Colorectal Cancer Survivors' Receptivity toward Genomic Testing and Targeted Use of Non-Steroidal Anti-Inflammatory Drugs to Prevent Cancer Recurrence.

Genomic testing and targeted use of non-steroidal anti-inflammatory drugs (NSAIDs) may mitigate cancer recurrence risks. This study examines colorectal cancer (CRC) survivors' interest and receptivity to these strategies. Patients diagnosed with stage I-III CRC in 2004-2012 were recruited through the New Mexico Cancer Registry to complete a cancer survivorship experiences survey. We assessed interest in genomic testing, daily aspirin (ASA) and NSAID use, and receptivity to future daily ASA/NSAIDs. Descriptive statistics and multivariable logistic regression models estimated factors associated with genomic testing interest. Receptivity to future ASA/NSAIDs use was estimated for non-users of ASA/NSAIDs. Among CRC survivors (n = 273), 83% endorsed interest in genomic testing, 25% were ASA users and 47% ASA/NSAIDs users. In our final model, genomic testing interest was associated with being uncoupled [OR = 4.11; 95% CI = 1.49-11.35], low income [OR = 0.35, 95% CI: 0.14-0.88], smoking history [OR = 0.35, 95% CI: 0.14-0.90], low [OR: 0.33, 95% CI: 0.07-1.43] and moderate [OR: 0.26, 95% CI: 0.11-0.61] health literacy, and personal CRC risk worry [OR: 2.86, 95% CI: 1.63-5.02, p = 0.0002]. In our final model, ASA use was associated with age [OR: 1.05, 95% CI: 1.01-1.10] and cardiovascular disease history [OR: 2.42, 95% CI: 1.23-4.73, p = 0.010]. Among non-users ASA/NSAIDs, 83% reported receptivity to ASA/NSAIDs to reduce cancer risks, and no significant correlates were identified. The majority of survivors' expressed genomic testing interest and endorsed receptivity toward ASA/NSAIDs use for cancer risk management. Further research to optimize ASA/NSAIDs use guided by genomic testing is warranted.

EGFR transactivates RON to drive oncogenic crosstalk.

Crosstalk between different receptor tyrosine kinases (RTKs) is thought to drive oncogenic signaling and allow therapeutic escape. EGFR and RON are two such RTKs from different subfamilies, which engage in crosstalk through unknown mechanisms. We combined high-resolution imaging with biochemical and mutational studies to ask how EGFR and RON communicate. EGF stimulation promotes EGFR-dependent phosphorylation of RON, but ligand stimulation of RON does not trigger EGFR phosphorylation - arguing that crosstalk is unidirectional. Nanoscale imaging reveals association of EGFR and RON in common plasma membrane microdomains. Two-color single particle tracking captured formation of complexes between RON and EGF-bound EGFR. Our results further show that RON is a substrate for EGFR kinase, and that transactivation of RON requires formation of a signaling competent EGFR dimer. These results support a role for direct EGFR/RON interactions in propagating crosstalk, such that EGF-stimulated EGFR phosphorylates RON to activate RON-directed signaling.

The Impact of Surgical Delays on Short- and Long-Term Survival Among Colon Cancer Patients.

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 (<1 week, 1-3 weeks, 3-6 weeks, 6-9 weeks, 9-12 weeks, and >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 <1 week, 30.5% waited 1-3 weeks, 29.0% waited 3-6 weeks, 9.7% waited 6-9 weeks, 3.3% waited 9-12 weeks, and 3.3% 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.

Operative Approach Does Not Impact Radial Margin Positivity in Distal Rectal Cancer.

BACKGROUND: 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). METHODS: 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. RESULTS: 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 < 0.001), pN2 stage (OR 1.98, p = 0.004), disseminated cancer (OR 1.90, p = 0.002), and lack of preoperative radiation (OR 1.98, p < 0.01). CONCLUSIONS: No difference in RMP was observed among R-APR, L-APR, and O-APR. Postoperatively, R-APR yielded greater benefit when compared to O-APR, but was comparable to that of L-APR. Minimally invasive surgery may be an appropriate option and worthy consideration for patients with distal rectal cancer requiring APR.

Impact of Treatment Coordination on Overall Survival in Rectal Cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Retrorectal cyst: proteus in the backyard-case series and literature review.

