Chemotherapy For Colon Cancer Research Articles

Prognostic Factors in Geriatric Patients with Metastatic Colon Cancer

Backgrounds: Colorectal cancer is an important contributor to cancer morbidity and mortality. Given that many older adult patients often have concomitant diseases and impairments in organ function, they are at increased risk for chemotherapy toxicity. Therefore, it is important to identify prognostic factors in older patients undergoing chemotherapy. Methods: We performed a retrospective chart review of colorectal cancer patients treated at Nagoya Memorial Hospital between 2012 and 2017 and selected those who received chemotherapy for metastatic colon cancer. Overall survival was calculated from the beginning of chemotherapy until death or the most recent follow-up date. We used the Kaplan-Meier method to plot survival curves and performed a statistical comparison using a log-rank test. In addition, multivariate analysis was performed using stepwise Cox proportional hazards models. Finally, a comprehensive geriatric assessment was conducted for older patients. The chart review was approved by the ethics committee of Nagoya Memorial Hospital. Results: The overall survival of metastatic colon cancer patients was not markedly different between patients aged ≥ 65 years of age (N = 37). Neither lesion site nor the RAS status affected survival, whereas the usage of three kinds of cytotoxic agents prolonged longevity. In a multivariate analysis of patients ≥ 65 years of age, the only independent prognostic factor for survival was the functional capacity, as measured by the Tokyo Metropolitan Institute of Gerontology (TMIG) index of competence. Conclusions: A combination of the comprehensive geriatric assessment and TMIG index was useful for predicting the longevity in patients with metastatic colon cancer ≥ 65 years of age.

Optimization of Dose Schedules for Chemotherapy of Early Colon Cancer Determined by High-Performance Computer Simulations.

Cancer chemotherapy dose schedules are conventionally applied intermittently, with dose duration of the order of hours, intervals between doses of days or weeks, and cycles repeated for weeks. The large number of possible combinations of values of duration, interval, and lethality has been an impediment to empirically determine the optimal set of treatment conditions. The purpose of this project was to determine the set of parameters for duration, interval, and lethality that would be most effective for treating early colon cancer. An agent-based computer model that simulated cell proliferation kinetics in normal human colon crypts was calibrated with measurements of human biopsy specimens. Mutant cells were simulated as proliferating and forming an adenoma, or dying if treated with cytotoxic chemotherapy. Using a high-performance computer, a total of 28 800 different parameter sets of duration, interval, and lethality were simulated. The effect of each parameter set on the stability of colon crypts, the time to cure a crypt of mutant cells, and the accumulated dose was determined. Of the 28 800 parameter sets, 434 parameter sets were effective in curing the crypts of mutant cells before they could form an adenoma and allowed the crypt normal cell dynamics to recover to pretreatment levels. A group of 14 similar parameter sets produced a minimal time to cure mutant cells. A different group of nine similar parameter sets produced the least accumulated dose. These parameter sets may be considered as candidate dose schedules to guide clinical trials for early colon cancer.

Successful surgical treatment of aortic heart disease as a complication after combined targeted therapy for cancer

Cardiovascular diseases and malignancies are leading causes of mortality in the world. Two categories of advanced age patients with cancer are observed in clinical practice. These are patients with cardiovascular diseases as comorbidities and patients with cardiovascular diseases as a complications of targeted therapy for cancer. Cardiac toxicity of chemotherapeutic drugs results myocardial dysfunction, occurrence or progression of heart valve disease, coronary artery disease, arterial hypertension and thromboembolism. A patient who underwent aortic valve replacement and coronary artery bypass surgery is discussed in the article. Aortic valve disease and coronary artery disease were complications of targeted radio- and chemotherapy for sigmoid colon cancer followed by lung and liver metastases. Questions of timely diagnosis and treatment of advanced age patients in multi-field surgical clinic are also analyzed.

