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Robotic surgery is attractive for resection of low rectal cancer due to greater dexterity and visualization, but its benefit is poorly understood. We aimed to determine if operative approach impacts radial margin positivity (RMP) and postoperative outcomes among patients undergoing abdominoperineal resection (APR). This was a retrospective cohort study of patients from the National Surgical Quality Improvement Program who underwent APR for low rectal cancer from 2016 to 2019. Patients were stratified by operative approach: robotic, laparoscopic, and open APR (R-APR, L-APR, and O-APR). Emergent cases were excluded. The primary outcome was RMP. 30-day postoperative outcomes were also evaluated, using logistic regression analysis. Among 1,807 patients, 452 (25.0%) underwent R-APR, 474 (26.2%) L-APR, and 881 (48.8%) O-APR. No differences regarding RMP (13.5% R-APR vs. 10.8% L-APR vs. 12.3% O-APR, p = 0.44), distal margin positivity, positive nodes, readmission, or operative time were observed between operative approaches. Adjusted analysis confirmed that operative approach did not predict RMP (p > 0.05 for all). Risk factors for RMP included American Society of Anesthesiologists (ASA) classification III (ASA I-II ref; OR 1.46, p = 0.039), pT3-4 stage (T0-2 ref, OR 4.02, p

Rectal cancer treatment is often multimodal, comprising of surgery, chemotherapy, and radiotherapy. However, the impact of coordination between these modalities is currently unknown. We aimed to assess whether delivery of nonsurgical therapy within same facility as surgery impacts survival in patients with rectal cancer.A patient cohort with rectal cancer stages II to IV who received multimodal treatment between 2004 and 2016 from National Cancer Database was retrospectively analyzed. Patients were categorized into three groups: (A) surgery + chemotherapy + radiotherapy at same facility (surgery + 2); (B) surgery + chemotherapy or radiotherapy at same facility (surgery + 1); or (C) only surgery at reporting facility (chemotherapy + radiotherapy elsewhere; surgery + 0). The primary outcome was 5-year overall survival (OS), analyzed using Kaplan-Meier curves, log-rank tests, and Cox proportional-hazards models.A total of 44,716 patients (16,985 [37.98%] surgery + 2, 12,317 [27.54%] surgery + 1, and 15,414 [34.47%] surgery + 0) were included. In univariate analysis, we observed that surgery+2 patients had significantly greater 5-year OS compared to surgery + 1 or surgery + 0 patients (5-year OS: 63.46% vs 62.50% vs 61.41%, respectively; P= .002). We observed similar results in multivariable Cox proportional-hazards analysis, with surgery + 0 group demonstrating increased hazard of mortality when compared to surgery + 2 group (HR: 1.09; P.001). These results held true after stratification by stage for stage II (HR 1.10; P= .022) and stage III (HR 1.12; P.001) but not for stage IV (P= .474).Greater degree of care coordination within the same facility is associated with greater OS in patients with stage II to III rectal cancer. This finding illustrates the importance of interdisciplinary collaboration in multimodal rectal cancer therapy.

Background The purpose of this study was to assess the impact of surgical delays on short- and long-term survival among colon cancer patients. Methods Adult patients undergoing surgery for stage I, II, or III colon cancer were identified from the National Cancer Database (2010-2016). After categorization by wait times from diagnosis to surgery (12 weeks), 30-day mortality, 90-day mortality, and 5-year overall survival were compared between patients both overall and after stratification by pathological disease stage. Results Among 187 394 colon cancer patients, 24.2% waited 12 weeks for surgery. Patients undergoing surgery 3-6 weeks after colon cancer diagnosis exhibited the best 30-day mortality (1.3%), 90-day mortality (2.3%), and 5-year overall survival (71.8%) ( P < .001 for all). After risk-adjusting for confounders, all wait times beyond 6 weeks were associated with worse 5-year overall survival (6-9 weeks: HR 1.10, 95% CI 1.06-1.15; 9-12 weeks: HR 1.25, 95% CI 1.18-1.33; >12 weeks: HR 1.43, 95% CI 1.35-1.52; P < .001 for all). Subgroup analysis after stratification by disease stage demonstrated that patients with stage III colon cancer were able to wait up to 9 weeks before exhibiting worse 5-year overall survival, compared to 6 weeks for patients with stage I or II disease. Conclusions Colon cancer patients should undergo surgery 3-6 weeks after diagnosis, as all surgical delays beyond 6 weeks were associated with worse 30-day mortality, 90-day mortality, and 5-year overall survival.

INTRODUCTION/BACKGROUND: Neoadjuvant chemoradiation therapy (nCRT) is the standard of care for locally advanced adenocarcinoma of the rectum, but it is currently unknown which patients will respond. This study tested the correlation between response to nCRT and intratumoral heterogeneity, measured using next-generation sequencing assays. MATERIALS AND METHODS: DNA was extracted from formalin-fixed, paraffin-embedded biopsy samples from a cohort of patients with locally advanced rectal adenocarcinoma (T3/4 or N1/2) who received nCRT. High read-depth sequencing of >400 cancer-relevant genes was performed using the Ion Ampliseq Comprehensive Cancer Panel™ assay. Tumor mutations and variant allele frequencies were used to calculate Mutant Allele Tumor Heterogeneity (MATH) scores as measures of intratumoral heterogeneity. Response to nCRT was pathologically scored after surgical resection. RESULTS: Biopsy samples from 21 patient tumors were analyzed. 8 patients were noted to have complete response, 2 were moderate, 4 minimal and 7 demonstrated poor response. Higher MATH scores correlated with poorer response to treatment, demonstrating significantly increased tumor heterogeneity compared to those with complete response (p=0.039). CONCLUSION: The application of MATH scores as a measure of tumor heterogeneity may provide a useful biomarker for treatment response in locally advanced rectal cancer.

Background: Cancer survivors increasingly report financial hardship as a consequence of the high cost of cancer care, yet the financial experience of rural cancer survivors remains largely unstudied. The purpose of this study was to investigate potential rural disparities in the likelihood of financial hardship and nonadherence to surveillance colonoscopy. Methods: Individuals diagnosed with localized or regional colorectal cancer between 2004 and 2012 were ascertained by the population-based New Mexico Tumor Registry. Participants completed a mailed questionnaire or telephone survey about their colorectal cancer survivorship experience, including treatment-related financial hardship and receipt of surveillance colonoscopy. Multivariable logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: Compared with urban colorectal cancer survivors (n = 168), rural colorectal cancer survivors (n = 109) were slightly older; more likely to be married (65% vs. 59%) and have an annual income Conclusions: Substantial rural disparities in the likelihood of financial hardship and nonadherence to surveillance colonoscopy exist. Impact: Treatment-related financial hardship among rural colorectal cancer survivors may negatively affect adherence to guideline-recommended follow-up care. Cancer Epidemiol Biomarkers Prev; 27(11); 1275–82. ©2018 AACR.