Retrorectal cysts are cystic lesions located in the retrorectal space and are a distinct subset of retrorectal tumours, which are often misdiagnosed due to their rarity and mimicry of symptoms caused by common diseases. We have described the presentation and management of four patients who were diagnosed with retrorectal cysts from a 10-year retrospective chart review at our institute, a tertiary care centre. In middle-aged women, the following should raise suspicion of retrorectal cyst: gastrointestinal or urinary obstructive features, mass or fullness palpable on the posterior wall on digital rectal examination, presacral dimple, perianal fistula and/or recurrent disease. Such features should prompt an MRI evaluation of the pelvis for definitive diagnosis.

Mechanisms of Immunosuppression in Colorectal Cancer.

CRC is the third most diagnosed cancer in the US with the second-highest mortality rate. A multi-modality approach with surgery/chemotherapy is used in patients with early stages of colon cancer. Radiation therapy is added to the armamentarium in patients with locally advanced rectal cancer. While some patients with metastatic CRC are cured, the majority remain incurable and receive palliative chemotherapy as the standard of care. Recently, immune checkpoint blockade has emerged as a promising treatment for many solid tumors, including CRC with microsatellite instability. However, it has not been effective for microsatellite stable CRC. Here, main mechanisms of immunosuppression in CRC will be discussed, aiming to provide some insights for restoring immunosurveillance to improve treatment efficacy in CRC.

Correlates of poor adherence to a healthy lifestyle among a diverse group of colorectal cancer survivors.

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 was 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.

Socioeconomic disparities in health-related quality of life among colorectal cancer survivors.

PURPOSE: Improvements in colorectal cancer (CRC) prevention, early detection, and treatment have resulted in substantial gains in survival. However, the health-related quality of life (HRQoL) of CRC survivors often depends on access to supportive care, which differs by survivors' socioeconomic characteristics. The purpose of this study was to investigate the relationship between socioeconomic characteristics and HRQoL in a diverse group of CRC survivors. METHODS: We conducted a population-based, cross-sectional study to examine the association between socioeconomic factors (household income, health literacy, and insurance status) and HRQoL domains of pain interference, fatigue, physical function, sleep disturbance, anxiety, and depression. PROMIS® Short Forms v.2.0 were used to assess domains of HRQoL. Linear regression modeling was used to estimate the coefficient representing the average HRQoL domain score and its 95% confidence interval (CI). RESULTS: Three hundred one CRC survivors participated in the survey. Low-income (≤ $30,000) CRC survivors had, on average, a 4.70-point (95% CI 1.10-8.28) higher pain interference score, a 7.02-point (95% CI 3.27-10.77) higher fatigue score, a 5.13-point (95% CI - 8.56 to - 1.71) lower physical function score, and a 4.44-point (95% 1.40-7.49) higher depression score than CRC survivors with an income ≥ $70,000. Survivors with Medicaid insurance reported significantly greater pain interference and worse physical function than privately insured survivors. Survivors with low health literacy reported significantly greater pain interference compared with survivors with high health literacy. CONCLUSIONS: Substantial socioeconomic disparities in HRQoL were observed in this diverse population of CRC survivors. IMPLICATIONS FOR CANCER SURVIVORS: Designing supportive care interventions to improve HRQoL among low-income and Medicaid-insured CRC survivors is critical for eliminating disparities in CRC outcomes.

Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) is the standard of care for locally advanced adenocarcinoma of the rectum, but it is currently unknown which patients have disease that will respond. This study tested the correlation between response to nCRT and intratumoral heterogeneity using next-generation sequencing assays. PATIENTS 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 disease) who received nCRT. High read-depth sequencing of > 400 cancer-relevant genes was performed. 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. Eight patients had disease noted to have complete response, 2 moderate, 4 minimal, and 7 poor. Higher MATH scores correlated with poorer response to treatment, demonstrating significantly increased tumor heterogeneity compared to complete response (P = .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.

Rural Disparities in Treatment-Related Financial Hardship and Adherence to Surveillance Colonoscopy in Diverse Colorectal Cancer Survivors.