Smart copolymer coated SPIONs for colon cancer chemotherapy

Human colon cancer is one of the higher aggressive solid tumors, whose high mortality, much like many other solid tumors, results from metastasis formation. To reduce this high mortality, more effective chemotherapy, allowing a specific tumor accumulation and an efficient early-stage medical imaging as well, are still needed. At this regard, stimuli-responsive nanocarriers for anticancer drug delivery are promising strategy in cancer therapy. For this purpose, a dual targeted redox-responsive drug delivery system, prepared by coating superparamagnetic nanoparticles (SPIONs) with the amphiphilic copolymer INU-LA-PEG-FA and loading doxorubicin (DOXO-SPIONs) was investigated as tool for solid tumor chemotherapy. Folic acid (FA) has been chosen as active targeting agent as its receptor is upregulated in many tumors, including colon cancer. Lipoic acid (LA) has been used to act as the redox-responsive moiety, due to the presence of the -S-S- linkage into its structure, which can undergo intracellular reductive-induced cleavage, and therefore, a modification of stability and release profile of the nanocarrier. Accumulation by magnetic attraction was used as synergistic targeting strategy. Improved anticancer activity was demonstrated in mice by evaluating tumor volume reduction, immunohistochemical analyses and imaging properties using magnetic resonance imaging (MRI).

Differences in the outcomes of adjuvant chemotherapy for colon cancer prescribed by physicians in different disciplines: a population-based study in Taiwan

ObjectivesOne feature unique to the Taiwanese healthcare system is the ability of physicians other than oncologists to prescribe systemic chemotherapy. This study investigated whether the care paths implemented by oncologists...

Bufalin-loaded vitamin E succinate-grafted-chitosan oligosaccharide/RGD conjugated TPGS mixed micelles demonstrated improved antitumor activity against drug-resistant colon cancer.

BackgroundMultidrug resistance (MDR) is the major reason for the failure of chemotherapy in colon cancer. Bufalin (BU) is one of the most effective antitumor active constituents in Chansu. Our previous study found that BU can effectively reverse P-glycoprotein (P-gp)-mediated MDR in colon cancer. However, the clinical application of BU is limited due to its low solubility in water and high toxicity. In the present study, a multifunctional delivery system based on vitamin-E- succinate grafted chitosan oligosaccharide (VES-CSO) and cyclic (arginine-glycine-aspartic acid peptide) (RGD)-modified d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared by emulsion solvent evaporation method for targeted delivery of BU to improve the efficacy of drug-resistant colon cancer therapy.MethodsThe cytotoxicity of BU-loaded micelles against drug-resistant colon cancer LoVo/ADR and HCT116/LOHP cells was measured by CCK-8 assay. The cellular uptake, Rho123 accumulation, and cell apoptosis were determined by flow cytometry. The expression of apoptosis-related protein and P-gp was measured by Western blot assay. The antitumor activity of BU-loaded micelles was evaluated in LoVo/ADR-bearing nude mice.ResultsBU-loaded VES-CSO/TPGS-RGD mixed micelles (BU@VeC/T-RGD MM) were 140.3 nm in diameter with zeta potential of 8.66 mV. The BU@VeC/T-RGD MM exhibited good stability, sustained-release pattern, higher intracellular uptake, and greater cytotoxicity in LoVo/ADR cells. Furthermore, the mechanisms of the BU@VeC/T-RGD MM to overcome MDR might be due to enhanced apoptosis rate and P-gp efflux inhibition. Subsequently, in vivo studies confirmed an enhanced therapeutic efficiency and reduced side effects associated with BU@VeC/T-RGD MM compared with free BU, owing to the enhanced permeation and retention effect, improved pharmacokinetic behavior, and tumor targeting, which lead to MDR-inhibiting effect in LoVo/ADR-bearing nude mice.ConclusionOur results demonstrated that VeC/T-RGD MM could be developed as a potential delivery system for BU to improve its antitumor activity against drug-resistant colon cancer.

