Retrospective Evaluation of the Impact of Dose Escalation Using Pre-operative Simultaneous Integrated Boost Volumetric Modulated Arc Therapy on the Outcome of Locally Advanced Rectal Cancer Patients.

PURPOSE: Evaluating the outcome of pre-operative simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) concomitant with capecitabine in patients diagnosed with locally advanced rectal cancer (LARC) at King Faisal Specialist Hospital and Research Centre (KFSH&RC), Riyadh, Saudi Arabia, during the period January 2013-December 2019. RESULTS: A total of 134 patients were enrolled. The median age at diagnosis was 59 years. All patients received pre-operative concurrent chemo-radiation therapy (CCRT) using SIB-VMAT with oral capecitabine. Neoadjuvant chemotherapy was administered prior to CCRT in 32 patients (23.9%). The dose of radiation was 55 Gy in 94 patients (70.1%), while 40 patients (29.9%) received 50 Gy. All patients completed the CCRT treatment without breaks. No records of acute and late grade III and IV toxicities. Curative surgery was performed in all patients with a median interval of 11 (6-52) weeks between the end of CCRT and the date of surgery. No reported 30-day postoperative mortality and no grade III and IV Clavien-Dindo complications. PCR was reported in 26 patients (19.4%), while pathologically negative nodes (pN0) were achieved in 103 patients (76.9%). Adjuvant chemotherapy was utilized in 57 patients (42.5%). The 5-year local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were 93.2%, 67.1%, and 87.3%, respectively. Only tumor regression grade (TRG) was significantly correlated with LRFS, (p value 0.043). On multivariate analysis, only TRG and achievement of pN0 were significantly correlated with DFS (p value < 0.001). CONCLUSION: Dose escalation utilization (SIB-VMAT) in the pre-operative treatment of LARC is well tolerated and provides effective local control.

Progress and remaining challenges for cancer control in the Gulf Cooperation Council.

Cancer is a growing global health-care problem, especially in under-resourced countries. Cancer prevalence in Gulf Cooperation Council (GCC) countries is projected to increase, potentially leading to a major burden on the economy. Policy makers in GCC countries have invested in the development of National Cancer Control Strategies to address the current and future burden of cancer through different initiatives and policies for prevention, early detection, and management of cancer. These strategies include capacity building, health education, and global partnerships to strengthen health-care systems. The aim of this Review is to highlight the status of cancer control programmes in GCC countries, describe what has been achieved to date, and identify the gaps, with recommendations on how to lower the burden of cancer in the Gulf region in the future. TRANSLATION: For the Arabic translation of the abstract see Supplementary Materials section.

Neoadjuvant concurrent chemoradiotherapy using infusional gemcitabine in locally advanced rectal cancer: A phase II trial.

INTRODUCTION: Gemcitabine is a well-known radiosensitizer. Herein, we tested the efficacy and toxicity of preoperative concurrent infusional gemcitabine and radiotherapy in locally advanced rectal cancer. PATIENTS AND METHODS: This was a phase II, single-arm trial. Eligible patients had a diagnosis of rectal adenocarcinoma with clinical stage T3-T4 and/or nodal involvement, age ≥18 years, and no prior chemotherapy or radiotherapy. Patients received preoperative radiation at a dose of 50.4-54 Gy over 28 days with concurrent infusional gemcitabine administered at a dose of 100 mg/m2 over the course of 24 h weekly for 6 weeks. The primary endpoint was pathological complete response (pCR). RESULTS: Forty patients were recruited. Only one patient did not complete therapy due to death. Eight patients did not undergo surgery, one died, two progressed to nonresectable disease, and five withdrew consent. Five patients progressed prior to surgery, with two having unresectable metastases and three having resectable liver metastases. One was found to have peritoneal metastasis during surgery. Out of the 32 patients who underwent surgery, seven achieved pCR at a rate of 20%. With a median follow-up of 30 months, four additional patients had a distant relapse (one had a subsequent local relapse). The 3-year event-free and overall survival rates were 70% and 85%, respectively. The commonest preoperative grade 3-4 toxicity included lymphopenia (50%), neutropenia (41%), anemia (15%), diarrhea (12%), abdominal pain (12%), and proctitis (8%). CONCLUSION: Concurrent preoperative chemoradiotherapy using infusional gemcitabine for locally advanced rectal cancer achieved an encouraging degree of local control with manageable toxicity.

Cancer Screening in the Coronavirus Pandemic Era: Adjusting to a New Situation.

