PIK3CA gene mutations in breast carcinoma in Malaysian patients.

Somatic mutations of phosphoinositide-3-kinase, catalytic, alpha; PIK3CA gene have been reported in several types of human cancers. The majority of the PIK3CA mutations map to the three "hot spots" - E542 K and E545 K in the helical (exon 9) and H1047R in the kinase (exon 20) domains of the p110alpha. These hot spot mutations lead to a gain of function in PI3 K signaling. We aimed to determine the frequency of PIK3CA mutations in the three most common Malaysian cancers. In this study, we assessed the genetic alterations in the PIK3CA gene in a series of 20 breast carcinomas, 24 colorectal carcinomas, 27 nasopharyngeal carcinomas (NPC), and 5 NPC cell lines. We performed mutation analysis of the PIK3CA gene by genomic polymerase chain reaction (PCR) and followed by DNA direct sequencing in exons 9 and 20. No mutations were detected in any of the 24 colorectal and 27 NPC samples, but one hot spot mutation located at exon 20 was found in a NPC cell line, SUNE1. Interestingly, PIK3CA somatic mutations were present in 6/20 (30%) breast carcinomas. Two of the six mutations, H1047R, have been reported previously as a hot spot mutation. Only one out of three hot spot mutations were identified in breast tumor samples. The remaining four mutations were novel. Our data showed that a higher incidence rate of PIK3CA mutations was present in Malaysian breast cancers as compared to colorectal and nasopharyngeal tumor tissues. Our findings also indicate that PIK3CA mutations play a pivotal role in activation of the PI3 K signaling pathway in breast cancer, and specific inhibitors of PIK3CA could be useful for breast cancer treatment in Malaysia.

Mucinous adenocarcinoma of the rectum with breast and ocular metastases.

We present the case of a 32-year-old woman who, 10 months after abdominoperineal resection and total mesorectal excision for a locally advanced mucinous adenocarcinoma of the rectum, presented with local recurrence and metastases to the breast, spine, the left eye and orbit. Following surgery, due to the patient's personal reasons, adjuvant chemoradiation was not given. The patient died 2 months later, with disseminated cancer. To the best of our knowledge, breast as well as ocular metastasis in a patient with mucinous adenocarcinoma of the rectum has never been reported and, therefore, needs to be documented.

A comparative study of the expression of Wnt-1, WISP-1, survivin and cyclin-D1 in colorectal carcinoma.

BACKGROUND AND AIMS: It is well accepted that activation of Wnt signalling occurs in colorectal carcinoma (CRC), but the correlation amongst the various proteins involved in primary tumours are still unclear. The expression of the inducer of this pathway, Wnt-1, and the downstream effectors, WISP-1, cyclin-D1 and survivin proteins, was compared in a series of CRC tissues with the apparently normal adjacent tissues to determine the relationship of these proteins. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded tissue samples of 47 CRCs surgically resected at the Kuala Lumpur Hospital (KLH) between 1999 and 2000 were used. Immunohistochemical staining with monoclonal antibodies against cyclin-D1 and survivin and polyclonal antibodies against Wnt-1 and WISP-1 was performed. Results of immunohistochemistry were analysed for correlation between biomolecules and histopathological data of the patients. RESULTS: Of the 47 CRCs, 26 (55.3%), 15 (31.9%), 5 (10.6%) and 28 (59.6%) of the tumours exhibited positivity for Wnt-1, WISP-1, cyclin D1 and survivin, respectively. A lower percentage of the 40 apparently normal adjacent tissues were found to be positive for Wnt-1 (7, 17.5%), WISP-1 (+/-5, 12.5%) and survivin (13, 32.5%), but cyclin D1 was not detected in any of them. Interestingly, the total scores of Wnt-1, WISP-1 and survivin were significantly higher in CRC tissues (p=0.001, 0.034 and 0.044, respectively). Using the Spearman rank correlation test, a positive linear relationship was found between total Wnt-1 score with total WISP-1 score (rho=0.319, p=0.003) and total survivin score (rho=0.609, p=or<0.001). The expression of WISP-1 in the CRC tissues was found to be positively correlated with patients older than 60 years old (p=0.011). In addition, nuclear cyclin-D1 expression was found to be associated with poorly differentiated CRC tissues (p<0.001, Table 5) and right-sided CRC tumour (p=0.019, Table 6). Total WISP-1 score was associated with well-differentiated CRC tissues (p=0.029). CONCLUSIONS: Overexpression and interplay between Wnt-1, WISP-1, survivin and cyclin-D1 may play a role in tumorigenesis, possibly by promoting cell cycle checkpoint progression, accelerating cell growth and inhibiting apoptosis. Our data may provide useful information towards the search for potent therapeutic targets towards the development of novel treatment strategies for CRC.

