BACKGROUND AND OBJECTIVESThe national data on colorectal cancer in Saudi Arabia has not been analyzed. The objective of this study is to describe the demographics, incidence and survival rates for colorectal cancer in Saudi Arabia for the period 1994–2010.DESIGNRetrospective analysis of the Saudi Cancer Registry data for the period 1994–2010.SETTINGData from the Saudi Cancer Registry was analyzed by stage at presentation (local, regional, distal, unknown) and survival rates were calculated using the Kaplan-Meier method.PATIENTSFrom 9889 colorectal cancer cases, a sample of 549 (5.6%) patients was selected and their living status ascertained to assess survival.RESULTSColorectal cancer has been the most common cancer among men and the third commonest among women since 2002 in Saudi Arabia. There has been a slight predominance among men with an average ratio of 116:100 over the years (range: 99:100–132:100). The overall age-standardized rate (ASR) approached a plateau of 9.6/100 000 in 2010. The incidence of the disease has been highest in the capital, Riyadh, where it reached 14.5/100 000 in 2010. Median age at presentation has been stable at around 60 years (95% confidence Interval (CI): 57–61 years) for men and 55 years (95% CI: 53–58 years) for women. Distant metastasis was diagnosed in 28.4% of patients at the time of presentation and rectal cancer represented 41% of all colorectal cancers diagnosed in 2010. The overall 5-year survival was 44.6% for the period 1994–2004. The ASR for all age groups below 45 years of age was lower than that for the United States.LIMITATIONSThe study was retrospective with a possibility of bias from inaccurate staging of patients, and inaccurate survival information and patient demographics due to the underdeveloped census system prior to 2001. Survival data for the period 2005–2010 are lacking.CONCLUSIONColorectal cancer presents at a younger age in Saudis, especially in women. This has a major implication for decisions about the threshold age for screening. The ASR has increased, but is still much lower than in developed countries. The lower overall 5-year survival compared with developed countries is due to lack of screening, a higher proportion of advanced stage cancer at presentation, lack of specialized care outside the major cities and a higher proportion of rectal cancer cases.

To identify genes potentially playing an important role in the progression of colorectal carcinoma (CRC), we screened global gene expression using cDNA expression array on 41 CRC tissue samples and 25 noncancerous colorectal tissue samples. Among the up-regulated genes, forkhead box M1 (FOXM1) has been shown to play a critical role in pathogenesis of various malignancies. Using immunohistochemistry on 448 Saudi CRC samples in tissue microarray format, FoxM1 protein overexpression was seen in 66% of CRC tissues and was significantly associated with poorly differentiated and highly proliferative tumors (P = 0.0200 and 0.0018, respectively). FoxM1 expression was also significantly associated with MMP-9 protein expression (P = 0.0002). In vitro data using CRC cell lines showed that inhibition of FoxM1 by thiostrepton resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. Overexpression of FoxM1 potentiated cell proliferation, cell transformation, and migration/invasion of CRC cells via up-regulation of FoxM1 target genes MMP2 and MMP9 and protected these cells from thiostrepton-mediated antiproliferative effects. Finally, in vivo, overexpression of FoxM1 promoted growth of CRC-cell line xenograft tumors in nude mice. Altogether, our data indicate that FoxM1 signaling contributes to aggressiveness in a subset of CRC and that the FOXM1 gene may serve as a useful molecular biomarker and potential therapeutic target.

Activation of the phosphatidylinositol 3 0 -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 ¼ 0.0046) while PTEN loss was more frequent in microsatellite stable (MSS) CRC (P ¼ 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.

Direct-acting oral anticoagulants (DOACs) have been introduced as alternatives to warfarin for stroke prevention in non-valvular atrial fibrillation and for treatment of venous thromboembolism. Many patients undergoing major gastrointestinal resections or bypass receive anticoagulants for various indications, including the treatment of thrombotic complication of surgery and prevention of visceral vessels events recurrence. DOACs have a wide therapeutic range that allows fixed dosing determined based on studies conducted in healthy subjects with normal absorptive capacity. Patients with significantly altered gastrointestinal tracts were not included in the Phase II and III studies that assessed DOAC efficacy and safety. The aim of this article is to review clinical data on DOACs use in patients with major surgical resection or bypass. MEDLINE and EMBASE were searched to identify studies and case reports of DOAC use in this population. Prescribing information for the four approved DOACs was also reviewed. The only types of available literature identified were case series and isolated case reports. Patients who underwent major distal intestinal resection were successfully anticoagulated with rivaroxaban, dabigatran was not effective. There is uncertainty about the efficacy of rivaroxaban and dabigatran in patients requiring anticoagulation after Roux-en-Y gastric bypass. Avoidance of rivaroxaban therapy in patients undergoing gastrectomy is advised Data are lacking regarding anticoagulation using apixaban and edoxaban in patients with major gastrointestinal resection or bypass is lacking. Clinicians should be aware of these limitations when using DOACs in this group of patients.