PURPOSE: The coronavirus-induced pandemic has put great pressure on health systems worldwide. Nonemergency health services, such as cancer screening, have been scaled down or withheld as a result of travel restrictions and resources being redirected to manage the pandemic. The present article discusses the challenges to cancer screening implementation in the pandemic environment, suggesting ways to optimize services for breast, cervical, and colorectal cancer screening. METHODS: The manuscript was drafted by a team of public health specialists with expertise in implementation and monitoring of cancer screening. A scoping review of literature revealed the lack of comprehensive guidance on continuation of cancer screening in the midst of waxing and waning of infection. The recommendations in the present article were based on the advisories issued by different health agencies and professional bodies and the authors' understanding of the best practices to maintain quality-assured cancer screening. RESULTS: A well-coordinated approach is required to ensure that essential health services such as cancer management are maintained and elective services are not threatened, especially because of resource constraints. In the context of cancer screening, a few changes in invitation strategies, screening and management protocols and program governance need to be considered to fit into the new normal situation. Restoring public trust in providing efficient and safe services should be one of the key mandates for screening program reorganization. This may be a good opportunity to introduce innovations (eg, telehealth) and consider de-implementing non-evidence-based practices. It is necessary to consider increased spending on primary health care and incorporating screening services in basic health package. CONCLUSION: The article provides guidance on reorganization of screening policies, governance, implementation, and program monitoring.

Clonal Evolution and Timing of Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide, where ~50% of patients develop metastasis, despite current improved management. Genomic characterisation of metastatic CRC, and elucidating the effects of therapy on the metastatic process, are essential to help guide precision medicine. Multi-region whole-exome sequencing was performed on 191 sampled tumour regions of patient-matched therapy-naïve and treated CRC primary tumours (n = 92 tumour regions) and metastases (n = 99 tumour regions), in 30 patients. Somatic variants were analysed to define the origin, composition, and timing of seeding in the metastatic progression of therapy-naïve and treated metastatic CRC. High concordance, with few genomic differences, was observed between primary CRC and metastases. Most cases supported a late dissemination model, via either monoclonal or polyclonal seeding. Polyclonal seeding appeared more common in therapy-naïve metastases than in treated metastases. Whereby, treatment prompted for the selection of distinct resistant clones, through monoclonal seeding to distant metastatic sites. Overall, this study reinforces the importance of early clinical detection and surgical excision of the CRC tumour, whilst further highlighting the clinical challenges for metastatic CRC with increased intratumour heterogeneity (either due to early dissemination or polyclonal metastatic spread) and the underlying risk of future therapeutic resistance in treated patients.

Strengthening the early detection of common cancers in the Eastern Mediterranean Region.

Cancer is the fourth leading cause of death in the Eastern Mediterranean Region (EMR) with an estimated 676 500 new cases and 419 000 cancer deaths in 2018. Population growth, ageing and the rise of risk factors may lead to double the incidence within the coming decades. Based on GLOBOCAN 2018 the most common cancers in the region are breast, colorectal, lung, liver and bladder cancer, closely followed by Non-Hodgkin lymphoma and leukemia. The most common cancers among men in the Region are lung (10.4%), liver (8.4%) and prostate cancer (8%), while the most common cancers among women are breast (34.7%), colorectal (5.7%) and cervical cancer (4.6%).

Dose Escalation with Simultaneous Integrated Boost (SIB) Using Volumetric Modulated Arc Therapy (VMAT) in Rectal Cancer.

PURPOSE: Assess feasibility-rate of PCR, short-term toxicity after neoadjuvant concurrent chemoradiation (NACRT) delivered via simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT) technique for locally advanced rectal cancer. METHODS: Retrospective evaluation of patients with locally advanced rectal cancer treated with VMAT-SIB technique preoperatively at an academic tertiary care center in Riyadh, Saudi Arabia between February 2013 and March 2017. RESULTS: One hundred patients with depth of invasion staged as T3/T4 or T2 in 93 and seven patients, respectively. Lymph node metastasis was staged as N1/N2 or N0 in 87 and 13 patients, respectively. Circumferential radial margin (CRM) was involved radiologically prior to treatment in 50 patients. A dose of 55 or 50 Gy was given to 71 and 29 patients, respectively. All treatments were completed without interruption. Grade 3/4 toxicity was not observed. Low anterior resection and abdominoperineal resection were performed with negative proximal, distal, and radial margins in 72 and 28 patients, respectively. There were no immediate significant postoperative complications. Histologically, no residual tumor (grade 0) was noted in 20 patients (pCR). Regression grade 1, 2, and 3 were noted in 31, 34, and 15 patients. Average number of lymph nodes retrieved in the surgical specimen was 12 (range 6-22). Lymph nodes were negative for cancer in 80 patients. CONCLUSION: Dose escalation with SIB-VMAT as NACRT for rectal cancer is feasible. Moreover, it can increase the rate of pathological complete response with a favorable toxicity profile. Clinical benefit of this approach needs to be validated in a larger cohort of patients with longer follow-up.