Adjuvant Chemotherapy of Locally Advanced Colon Cancer: Final Results of a Randomized Trial Comparing 5-Fluorouracil and Folinic Acid with Folfiri

Background: There is still the need to optimize adjuvant treatment of colon cancer (CC). Standard adjuvant chemotherapy using 5-fluorouracil (FU) and folinic acid (FA) was compared with a combination including irinotecan (Folfiri). The aim of the present report was to analyze overall survival (OS) after long-term follow-up, to summarize final recurrence rates and toxicity data, and to identify possible clinical and pathological factors associated with prognosis. Methods: Patients (CC stage IIb and III) were randomized to a 6-month treatment with FUFA or Folfiri. The trial was closed after 275 of 588 planned patients, 269 of which were included in the intention-to-treat analysis. Results: 133 and 136 patients received FUFA and Folfiri, respectively. Adjuvant therapy was not completed for 16 FUFA (12.0%) and 44 Folfiri (32.4%) patients. Toxicities grade III and IV were observed in 17 (12.8%) patients treated with FUFA and in 50 (36.8%) patients treated with Folfiri. Recurrences occurred in 46 of 133 (34.6%) and in 47 of 136 (34.6%) patients who received FUFA and Folfiri, respectively. 5-year OS rates were 69.9% (95% confidence interval (CI): 61.2-77.1) for FUFA and 72.7% (95% CI: 63.9-79.8) for Folfiri. OS was associated with tumor grading (1 & 2 vs. 3), tumor sub-stage (II vs. IIIa vs. IIIb vs. IIIc), and tumor location (left vs. right colon). Conclusion: Folfiri cannot be generally recommended for adjuvant chemotherapy of CC. Besides tumor grading and sub-staging, prognosis of CC may depend on tumor location. Left-sided tumors had a significantly better prognosis irrespective of treatment.

Clinical Factors Affecting Bevacizumab Efficacy With and Without Conventional Chemotherapy in Metastatic Colon Cancer.

Bevacizumab (BZ) combined with first line chemotherapy (CC) has shown good clinical outcomes in metastatic colorectal cancer (mCRC). Overall survival (OS) and/or progression free survival in mCRC patients receiving BZ with or without 5FU-based CC is thought to be affected by clinical and morphological factor(s). We reviewed retrospective medical records of all consecutive mCRC patients treated with BZ with or without CC at tertiary care center between 2003 and 2009 out of which149 patients (m = 77, f = 72) were eligible. Our study population had a mean age at diagnosis of 63.5 years (SD = 11) with median follow-up period of 19.4 months. On initial radiological evaluation following BZ therapy, 56 patients (m = 31, f = 25) had complete or partial response categorized as "early responders." Remaining patients (m = 46, f = 47) who were either stable or showed progressive disease were categorized as "non-responders." Fifty percent among early responders and 60% among non-responders [relative risk (RR) 0.67 (95% confidence interval (CI), 0.43-1.06)] demonstrated disease progression on follow up. There was a slightly better OS among early responders compared to non-responders (median 21.5 months days versus 16.8 months, P = 0.07). Cox regression analysis suggested male sex (RR 0.65, 95% CI, 0.43-0.98), hematochezia (RR 0.63, 95% CI, 0.4-0.98), resectable primary tumor (RR 0.42, 95% CI, 0.24-0.72) and resectable metastatic mass (RR 0.32, 95% CI, 0.14-0.74) were found to be associated with longer OS. Abdominal pain (RR 1.76, 95% CI, 1.1-2.8), accompanying diabetes (RR 1.76, 95% CI, 1.09-2.85), and unexplained weight loss (RR 2.73, 95% CI, 1.73-4.29) were associated with poor OS. Better OS among mCRC patients with resectable primary and metastatic tumors was seen. This is the first study to demonstrate slightly better outcome in males and negative influence of diabetes on outcome in mCRC treated with BZ.

Noninferiority of three months versus six months of oxaliplatin-based adjuvant chemotherapy for resected colon cancer. How should IDEA findings affect clinical practice?

The eagerly awaited results of the multi-continental International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project have recently been presented at major oncological meetings. The 3-year disease-free survival (DFS) was presented for 12,834 Stage III colon cancer patients in a pooled analysis of 6 individual noninferiority phase III randomized trials, all investigating three versus six months of oxaliplatin-based adjuvant therapy. Noninferiority (NI) could not be demonstrated for the whole population as the DFS hazard ratio (HR) of 1.07 with its 95% CI of 1.00-1.15 crossed the postulated NI boundary of 1.12. However, there was an expected reduction in the incidence of specific side effects with the three months treatment. NI could be demonstrated for the T3N1 subgroup (∼60% of patients, HR for DFS 1.01, 95% CI 0.90-1.12). Moreover, NI was also declared for the subgroup treated with the CAPOX regimen (capecitabine plus oxaliplatin, ∼40% of patients), but the CAPOX choice was physician-based and not subject to randomization. Overall, the IDEA results indicate that three months of therapy might be adequate for most of Stage III tumors; however, a small subset of these patients still have high risk of recurrence and death with short treatment duration. Precise predictors of benefit need to be identified, nonetheless tumor-intrinsic factors, such as tumor stage, might currently be considered as useful tools to inform the decision-making process.