Diagnostic value of plain abdominal radiographs in patients with acute abdominal pain.

OBJECTIVE: A prospective study was performed over a 3-month period in a tertiary referral centre to evaluate the appropriateness and contribution of plain abdominal radiographs (PAR) in the diagnosis and management of adult patients presenting with acute abdominal pain. METHODS: Forward stepwise logistic regression was used to examine the correlation between PAR findings and the final diagnosis. The Chi-squared test was used to determine any changes in patient management including requirement for surgical intervention based on PAR findings (p < 0.05). RESULTS: Of 168 patients (246 PAR), 59 (35%) had positive findings on PAR. PAR were most sensitive in cases of intestinal obstruction (odds ratio, OR = 33.548, r = 0.561). The sensitivity was further increased if three of the following predictive signs were present: exaggerated bowel sounds (OR = 13.350, r = 0.154), abdominal distension (OR = 2.993, r = 0.234) and age over 50 years (OR = 2.301, r = 0.027). PAR were non-diagnostic in 82% of patients with acute abdominal pain (p < 0.001). CONCLUSION: PAR do not play a major role in influencing the management of patients with acute abdominal pain without coexisting bowel obstruction.

Appropriate antibiotic administration in elective surgical procedures: still missing the message.

OBJECTIVE: The aim of this study was to determine the appropriateness of antibiotic prophylaxis in selected elective surgical procedures in a tertiary referral centre. METHODS: A cross-sectional study using retrospective data from January 2000 to May 2002 was performed pertaining to elective colorectal surgery, cholecystectomy and inguinal hernia repairs. Appropriateness of antibiotic administration was determined based on compliance with national and internationally accepted guidelines on prophylactic antibiotic prescribing policy. A single dose or omission of antibiotic administration was judged appropriate for cholecystectomy and inguinal hernia repair, while up to 24 hours' dosing was considered appropriate practice for colorectal surgery. RESULTS: Of 419 cases, there were 55 (13.1%) colorectal procedures, 97 (23.2%) cholecystectomies and 267 (63.7%) inguinal hernia repairs. Antibiotics were administered in a total of 306 (73%) cases, with single-dose prophylaxis in only 125 (41%) of these. Prophylaxis was inappropriately prolonged in 80%, 52% and 31% of colorectal, cholecystectomy and inguinal hernia cases, respectively. The corresponding mean duration of anti-biotic administration was 2.4+/-2.2, 1.6+/-1.8 and 1.1+/-1.3 days, respectively. CONCLUSION: Antibiotic prophylaxis in elective surgery continues to be administered haphazardly. This study supports close surveillance of antibiotic utilization by a dedicated team, perhaps consisting of microbiologists or pharmacists, to minimize inappropriate administration.

Venous thromboembolic disease prophylaxis among general surgeons in Malaysia.

OBJECTIVE: The aim of this study was to analyse the current practice of venous thromboembolism (VTE) prophylaxis among general surgeons in Malaysia. METHODS: A questionnaire survey was conducted among general surgeons attending the annual Malaysian College of Surgeons meeting in 2002. A total of 110 questionnaires were distributed to specialist-grade general surgeons with varying subspecialty interests. RESULTS: Seventy-seven (70%) surgeons returned the questionnaire. Of these, 43% were of the opinion that VTE was as common in Asian patients as in the West. Selective VTE prophylaxis was used by 99% in their practice. The indications for use, in order of frequency, were: previous VTE disease, risk grading, prolonged surgery, obesity, malignancy and age. Low molecular weight heparin was the most common type of prophylaxis used. VTE-related morbidity was reported by 44 surgeons (57%) over the past year, and 39% of these cases were fatal. CONCLUSION: The high incidence of VTE-related complications indicates that the use of thromboprophylaxis is either insufficient or not matched to the level of risk. Updated guidelines on VTE prophylaxis should be used so that a standardized approach can ensure that patients receive adequate prophylaxis where indicated.