MED12 is recurrently mutated in Middle Eastern colorectal cancer.

OBJECTIVE: Colorectal cancer (CRC) is a common cancer and a leading cause of cancer deaths. Previous studies have identified a number of key steps in the evolution of CRC but our knowledge of driver mutations in CRC remains incomplete. Recognising the potential of studying different human populations to reveal novel insights in disease pathogenesis, we conducted genomic analysis of CRC in Saudi patients. DESIGN: In the discovery phase of the study, we conducted whole genome sequencing of tumour and corresponding germline DNA in 27 patients with CRC. In addition to known driver mutations, we identified three MED12 somatic mutations. In the replication phase, we employed a next-generation sequencing approach to capture and sequence MED12 and other candidate genes in a larger sample of 400 patients with CRC and confirmed the enrichment for recurrent MED12 mutations. RESULTS: In order to gain insight into a plausible biological mechanism for the potential role of MED12 mutations in CRC, we studied CRC cell lines that differ substantially in the expression level of MED12, and found the latter to be correlated inversely with transforming growth factor (TGF)-ß signalling and directly with apoptosis in response to chemotherapeutic agents. Importantly, these correlations were replicated when MED12 expression was experimentally manipulated. CONCLUSIONS: Our data expand the recently described role of MED12 as a tumour suppressor in other cancers to include CRC, and suggest TGF-ß signalling as a potential mediator of this effect.

Expanding the spectrum of germline variants in cancer.

Our ability to identify germline variants in hereditary cancer cases remains challenged by the incomplete cataloging of relevant genes and lack of consensus on who should be tested. We designed a panel [hereditary oncogenesis predisposition evaluation (HOPE)] that encompasses most of the genes known to be associated with cancer development and tested its yield on more than 1300 samples of cancer patients. Pathogenic or likely pathogenic variants in high and intermediate risk genes were identified in 16, 23.9, 9.7 and 2.7%, respectively, of peripheral blood or normal tissue samples taken from patients with breast, ovarian, colorectal and thyroid cancer. To confirm specificity of these findings, we tested an ethnically matched cohort of 816 individuals and only identified pathogenic or likely pathogenic variants in 1.59% (0.98% in high risk and 0.61% in intermediate risk). Remarkably, pathogenic or likely pathogenic alleles in DNA repair/genomic instability genes (other than BRCA2, ATM and PALB2) accounted for at least 16.8, 11.1, 50 and 45.5% of mutation-positive breast, ovarian, thyroid and colorectal cancer patients, respectively. Family history was noticeably lacking in a substantial fraction of mutation-positive cases (63.7, 81.5, 42.4 and 87.5% in breast, ovarian, colorectal and thyroid, respectively). Our results show high contribution of germline mutations to cancer predisposition that extends beyond "classical" hereditary cancer genes. Family history was lacking in 63.5% mutation-positive cases, shows that hereditary cancer need not appear familial and suggests that relaxed selection of cancer patients for hereditary cancer panels should be considered.

Pre-operative chemoradiotherapy using capecitabine and cetuximab followed by definitive surgery in patients with operable rectal cancer.

BACKGROUND: Achieving a high rate of complete pathological response with pre-operative chemoradiotherapy in rectal cancer is an unmet need. We evaluated the efficacy and toxicity of the combination of cetuximab, capecitabine and radiation therapy in the pre-operative setting of localized rectal cancer. PATIENTS AND METHODS: Patients with clinically staged T3, T4 or nodepositive rectal cancer were treated with concurrent capecitabine and radiotherapy with weekly cetuximab starting one week before the start of radiation. This was followed by total mesorectal excision within 6-8 weeks. All patients achieving R0 resection received adjuvant capecitabine for 6 cycles. RESULTS: Fifteen patients were treated and all underwent surgery. Sphincter preservation was achieved in 11 patients (73.3%) and pathological complete response in two. With a median follow up of 48 months (range 8.4-57.5), 12 patients were relapse-free and 14 were alive with 4-year relapse free survival of 80%. Overall survival was 93%. Significant grade 3 and 4 toxicity was mainly cetuximab-induced skin reactions (33%), radiation-induced skin toxicity (13%) and diarrhea (20%). CONCLUSIONS: Adding cetuximab to pre-operative concurrent capecitabine and radiotherapy provides modest efficacy with manageable toxicity.

Colorectal cancer in Saudi Arabia: incidence, survival, demographics and implications for national policies.