PURPOSE: Lifestyle factors may have a synergistic effect on health. We evaluated the correlates of poor adherence to a healthy lifestyle among a diverse sample of colorectal cancer (CRC) survivors to inform future lifestyle promotion programs. METHODS: Lifestyle questions from a cross-sectional survey were completed by 283 CRC survivors (41% Hispanic, 40% rural; 33% low income). Adherence to recommendations (yes/no) for physical activity, fruit and vegetable servings/day, avoiding tobacco, and healthy weight were summed to create an overall lifestyle quality score. Polytomous logistic regression was used to evaluate correlates of good (reference group), moderate and poor overall lifestyle quality. Potential correlates included sociodemographic characteristics, cancer-related factors, and indicators of health and well-being. RESULTS: CRC survivors with poor adherence were 2- to 3.4-fold significantly more likely to report multiple comorbidities, poor physical functioning, fatigue, anxiety/depressive symptoms, and poor social participation. In multivariable analyses, poor physical functioning was the only significant correlate of poor adherence to lifestyle recommendations, compared to good adherence (OR [95% CI] =3.4 [1.8–6.4]). The majority of survivors, 71% and 78%, indicated interest in receiving information on exercise and eating a healthy diet, respectively. CONCLUSION: Future lifestyle promotion programs for CRC survivors should carefully consider indicators of physical and psychosocial health and well-being, especially poor physical functioning, in the design, recruitment, and implementation of these health programs.

Microsatellite instability (MSI), which occurs in 15% of colorectal cancer, has been shown to have a lower incidence of metastasis and better patient survival rates compared with microsatellite stable colorectal cancer. However, a mechanistic understanding of the basis for this difference is very limited. Here, we show that restoration of TGFβ signaling by re-expression of TGFβ receptor II in MSI colon cancer cells increased PI3K/AKT activation, conferred resistance to growth factor deprivation stress-induced apoptosis, and promoted cell motility in vitro. Treatment with a potent PI3K inhibitor (LY294002) blocked the prosurvival and promotility effects of TGFβ, indicating that TGFβ-mediated promotion of cell survival and motility is dependent upon activation of the PI3K/AKT pathway. Analysis of apoptotic effectors that are affected by TGFβ signaling indicated that Bim is an effector of TGFβ-mediated survival. In addition, TGFβ-induced down-regulation of E-cadherin contributed to the prosurvival effect of TGFβ, and restoration of TGFβ signaling in MSI colon cancer cells increased liver metastasis in an orthotopic model in vivo. Taken together, our results demonstrate that restoration of TGFβ signaling promotes cell survival, motility, and metastatic progression in MSI colon cancer cells and indicate that TGFβ receptor II mutations contribute to the favorable outcomes in colon cancer patients with MSI.

Introduction Hispanics in New Mexico are diagnosed with more later-stage colorectal cancer (CRC) than non-Hispanic Whites (NHW). Our study evaluated the interaction of race/ethnicity and risk factors for later-stage III and IV CRC among patients in New Mexico. Method CRC patients ages 30 to 75 years ( n = 163, 46% Hispanic) completed a survey on key explanatory clinical, lifestyle, preventive health, and demographic variables for CRC risk. Adjusted logistic regression models examined whether these variables differentially contributed to later-stage CRC among NHW versus Hispanics. Results Compared with NHW, Hispanics had a higher prevalence of later-stage CRC ( p = .007), diabetes ( p = .006), high alcohol consumption ( p = .002), low education ( p = .003), and CRC diagnosis due to symptoms ( p = .06). Compared with NHW, Hispanics reporting high alcohol consumption (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.31-43.92), lower education (OR = 3.5; 95% CI = 1.28-9.65), being nondiabetic (OR = 3.23; 95% CI = 1.46-7.15), or ever smokers (OR = 2.4; 95% CI = 1.03-5.89) were at higher risk for late-stage CRC. Adjusting for CRC screening did not change the direction or intensity of the odds ratios. Conclusion The ethnicity-risk factor interactions, identified for late-stage CRC, highlight significant factors for targeted intervention strategies aimed at reducing the burden of later-stage CRC among Hispanics in New Mexico with broad applicability to other Hispanic populations.

Introduction: American Society of Clinical Oncology (ASCO) guidelines recommend that all patients with metastatic colorectal cancer (mCRC) receive KRAS testing to guide anti-EGFR monoclonal antibody treatment. The aim of this study was to assess for disparities in KRAS testing and mutational status. Methods: The New Mexico Tumor Registry (NMTR), a population-based cancer registry participating in the National Cancer Institute’s Surveillance, Epidemiology and End Results program, was queried to identify all incident cases of CRC diagnosed among New Mexico residents from 2010 to 2013. Results: Six hundred thirty-seven patients were diagnosed with mCRC from 2010–2013. As expected, KRAS testing in Stage 4 patients presented the highest frequency (38.4%), though testing in stage 3 (8.5%), stage 2 (3.4%) and stage 1 (1.2%) was also observed. In those with metastatic disease, younger patients (≤ 64 years) were more likely to have had testing than patients 65 years and older (p < 0.0001). Patients residing in urban areas received KRAS testing more often than patients living in rural areas (p = 0.019). No significant racial/ethnic disparities were observed (p = 0.66). No significant differences were seen by year of testing. Conclusion: Age and geographic disparities exist in the rates of KRAS testing, while sex, race/ethnicity and the year tested were not significantly associated with testing. Further study is required to assess the reasons for these disparities and continued suboptimal adherence to current ASCO KRAS testing guidelines.

Lessons Learned Colorectal cancers exhibit a high level of cyclooxygenase-2 (COX-2) expression with strong preclinical rationale for improved clinical outcomes with COX-2 inhibition. Celecoxib is a COX-2 inhibitor and we have shown that it can be safely combined with capecitabine and oxaliplatin as part of neoadjuvant treatment with radiation therapy (RT) in rectal cancer. There was a significant improvement in skin toxicity with this combination as compared with historical data. Considering the field has moved on to single-agent capecitabine, we believe future trials with capecitabine and celecoxib hold potential. Background Improved survival is seen among patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant therapy. Cyclooxygenase-2 (COX-2) expression is increased in gastrointestinal malignancies and it may serve as a target to enhance pathologic response. A trial combining chemoradiation and COX-2 inhibition was conducted to evaluate the pCR rate, surgical outcomes, survival, and treatment toxicity. Methods Patients with resectable (T3-4, N1-2) rectal cancer within 12 cm of the anal verge were included in this phase II clinical trial. The neoadjuvant treatment consisted of capecitabine 850 mg/m2 b.i.d. Monday through Friday for 5 weeks, weekly oxaliplatin 50 mg/m2 intravenous (IV), celecoxib 200 mg b.i.d. daily, along with concurrent 45 gray radiation therapy in 25 fractions. Results Thirty-two patients were included in the final analysis. The primary endpoint was pCR: 31% (95% confidence interval [CI]: 16%–50%). Secondary endpoints were surgical downstaging (SD): 75% (95% CI: 57%–89%) and sphincter-sparing surgery (SSS): 56% (95% CI: 38%–74%). Common grade >3 toxicities were diarrhea and abnormal liver function tests (9% each). Grade 0 and 1 toxicities included radiation dermatitis (59% and 34%, respectively) and proctitis (63% and 28%, respectively). At 3 years, disease-free survival and overall survival (OS) were 84% (95% CI: 65%–93%) and 94% (95% CI: 77%–98%), respectively. Conclusion Chemoradiation with celecoxib in rectal cancer was well tolerated and demonstrated high rates of pCR, SD, and SSS. Improvement in skin toxicity (34% grade 1 and no grade 3/4) as compared with historical results (43%–78% grade 3/4) seems to be a significant improvement with addition of celecoxib to neoadjuvant chemotherapy.

