Award: induction of apoptosis following traumatic head injury in humans.

Apoptosis or programmed cell death plays an important role in many developmental and pathological processes of the central nervous system. In head injury, apoptosis has been recently implicated in many studies on animal brain samples the phenomenon of apoptotic gene expression (bax and bcl-2). Twenty specimens of contused brain tissue (temporal and frontal lobe) from 20 patients who underwent emergency craniotomy and removal of mass lesions were obtained from May to October 1997. The samples collected were immediately snap frozen in liquid nitrogen and stored at -80 degrees C. Immunohistochemical analysis was performed to detect the expression of bcl-2, bax and p53 using standard avidin-biotin complex second antibody conjugate methodology utilising commercially available primary and secondary antibodies. The average age of cohort was 46.24 +/- 22.17 years, the average Glasgow Coma Scale on admission was 9.19 +/- 4.72, and the average duration from injury to collection of the sample was 20.62 +/- 40.57 hours. There was documented hypoxia and hypotension seen in 5 of the 20 patients (25%). Significant levels of bax protein expression were noted in all samples, and p53 expression in 30% of samples. No bcl-2 expression was observed. Our study showed that for the first time the strong expression of the pro-apoptotic gene (bax) and low levels of the anti-apoptotic gene (bcl-2), thus implicating the mechanism of apoptosis in brain injury following trauma. The use of agents to inhibit apoptosis may be beneficial in head injury patients.

Apoptosis↗
PubMed1997

Abnormal expression of the p53 tumor suppressor gene in the conjunctiva of patients with pterygium.

PURPOSE: To determine whether pterygium is a disorder of abnormal growth by examining the expression of the p53 gene in the conjunctiva of patients with pterygium. METHODS: Immunostaining for abnormal expression of p53 was performed using mouse monoclonal antibody to human p53, pAb 240, on six eyes with primary pterygium and two eyes with recurrent pterygium. RESULTS: In three of the eight eyes with pterygium, specimens were positive for abnormal expression in the epithelium of the pterygium and in the superior bulbar conjunctiva. CONCLUSION: Abnormal p53 expression in the epithelium of primary and recurrent pterygium specimens suggests that pterygium is a growth disorder rather than a degeneration.

Antibodies, Monoclonal↗
PubMed1997

CMV colitis masquerading as colon cancer--an unusual presentation of acquired immunodeficiency syndrome.

We present a case-report of a patient with a typical history and a barium enema study diagnostic of right-sided colonic cancer. Laparotomy and right hemicolectomy was carried out. Histological examination revealed Cytomegalovirus (CMV) colitis and the patient was subsequently tested positive for Human immunodeficiency Virus (HIV). Gastrointestinal symptoms are common in patients with Acquired Immune Deficiency Syndrome (AIDS) and up to 10% of all AIDS patients have CMV colitis. The diagnostic criteria for CMV colitis is reviewed. AIDS is likely to become more common and we stress the awareness of this condition as well as the need for preoperative colonoscopy and histological diagnosis in patients with radiological diagnosis of colorectal carcinoma.

AIDS-Related Opportunistic Infections↗
PubMed1996

Bowel function survey after segmental colorectal resections.

PURPOSE: Long-term bowel function after right hemicolectomy (RHC), extended right hemicolectomy (ERHC), left hemicolectomy (LHC), sigmoid colectomy (SC), and anterior resection (AR) was evaluated. METHOD: Three hundred fifteen patients (52.3 percent) replied to a questionnaire on stool frequency, fecal continence, and defecation problems. All patients had undergone surgery at least one year before questionnaire was sent to them. Patients with anastomotic leaks and recurrences were excluded. RESULTS: Stool frequency was one to two bowel movements per day in 78 percent of patients after RHC, 75 percent after ERHC, 57.6 percent after LHC, 64.3 percent after SC, and only 44.8 percent after AR (P = 0.01). Continence affected lifestyle in 32 percent of patients after AR, but affected only up to 11.5 percent of patients who had had more proximal resections (P = 0.001). Defecation problems occurred in less than 15.4 percent after RHC, ERHC, and LHC but were encountered more frequently after SC (25 percent) and AR (28.4 percent; P = 0.009). CONCLUSIONS: Problems with postoperative bowel function were appreciably more common after SC and AR.

Colectomy↗
PubMed1996

Clinical and physiologic effects of biofeedback in outlet obstruction constipation.

PURPOSE: We report the results of biofeedback (BF) on patients with outlet obstruction defecation (OOC), including those with and without measurable paradoxical puborectalis contractions (PP). Clinical and anorectal physiologic parameters (ARP) were assessed one week before and after a standardized course of BF. METHODS: Sixty-two consecutive patients (24 men, 38 women; mean age, 48 (standard error of the mean, 2.3) years) were recruited. All had persistent constipation despite six weeks of dietary fiber supplements. Colonic inertia was excluded by transit marker studies. Defecating proctography excluded anatomic abnormalities causing outlet obstruction. Patients underwent four outpatient sessions of biofeedback, each session lasting one hour. RESULTS: After BF, 56 patients (90.3 percent) were subjectively improved. Frequency of spontaneous bowel movements were significantly increased (P = 0.003). Frequency of laxative-induced (P = 0.004) and enema-induced (P = 0.005) stools were reduced. Anal resting (P = 0.04) and squeeze (P = 0.002) pressures were increased. Number of patients with PP was reduced from 40 to 31 (P = 0.004). Presence of PP did not affect response to BF. There were no differences in ARP between the 56 patients who improved and the 6 who did not. There were no side effects or clinical regressions after a mean follow-up of 14.9 (standard error of the means, 0.9) months. CONCLUSIONS: BF effectively treated OOC in 90.3 percent, regardless of PP. Anal pressures were increased, and PP was decreased.