Somatic KRAS mutation is an early well-known event in colorectal carcinogenesis but a complete understanding of RAS function and dysfunction in colorectal cancer is still to come. Our aim was to study the incidence of KRAS mutation; KRAS splice variants: KRAS4A and KRAS4B; and their relationships with various clinico-pathological characteristics in colorectal cancer (CRC).In this study, 285 CRC cases were analysed for KRAS mutation by direct DNA sequencing followed by immunohistochemical analysis after validation with real-time PCR assay, to study the protein expression of KRAS4A and -4B isoforms. KRAS gene mutations were seen in 80/285 CRCs (28.1%) and of the mutated cases, the majority of the mutations were seen in codon 12 (81.2%) as opposed to codon 13 (18.8%). CRCs with KRAS mutations were associated with a poor overall survival (p = 0.0009). Furthermore, KRAS mutations at codon 12 were associated with a poor overall survival of 64.4% at 5 years compared with a 5-year overall survival of 75.8% and 78.2% with codon 13 mutation and absence of KRAS mutations, respectively (p = 0.0025). KRAS4A protein expression was predominantly seen in the cytoplasm, while KRAS4B protein was nuclear. KRAS4A overexpression was significantly associated with left colon, histology subtype of adenocarcinoma, p27kip1, and cleaved caspase3 expression. Interestingly, KRAS4A overexpression was associated with a better overall survival (p = 0.0053). On the other hand, KRAS4B overexpression (33.2%) was significantly associated with larger tumour size (p = 0.0234) and inversely correlated with p27kip1 protein (p = 0.0159). Both KRAS mutation and KRAS4A were independent prognostic markers in a multivariate analysis with age, gender, stage, differentiation, and MSI status. Our results highlight the differential role of KRAS isoforms in CRC, their utility as a prognostic biomarker, and underline the importance of KRAS alterations as a potential therapeutic target for CRC.

BACKGROUNDColorectal cancer is the most common cancer among Saudi men and the third commonest among Saudi women. Given the predominance of colorectal cancer compared with other cancers in Saudi Arabia, context-specific guidelines are needed for screening.METHODSThe Saudi Centre for Evidence-Based Healthcare assembled a panel of experts from the Saudi Society of Colon and Rectal Surgery, Saudi Gastroenterology Association, the Saudi Oncology Society, the Saudi Chapter of Enterostomal Therapy, the Family Medicine and Department of Public Health at the Saudi Arabian Ministry of Health and a patient advocate. The panel collaborated with a methodological team from McMaster University, Canada to develop national guidelines for colorectal cancer screening. After identifying key questions, the panel conducted a systematic review of all reports on the utility of screening, the cost of screening for colorectal cancer in Saudi Arabia and on the values and preferences of Saudi patients. Meta-analyses, when appropriate, were performed to generate pooled estimates of effect. Using the GRADE approach, the panel used the evidence-to-decision (EtD) framework to assess all domains important in determining the strength and direction of the recommendations (benefits and harms, values and preferences, resource implications, equity, acceptability, and feasibility). Judgments related to the EtD domains were resolved through consensus or voting, if consensus was not reached. The final recommendations were developed during a two-day meeting held in Riyadh, Saudi Arabia in March 2015. Conflicts of interests among the panel members were handled according to the World Health Organization rules.LIMITATIONSThere is lack of national data on the incidence of adenomatous polyps or the age groups in which the incidence surges. There were no national clinical trials assessing the effectiveness of the different modalities of screening for colorectal cancer and their impact on mortality.CONCLUSIONThe panel recommends screening for colorectal cancer in Saudi Arabia in asymptomatic Saudi patients at average risk of colorectal cancer. An infrastructure should be built to achieve that goal.

We investigated the role of leptin receptor (Ob-R) and its relationship with phosphatidylinositol 3-kinase (PI3K)/AKT activation in colorectal carcinomas (CRCs) tissues followed by in vitro studies using a panel of CRC cell lines. Obesity serves an important risk factor of several cancers including CRC that ranks as the second most common cancer in Saudi Arabia. High levels of adipokine leptin (Ob) and its Ob-R are seen in obesity and also in various carcinomas including CRC. We investigated the proliferative and antiapoptotic effect of Ob on human CRC cell lines Caco-2, HT-29 and SW-840 and the role of PI3K/AKT-signaling pathway in mediating these actions. Then the expression of Ob-R and its relationship with clinicopathological features was analyzed in 448 CRC, 229 normal colon mucosa and 24 colorectal adenomas using tissue microarray technology. Treatment with Ob resulted in increased proliferation of CRC cell lines and involved activation of PI3K/AKT-signaling pathway. Pretreatment with Ob-R small interfering RNA or PI3K inhibitor inhibited these responses. Ob-R was significantly overexpressed in primary CRC relative to adenomas and normal colonic mucosa. In primary CRC, Ob-R significantly correlated with Ob expression, early stage and well-differentiated tumors. Intriguingly, patient with Ob-R positive tumors showed significantly better overall survival (P = 0.0098). Ob plays a critical role in CRC carcinogenesis through PI3K/AKT pathway via Ob-R. Ob-R is a prognostic marker associated with better survival.

S-phase kinase protein 2 (SKP2), an F-box protein, targets cell cycle regulators including cycle-dependent kinase inhibitor p27Kip1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancers. We investigated the role of SKP2 and its ubiquitin-proteasome pathway in colorectal carcinoma using a panel of cell lines, clinical samples, and the NUDE mouse model. Using immunohistochemical analysis on a large tissue microarray of 448 samples, an inverse association of SKP2 expression with p27Kip1 protein levels was seen. A colorectal cancer (CRC) subset with high level of SKP2 and low level of p27Kip1 showed a decreased overall survival (P = 0.0057). Treatment of CRC cell lines with bortezomib or expression of small interfering RNA of SKP2 causes down-regulation of SKP2 and accumulation of p27Kip1. Furthermore, treatment of CRC cells with bortezomib causes apoptosis by involving the mitochondrial pathway and activation of caspases. In addition, treatment of CRC cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Finally, treatment of CRC cell line xenografts with bortezomib resulted in growth inhibition of tumors in NUDE mice via down-regulation of SKP2 and accumulation of p27Kip1. Altogether, our results suggest that SKP2 and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention for treatment of CRC. [Cancer Res 2008;68(9):3379-88]