Colorectal cancer (CRC) is the second largest cause of cancer deaths in the United States. A key barrier that prevents better outcomes for this type of cancer as well as other solid tumors is the lack of effective therapies against the metastatic disease. Thus there is an urgent need to fill this gap in cancer therapy. We utilized a 2D-DIGE proteomics approach to identify and characterize proteins that are differentially regulated between primary colon tumor and liver metastatic deposits of the IGF1R-dependent GEO human CRC xenograft, orthotopically implanted in athymic nude mice that may serve as potential therapeutic targets against CRC metastasis. We observed increased expression of ezrin in liver metastasis in comparison to the primary colonic tumor. Increased ezrin expression was further confirmed by western blot and microarray analyses. Ezrin, a cytoskeletal protein belonging to Ezrin-Radixin-Moesin (ERM) family plays important roles in cell motility, invasion and metastasis. However, its exact function in colorectal cancer is not well characterized. Establishment of advanced GEO cell lines with enhanced liver-metastasizing ability showed a significant increase in ezrin expression in liver metastasis. Increased phosphorylation of ezrin at the T567 site (termed here as p-ezrin T567) was observed in liver metastasis. IHC studies of human CRC patient specimens showed an increased expression of p-ezrin T567 in liver metastasis compared to the primary tumors of the same patient. Ezrin modulation by siRNA, inhibitors and T567A/D point mutations significantly downregulated inhibitors of apoptosis (IAP) proteins XIAP and survivin that have been linked to increased aberrant cell survival and metastasis and increased cell death. Inhibition of the IGF1R signaling pathway by humanized recombinant IGF1R monoclonal antibody MK-0646 in athymic mouse subcutaneous xenografts resulted in inhibition of p-ezrin T567 indicating ezrin signaling is downstream of the IGF1R signaling pathway. We identified increased expression of p-ezrin T567 in CRC liver metastasis in both orthotopically implanted GEO tumors as well as human patient specimens. We report for the first time that p-ezrin T567 is downstream of the IGF1R signaling and demonstrate that ezrin regulates cell survival through survivin/XIAP modulation.

Background Mutational loss of tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) is associated with malignant progression in many cancers, including colorectal cancer (CRC). PTEN is involved in negatively regulating the phosphatidylinositol 3-kinase/AKT oncogenic signaling pathway and has been implicated in the metastatic colonization process. Few in vivo models are available to study CRC metastasis. The purpose of this study was to determine the effect of restoring PTEN activity on metastases in an orthotopic murine model. Methods Green fluorescent protein labeled TENN, a highly metastatic human colon cancer cell line with mutational loss of PTEN gene and TENN clones (with restoration of PTEN gene) tumors were orthotopically implanted onto the colons of BALB/c nude mice and allowed to develop primary and metastatic tumors. Seven weeks post-implantation, mice were euthanized and organs extracted for examination. Results Both TENN and TENN clone cell lines demonstrated 100% primary invasion. However, compared with the parental TENN cells, which demonstrated 62% metastases to both lungs and liver, TENN clone cells showed an approximately 50% reduction in metastasis, with only 31.6% liver metastasis and no metastasis to the lungs ( P = 0.02). Conclusions Our study shows that reactivation of PTEN tumor suppressor pathway leads to a 50% reduction in CRC metastasis without affecting primary tumor formation. Importantly, PTEN restoration also changed the organotropic homing from liver and lung metastasis to liver metastasis only. This in vivo study demonstrates that PTEN might act specifically as a metastasis suppressor and, thus, efforts to target the phosphatidylinositol 3-kinase/PTEN pathway are legitimate.

Metastases are largely responsible for cancer deaths in solid tumors due to the lack of effective therapies against disseminated disease, and there is an urgent need to fill this gap. This study demonstrates an orthotopic colorectal cancer (CRC) mouse model system to develop spontaneous metastasis in vivo and compare its reproducibility against human CRC. IGF1R-dependent GEO human CRC cells were used to study metastatic colonization using orthotopic transplantation procedures and demonstrated robust liver metastasis. Cell proliferation assays were performed both in the orthotopic primary colon and liver metastatic tumors, and human CRC patient’s specimen and similar patterns in H&E and Ki67 staining were observed between the orthotopically generated primary and liver metastatic tumors and human CRC specimens. Microarray analysis was performed to generate gene signatures, compared with deposited human CRC gene expression data sets, analyzed by Oncomine, and revealed similarity in gene signatures with increased aggressive markers expression associated with CRC in orthotopically generated liver metastasis. Thus, we have developed an orthotopic mouse model that reproduces human CRC metastasis. This model system can be effective in developing new therapeutic strategies against disseminated disease and could be implemented for identifying genes that regulate the development and/or maintenance of established metastasis.

Background Colorectal cancer is a leading cause of cancer-related mortality, has a very broad mutational spectrum, and there is no clinically available biomarker that can predict which patients with stage II or stage III colorectal cancer will develop metastatic disease. Patients and Methods We used a targeted next-generation sequencing approach to analyze the mutational spectra in stage II and III colon cancer patient samples. Results Amidst a broad range of acquired mutations and variants, we found evidence of tumor heterogeneity that distinguished the tumors in different groups. When heterogeneity was quantified using the Mutant-Allele Tumor Heterogeneity (MATH) score, there was a strong correlation between higher MATH score and risk of metastases. Conclusions Measures of tumor heterogeneity might be useful biomarkers for identifying patients with colon cancer who are at risk of developing metastases. This might allow for more specific, tailored follow-up and adjuvant therapies after standard surgery.

Microsatellite instability (MSI), which occurs in 15% of colorectal cancer, has been shown to have a lower incidence of metastasis and better patient survival rates compared with microsatellite stable colorectal cancer. However, a mechanistic understanding of the basis for this difference is very limited. Here, we show that restoration of TGFβ signaling by re-expression of TGFβ receptor II in MSI colon cancer cells increased PI3K/AKT activation, conferred resistance to growth factor deprivation stress-induced apoptosis, and promoted cell motility in vitro. Treatment with a potent PI3K inhibitor (LY294002) blocked the prosurvival and promotility effects of TGFβ, indicating that TGFβ-mediated promotion of cell survival and motility is dependent upon activation of the PI3K/AKT pathway. Analysis of apoptotic effectors that are affected by TGFβ signaling indicated that Bim is an effector of TGFβ-mediated survival. In addition, TGFβ-induced down-regulation of E-cadherin contributed to the prosurvival effect of TGFβ, and restoration of TGFβ signaling in MSI colon cancer cells increased liver metastasis in an orthotopic model in vivo. Taken together, our results demonstrate that restoration of TGFβ signaling promotes cell survival, motility, and metastatic progression in MSI colon cancer cells and indicate that TGFβ receptor II mutations contribute to the favorable outcomes in colon cancer patients with MSI.

