Cost-Consequence Analysis of Colon Cancer Screening among Patients with Long-Standing Ulcerative Colitis: 11 Years' Experience of Saudi Population.

Background: Clinical guidelines recommend that patients with long-standing ulcerative colitis (UC) should undergo periodic surveillance colonoscopy. However, the cost and clinical value of performing annual colonoscopy among high-risk patient populations is largely unknown in the Middle East. Therefore, this study aimed to examine the cost and consequence of annual colonoscopy among high-risk UC patients in Saudi Arabia. Methods: A retrospective cohort study was conducted on UC patients who had UC for ≥ 8 years or had primary sclerosing cholangitis (PSC) at any time during their disease,and underwent colonoscopy surveillance between 2010 and 2021 at a university-affiliated tertiary care center. Patients who underwent annual screening were considered adherent, and those who did not were considered non-adherent. The dysplasia detection rate (%) and the costs were expressed in United States Dollars (USD). To generate the 95 % confidence intervals for annual cost and clinical consequence, nonparametric bias-corrected accelerated bootstrapping with 10,000 simulations were conducted. Results: Two-hundred and sixty-one UC patients met the inclusion criteria and were included. Most of the patients 54 % (141 patients), were non-adherent to annual screening, and the patients' mean age and duration of illness were 45 years and 15 years, respectively. The mean annual direct medical costs were USD 10,210.6 for patients who adhered to the annual screening program and USD 6,191.77 for those who did not adhere. The mean rates of dysplasia detection were 1.66 % and 7.09 % for patients who adhered and patients who did not adhere to annual colonoscopy, respectively. The difference in costs and rates of dysplasia detections between those who adhered to the annual screening and those who did not were USD 4,018.88 (95 % CI: 3097.46 - 6,798.06) and -5.43 % (95 % CI: -10.019 - -1.58730), respectively, resulting in an incremental cost-effectiveness ratio (ICER) of USD 740.125 per 1 % reduction in the rates of dysplasia. According to the bootstrap cost effectiveness distributions, adherence to the annual screening for UC patients would result in higher cost and lower rates of dysplasia development with more than 99 % confidence level. Conclusion: Adherence to annual colonoscopy screening detects more dysplasia in UC patients but with an increased cost. Considering the low rate of progression to colorectal cancer among UC patients, the annual screening might not be cost effective.

The Long-Term Clinical Effectiveness of Ustekinumab in Antitumor Necrosis Factor-Experienced Crohn's Disease Patients.

Background Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology. Ustekinumab (UST), an interleukin (IL)-12 and IL-23 antibody, has been approved in the recent years to treat IBD, both Crohn's disease and ulcerative colitis. This study clarifies the long-term effectiveness of ustekinumab (UST) in antitumor necrosis factor (anti-TNF) refractory Crohn's disease in Middle Eastern patients. Methods A retrospective review study, including 30 refractory or medication-intolerant patients with Crohn's disease, was conducted at a tertiary care center in Riyadh, Saudi Arabia. The patients were started on ustekinumab and followed up for at least 52 weeks. Follow-up was performed on weeks 12, 24, and 52. Data related to demographic and laboratory parameters, the dosing schedule of ustekinumab administration, and the Harvey-Bradshaw index (HBI) were collected. Clinical remission and response rates were assessed. Statistical analysis was performed using SPSS Statistics version 28.0 (IBM Corp., Armonk, NY, USA). A statistical significance threshold of p < 0.05 was adopted. Results The mean age of the study subjects was 34.2 ± 17.9 years (95% confidence interval (CI): 27.5-40.9), with a mean disease duration of 10.6 ± 4.9 years (95% CI: 8.8-12.5). Of our cohort, 56.7% failed two biologics during their disease course, and about 20% failed three different biologics. The percentage of patients who used thiopurines was 76.7%, while 6.7% used methotrexate. Concurrent immunomodulators were used by 58.6% of the patients. Corticosteroids were given to 13.3% of the patients. Intravenous induction of UST at 6 mg/kg was used for 90% of the patients, while only 10% used a 260 mg subcutaneous dose. At week 12, 73.3% of the patients had a clinical response, and 66.7% achieved clinical remission. Corticosteroid-free remission, clinical response, and clinical remission showed a decreasing percentage trend between weeks 12 and 24 compared to week 52 where a spike was observed in all aforementioned parameters. The clinical response rate at week 52 was 76.7%. The p-values from cross-tabulation were significant for clinical response and remission when comparing week 12 to weeks 24 and 52. Conclusion Ustekinumab presents a safe and effective treatment option in moderate to severe Crohn's disease patients with previous exposure to multiple biologics.