Biofeedback, Psychology↗
PubMed1996

C-KI-RAS activation and the biological behaviour of proximal and distal colonic adenocarcinomas.

One hundred and forty colonic adenocarcinomas originating on the left side of the colorectum and 70 colorectal carcinomas originating on right side of the colorectum were examined for activating mutations of codons 12 and 13 of the C-KI-RAS proto-oncogene. Rates of mutation were significantly different (right colon 43%, 30/70 versus left colon 23%, 32/140; P = 0.0025). Adenocarcinomas from the left side of the colorectum showed a significant association between C-KI-RAS activation and tumour progression, including the presence of distant organ metastasis at the time of surgery (P = 0.0039), and during patient follow-up (P = 0.00027), whereas those from the right of the colorectum did not (P = 0.4 and P = 0.5, respectively). Mutation of the C-KI-RAS proto-oncogene was found to be associated with a significantly poorer patient prognosis on the left of the colorectum (P = 0.0001 by log rank analysis of Kaplan-Meier plots) but not on the right (P = 0.7). These results demonstrate that, not only is the timing and frequency of C-KI-RAS activation different between carcinomas originating on the left or right of the colorectum, but also that the biological consequences of such mutations may differ.

Adenocarcinoma↗
PubMed1996

Prognostic significance of p53 overexpression and mutation in colorectal adenocarcinomas.

The p53 tumour-suppressor gene is found altered in the majority of colorectal cancers. Lesions include allelic loss, mutation of the gene and overexpression of the p53 protein. All of these lesions have been analysed for prognostic significance, and whereas both mutation and allelic loss have been shown to be reasonably useful markers of prognosis, the utility of overexpression of the p53 protein is more ambiguous. Given that many authors use p53 overexpression as a marker for point mutation this issue is of some importance. We have therefore examined 100 colorectal carcinomas for mutation of the p53 gene, as well as overexpression of the p53 protein. Results show that whereas mutation of the p53 gene is associated with p53 overexpression, the degree of association depends, at least in part, upon the particular antibody used. Moreover, although mutation of the p53 gene does provide prognostic information, overexpression of the p53 protein, as detected with two antibodies, does not. These results suggest that immunohistochemistry is not a suitable alternative to direct detection of mutation in assessing prognosis in colorectal cancer patients.

Adenocarcinoma↗
PubMed1996

p53 and prognosis in colorectal cancer.

The p53 tumour suppressor gene is found altered in the majority of colorectal adenocarcinomas. While these changes are believed to reflect underlying mechanisms of tumour development and progression, it is becoming increasingly clear that such changes may also reflect the macroscopic biological behaviour of the course of the disease. Knowledge of the p53 tumour suppressor gene status may therefore provide important prognostic information. This review examines some of the data that are beginning to show that p53 tumour suppressor gene status may be an important prognostic indicator.

Adenocarcinoma↗
PubMed1996

Molecular changes of colorectal cancer in Singapore.

Improved success in the management of colorectal cancer requires a better understanding of its development and biological behaviour. The key for this is molecular genetics. Gene changes parallel the multi-step changes in the adenoma-carcinoma sequence. Cancer results from a variable combination of defects in oncogenes, tumour suppressor, mutator and apoptotic genes. These changes are similar whether they occur in inherited disorders like adenomatous polyposis coli (APC) and hereditary non-polyposis colorectal cancer (HNPCC) or acquired cancer in the elderly. In Singapore, the c-myc and c-Ki-ras proto-oncogenes are found to be activated in 70% and 29% of tumours respectively. Allelic loss of chromosome 5q and 17p occurs in 25% and 70% of tumours respectively, while point mutation of the p53 tumour suppressor gene occurs in 50% of colorectal cancers. Both the frequency and the nature of the lesion occurring are compatible to the changes detected in Caucasian patients, suggesting common aetiological factors. The biological behaviour of colorectal adenocarcinomas is determined by the nature of defects or mutations in key genes such as the p53 tumour suppressor gene. Lymphatic spread is associated with the presence of point mutations and haematogenous spread is associated with loss of heterozygosity of p53. Survival is worse when conserved regions of the gene are mutated compared with those outside, and worst when codon 175 is mutated. Sensitivity to radiotherapy and chemotherapy is also determined by p53 mutation which controls apoptosis. Prognosis could now be individualised and with the prospect of gene therapy, molecular genetics will have a major impact on the management of colorectal cancer.

Adenocarcinoma↗
PubMed1996

Use of molecular methods in the early diagnosis of familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.

Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) are the most well-defined heritable conditions which predispose to colorectal cancer at a young age. Significant progress in understanding the pathogenesis of FAP and HNPCC has led to the development of techniques which can be used for the diagnosis of these two conditions. In this article, the technical aspects and clinical applications of molecular methods such as linkage analysis, mutational analysis and in vitro synthesised-protein assay for FAP and microsatellite instability or replication error (RER) assay for HNPCC are described and discussed. The potential of such molecular tests is the identification of affected individuals for proper surveillance and management as well as the identification of non-affected individuals to free them from the trauma of uncertainty and repeated unnecessary colonoscopies.

Adenomatous Polyposis Coli↗