BACKGROUND AND OBJECTIVES: The 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. DESIGN: Retrospective analysis of the Saudi Cancer Registry data for the period 1994-2010. SETTING: Data 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. PATIENTS: From 9889 colorectal cancer cases, a sample of 549 (5.6%) patients was selected and their living status ascertained to assess survival. RESULTS: Colorectal 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 9.6/100000 in 2010. The incidence of the disease has been highest in the capital, Riyadh, where it reached 14.5/100000 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. LIMITATIONS: The 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. CONCLUSION: Colorectal 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.

National Guidelines for Colorectal Cancer Screening in Saudi Arabia with strength of recommendations and quality of evidence.

BACKGROUND: Colorectal 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. METHODS: Experts from the Saudi Society of Colon and Rectal Surgery, Saudi Gastroenterology Association, Saudi Oncology Society, Saudi Chapter of Enterostomal Therapy, Family Medicine and Department of Public Health at the Saudi Arabian Ministry of Health and a patient advocate was assembled by the Saudi Centre for Evidence-Based Healthcare, a subsidiary of the Saudi Arabian Ministry of Health. 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. LIMITATIONS: There 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. CONCLUSION: The 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.

Tackling cancer control in the Gulf Cooperation Council Countries.

Cancer is a major health problem in both high income and middle-to-low income countries, and is the second leading cause of death in the world. Although more than a third of cancer could be prevented and another third could be cured if diagnosed early, it remains a huge challenge to health-care systems worldwide. Despite substantial improvements in health services some of the countries in the Gulf region, the burden of non-communicable diseases is a major threat, primarily due to the rapid socioeconomic shifts that have led to unfavourable changes in lifestyle such as increased tobacco use, decreased physical activity, and consumption of unhealthy food. In the Gulf Cooperation Council states (United Arab Emirates, Bahrain, Saudi Arabia, Oman, Qatar, and Kuwait), advanced breast cancer, colorectal cancer, leukaemia, thyroid cancer, and non-Hodgkin lymphomas are the most common cancers affecting younger populations compared with other countries. By contrast with cancer prevalence in developed countries, prostate, lung, and cervical cancers are not among the most common cancers in the Gulf region. In view of the increased cost of cancer management worldwide, integrated approaches between primary, secondary, and tertiary health-care systems with special focus on prevention and early detection is an essential step in the countries' efforts in the fight against cancer.

Risk Factors for Abdominal Incision Infection after Colorectal Surgery in a Saudi Arabian Population: The Method of Surveillance Matters.

BACKGROUND: Reported surgical site infection rates range from 2.1% to 40% after colorectal surgery and are believed to be underestimated depending on the method of surveillance. The study aims were to identify an accurate incidence and associated risk factors for abdominal incision surgical site infection after elective open colorectal surgery in a Saudi population. METHODS: This was a prospective observational longitudinal study of 300 consecutive adult patients, recruited upon admission to an 800-bed tertiary referral center. All consenting adults admitted for elective open colorectal surgery were included. Patients were followed for 36 d post-surgery by two certified and experienced wound care experts who diagnosed abdominal incision surgical site infections. The definition provided by the U.S. Centers for Disease Control and Prevention was used. Statistical analysis was performed using both univariate and multivariable logistic regression. RESULTS: Data were analyzed for 296 patients; the incidence of abdominal surgical site infection was 30%. Factors associated with surgical site infection by univariate analysis were pre-operative pre-albumin (p=0.04, odds ratio [OR] 0.81, 95% confidence interval [CI] 0.66-0.99); operative difficulty because of truncal obesity (p=0.006, OR 2.19, 95% CI 1.25-3.84) and obesity measured by body mass index (p=0.002, OR 4.00, 95% CI 1.95-8.20). Multivariable analysis identified only two significant risk factors: Pre-operative pre-albumin (p=0.02, OR 0.76, 95% CI 0.60-0.96), and obesity measured by body mass index (BMI; p=0.001, OR 4.71, 95% CI 2.20-10.10). CONCLUSION: Obesity and nutritional status correlated with post-operative abdominal surgical site infection. The method of surveillance and length of follow-up impact the rate reported.

Coexpression of activated c-Met and death receptor 5 predicts better survival in colorectal carcinoma.