Predictors of Anti-TNF Therapy Failure among Inflammatory Bowel Disease (IBD) Patients in Saudi Arabia: A Single-Center Study.

BACKGROUND: The advent of monoclonal antibodies (mAbs) has revolutionized the management of many immune-mediated diseases such as inflammatory bowel disease (IBD). Infliximab and adalimumab were the first mAbs approved for the management of IBD, and are still commonly prescribed for the treatment of both Crohn's disease (CD) and ulcerative colitis (UC). Although mAbs have demonstrated high effectiveness rates in the management of IBD, some patients fail to respond adequately to mAbs, resulting in disease progression and the flare-up of symptoms. OBJECTIVE: The objective was to explore the predictors of treatment failure among IBD patients on infliximab (INF) and adalimumab (ADA)-as demonstrated via colonoscopy with a simple endoscopic score (SES-CD) of ≥1 for CD and a Mayo score of ≥2 for UC-and compare the rates of treatment failure among patients on those two mAbs. METHODS: This was a prospective cohort study among IBD patients aged 18 years and above who had not had any exposure to mAbs before. Those patients were followed after the initiation of biologic treatment with either INF or ADA until they were switched to another treatment due to failure of these mAbs in preventing the disease progression. Univariate and multiple logistic regressions were conducted to examine the predictors and rates of treatment failure. RESULTS: A total of 146 IBD patients (118 patients on INF and 28 on ADA) met the inclusion criteria and were included in the analysis. The mean age of the patients was 31 years, and most of them were males (59%) with CD (75%). About 27% and 26% of the patients had penetrating and non-stricturing-non-penetrating CD behavior, respectively. Patients with UC had significantly higher odds of treatment failure compared to their counterparts with CD (OR = 2.58, 95% CI [1.06-6.26], p = 0.035). Those with left-sided disease had significantly higher odds of treatment failure (OR = 4.28, 95% CI [1.42-12.81], p = 0.0094). Patients on ADA had higher odds of treatment failure in comparison to those on INF (OR = 26.91, 95% CI [7.75-93.39], p = 0.0001). CONCLUSION: Infliximab was shown to be more effective in the management of IBD, with lower incidence rates of treatment failure in comparison to adalimumab.

Rate and risk factors of postoperative endoscopic recurrence of moderate- to high-risk Crohn's disease patients - A real-world experience from a Middle Eastern cohort.

Background: Crohn's disease (CD) frequently recurs after intestinal resection. Azathioprine (AZA) and biological therapies have shown efficacy in preventing postoperative recurrence (POR). Data on POR from Middle Eastern populations is lacking. This study aimed to evaluate the rate of endoscopic POR in a cohort of CD patients who underwent ileocecal resection (ICR), and to assess the effectiveness of AZA and biological therapies in reducing the risk of disease recurrence. Methods: We performed a retrospective cohort study on 105 CD patients followed at our center, who underwent ileal resection and were at moderate to high risk for POR. Clinical and laboratory data were collected; the primary endpoint was post ICR endoscopic recurrence at 24 months defined by Rutgeerts' score of i2 or more despite treatment. Results: In total, 105 patients with Crohn's disease met our inclusion criteria; 76.2% were in remission and did not have endoscopic POR at 24 months. Further, 41.9% were on biological therapy, and 34.3% were mainly on AZA. Out of the 28.2% who had POR, approximately 15% were on biological therapies. Penetrating phenotype was the only predictive factor for decreasing POR (OR = 0.19, 95% CI: 0.04-0.98, P = 0.04) as identified in multiple logistic regression analysis. Conclusions: The use of biological therapies post-surgery was not superior than AZA in reducing the endoscopic POR for mod- high risk CD patients. Only penetrating behavior of the CD was associated with significantly lower risk of endoscopic recurrence. This finding is worth further investigation in more robust study designs and among larger samples of patients.