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 <$30,000 (37% vs. 27%); and less likely to be employed (35% vs. 41%), have a college degree (28% vs. 38%), or a high level of health literacy (39% vs. 51%). Rural survivors were twice as likely as urban survivors to report treatment-related financial hardship (OR, 1.86; 95% CI, 1.06-3.28) and nonadherence to surveillance colonoscopy guidelines (OR, 2.28; 95% CI, 1.07-4.85). In addition, financial hardship was independently associated with nonadherence to surveillance colonoscopy (OR, 2.17; 95% CI, 1.01-4.85).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.

Phase II Trial Using a Combination of Oxaliplatin, Capecitabine, and Celecoxib with Concurrent Radiation for Newly Diagnosed Resectable Rectal Cancer.

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.

Racial-Ethnic Disparities in Late-Stage Colorectal Cancer Among Hispanics and Non-Hispanic Whites of New Mexico.

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.

KRAS biomarker testing disparities in colorectal cancer patients in New Mexico.

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.

Surgical management of isolated mesenteric autoimmune disease: addressing the spectrum of IgG4-related disease and sclerosing mesenteritis.

IgG4-related disease (IgG4-RD) is a rare form of autoimmune sclerosing disease, characterised by elevated serum IgG4 and tissue IgG4 levels, specific histopathological findings, multiorgan involvement and adequate response to glucocorticoid treatment. The low incidence and the heterogeneous nature of the disease has made consensus on diagnostic criteria for IgG4-RD difficult. Whether sclerosing mesenteritis (SM) is considered a manifestation of IgG4-RD is strongly debated. We present the case of a patient with a history of rheumatoid arthritis who presented with a calcified abdominal mass. She was found to have an isolated, pedunculated mesenteric mass positive for IgG4 and concurrently elevated serum IgG4 levels. Clinical features did not classify her disease as either SM or IgG4-RD as currently described in consensus statements. Concurrent diagnoses of IgG4-RD, SM and other autoimmune disorders, as well as postoperative recommendations for resected isolated IgG4-positive masses, are discussed.

Mutant-Allele Tumor Heterogeneity Scores Correlate With Risk of Metastases in Colon Cancer.

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.

Hibernoma: diagnostic and surgical considerations of a rare benign tumour.

Hibernoma is a rare, benign tumour of brown fat origin. Less than 250 cases have been reported in the literature. We present a case of a 19-year-old man referred to surgical oncology for evaluation of a large soft tissue mass near the apex of his right scapula. Complete surgical excision was performed, sparing the overlying latissimus dorsi musculature. Surgical pathology revealed findings were consistent with hibernoma, grossly showing a well-encapsulated fluctuant mass measuring 21.4×14.4×5.3 cm, and histologically composed of brown fat adipocytes. The mainstay of treatment is surgical excision of the mass. Primary goals of the operation include complete removal of the mass to prevent recurrence and sparing of adjacent structures as it is a benign, non-invasive tumour. We present a case of a large chest wall hibernoma in a young adult, diagnosed on final pathology after complete surgical excision.

RON kinase isoforms demonstrate variable cell motility in normal cells.

INTRODUCTION: Aberrant RON (Recepteur d'Origine Nantais) tyrosine kinase activation causes the epithelial cell to evade normal growth pathways, resulting in unregulated cell proliferation, increased cell motility and decreased apoptosis. Wildtype (wt) RON has been shown to play a role in metastasis of epithelial malignancies. It presents an important potential therapeutic target for colorectal, breast, gastric and pancreatic cancer. Little is known about functional differences amongst RON isoforms RON155, RON160 and RON165. The purpose of this study was to determine the effect of various RON kinase isoforms on cell motility. METHODS: Cell lines with stable expression of wtRON were generated by inserting the coding region of RON in pTagRFP (tagged red fluorescence protein plasmid). The expression constructs of RON variants (RON155, RON160 and RON165) were generated by creating a mutagenesis-based wtRON-pTag RFP plasmid and stably transfected into HEK 293 cells. The wound closure scratch assay was used to investigate the effect on cell migratory capacity of wild type RON and its variants. RESULTS: RON transfected cells demonstrated increased cell motility compared to HEK293 control cells. RON165 cell motility was significantly increased compared to RON160 (mean percentage of wound covered 37.37% vs. 32.40%; p = 0.03). CONCLUSIONS: RON tyrosine kinase isoforms have variable cell motility. This may reflect a difference in the behavior of malignant epithelial cells and their capacity for metastasis.