ALK gene amplification is associated with poor prognosis in colorectal carcinoma.

BACKGROUND: Recently, the anaplastic lymphoma kinase (ALK) has been found to be altered in several solid and haematological tumours. ALK gene copy number changes and mutations in colorectal cancers (CRCs) are not well characterised. We aimed to study the prevalence of ALK copy number changes, translocations, gene mutations and protein expression in 770 CRC patients, and correlate these findings with molecular and clinico-pathological data. METHODS: ALK gene copy number variations and ALK expression were evaluated by fluorescence in situ hybridisation (FISH) and immunohistochemistry, respectively. RESULTS: Translocations of the ALK gene were not observed; 3.4% (26 out of 756) of the CRC patients tested had an increase in ALK gene copy number either amplification or gain. Interestingly, increased ALK gene copy number alteration was associated with poor prognosis (P=0.0135) and was an independent prognostic marker in multivariate Cox proportional hazards model. The study reveals a significant impact of ALK gene copy number alterations on the outcome of patients with CRC. CONCLUSION: The findings of our study highlight a potential role of targeting ALK in advanced CRCs by using ALK FISH and ALK IHC as a screening tool to detect ALK alterations. Based on these findings, a potential role of ALK inhibitor as a therapeutic agent in a subset of CRC merits further investigation.

Carcinogen DNA adducts and the risk of colon cancer: case-control study.

Colorectal cancer represents 8.5% of all tumours at the King Faisal Specialist Hospital & Research Centre. Environmental and dietary carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs) have long been suspected to play a prominent role in colon cancer aetiology. We designed a case-control study to test the hypothesis of whether or not the presence of DNA adducts can play a role in the aetiology of colon cancer. DNA adducts were measured in 24 cancerous and 20 non-cancerous tissue samples of newly diagnosed colon cancer patients by (32)P-post-labelling technique. Normal tissue from 19 hospital patients served as controls. The mean levels of adducts per 10(10) nucleotides in cancerous and non-cancerous tissue were 151.75+/-217.27 and 114.81+/-186.10, respectively; however, only adducts in cancerous tissue were significantly higher than controls (32.78+/-57.51 per 10(10) nucleotides) with p-values of 0.017. No BPDE-DNA adducts were found. No relationship was found between urinary cotinine as a marker of tobacco smoke and 1-hydroxypyrene as an indicator of an individual's internal dose of PAHs and DNA adducts. In a logistic regression model, only adducts in cancerous tissue were associated with the subsequent risk of colon cancer, with an odds ratio of 3.587 (95% confidence interval 0.833-15.448) after adjustment for age and the duration of living in the current region, but of a borderline significance (p=0.086). Although it is difficult to arrive at a definite conclusion from a small dataset, our preliminary results suggest the potential role of DNA adducts in the colon carcinogenesis process. Additional studies with larger sample sizes are needed to confirm our preliminary finding. It is also important to identify the structural characterization of these unknown DNA adducts in order to have a better understanding of whether or not environmental carcinogens play a role in the aetiology of colon cancer.

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population.

Activation of the phosphatidylinositol 3'-kinase (PI3K)/AKT pathway results in an increase in cell proliferation and survival. Somatic mutations within the PI3K catalytic subunit, PIK3CA are common cause of increasing PI3K activity and are believed to be oncogenic in many cancer types. Few reports addressed the association between PIK3CA mutations and tumor progression specifically in microsatellite instable (MSI) colorectal cancer (CRC). In the present study, we have evaluated PIK3CA mutational status in a series of 410 Middle Eastern CRC and 13 colon cell lines to study the prevalence of PIK3CA mutations in MSI cases, PTEN expression in CRC and possibility of therapeutic targeting of this set of patients. PIK3CA mutations were found in four of the cell lines tested and 51 colorectal carcinomas (12.2%). Three of these four mutated cell lines were MSI. PTEN was inactivated in 66.1% of the CRC. Furthermore, we observed a strong association between PIK3CA mutations and MSI status (P=0.0046) while PTEN loss was more frequent in microsatellite stable (MSS) CRC (P=0.043). A high prevalence of genetic alterations in PI3K/AKT pathway in Saudi cohort of CRC, predominance of PIK3CA mutations in the MSI subgroup and their possible involvement in development/progression of this subset of CRC are some of the significant findings of our study.

The cutting seton: an experience at King Faisal Specialist Hospital.

PURPOSE: A 30-percent gas incontinence rate has been reported after the use of the cutting seton in complex anal fistulas. This study was undertaken to determine the morbidity and efficacy of the cutting seton in the management of complex anal fistulas at the King Faisal Specialist Hospital. METHODS: All patients who had a cutting seton inserted in the colorectal unit at King Faisal Specialist Hospital between 1990 and 1998 were identified from a colorectal data base. The charts of these patients were examined and form the basis of this report. Setons were inserted and tied under general anesthesia after the fistula tract had been identified. All fistulas were transsphincteric, and if it seemed that more than 30 percent of the internal sphincter would need to be divided to "lay open" the tract, a seton was used. Fistulas were designated "high" if the internal opening was above the level of the anal crypts. Setons were tightened under general anesthesia at intervals of three to four weeks until cutting was complete. Patients were followed up until wounds had healed and fistula symptoms had resolved. RESULTS: Data from 47 patients were analyzed. The mean duration of disease before surgery was 39.1 months. Twenty-five patients had had previous anorectal abscess drainage. The mean number of previous fistula operations was 2.2. Before seton insertion five patients were incontinent to gas, two to liquid stool, and none to solid stool. Continence status before seton surgery was unknown in 11 patients. There were 16 "high" fistulas. Methylene blue dye was used to identify the internal opening in 14 patients when simple probing failed. Setons were tightened on three or more occasions in 12 patients, twice in 19 patients, and once in 16 patients. Mean perineal wound healing time was six months. The mean length of follow-up was 1.1 years, and during this time one fistula recurred. After treatment a total of 17 patients (36.2 percent) were incontinent to gas, 4 to liquid feces (8.5 percent), and 1 to solid feces (2.3 percent). Four patients complained of soiling. Of previously continent patients, 9.5 percent were significantly incontinent to gas, but in addition 21.4 percent were "occasionally" incontinent for gas. CONCLUSION: The use of the cutting seton resulted in a significant gas incontinence rate of 9.5 percent after a mean follow-up of 1.1 years. Only 1 fistula recurred.