Association of HER1 and HER2 Gene Variants in the Predisposition of Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is a major health concern worldwide. A series of sequential accumulation of genetic and epigenetic changes are responsible for the initiation and progression of diseases via the normal > adenoma > carcinoma sequence. Genetic variants in crucial cancer-causing genes are known to mediate the risk of cancer. OBJECTIVE: In this case-control study, we examined single nucleotide polymorphism (SNP) in HER1 (rs763317 and rs3752651) and HER2 (rs1136201 and rs1058808) genes to assess their role in the susceptibility of CRC in a Saudi population. METHODS: TaqMan allelic discrimination assay was utilized to identify the genotypes in 163 normal and 143 CRC patients. RESULTS: In the overall analysis, the rs3752651 and rs1136201 were significantly associated with the risk of CRC. Although none of the examined SNPs had any impact on the age at which CRC was diagnosed, interestingly, three SNPs showed a significant association based on gender. The rs3752651 conferred significant protection only in men, whereas rs1136201 diminished the risk and rs1058808 considerably increased the susceptibility of CRC only in women. CONCLUSIONS: Our result suggests that these SNPs in HER1 and HER2 after validation in larger cohorts of different ethnicities may be utilized as genetic screening markers for predicting colorectal cancer predisposition.

Expression and Polymorphism of TSLP/TSLP Receptors as Potential Diagnostic Markers of Colorectal Cancer Progression.

Colorectal cancer (CRC) is the third most common malignancy and the fourth leading cause of cancer-related mortality worldwide. Inflammation is considered as a critical driver for CRC development and growth. We investigated the association between polymorphisms/expression levels of thymic stromal lymphopoietin (TSLP) /TSLP receptors and CRC risk in Saudi population. DNA samples were isolated from blood samples from 220 participants. Case subjects were 112 patients diagnosed with CRC, while control subjects were 108 healthy individuals, who were not diagnosed with any type of malignancy. We selected two single nucleotide polymorphisms (SNPs) located in the thymic stromal lymphopoietin gene (rs10043985 and rs2289276), three SNPs in TSLP receptor gene (TSLPR; rs36139698, rs36177645, and rs36133495), and two other SNPs in interleukin-7 receptor gene (IL-7R; rs12516866 and rs1053496), and designated these SNPs for a case-control genotyping study. The gene expression was analyzed using quantitative RT-PCR and immunohistochemistry assays array on 20 matching colorectal cancer/normal tissues. mRNA expressions and protein levels of TSLP, TSLPR-α subunit, and IL-7R-α subunit showed a 4-fold increase in colon cancer tissues when compared to normal colon tissues. Furthermore, two SNPs (rs10043985 of TSLP and rs1053496 of IL-7R) showed statistically significant correlations with CRC susceptibility. Interestingly, only rs10043985 showed a statistically significant association (p < 0.0001) in the genotypic and phenotypic levels with CRC for all clinical parameters (age, gender, and tumor location) tested. However, IL-7R rs1053496 genotyping results presented a significant correlation (p < 0.05) in male CRC patients and in individuals under 57 years of age. TSLP rs2289276, IL-7R rs12516866, and all TSLPR variants did not display any significant genotypic or phenotypic correlations in all tested clinical parameters. This study identified that TSLP rs10043985 and IL-7R rs1053496 SNPs, and the expression levels of TSLP and TSLPR-α subunit, can be used as markers for CRC development and treatment. However, additional investigations are required on larger group of patients from diverse ethnicities to confirm the genetic association of these variants to CRC.

NOTCH Single Nucleotide Polymorphisms in the Predisposition of Breast and Colorectal Cancers in Saudi Patients.

Breast cancer (BC) is a heterogeneous disease and is one of the most common malignancy affecting women worldwide while colorectal cancer (CRC) is estimated to be the third common cancer and second leading cause of cancer related death globally. Both BC and CRC involve multiple genetic and epigenetic alterations in genes belonging to various signaling pathways including NOTCH that has been implicated in the development of these cancers. We investigated four single nucleotide polymorphisms, each in genes encoding NOTCH1-4 receptors for their role in susceptibility to breast and colorectal cancers in Saudi population. In this case-control study, TaqMan genotypic analysis of rs3124591 in NOTCH1 and rs3820041 in NOTCH4 did not exhibit association with breast as well as colorectal cancers. However, a strong association of rs11249433 which is in close proximity to NOTCH2 was observed with breast cancer susceptibility especially with those having an early onset of the disease. Interestingly, the rs1043994 located in NOTCH3 showed gender preference and was found to be significantly associated with colorectal cancers in males. Validation of these findings in bigger populations of different ethnicities may prove beneficial in identifying rs11249433 and rs1043994 as genetic screening markers for early detection of breast and colorectal carcinomas, respectively.