Adult intussusception secondary to inflammatory polyps.

Adult intussusception is a rare entity that may present in the acute and subacute setting principally related to the degree of bowel obstruction. Preoperative diagnosis of this condition may be difficult. The intussusception is usually due to a definable intraluminal lesion, most probably neoplasia, unlike intussusception in children. We present the cases of two adult male patients with intussusception. The first presented with acute small-bowel obstruction secondary to a retrograde ileojejunal intussusception with a pseudopolyp as the lead point. This was possibly due to a retrograde ball-valve effect. The intussuscepting segment was resected. The second patient presented with unexplained chronic diarrhoea and an intussusception occurring within the caecum, as demonstrated at colonoscopy, with a terminal ileal pedunculated fibroid polyp as the lead point. A limited right hemicolectomy was performed. Both patients recovered uneventfully and have remained well. A brief literature review of adult intussusception complements the case reports, with an emphasis on the pathogenesis of inflammatory polyps and recommended surgical management.

Diet and lifestyle intervention among patients with colorectal adenomas: rationale and design of a Malaysian study.

Comprehensive evaluation of the large body of consistent evidence from laboratory, epidemiologic and clinical studies has led to the conclusion that modification of the dietary and lifestyle patterns of populations has considerable potential for reducing cancer risk. This paper describes a randomized-controlled trial involving a diet and lifestyle intervention for patients with history of colorectal adenomas. The primary aim of this trial is to evaluate the effectiveness of the intervention with reference to recurrence of adenomatous polyps over a two year period--the first year being the intervention period and the second year of the study allowing for post-intervention follow-up. Subjects found to fit the inclusion criteria are recruited and randomized to two groups: the intervention group and the control group. The intervention group subjects will attend a monthly lecture-discussion session for 10 months and small group counseling on modification of lifestyle behavior and diet as well as receive educational materials which were adapted from the WCRF Diet and Health Recommendations for Cancer Prevention. Control subjects will be provided with the usual care given to such patients. One hundred and sixteen patients who were diagnosed with colorectal adenomatous polyps in the previous twelve months at the Hospital Kuala Lumpur have already been enrolled in this trial. Baseline data collection is on-going.

Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 473 but not threonine 308 in colorectal carcinoma.

The enhancement of cell proliferation and promotion of cell survival via the inhibition of apoptosis is thought to be the key to the initiation and progression of cancers. The phosphatidylinositol-3 kinase (PI3K)/Akt is an important survival signal pathway that has been shown to be crucial in the regulation of balance between pro-apoptotic and survival (anti-apoptotic) signal. In this study, the expression of phosphorylated Akt at Thr308 and Ser473, BCL-2-antagonist of cell death (BAD) at Ser136 and glycogen synthase kinase-3beta (GSK-3beta) at Ser9 in 47 paraffin-embedded human colorectal carcinoma (CRC) tissues were determined by immunohistochemical staining in order to dissect the alterations in the signal transduction pathways in CRC. Our results showed that there was a significant increase in the expression of these biomolecules in CRC tissues compared to the apparently normal adjacent tissues. The frequency of increased expression in tumor colonic mucosa were as follows: p-Akt1/2/3 (Thr308) = 16/47 (34%); p-Akt1 (Ser473) = 21/47 (44.7%); phospho-BAD (p-BAD) Ser136 = 27/47 (57.4%) and phospho-GSK-3beta (p-GSK-3beta) = 21/47 (44.7%). Analysis of the total p-Akt1 (Ser473), p-Akt1/2/3 (Thr308), p-GSK-3beta (Ser9) and p-BAD (Ser136) score found that there was a statistically significant relationship with each other. A statistically significant positive linear relationship was found between total p-Akt (Ser473) score and total p-GSK-3beta (Ser9) score as well as with total p-BAD (Ser136) score. On the other hand, total p-Akt1/2/3 (Thr308) scores had a statistically significant positive linear relationship with p-GSK-3beta (Ser9) only. The Akt targets, p-GSK-3beta (Ser9) and p-BAD (Ser136) were positively correlated to each other. There was no significant correlation between clinico-pathological data with total p-Akt1 (Ser473), p-Akt1/2/3 (Thr308), p-GSK-3beta (Ser9) and p-BAD (Ser136) score except for age. The total scores of p-GSK-3beta were found to be higher in patients in the age group of greater than 60. This is the first report of p-Akt1/2/3 (Thr308) and p-BAD (Ser136) expression in primary colorectal tumor tissue. Our data further supports the role of PI3K/Akt signaling pathways in the pathogenesis of CRC and contributes to the identification of target molecules in the signal transduction pathway for cancer therapy.