Dysregulated overexpression of hepatocyte growth factor and its receptor, c-Met, has been reported in various cancers, but its role in colorectal carcinoma (CRC) has not been elucidated. Therefore, we investigated the role of phosphorylated Met (p-Met) in Middle Eastern CRC patient samples and cell lines. The p-Met was overexpressed in 80.8% of CRCs and strongly associated with the expression of p-AKT, DR5, and Ki-67 by immunohistochemistry. Coexpression of p-Met and DR5 was seen in 53.1% of CRC cases and was associated with a less aggressive phenotype, characterized by a histological subtype of adenocarcinomas, well-differentiated tumors, and was an independent prognostic marker for better overall survival. PHA665752, a selective p-Met inhibitor, induced apoptosis in CRC cells via inactivation of c-Met and AKT. PHA665752 treatment also caused increased expression of DR5 via generation of reactive oxygen species, and combination treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and PHA665752 induced significant apoptosis. In vivo, cotreatment of a CRC xenograft with PHA665752 and TRAIL significantly reduced tumor volume and weight. These data demonstrate a significant correlation between p-Met and DR5 in patients with CRC. Furthermore, inhibition of p-Met signaling by PHA665752 in combination with TRAIL significantly inhibited cell growth and induced apoptosis in CRC cell lines, suggesting that this may have significant clinical implications as a therapeutic target in the treatment of CRC.

Bortezomib stabilizes mitotic cyclins and prevents cell cycle progression via inhibition of UBE2C in colorectal carcinoma.

Substantial evidence implicates the ubiquitin-conjugating enzyme E2C (UBE2C) gene, in several human cancers, including colorectal carcinoma (CRC). We therefore investigated the prognostic value of UBE2C alterations in CRC and UBE2C signaling in CRC cell lines. UBE2C protein expression and UBE2C gene copy number were evaluated on clinical samples by immunohistochemistry and fluorescence in situ hybridization in a TMA format. The effect of the proteasome inhibitor bortezomib and small-interfering RNA knockdown was assessed by apoptotic assays and immunoblotting. UBE2C dysregulation was associated with proliferative marker Ki-67, accumulation of cyclin A and B1, and a poor overall survival. UBE2C expression was an independent prognostic marker in early-stage (I and II) CRC. UBE2C depletion resulted in suppression of cellular growth and accumulation of cyclin A and B1. In vitro, bortezomib treatment of CRC cells caused inhibition of cell viability via down-regulation of UBE2C. UBE2C knockdown by bortezomib or transfection with specific small-interfering RNA against UBE2C also caused cells to be arrested at the G2/M level, leading to accumulation of cyclin A and cyclin B1. In vivo, a significant reduction in tumor volume and weight was noted in mice treated with a combination of subtoxic doses of oxaliplatin and bortezomib compared with treatment with oxaliplatin or bortezomib alone. Altogether, our results suggest that UBE2C and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention in CRC.

Genome-wide expression analysis of Middle Eastern colorectal cancer reveals FOXM1 as a novel target for cancer therapy.

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.

Prognostic significance of TRAIL death receptors in Middle Eastern colorectal carcinomas and their correlation to oncogenic KRAS alterations.

BACKGROUND: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumour necrosis factor cytokine family that induces apoptosis upon binding to its death domain containing receptors, TRAIL receptor 1 (DR4) and TRAIL receptor 2 (DR5). Expression of TRAIL receptors is higher in colorectal carcinoma (CRC) as compared to normal colorectal mucosa and targeted therapy with TRAIL leads to preferential killing of tumor cells sparing normal cells. METHODS: We investigated the expression of TRAIL and its receptors in a tissue microarray cohort of 448 Middle Eastern CRC. We also studied the correlation between TRAIL receptors and various clinico-pathological features including key molecular alterations and overall survival. RESULTS: CRC subset with TRAIL-R1 expression was associated with a less aggressive phenotype characterized by early stage (p = 0.0251) and a histology subtype of adenocarcinomas (p = 0.0355). Similarly CRC subset with TRAIL-R2 expression was associated with a well-differentiated tumors (p < 0.0001), histology subtype of adenocarcinomas (p = 0.0010) and tumors in left colon (p = 0.0009). Over expression of pro apoptotic markers: p27KIP1 and KRAS4A isoforms was significantly higher in CRC subset with TRAIL-R1 and TRAIL-R2 expression; TRAIL-R1 expression was also associated with cleaved caspase-3(p = 0.0011). Interestingly, TRAIL-R2 expression was associated with a microsatellite stable (MS--S/L) phenotype (p = 0.0003) and with absence of KRAS mutations (p = 0.0481). CONCLUSION: TRAIL-R1 expression was an independent prognostic marker for better survival in all CRC samples and even in the CRC group that received adjuvant therapy. The biological effects of TRAIL in CRC models, its enhancement of chemosensitivity towards standard chemotherapeutic agents and the effect of endogenous TRAIL receptor levels on survival make TRAIL an extremely attractive therapeutic target.

Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinoma.

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.