Clinical characteristics, natural history, and outcomes of Crohn's-related intra-abdominal collections.

BACKGROUND: Intra-abdominal collections in the form of abscesses or matted bowel loops, called phlegmons, might occur in patients with Crohn's disease (CD). The clinical characteristics and management of such conditions are not well described. We aim to characterize CD-related intra-abdominal collections clinically, and identify predictors of need for surgical interventions and the time to surgery. METHODS: We utilized the Saudi Inflammatory Bowel Disease Information System (IBDIS) database to identify all patients treated for radiologically proven intra-abdominal abscesses or phlegmons since inception. Demographics, clinical data, clinical course, and treatment outcomes were recorded. Logistic regression analysis and survival analysis were used to identify predictors of surgical resection and differences in time to surgery between patient subgroups, respectively. RESULTS: A total of 734 patients with a diagnosis of CD were screened and 75 patients were identified. The mean age was 25.6 ± 9.9 years and 51% were males. Nearly 60% of patients had abscesses larger than 3 cm while 13% had smaller abscesses and 36% had phlegmons. On presentation, the most commonly reported symptom was abdominal pain (99%) followed by weight loss (27%). About 89% of patients were treated with antibiotics during hospitalization for an average of 2.7 weeks. Steroids were prescribed for 52% of patients and tumor necrosis factor alpha (TNF-alpha) antagonists for 17%. Surgical resection was required for 33 patients (44% of the cohort) while 51% were managed with antibiotics and/or percutaneous drainage. The most common surgical intervention was ileocecal resection (45%). Although patients who underwent follow-up imaging were more likely to require early surgical intervention (P = 0.04), no statistically significant predictor of surgery could be identified from this cohort. Time to surgery varied numerically according to abscess size (HR = 1.18, 95% CI = 0.62-2.27, P = 0.61). CONCLUSIONS: Although the majority of patients with CD-related intra-abdominal collections underwent surgical resection in this cohort, no obvious predictors of surgical intervention could be identified. The decision to perform early surgery appeared to be influenced by the findings observed on cross-sectional imaging during the follow-up of these collections.

Time trends of causes of upper gastrointestinal bleeding and endoscopic findings.

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a frequent cause for emergency endoscopy and, in a proportion, requires the application of endotherapy. We aim to evaluate the proportion of variceal and nonvariceal upper gastrointestinal bleeding (NVUGIB), the endoscopic findings that were detected, as well as the temporal trends of endoscopic findings over a period of 13 years. METHODS: This is a retrospective study of patients who underwent an esophagogastroduodenoscopy with an indication of UGIB or presented with hematemesis, melena, or both, as well as those who had hematochezia, from January 2004 to December 2016 (13 years). RESULTS: A total of 2075 patients were included with a mean age of 56.8 years (range 18-113) and males constituted 67.9%, while 65.9% had at least one comorbidity. Symptoms on presentation included hematemesis (52.5%), melena (31.2%), both hematemesis & melena (15.1%), and hematochezia (1.2%). The majority of UGIB were from a NVUGIB source (80.5%) and a variceal source was found in 13.1%, while no endoscopic findings were found in 6.4% of cases. The most common endoscopic diagnosis was gastroduodenal erosions (23.8%), duodenal ulcers (23.5%), reflux esophagitis (16.0%), esophageal varices (12.1%), and gastric ulcers (10.8%). There was no change in the endoscopic findings over the time period of the study. A third of duodenal ulcers (33.3%) as well as 21.9% of gastric ulcers were actively bleeding at the time of endoscopy, while 3.3% of duodenal ulcers had an adherent clot. CONCLUSIONS: NVUGIB composed the majority of cases presenting with UGIB and variceal bleeding was lower than that described in prior studies, but there were no clear trends in the proportion of causes of UGIB during the study duration.

Factors associated with major radiological progression of primary sclerosing cholangitis in patients with inflammatory bowel disease.