Metastasis causes most deaths from cancer yet mechanistic understanding and therapeutic options remain limited. Overexpression of the phosphatase PRL-3 (phosphatase of regenerating liver) is associated with metastasis of colon cancer. Here, we show that PRL-3 is a direct target of signaling by TGFβ, which is broadly implicated in progression and metastasis. We found that suppression of PRL-3 expression by TGFβ was mediated by Smad-dependent inhibition of PRL-3 transcription at the level of promoter activity. PRL-3 activation stimulated PI3K/AKT signaling that caused resistance to stress-induced apoptosis. PRL-3 overexpression promoted metastatic colonization in an orthotopic mouse model of colon cancer, whereas PRL-3 knockdown reduced metastatic potential. Altered metastatic phenotypes were not derivative of primary tumor development or local invasion but could be attributed to PRL-3–mediated cell survival. Our findings suggest that inhibiting PRL-3 expression might be an important mechanism through which TGFβ suppresses metastasis in colon cancer. In addition, our findings suggest that loss of TGFβ signaling, which occurs commonly during colon cancer progression, is sufficient to activate a PRL-3–mediated cell survival pathway that can selectively promote metastasis. Therefore, a major implication of our findings is that PRL-3 antagonists may offer significant value for antimetastatic therapy in patients with colon cancer. Cancer Res; 71(1); 234–44. ©2010 AACR.

Introduction: Cancer survivors increasingly report financial hardship as a consequence of the high cost of cancer care, yet the financial experience of traditionally underserved patients, including racial/ethnic minorities, non-English speakers, and rural residents, remains largely unstudied. The purpose of this study was to investigate potential disparities in the likelihood of financial hardship and nonadherence to surveillance colonoscopy. Methods: In this cross-sectional study, individuals diagnosed with localized or regional colorectal cancer between 2004-2012 were ascertained by the population-based New Mexico Tumor Registry. Participants completed a mailed questionnaire or telephone survey about their cancer survivorship experience, including treatment-related financial hardship and receipt of surveillance colonoscopy. Participants were considered to have experienced treatment-related financial hardship if they reported any debt accumulation, bankruptcy filing, other financial sacrifices, or inability to pay medical bills as a consequence of their illness, its treatment, or its lasting effects. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Results: In this sample of 277 colorectal cancer survivors, 44% of participants reported financial hardship. Individuals with low health literacy (OR 5.41, 95% CI 1.45-20.1), Spanish-speaking Hispanics (OR 3.09, 95% CI 1.39-6.87), divorced, separated or single survivors (OR 1.94, 95% CI 1.94, 95% CI 1.06-3.54), and rural residents (OR 1.86, 95% CI 1.06-3.28) were more likely to report financial hardship. Nonadherence to surveillance colonoscopy guidelines was two times as likely among participants reporting financial hardship (OR 2.17 95% CI 1.01-4.67) and among rural residents (OR 2.28, 95% CI 1.07-4.48) than those reporting no financial hardship and urban residents, respectively. Conclusions: Substantial disparities in the likelihood of financial hardship and nonadherence to surveillance colonoscopy exist. Identifying patients at risk of financial hardship and developing interventions to reduce the financial burden of cancer may improve adherence to surveillance recommendations. Citation Format: Jean A. McDougall, Matthew P. Banegas, Charles Wiggins, Ashwani Rajput, Vi K. Chiu, Kristina G. Flores, Anita Y. Kinney. Disparities in treatment-related financial hardship and adherence to surveillance colonoscopy guidelines in ethnically, linguistically, and geographically diverse colorectal cancer survivors [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C52.

PURPOSE Hyaluronan and hyaluronan synthases have been implicated in cancer progression. Hyaluronan synthase-3 is up-regulated in metastatic colon cancer cells (SW620), and its expression mediates cellular growth in vitro. We hypothesized that inhibition of hyaluronan synthase-3 would decrease tumor formation and/or alter the pattern of metastasis in mouse models of colon cancer growth. METHODS Hyaluronan synthase-3 was inhibited in SW620 cells by transfection with small interfering RNA (silenced cells); a scrambled sequence served as a negative control. To study primary tumor growth, transfected cells were injected into the flanks of BALB/c nude mice. To study metastasis, an orthotopic model was used. Metastases were confirmed histologically. Student t test and Fisher exact probability test were used for statistical analysis. RESULTS Inhibition of hyaluronan synthase-3 significantly decreased subcutaneous tumor growth; tumor weight was 0.94 +/- 0.17 g in the hyaluronan synthase-3-silenced group vs 1.70 +/- 0.26 g in the control scrambled group (P < .01). In contrast, metastases were similar in both groups: liver metastases were present in 22% of the silenced group vs 11% of the scrambled group; lung metastases were present in 6% of the silenced group vs 0% of the scrambled group (P = not significant). CONCLUSION Inhibition of hyaluronan synthase-3 expression in SW620 colon cancer cells decreases subcutaneous tumor growth in mice, but has less of an effect on lung and liver metastases. This observation suggests that hyaluronan synthase-3 may enhance primary colon cancer growth.

Background Colorectal cancer is the second leading cause of cancer related mortality, with a majority of deaths resulting from metastases. Few in vivo models allow for the study of the complex process of metastasis. The purpose of this study was to determine the effects of epidermal growth factor receptor activation and TGFβ pathway attenuation in FET, a weakly tumorigenic human colon cancer cell line, in an orthotopic model. Methods and Results Using FET, FETα, FETαDNRII, and FETDNRII cells were constructed. Tumors were orthotopically implanted onto the colons of BALB/c nude mice. After 7 wk, the mice were euthanized and organs extracted for examination. All cell lines demonstrated primary invasion. FETα was weakly metastatic compared with FETαDNRII and FETDNRII, which demonstrated metastases to the lung and liver, respectively. Conclusion Epidermal growth factor receptor (EGFR) activation transforms a nontumorigenic cell line into a tumorigenic but not metastatic one. The tumorigenic line becomes metastatic with the attenuation of TGFβ signaling. Loss of EGFR activation in the TGFβ inhibited line results in a decreased metastatic burden, but importantly, changes the organotropic homing from lung to liver. Thus, these in vivo studies demonstrate that EGFR activation and TGFβ signaling pathways play a role in tumorigenicity and in pattern of metastases.

OBJECTIVE To assess whether TNODS is an independent prognostic factor after adjusting for the lymph node ratio (LNR). SUMMARY BACKGROUND DATA The medical literature has suggested that the TNODS is associated with better survival in stage II and III colon cancer. Thus TNODS was endorsed as a quality measure for patient care by American College of Surgeons, National Quality Forum. There is, however, little biologic rationale to support this linkage. METHODS : A total of 24,477 stage III colon cancer patients were identified from Surveillance, Epidemiology, and End Results cancer registry and categorized into 4 groups, LNR1 to LNR4, according to LNR interval: 0.50. Patients were also stratified according to TNODS into high TNODS (> or = 12) and low TNODS (

Background Because of the increase in the geriatric population, an increasing number of elderly patients are being treated for colorectal cancer. The purpose of this study was to evaluate perioperative morbidity and mortality in this population. Methods A retrospective chart review was performed for patients 80 years of age or older who underwent surgery for colorectal cancer (1993–2006). Results Ninety patients were identified, with a median age of 84 years. More than 90% presented with symptoms; the remaining were diagnosed by screening colonoscopy. Emergent surgery was required in 10%. The morbidity rate was 21% and the overall 30-day mortality rate was 1.1%. Morbidity was higher in patients who required surgery emergently. Conclusions Despite advanced age, the majority of patients in this study did well. Postoperative morbidity was higher than in the general population, but we believe it was acceptably low in most patients. Colorectal surgery appears to be safe in most elderly patients.