Expression of beta-catenin, COX-2 and iNOS in colorectal cancer: relevance of COX-2 adn iNOS inhibitors for treatment in Malaysia.

BACKGROUND: Promising new pharmacological agents and gene therapy targeting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) could modulate treatment of colorectal cancer in the future. The aim of this study was to elucidate the expression fo beta-catenin and teh presence of COX-2 and iNOS in colorectal cancer specimens in Malaysia. This is a useful prelude to future studies investigating interventions directed towards COX-2 adn iNOS. METHODS: A cross-section study using retrospective data over a 2-year period (1999-2000) involved 101 archival, formalin-fixed, paraffin-embedded tissue samples of colorectal cancers that were surgically resected in a tertiary referral. RESULTS: COX-2 production was detected in adjacent normal tissue in 34 sample (33.7%) and in tumour tissue in 60 samples (59.4%). More tumours expressed iNOS (82/101, 81.2%) than COX-2. No iNOS expression was detected in adjacent normal tissue. Intense beta-catenin immunoreactivity at the cell-to-cell border. Poorly differentiated tumours had significantly lower total beta-catenin (p = 0.009) and COX-2 scores (p = 0.031). No significant relationships were established between pathological stage and beta-catenin, COX-2 and iNOS scores. CONCLUSIONS: the accumulation of beta-catenin does not seem to be sufficient to activate pathways that lead to increased COX-2 and iNOS expression. A high proportion of colorectal cancers were found to express COX-2 and a significant number produced iNOS, suggesting that their inhibitors may be potentially useful as chemotherapeutic agents in the management of colorectal cancer.

Appropriateness of colonoscopy in a tertiary referral centre.

The aim of this study was to determine the appropriateness of colonoscopy in relation to its diagnostic yield, with reference to the guidelines set by the American Society of Gastrointestinal Endoscopy (ASGE). A prospective 90-day audit was performed at Hospital Kualal Lumpur, which is a tertiary referral centre in Malaysia, to examine the appropriateness of colonoscopy by indication. During that time, 257 colonoscopies were performed in 244 patients. The predominant indications for colonoscopy were altered bowl habit (37%) and rectal bleeding (18%). Of the 257 colonoscopies, 216 (84%) were judged to be appropriate by ASGE guidelines. Only 43% of all colonoscopies had positive findings. Positive findings were found in 93% of cases judged appropriate compared with only 7% found in cases deemed inappropriate. There were statistically significant relationships between appropriateness and overall positive yield and between appropriateness and neoplastic findings (p < 0.05). Colonoscopy performed for appropriate indications yield more significant findings, this, we advocate the use of accepted guidelines to maintain or improve the standard colonoscopy services.

Postoperative venous thromboembolism in Asia: a critical appraisal of its incidence.