BACKGROUND/PURPOSE OF THE STUDY: Primary sclerosing cholangitis (PSC) is the most common hepatobiliary manifestation of inflammatory bowel disease (IBD). Magnetic resonance cholangiography (MRC) has become the primary diagnostic modality for PSC. However, data on radiological progression over time of large-duct PSC-IBD are limited. METHODS: We performed a nested case-control study to estimate the frequency of PSC in adult patients with IBD from a Middle Eastern population to assess the risk factors associated with major disease progression (formation of dominant strictures or cholangiocarcinoma) over time. RESULTS: Data of IBD patients who were registered in the Saudi IBD Information System at tertiary care center were analyzed. Among 960 patients [477 ulcerative colitis (UC); 483 Crohn's disease (CD)], 40 PSC-IBD patients with at least two MRC performed in a one-year interval were matched with 141 IBD patients without PSC. The frequency of PSC was 4.1%. UC patients (6.2%) compared to CD (2%), 65% had extensive colitis. The incidence rate of PSC among our cohort was increased from 2.62 to 10 per 1000 patient-years between 2005 and 2019. MRC features stabilized in (46.7%); worsened in (36.9%) and 15.4% of patients developed CCA. Alkaline phosphatase (ALP) levels of PSC patients who had major changes or CCA increased significantly after 44 months of follow-up (p = 0.01). The propensity score adjusted showed that hospitalization rate among PSC patients was higher than their non-PSC counterparts (OR 8.24; 95% CI 3.16-21.47; p < 0.01). CONCLUSION: ALP rise and hospitalization history as clinical outcome were the only factors associated with PSC-IBD major progression on MRCP.

Development and validation of metric-based-training to proficiency simulation curriculum for upper gastrointestinal endoscopy using a novel assessment checklist.

BACKGROUND/AIMS: : This study aimed to design a structured simulation training curriculum for upper endoscopy and validate a new assessment checklist. MATERIALS AND METHODS: A proficiency-based progression stepwise curriculum was developed consisting of didactic, technical and non-technical components using a virtual reality simulator (VRS). It focused on: scope navigation, anatomical landmarks identification, mucosal inspection, retro-flexion, pathology identification, and targeting biopsy. A total of 5 experienced and 10 novice endoscopists were recruited. All participants performed each of the selected modules twice, and mean and median performance were compared between the two groups. Novices pre-set level of proficiency was set as 2 standard deviations below the mean of experts. Performance was assessed using multiple-choice questions for knowledge, while validated simulator parameters incorporated into a novel checklist; Simulation Endoscopic Skill Assessment Score (SESAS) were used for technical skills. RESULTS: : The following VRS outcome measures have shown expert vs novice baseline discriminative ability: total procedure time, number of attempts for esophageal intubation and time in red-out. All novice trainees achieved the preset level of proficiency by the end of training. There were no statistically significant differences between experts' and trainees' rate of complications, landmarks identification and patient discomfort. SESAS checklist showed high degree of agreement with the VRS metrices (kappa = 0.83) and the previously validated direct observation of procedural skills tool (kappa = 0.90). CONCLUSION: : The Fundamentals of Gastrointestinal Endoscopy simulation training curriculum and its SESAS global assessment tool have been primarily validated and can serve as a valuable addition to the gastroenterology fellowship programs. Follow up study of trainee performance in workplaces is recommended for consequences validation.

The cost-effectiveness of biologic versus non-biologic treatments and the health-related quality of life among a sample of patients with inflammatory bowel disease in a tertiary care center in Saudi Arabia.

AIMS: This study's objectives were to examine and compare the cost-effectiveness of biologic and non-biologic therapies in the improvement of the health-related quality of life (HRQoL) of patients with inflammatory bowel disease (IBD) in Saudi Arabia. MATERIALS AND METHODS: This retrospective cohort study analyzed data from the medical records of patients with IBD treated at a tertiary-care hospital in Riyadh, Saudi Arabia. Drug utilization costs and HRQoL scores were evaluated at baseline and after six months of treatment. Patients' HRQoL was measured using the Arabic version of the standardized EuroQol 5 Dimensional 3 Level (EQ-5D-3L) questionnaire with a visual analog scale (VAS). RESULTS: Eighty-seven patients with Crohn's disease (CD) and 69 patients with ulcerative colitis (UC) were included in the study (N = 156), and 59 (37.82%) were treated with biologics. Similar effects of both types of medications were found on the HRQoL domains of mobility, usual activities, and pain and discomfort, while biologics outperformed non-biologics on the self-care domain. The mean utilization cost of a biologic-based treatment over a six-month period was SAR 25,690.46 (USD 6,850.79) higher than that of the non-biologic treatment (95% confidence interval (CI): 24,548.55-27,465.11), and the change in the ED-5D-3L VAS score from baseline to follow-up was 4.78 points (95% CI: 1.96-14.00). A probabilistic sensitivity analysis demonstrated that IBD therapy with biologic-based treatment is always more expensive, but also more effective in improving HRQoL 99.45% of the time. Adalimumab was found to be less cost effective than infliximab in the management of CD. LIMITATIONS: Information bias cannot be ruled out, as this investigation was a retrospective cohort study with a relatively small sample that was not randomized. CONCLUSIONS: The results of this analysis can serve as a foundation to introduce HRQoL-based recommendations for the use of biologics in the management of IBD in Saudi Arabia.