Mutations in the PIK3CA gene are common in human cancers, including colon cancer. We compared two pairs of colon cancer cells (HCT116 and DLD1) bearing only the wild-type (WT) or mutant (MUT) PIK3CA allele for their survival capacity under stress conditions in vitro as well as their metastatic properties in an in vivo orthotopic model. When subjected to growth factor deprivation stress (GFDS), the MUT PIK3CA cells displayed resistance to GFDS-induced apoptosis relative to the WT cells. Phosphatidylinositol 3-kinase (PI3K) and its downstream effector AKT were constitutively activated during stress conditions in the MUT PIK3CA cells but not in the WT cells. The MUT cells showed hypersensitivity to PI3K inhibition. Moreover, the proapoptotic protein Bax was expressed at a very high level in the WT PIK3CA cells, whereas it was almost undetectable in the MUT cells. Inhibition of Bax expression by small interfering RNA protected the WT PIK3CA cells from GFDS-induced apoptosis, suggesting an important role of Bax in GFDS-induced apoptosis. These results indicated that the MUT PI3K confers resistance to GFDS-induced apoptosis and that the MUT cells are more dependent on the PI3K pathway for survival. In vivo studies showed that the MUT PIK3CA-bearing cells were more metastatic than the WT cells in an orthotopic model of colon cancer. Taken together, these results suggest that MUT PI3K imparts a more aggressive phenotype in colon cancer cells and could be a potential therapeutic target for treatment of colon cancer patients bearing PIK3CA mutations. [Cancer Res 2007;67(12):5851–8]

Death review was conducted for the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial to avoid the biases associated with causes of death entered on death certificates. An algorithm selected deaths for review. Records on diagnosis and terminal illness were perused in the coordinating center and by the chair of the death review committee (DRC). Identifying information and randomization arm was removed. Three reviewers independently determined the cause of death. Disagreement was resolved at a meeting of the DRC. This process was subsequently simplified. The cause of death was determined by one DRC member and compared to the death certificate. With agreement the case was finalized. When discordant, the records were sent to a second DRC member. If the reviewers agreed, the case was finalized. If not, a third member reviewed. If two of the three reviewers agreed, the case was sent back to the discordant reviewer. If the reviewer remained discordant the case was resolved by a conference call. Of the 4728 death reviews that were completed, the DRC confirmed the death certificate underlying cause for over 90%. Between 5% and 13% of the certified deaths were regarded as indirect causes of death, associated with the treatment of the ascertained cancer; differential for prostate cancer, 11% in the intervention arm and 6% in the control. Without review, between 1% and 6% of the deaths that occurred would not have been assigned to the relevant PLCO cancer. The DRC completed 76% of those requiring review before the process ceased.

Purpose: We conducted a Phase I study to determine the maximum tolerated dose (MTD) of neoadjuvant capecitabine, oxaliplatin, and radiation therapy (RT) in Stage II to III rectal adenocarcinoma. Methods and Materials: Capecitabine was given orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given i.v. once weekly × 5 (for 5 weeks) starting the first day of RT. RT was given daily except on weekends and holidays at 1.8 Gy per fraction × 28. Escalation for capecitabine or oxaliplatin was to occur in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Endorectal tumor biopsy samples were obtained before and on Day 3 of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase, DNA repair, and apoptosis. Results: Twelve patients were enrolled on this study. Two of 6 patients at dose level (DL) 1 (capecitabine 825 mg/m 2 orally (p.o.) given twice daily (b.i.d.); oxaliplatin 50 mg/m 2 /week) had a dose-limiting diarrhea. One of 6 patients at DL (−)1 (capecitabine 725 mg/m 2 p.o., b.i.d.; oxaliplatin 50 mg/m 2 /week) experienced-dose-limiting diarrhea. Three of 11 patients who underwent resection had a complete pathologic response. No remarkable variations in rectal tumor biologic endpoints were noted on Day 3 of treatment in comparison to baseline. However, a higher apotosis index was observed at baseline and on Day 3 in complete pathologic responders (no statistical analysis performed). Conclusions: Capecitabine 725 mg/m 2 p.o., twice daily in combination with oxaliplatin 50 mg/m 2 /week and RT 50.4 Gy in 28 fractions is the recommended dose for future studies.

Objectives: To investigate the incidence of carcinoembryonic antigen (CEA) surge in patients with metastatic colorectal cancer (MCRC) and its implications on clinical outcome. Methods: A retrospective chart review of patients with MCRC treated with chemotherapy at Roswell Park Cancer Institute from January 2000 to May 2004 was conducted. A CEA surge was defined as an increase of >20% from baseline followed by a >20% drop in one or more subsequent CEA levels compared to baseline. The incidence of CEA surge and its association with clinical outcome was investigated. Results: Eighty-nine patients were evaluable for CEA surge. A CEA surge was documented in 10 patients. The CEA surge lasted Conclusions: CEA surges can be observed in patients receiving chemotherapy for MCRC and are often associated with a clinical benefit. None of the CEA surges satisfied the American Society of Clinical Oncology definition of CEA progression. A rise in CEA after initiation of chemotherapy, unless lasting >4 months, cannot be used as an indicator of progressive disease.

INTRODUCTIONInflammatory cap polyposis (CP) is an uncommon, non-malignant condition whose pathogenesis is poorly understood. Initial presentation of CP may mimic other gastrointestinal conditions like inflammatory bowel disease, pseudomembranous colitis, irritable bowel syndrome, and colon cancer.PRESENTATION OF CASEA 42-year-old male presented with symptoms of constipation, abdominal pain and weight loss, which were suggestive of a malignancy.DISCUSSIONSince the symptoms of CP resemble closely those of other gastrointestinal diseases, particularly colon cancer, making the initial diagnosis can be challenging and it is often delayed. The mainstay of initial treatment is conservative, however symptomatic and complicated cases require prompt surgical intervention with close clinical follow-up.CONCLUSIONWe chose to report this case because it represents a rare and unique disease process that may masquerade as a colon cancer. It is important for surgeons to be aware of this non-malignant condition since inadequate surgery usually results in recurrence.

Introduction: Schwannomas are benign tumors arising from the cells responsible for producing the myelin sheath surrounding peripheral nerve cells. Presentation of case: A patient presented with intermittent bloody stools and diarrhea. Following a work-up, including colonoscopy, computed tomography (CT) scan, and endorectal ultrasound and biopsy, he was found to have a clinical T3N1 rectal adenocarcinoma. The CT scan also showed an incidental mass in the right seminal vesicle that on biopsy was consistent with a benign stromal nodule. After neoadjuvant chemoradiation, a low anterior resection (LAR) and concomitant resection of the right seminal vesicle was performed. Pathologic evaluation of the right seminal vesicle revealed a benign schwannoma. Discussion: This unusual case of a solitary schwannoma of the seminal vesicle in a patient with a locally advanced rectal adenocarcinoma illustrates the difficulty in diagnosing these rare lesions because of their generally asymptomatic nature.

e18067 Background: The high cost of cancer care creates adverse financial consequences for cancer patients, impacting adherence to treatment, clinical outcomes, and quality of life. Prior studies estimate that 40% of colorectal cancer (CRC) patients experience treatment-related financial burden. This study aims to identify factors associated with financial burden and evaluate its relationship with cancer recurrence. Methods: This cross-sectional study identified individuals diagnosed with stages I-III CRC between 2001 and 2012 through the statewide New Mexico Tumor Registry. A comprehensive survey was administered in 2014. Participants were considered to have experienced financial burden if they reported any treatment-related debt accumulation, bankruptcy filing, other financial sacrifices, or inability to pay medical bills. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Results: Among the 277 CRC survivors who participated in this study, 40% identified as Hispanic and 39% lived in a rural area. Financial burden was reported by 43% of CRC survivors. In a model adjusted for age at diagnosis, sex, race, ethnicity, education, and years since diagnosis, participants who spoke a mixture of English and Spanish (OR: 3.5, 95% CI: 1.3-9.5), those with low health literacy (OR: 2.4, 95% CI: 1.2-4.7), and those with public insurance (OR: 2.2, 95% CI: 1.2-4.4) were more likely to report financial burden. Ethnicity and rural status were not independently associated with financial burden. Six percent (n = 16) of participants experienced a CRC recurrence. Survivors who reported financial burden were 4-times as likely to experience a recurrence (OR: 4.3, 95% CI 1.1-17.7) as those who did not report financial burden. Conclusions: Language, low health literacy, and public insurance may increase the likelihood that CRC survivors experience financial burden. These disparities are alarming given the observed association between financial burden and CRC recurrence. Larger, prospective studies are needed to confirm the association between financial burden and recurrence and to identify potential intervention targets.