OBJECTIVES: Venous thromboembolism (VTE) has historically been perceived to be a rare disorder in Asia. However, new evidence has emerged recently that contradicts this perception. The question of routine VTE prophylaxis has been hotly debated in Asia due to disagreement on its incidence. We reviewed and analysed studies on postoperative VTE in Asian patients to determine if the condition was indeed rare and if the routine prophylactic measures as recommended by internationally accepted guidelines should be adopted in Asia. METHODS: A review of published reports, from 1966 to December 2002, on deep vein thrombosis (DVT) and pulmonary embolism (PE) in the Asian population was made. A literature search of studies published in English was conducted via a detailed MEDLINE search. Studies had to attain a minimum inclusion and quality criteria to be accepted for the review, including the diagnostic modality used for the diagnosis of VTE. The appraisal was carried out independently and accepted by at least two of the three authors. The study population was classified into orthopaedic and general surgical/colorectal groups. RESULTS: Twelve orthopaedic publications reviewed revealed an incidence of postoperative DVT of 10% to 63%. Six general and colorectal surgical publications reported an incidence of DVT ranging from 3% to 28%. The incidence was slightly lower than the reported incidence of 40% to 80% following orthopaedic surgery and 28% to 44% following general surgical operations in studies reporting on Caucasian populations. CONCLUSION: While there is a wide variation in the incidence of DVT and VTE as reported in the Asian population, these diseases are by no means rare. The wide variation could be due to the study designs, heterogeneity of the procedures performed and the application of different diagnostic criteria. Results based on prospective studies with objective diagnostic criteria confirm the incidence of VTE as common. Routine chemoprophylaxis must be seriously considered in high-risk patients.

Pharmacotherapy for chronic hemorrhagic radiation proctitis.

Endoscopic thermal therapy and formalin are being increasingly recommended for the treatment of chronic hemorrhagic radiation proctitis. It may be too early, however, to discard pharmacologic agents from the management process, especially in medical institutions where specialized equipment is unavailable. We prospectively assessed the effectiveness of medical therapy in 14 consecutive patients with chronic hemorrhagic radiation proctitis from July 1999 to June 2001. All 14 subjects were women (mean age 56 years), 13 of whom had had radiotherapy for cancer of the cervix. The median time to onset of symptoms following irradiation was 16 months. Six patients had a hemoglobin level of < 8 g/dl, and blood transfusion was required in 11 patients. In five patients (36%) initially treated with hydrocortisone enemas prior to referral, this treatment continued; and the remaining nine patients were commenced on sucralfate enemas. Two patients given rectal hydrocortisone continued to bleed and were treated with sucralfate enemas and topical formalin, respectively. Rectal sucralfate suspension effectively procured symptomatic alleviation in all 11 patients. Rectal bleeding recurred in two patients who had been managed exclusively with hydrocortisone and sucralfate enemas, respectively, over a mean follow-up of 6 months. Both patients were managed with topical formalin, which controlled their symptoms. Even though the number of subjects in this study is small, sucralfate enema can be recommended as an effective first-line agent for managing patients with chronic hemorrhagic radiation proctitis. The use of more specialized therapy can therefore be reserved for cases where primary treatment failure occurs with sucralfate therapy.

Antibiotic prophylaxis in elective colorectal surgery.

BACKGROUND: Antibiotics are often administered in elective colorectal surgery to prevent wound infection. The tendency for surgeons to prolong the administration of prophylactic antibiotic therapy in the postoperative period is a well-known fact. The aim of this study was to elucidate the pattern of prophylactic antibiotic utilization in elective colorectal surgery and to determine if evidence-based medicine is employed in relation to this practice. METHODS: A cross-sectional study encompassing general surgeons performing elective colorectal surgery was performed. Questionnaires were distributed to 144 surgeons (national, academic and private health care). Questions pertaining to the type, timing and duration of antibiotic administration were asked. The prevalence of wound infection audit rate and whether or not there were specific guidelines related to antibiotic administration were also determined. RESULTS: The response rate obtained was 67% (n = 96). Although evidence from the current medical literature and recommended national guidelines support the use of single-dose prophylactic antibiotics, 72% of the respondents used more than a single dose. Forty surgeons (42%) claimed that their prescribing practice was supported by the medical literature, 31 respondents (32%) based their practice on hospital guidelines and personal preference was cited as a reason by 21 surgeons (22%). The remaining four respondents (4%) used a similar scheduling policy to that practiced by their colleagues in relation to antibiotic administration. There was no significant difference in antibiotic dose scheduling between national, private and university academic institutions (P = 0.85). CONCLUSIONS: These results suggest that a significant proportion of surgeons administer excessive and unnecessary doses of antibiotics in elective colorectal surgery. Further studies are required to uncover the reasons but lack of appropriate guidelines and failure to exercise evidence-based medicine are major factors that account for this practice.