Frequent Activation of Notch Signaling Pathway in Colorectal Cancers and Its Implication in Patient Survival Outcome.

Colorectal cancer is a major health concern as it ranks third in incidence and second major cause of cancer-related deaths worldwide. A leading cause of treatment failure has been attributed to cancer stem cells that can invariably resist existing chemotherapeutic regimens. Notch signaling pathway has been involved in the maintenance of stem cells besides being crucial in cell fate decision and embryonic development. This pathway has also been implicated in several human malignancies including colorectal cancer. We investigated mRNA expression of four Notch receptors (Notch1-4), five ligands (Jag1, Jag2, Dll1, Dll3, and Dll4), and four target genes (Hes1, Hes5, Hey1, and Hey2) using highly specific TaqMan gene expression assays in colorectal adenomas and cancers. Upregulated expression of Notch receptors ranged between 29 and 73% in colorectal cancers and between 11 and 56% in adenomas. Expression of Notch3 and Notch4 receptors was significantly higher in colorectal cancers compared to normal and adenoma tissues. The Jagged and Delta-like ligands were overexpressed between 25 and 52% in colorectal cancers, while in adenomas, it ranged between 0 and 33%. Combining the data for upregulation of receptors and ligands suggests that 86% colorectal cancers and 56% adenomas exhibited overexpression of Notch pathway genes in our cohort. Notch target genes were upregulated between 24 and 33% in colorectal cancers and between 11 and 22% in adenomas. Collating upregulation of Notch receptors and ligands with the target genes showed concordance in 58% colorectal tumors. Additionally, we evaluated expression of Notch receptors, ligands, and target genes with prognosis using the TCGA mRNA expression dataset. Patients overexpressing Notch3, Notch4, and Hey1 had significantly poorer overall survival relative to those having lower levels of these genes. Taken together, Notch signaling components are aberrantly overexpressed in colorectal tumors, and development of therapeutics targeting the Notch pathway may prove to be beneficial in the management of colorectal cancers.

Predictors of Survival Among Colorectal Cancer Patients in a Low Incidence Area.

BACKGROUND: Colorectal cancer is the third most common malignancy in Saudi Arabia. The best therapeutic regimen for colorectal cancer is a matter of ongoing debate and data on its treatment in Saudi Arabia are limited. PURPOSE: The objective of this study was to explore the predictors of survival and to compare the risk of mortality among colorectal cancer patients treated with different therapeutic modalities. PATIENTS AND METHODS: The study utilized data from the electronic colorectal cancer registry of a university-affiliated tertiary care hospital. The Kaplan-Meier survival analysis was used to estimate the survival rates over 36 months of follow-up across rectal and colon cancer patients as well as different sociodemographic and medical characteristics. Bivariate and multiple Cox proportional-hazards regressions were conducted to estimate the risk of mortality among rectal and colon cancer patients undergoing different treatments. RESULTS: The number of patients in the registry who were followed up for 36 months was 143 patients. The majority of patients had colon cancer (74.13%). Rectal cancer patients had generally better survival estimates compared to their colon cancer counterparts. Colon cancer patients treated with chemotherapy had a significantly lower risk of mortality controlling for the use of surgery, radiotherapy, and other variables including age, gender, stage of cancer, and family history of colorectal cancer (HR=0.33; P=0.03). Additionally, colon cancer patients with a family history of colorectal cancer had significantly higher risk of mortality (HR=3.40; P=0.02). CONCLUSION: The findings of this study highlight the value of chemotherapy in managing colon cancer patients.