Background.Previous analyses indicated that New Mexican Hispanics and American Indians (AI) did not experience the declining colorectal cancer (CRC) incidence and mortality rates observed among non-Hispanic whites (NHW). We evaluated more recent data to determine whether racial/ethnic differences persisted.Methods.We used New Mexico Surveillance Epidemiology and End Results data from 1995 to 2009 to calculate age-specific incidence rates and age-adjusted incidence rates overall and by tumor stage. We calculated mortality rates using National Center for Health Statistics’ data. We used joinpoint regression to determine annual percentage change (APC) in age-adjusted incidence rates. Analyses were stratified by race/ethnicity and gender.Results.Incidence rates continued declining in NHW (APC −1.45% men, −1.06% women), while nonsignificantly increasing for AI (1.67% men, 1.26% women) and Hispanic women (0.24%). The APC initially increased in Hispanic men through 2001 (3.33%,P=0.06), before declining (−3.10%,P=0.003). Incidence rates declined in NHW and Hispanics aged 75 and older. Incidence rates for distant-stage cancer remained stable for all groups. Mortality rates declined significantly in NHW and Hispanics.Conclusions.Racial/ethnic disparities in CRC persist in New Mexico. Incidence differences could be related to risk factors or access to screening; mortality differences could be due to patterns of care for screening or treatment.

Background: Colorectal cancer (CRC) metastasis is a leading cause of cancer-related deaths in the United States. The molecular mechanisms underlying this complex, multi-step pathway are yet to be completely elucidated. Recent reports have stressed the importance of intra-tumoral heterogeneity in the development of a metastatic phenotype. The purpose of this study was to characterize the intra-tumoral phenotypic heterogeneity between two iso-clonal human colon cancer sublines HCT116 and HCT116b on their ability to undergo metastatic colonization and survive under growth factor deprivation stress (GFDS). Materials and Methods: HCT116 and HCT116b cells were transfected with green fluorescence protein and subcutaneously injected into BALB/c nude male mice. Once xenografts were established, they were excised and orthotopically implanted into other male BALB/c nude mice using microsurgical techniques. Animal tissues were studied for metastases using histochemical techniques. Microarray analysis was performed to generate gene signatures associated with each subline. In vitro assessment of growth factor signaling pathway was performed under GFDS for 3 and 5 days. Results: Both HCT116 and HCT116b iso-clonal variants demonstrated 100% primary tumor growth, invasion and peritoneal spread. However, HCT116 was highly metastatic with 68% metastasis observed in liver and/or lungs compared to 4% in HCT116b. Microarray analysis revealed an upregulation of survival and metastatic genes in HCT116 cells compared to HCT116b cells. In vitro analysis showed that HCT116 upregulated survival and migratory signaling proteins and downregulated apoptotic agents under GFDS. However, HCT116b cells effectively showed the opposite response under stress inducing cell death. Conclusions: We demonstrate the importance of clonal variation in determining metastatic potential of colorectal cancer cells using the HCT116/HCT116b iso-clonal variants in an orthotopic metastatic mouse model. Determination of clonal heterogeneity in patient tumors can serve as useful tools to identify clinically relevant biomarkers for diagnostic and therapeutic assessment of metastatic colorectal cancer.

Background Understanding drivers for metastasis in human cancer is important for potential development of therapies to treat metastases. The role of loss of TGFβ tumor suppressor activities in the metastatic process is essentially unknown. Methodology/Principal Findings Utilizing in vitro and in vivo techniques, we have shown that loss of TGFβ tumor suppressor signaling is necessary to allow the last step of the metastatic process - colonization of the metastatic site. This work demonstrates for the first time that TGFβ receptor reconstitution leads to decreased metastatic colonization. Moreover, we have identified a novel TGFβ/PKA tumor suppressor pathway that acts directly on a known cell survival mechanism that responds to stress with the survivin/XIAP dependent inhibition of caspases that effect apoptosis. The linkage between the TGFβ/PKA transduceome signaling and control of metastasis through induction of cell death was shown by TGFβ receptor restoration with reactivation of the TGFβ/PKA pathway in receptor deficient metastatic colon cancer cells leading to control of aberrant cell survival. Conclusion/Significance This work impacts our understanding of the possible mechanisms that are critical to the growth and maintenance of metastases as well as understanding of a novel TGFβ function as a metastatic suppressor. These results raise the possibility that regeneration of attenuated TGFβ signaling would be an effective target in the treatment of metastasis. Our work indicates the clinical potential for developing anti-metastasis therapy based on inhibition of this very important aberrant cell survival mechanism by the multifaceted TGFβ/PKA transduceome induced pathway. Development of effective treatments for metastatic disease is a pressing need since metastases are the major cause of death in solid tumors.

Insulin-Like Growth Factors (IGFs) and their receptor, IGF-1R, are frequently expressed in human colon cancers and play important roles in promoting malignancy. We demonstrate that colon cancer cells show dependence upon an IGF2/IGF-1R autocrine loop and have characterized the effects of an IGF1R kinase inhibitor (designated PQIP in vitroand in vivo). PQIP abrogated IGF-1R mediated activation of IRS-1/Akt to inhibit survival signaling and induce apoptosis. Furthermore, PQIP inhibited mitogenesis and anchorage-independent growth in soft agarose at concentrations consistent with inhibition of IGF-1R phosphorylation. Thus, PQIP showed potent in vitro antitumor activity in colon cancer cells. The effects of PQIP on the growth of orthotopically implanted GEO colon cancer xenografts were determined following daily treatment with 75 mg/Kg of drug by oral gavage. Decreased tumor burden in BALB/c nude mice without significant weight loss and toxicity was observed. Fluorescence intensity of the GFP labeled tumors was 3-fold higher in control mice than in treated mice. MRI analysis showed a 5-fold decrease tumor volume in treatedmice. TUNEL analysis of treated and sham treated tumors indicated an 8-fold higher rate of apoptosis in PQIP treatedtumors. Western blot analysis of the treated tissue samples showed inhibition of IGF1R activation and Akt signalingrelative to sham treated animals. Therefore, PQIP represents an attractive therapeutic candidate for targeting IGF1R-dependent colon cancer.