Predictors of long-term outcomes of radiologically defined perianal fistulizing Crohn's disease treated with antitumor necrosis factor-alpha agents based on Parks' classification.

BACKGROUND AND AIMS: Perianal fistulizing Crohn's disease (PFCD) leads to significant disability. Data assessing healing of complex PFCD based on pelvic MRI using Parks' classification remains sparse. We aimed to assess the frequency of closure of fistula tract on MRI in patients treated with antitumor necrosis factor alpha antagonists and identify predictors of poor response. MATERIALS AND METHODS: We retrospectively identified patients registered in the Saudi Inflammatory Bowel Disease Information System registry, who were diagnosed as PFCD based on MRI and treated with infliximab or adalimumab. Fistulae were classified based on Parks' classification and response to treatment was determined as full, partial, or no response, after at least 12 months of treatment. RESULTS: Out of 960 patients, 61 had complex PFCD that required treatment with an anti-TNF agent. The median age was 27 years (range: 14-69 years) and the median duration of disease was 6.2 ± 5.8 years. A full response to treatment was achieved in 27 (44.4%), whereas 10 patients (16.3%) had partial response and 24 (39.3%) had no response. On univariable analysis, a statistically significant association was observed between poor fistula response and low BMI, rectal involvement, fistulae classification, and the presence of an abscess. According to multivariable regression, only low BMI predicted poor fistulae outcome (odds ratio = 1.37, 95% confidence interval: 0.69-0.98). CONCLUSION: Less than half of this cohort of patients with PFCD achieved complete radiological fistula healing with anti-TNF therapy. Low BMI appears to be the only predictor of poor outcome.

Genetic variants in the WNT signaling pathway are protectively associated with colorectal cancer in a Saudi population.

The Wnt/ß-catenin signaling pathway has been etiologically implicated in the development and progression of colorectal cancer. We studied thirteen single nucleotide polymorphisms (SNPs) located in SFRP3 (rs7775), CTNNB1 (ß-catenin) [rs4135385, rs13072632], APC (rs454886, rs459552), LRP6 (rs2075241, rs2284396), DKK4 (rs3763511), DKK3 (rs6485350), TCF4 (rs12255372) and AXIN2 (rs3923086, rs3923087, rs4791171) in patients with colorectal cancer (n = 122) and controls (n = 110). Evaluation of WNT pathway SNPs showed protective association for rs4135385, located in ß-catenin. Additionally, variants in SFRP3 (rs7775) and LRP6 (rs2284396) which did not show any association in the overall analysis were significantly associated with female and old aged colorectal cancer patients, respectively.

Association between polymorphisms in PRNCR1 and risk of colorectal cancer in the Saudi population.

LncRNA Prostate cancer non-coding RNA (PRNCR1) is downregulated in many types of cancer. The current case-control study was performed on 144 patients with colorectal cancer and 130 matching controls. Genotyping was performed using TaqMan assays for four Single Nucleotide Polymorphisms (SNPs) in PRNCR1. RNAsnp Web Server was used to detect variations in the secondary structure for each SNP. The genotyping analysis for SNP rs1456315 showed increased association with colorectal cancer with the homozygous CC variant allele (OR: 2.09; χ2 = 4.95; CI: 1.08-4.02; p = 0.02), the minor allele frequency, and additive genotype, respectively (OR: 1.55; χ2 = 6.24; CI: 1.09-2.19; p = 0.01) & (OR: 1.64; χ2 = 4.04; CI: 1.01-2.67; p = 0.04). A risk association was also observed among younger age patients (≤57) and in female patients as well as in patients with tumors of the colon. For the other SNPs tested (rs16901946, rs13252298, rs1016343), no significant association was observed. The secondary structure of the rs1456315 mutant is different from that of the wild-type. Our findings suggest that the upregulation of PRNCR1 and its variants is associated with increased risk of colorectal cancer in Saudi patients, indicating that PRNCR1 might be a unique and valuable signature for predicting the risk of colorectal cancer in a Saudi population.

Toll-like receptor 6 expression, sequence variants, and their association with colorectal cancer risk.

This is the first study to examine the potential correlation of the rs3796508 and rs5743810 SNPs of the TLR6 gene in patients with colorectal cancer (CRC) in a subset of the Saudi population. TLR6 gene expression was studied by real-time PCR assaysin 10 matching normal and cancer colon tissues. TLR6 expression at the protein level was determined by immunohistochemistry. A case-control search was conductedon 115 case patients and 102 controls. All samples were genotyped with the TaqMan assay for the TLR6 gene. Odds ratios and 95% confidence interval were computed from logistic regression models after adjusting for age, sex, and tumor localization. Our findings showed a decrease in TLR6 expression (p <0.001) in colon cancer tissues when compared to normal colon tissues. Global analysis revealed no significant association between the TLR6 rs3796508 and rs5743810 and CRC in this population. However, the Val/Met genotype of rs3796508 had a significantly higher frequency in the control group than in the cases for the male group (OR= 0.095, and p= 0.03385) or the volunteers aged more than 57 years OR= 0.152; and p= 0.04069, respectively). Two non-synonymous single nucleotide polymorphisms (SNP; S249P and V327M) were common in a few patients and were predicted as damaging by SIFT and Polyphen and were further analyzed for their protein stability and function using advanced bioinformatics tools. The results suggest that TLR6 rs3796508 has a crucial role as a protective factor against colorectal cancer in the older Saudi male population.

TDG Gene Polymorphisms and Their Possible Association with Colorectal Cancer: A Case Control Study.

Genetic alterations that might lead to colorectal cancer involve essential genes including those involved in DNA repair, inclusive of base excision repair (BER). Thymine DNA glycosylase (TDG) is one of the most well characterized BER genes that catalyzes the removal of thymine moieties from G/T mismatches and is also involved in many cellular functions, such as the regulation of gene expression, transcriptional coactivation, and the control of epigenetic DNA modification. Mutation of the TDG gene is implicated in carcinogenesis. In the present study, we aimed to investigate the association between TDG gene polymorphisms and their involvement in colon cancer susceptibility. One hundred blood samples were obtained from colorectal cancer patients and healthy controls for the genotyping of seven SNPs in the TDG gene. DNA was extracted from the blood, and the polymorphic sites (SNPs) rs4135113, rs4135050, rs4135066, rs3751209, rs1866074, and rs1882018 were investigated using TaqMan genotyping. One of the six TDG SNPs was associated with an increased risk of colon cancer. The AA genotype of the TDG SNP rs4135113 increased the risk of colon cancer development by more than 3.6-fold, whereas the minor allele A increased the risk by 1.6-fold. It also showed a 5-fold higher risk in patients over the age of 57. SNP rs1866074 showed a significant protective association in CRC patients. The GA genotype of TDG rs3751209 was associated with a decreased risk in males. There is a significant relationship between TDG gene function and colorectal cancer progression.

Findings during screening colonoscopies in a Middle Eastern cohort.

BACKGROUND/AIMS: Colorectal cancer is the most common cancer in males and the third most common cancer in females. We aim to determine the polyp and adenoma prevalence in a cohort of patients who underwent opportunistic screening colonoscopies. PATIENTS AND METHODS: A retrospective cohort study was conducted using an endoscopic reporting database of individuals seen at three tertiary care hospitals (two public hospitals and one private) in Riyadh, Saudi Arabia. Consecutive patients who were 45 years of age and older and underwent opportunistic screening colonoscopies between November 2016 and October 2017 were included. We excluded those with a history of colon cancer or colonic resection for any reason, inflammatory bowel disease, gastrointestinal bleeding, or anemia. RESULTS: Around 1180 patients were included in the study with a mean age of 58.6 years (SD = 7.3), with males representing 53.6% and an overall cecal intubation rate of 92.4%. Masses were found in 1.6% of the study population (50% in the sigmoid or rectosigmoid, 37.5% in the rectum). The polyp detection rate in colonoscopies was 24.8% and the adenoma detection rate was 16.8%. The histology of removed polyps was tubular adenomas in 56.6%, hyperplastic polyps in 32.7%, tubulovillous adenomas in 8.2%, and villous adenomas in 2.5%. The majority of the polyps were in the sigmoid colon (28.3%) and rectum (22.0%), followed by the ascending colon (11.2%) and cecum (10.3%), then the transverse colon and descending colon (9.4% each), and multiple locations in the remainder. CONCLUSION: The prevalence of polyps and adenomas in this cohort is less than that reported in the Western populations.