Background Failing to meet the benchmark of 12 lymph nodes in resection specimens is an indication for adjuvant chemotherapy in stage II colon cancer. Methods Among consecutive eligible patients with pathologic stage II colon cancer treated at eight NCI-designated comprehensive cancer centers between September 1, 2005 and February 19, 2008, we analyzed receipt of adjuvant chemotherapy, with less than 12 versus 12+ lymph nodes removed and examined the primary explanatory variable of interest. Results Among 258 patients, 46% received adjuvant chemotherapy. An oxaliplatin-containing regimen was used 67% of the time. Younger age (

To determine rate and predictors of sphincter-preserving surgery (SPS) for rectal cancer patients treated at specialty institutions.SPS has been considered a surrogate for surgical quality, and sphincter preservation is tremendously important to patients. Evidence of association between case volume and SPS rate has prompted recommendations that all rectal cancer patients undergo surgery at specialty institutions. However, rates of SPS, and the factors associated with ability to perform SPS, have not been well-characterized.A prospective registry of all colorectal cancer patients treated at 7 National Comprehensive Cancer Network institutions was used to identify patients with clinical stage I-III rectal cancer undergoing surgery (n = 674) between September 2005 and October 2007. Patient, tumor and treatment factors were abstracted; patients' clinical characteristics with and without SPS were compared using descriptive statistics and multivariable logistic regression.Of 674 identified patients (median age, 58.2; 60% male), 520 (77%) had SPS. Of these, 240 had low anterior resection with coloanal anastomosis, 268 low anterior resection without coloanal anastomosis; 12 had other SPS procedures. Sixty-two percent had a temporary diverting stoma. On multivariable analyses, independent predictors of SPS included younger age at diagnosis, proximal location in the rectum, nonfixed tumor, and institution.SPS rates at National Comprehensive Cancer Network institutions exceed those seen in population-based samples and clinical trials. In addition to expected variation in SPS rates based on patient and tumor characteristics, we identified variation among institutions. Although the optimal rate of SPS remains unknown, this provides areas for further research and potential performance improvement.

Background The National Comprehensive Cancer Network (NCCN) Outcomes Database was created to assess concordance to evidence- and consensus-based guidelines and to measure adherence to quality measures on an ongoing basis. The Colorectal Cancer Database began in 2005 as a collaboration among 8 NCCN centers. Methods Newly diagnosed colon and rectal cancer patients presenting to 1 of 8 NCCN centers between September 1, 2005, and May 21, 2008, were eligible for analysis of concordance with NCCN treatment guidelines for colorectal cancer and with a set of quality metrics jointly developed by ASCO and NCCN in 2007. Adherence rates were determined for each metric. Center-specific rates were benchmarked against mean concordance rates for all participating centers. Results A total of 3443 patients were evaluable. Mean concordance rates with NCCN colorectal cancer guidelines and ASCO/NCCN quality measures were generally high ( >or= 90%). However, relatively low mean concordance rates were noted for adjuvant chemotherapy treatment recommendations within 9 months of diagnosis of stage II to III rectal cancer (81%), and neoadjuvant chemoradiation in clinical T4 rectal primaries (83%). These low rates of concordance seemed to be consistent across centers. Conclusions Adherence to guidelines and quality measures is generally high at institutions participating in the NCCN colorectal cancer database. Lack of documentation, patient refusal, delayed treatment initiation, and lack of consensus about whether treatment was essential were the primary reasons for nonconcordance. Measurement of concordance and the reasons for nonconcordance enable participating centers to understand and improve their care delivery systems.

551 Background: ASCO guidelines published in 2009 recommend all patients with metastatic colorectal cancer (CRC) receive KRAS testing to guide anti-EGFR monoclonal antibody treatment. Recent literature examining nation-wide trends via the Surveillance, Epidemiology, and End Results (SEER) database showed New Mexico to exhibit the highest KRAS rates of testing out of 18 registries. We aim to explore disparities in KRAS testing in the state of New Mexico. Methods: The New Mexico Tumor Registry (NMTR), a population-based cancer registry participating in the SEER Program, was queried to identify all incident cases of CRC among New Mexico residents from 2010 to 2013. Chi-square tests were used to identify disparity in KRAS testing with a p-value ≤ 0.05 considered significant. Results: A total of 637 patients were diagnosed with metastatic CRC from 2010-2013. As expected, KRAS testing in Stage 4 patients presented the highest frequency (38.4%), though testing in stage 3 (8.5%), stage 2 (3.4%) and stage 1 (1.2%) was also seen. In those with metastatic disease, younger patients (ages 22-39 and 40-64 years) were more likely to receive testing than patients 65 years and older (p < 0.0001). Patients living in or near a metropolitan center received KRAS testing more often than patients living in non-metro and rural areas (p = 0.016). There were no disparities in testing between male and female patients (39.1 v. 37.7%; p = 0.71) or amongst the predominant ethnic groups (p = 0.66). A small increase in the occurrence of KRAS testing was noted from 2010 to 2013 (34.2 to 42.2%); this trend approached though did not obtain significance (p = 0.07). In stage 4 patients, there were no significant differences in rates of wild-type versus mutant status when examined by age (p = 0.95), sex (p = 0.41), ethnicity (p = 0.41), by progressive years (p = 0.42) or geography (p = 0.35). Conclusions: New Mexico exhibits high rates of KRAS biomarker testing in patients with metastatic CRC. Age and geographic disparities exist in the rates of testing, while sex, ethnicity and the year tested showed no differences. Further study is required to explore the reasons for this disparity in KRAS testing, as well as to determine the motivation for testing in stage 1 through 3 CRC which is contrary to current treatment guidelines.

Primary tumor resection in patients with metastatic colorectal cancer is considered highly controversial. Historical data suggest a low risk of primary tumor-related complications in patients treated with first-line 5-fluorouracil (5-FU) chemotherapy. However, there are very limited data on the safety and efficacy of first-line combination chemotherapy in this unresected-primary population, especially in the setting of rectal cancer.We performed a single-institution retrospective study to evaluate the primary tumor-related complication rate and outcome of patients with unresected metastatic colorectal cancer treated with first-line chemotherapy. Estimation of the overall and progression-free survival distributions were done using the Kaplan-Meier method.Thirty-eight patients were identified: 26 had primary colon cancers and 12 had primary rectal cancers. Thirty-one patients were treated with first-line FOLFOX (oxaliplatin/leucovorin/5-FU) with or without bevacizumab. In patients with colon tumors, only 2 (7%) required surgery, both for obstruction. In patients with rectal tumors, 3 (25%) developed progressive obstructive symptoms, and 2 developed worsening pain. Four of these patients were adequately palliated with chemoradiation; only 1 patient required a diverting colostomy. The median progression-free survival was 7 months, and overall survival was 17.3 months. Twenty-two patients died because of disease progression, only 3 of whom developed obstructive symptoms at the primary tumor site before death.First-line chemotherapy is feasible and safe in patients with unresected colon and nonirradiated rectal cancer. The rate of bowel obstruction requiring surgical intervention in this population was10%. These results support an approach that defers surgery in non-obstructed, noncurable patients in favor of systemic chemotherapy as initial treatment.

Purpose To evaluate the efficacy of a combination of capecitabine, oxaliplatin, and radiotherapy (RT) in the neoadjuvant treatment of Stage II and III rectal cancers. Methods Capecitabine was given at 725 mg/m 2 orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given intravenously at 50 mg/m 2 once weekly five times starting the first day of RT. The radiation dose was 50.4 Gy in 28 fractions (1.8 Gy/fraction), five fractions weekly. Endorectal tumor biopsies were obtained before treatment and on the third day of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), and apoptosis. Results A total of 25 patients were enrolled in this study; 6 patients (24%) had a complete pathologic response. T-downstaging occurred in 52% of patients, and N-downstaging occurred in 53%. Grade 3 diarrhea was the most common Grade 3-4 toxicity, occurring in 20% of patients. Only 2 patients experienced disease recurrence, with a median of 20 months of follow-up. Thymidylate synthase, thymidine phosphorylase, ERCC1, and apoptosis did not vary significantly between the pretreatment and Day 3 tumor biopsies, nor did they predict for T-downstaging or a complete pathologic response. Conclusion Capecitabine at 725 mg/m 2 orally twice daily, oxaliplatin 50 mg/m 2 /wk, and RT at 50.4 Gy is an effective neoadjuvant combination for Stage II and III rectal cancer and results in a greater rate of complete pathologic responses than historically shown in fluoropyrimidine plus RT controls.

Rectal cancer affects more than 40,000 people in the United States annually. Despite recent advances in radiation and chemotherapy, surgical resection remains an integral part of curative therapy for this disease. Although rectal cancer is thought to be biologically similar to colon cancer, the anatomic complexity of the pelvis makes therapy for this disease considerably more complicated. Local recurrence is also a greater concern in rectal cancer than in colon cancer. The choice of surgical therapy depends on the location of the tumor, depth of rectal wall invasion, and clinical stage. Surgical options include local excision (transanal excision and transanal endoscopic microsurgery) and radical resection (low anterior resection, extended low anterior resection with coloanal anastomosis, abdominoperineal resection [APR], and pelvic exenteration). Technical advances such as transanal endoscopic microsurgery and laparoscopy also are changing the surgical approach to rectal tumors. Finally, chemotherapy and radiation are now frequently recommended in conjunction with surgical therapy. This article reviews the current surgical approach to treating patients with rectal cancer.

Background Colorectal cancer metastases result in a significant number of cancer related deaths. The molecular mechanisms underlying this complex, multi-step pathway are yet to be completely elucidated. In the absence of any transgenic models of colon cancer metastases, an in vivo model system that fulfills the rate limiting steps of metastasis (local invasion and distant colony formation) is needed. The purpose of this study was to characterize the behavior of a human colon cancer cell line, HCT116 in an orthotopic model. Materials and methods HCT116 cells were transfected with green fluorescence protein and subcutaneously injected into BALB/c nude male mice. Once xenografts were established, they were excised and orthotopically implanted into 32 other male BALB/c nude mice using microsurgical techniques. Animals were serially imaged and euthanized at 6–8 weeks post-implantation. Tissues were procured and processed for hematoxylin and eosin analysis. Results All 32 animals demonstrated primary tumor growth, invasion and peritoneal spread. Liver metastases were identified in 15/32 (47%), and lung metastases were confirmed in 13/32 (41%). In total, 19/32 (59%) animals demonstrated distant metastatic colony formation. Conclusions This orthotopic model of colon cancer fulfills the rate limiting steps of local invasion and distant colony formation in the process of metastases. HCT116 human colon cancer cell line in this in vivo model system provides a tool to dissect the molecular mechanism involved in the metastatic cascade.

Introduction: Colorectal Cancer(CRC) metastasis to distant organ sites is a major cause of CRC-related death. To date, there are no effective anti-metastatic therapies available. The purpose of this study was to use a proteomics-based approach to identify and characterize molecular targets associated with CRC metastasis. Methods: GFP-labeled GEO human CRC cells were used to generate subcutaneous xenografts in BALB/c nude mice, which in turn were orthotopically implanted. This model allows for reproducible quantitative analysis of metastasis to liver and lungs. Primary and liver metastases were collected and a 2D-DIGE proteomics approach was used to characterize the global protein expression in the primary tumors and the corresponding liver metastases. Tissues were labeled with CyDye DIGE fluors and analyzed on a single multiplexed gel. DeCyder “in-gel” analysis software was used to compare all protein spots and protein expression ratios between the primary tumor and liver metastasis were generated. Differential spots were selected, in-gel digested and peptide mass fingerprints were obtained. Gene microarray analysis using the Illumina platform was also performed on primary and metastatic tumors. Westerns were performed to confirm protein expression. Survival signaling in GEO cells is dependent on the IGF1R pathway and thus, an IGF1R monoclonal antibody, MK-0646 was used to assess downstream effects. Results: Differential expression of Ezrin was identified, as it was increased in liver metastases compared to primary tumors. This was validated by microarrays and westerns. Ezrin, a protein belonging to the Ezrin-Radixin-Moesin (ERM) family plays important roles in cell motility, invasion, tumor progression and metastasis. We also observed that T567 hyperphosphorylation of Ezrin was correlated to CRC metastasis by western blot analysis of primary tumor with liver metastases. This was further confirmed by IHC on human CRC patient specimens. Moreover, inhibition of the IGF-1R signaling pathway by mAb MK-0646 in mouse GEO CRC subcutaneous xenografts resulted in inhibition of Ezrin phosphorylation at T567, indicating that Ezrin signaling is downstream of the IGF-1R signaling pathway. SiRNA knockdown of Ezrin significantly downregulated XIAP, which is a metastasis gene in this model. Therefore, XIAP is downstream of IGF-1R-Ezrin signaling. Conclusions: Using a proteomics approach, we identified ezrin as a potential biomarker for metastasis in CRC. We show for the first time that Ezrin activation at T567 is downstream of the IGF-1R signaling pathway and contributes to cell survival in CRC metastasis. Thus, ezrin might be a novel target that could be utilized for the development of effective anti-metastatic therapies against CRC. Citation Format: Premila Devi Leiphrakpam, Ashwani Rajput, Michael G. Brattain, Sanjib Chowdhury. The expression and clinical significance of Ezrin in colorectal cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3887. doi:10.1158/1538-7445.AM2013-3887

Introduction. The human colon cancer cell line HCT116 has constitutive activation of Epidermal Growth Factor Receptor (EGFR) and subsequently is tumorigenic in xenograft models. These models, however, do not allow for the study of the metastatic process. The objective of this study was to determine the behavior of HCT116 in an orthotopic model of colon cancer. Methods. 5 × 106 HCT116 cells were subcutaneously injected into BALB/c nude male mice. At 1 cm3 the xenograft was explanted, and two 1-mm3 pieces were subserosally implanted on to the colons of 13 other BALB/c nude male mice. Animals with green fluorescent protein (GFP) transfected HCT116 were imaged weekly for GFP expression for up to 8 weeks when all animals were euthanized and autopsied. Tissues were submitted for histologic evaluation. Results. All 13 animals showed primary tumor growth and peritoneal metastases (Fig. A, day 16 postimplant; Fig B, day 45). Histologic evaluation confirmed primary tumor invasion, growth, and peritoneal disease in all 13 animals. Liver and lung metastases were histologically confirmed in 9 and 7 mice, respectively (Fig. C). Immunohistochemical stains confirmed the activation status of EGFR. Conclusions. HCT116 demonstrates a highly metastatic phenotype in an orthotopic colon cancer model that mimics aggressive colon cancer behavior in humans. The rate-limiting steps in metastasis of local invasion and distant colony formation are fulfilled. Thus, this model will allow for the study of the complex process of metastasis. Download : Download full-size image