Efficacy of continuing anti-angiogenic agents in the second-line treatment for metastatic colon cancer depending on the KRAS mutation status: a meta-analysis

Objective: to assess the efficacy of anti-angiogenic agents incorporated into second-line chemotherapeutic regimens for metastatic colon cancer depending on the KRAS gene mutation status.Materials and methods. We selected completed prospective randomized controlled phase III clinical trials evaluating the efficacy of antiangiogenic agents (bevacizumab, ramucirumab and aflibercept) added to second-line chemotherapy for metastatic colon cancer with subanalysis of treatment efficacy depending on the KRAS gene mutation status. Meta-analysis was performed using the ReviewManager (RevMan) v. 5.3 (The Cochrane Collaboration, Denmark).Results. Three studies (ML18147, RAISE, VELOUR) involving 2165 patients (1137 with KRAS wild-type tumors and 1028 with KRAS-mutant tumors) met the inclusion criteria and were included into this meta-analysis. The majority of patients (84 %) received bevacizumab in the first-line treatment. The results of our meta-analysis suggest that adding an anti-angiogenic drug to chemotherapy in patients with KRAS wildtype colon cancer significantly improved both progression-free survival (hazard ratio (HR) 0.71; 95 % confidence interval (CI) 0.62–0.80; р<0.00001; I2 = 22 %, p = 0.21) and overall survival (HR 0.76; 95 % CI 0.66–0.88; р= 0.0001; I2 = 0, p = 0.59). In patients with KRASmutant colon cancer, incorporation of an anti-angiogenic drug into the treatment regimen was not associated with better overall survival (ОР0.9; 95 % CI 0.79–1.03; р= 0.11; I2 = 0, p = 0.98), although improved progression-free survival (HR 0.78; 95 % CI 0.68–0.89; р= 0.0002; I2 = 0, p = 0.46). Conclusion. Continuation of anti-angiogenic therapy in the second-line treatment for metastatic colon cancer is most effective in patients with KRAS wild-type tumors. In individuals with KRAS-mutant tumors, continuation of bevacizumab or switch to another anti-angiogenic agent in the second-line treatment improves progression-free survival and has a statistically insignificant effect on overall survival.

26 Overcoming the limitations of lung cancer radiotherapy by targeting the CD73/adenosine immune checkpoint

IntroductionCalponin 3 (CNN3) is one of the three isoforms in the Calponin family of actin-binding proteins. It is expressed in smooth muscle cells and non-smooth muscle cells and is required for cytoskeletal rearrangement and wound healing. Epithelial to Mesenchymal Transition (EMT) is important step in the development of epithelial cancers during which the cancer cell exploit the preexisting wound healing program. Therefore, it is expected that CNN3 plays a role in EMT. The few available data on the role of CNN3 in cancer shows that CNN3 is expressed in mammary cells in response to ErbB2-overexpression and in Duke’s stage C of colon cancer, but there is no comprehensive analysis of its role in cancer which is the aim of this study.Material and methodsTotal of 21 cell lines were included in this study (8 from breast cancer, 12 from colon cancer, and a cervical cancer cell (HeLa) as a positive control for EMT). CNN3 expression was examined by Western blotting, followed by siRNA silencing in the metastatic cell line SW620. The influence of CNN3 silencing on EMT was detected by EMT markers expression by Western blot and collagen invasion assay. Cell viability was performed after exposure to 5 Fluorouracil (5FU) using Sulforhodamine B (SRB) assay. Furthermore CNN3 expression was examined by immunohistochemistry in 56 formalin-fixed paraffin-embedded (FFPE) colon cancer tissue samples.Results and discussionsCNN3 showed positive expression in 6/8 breast lines and 7/12 colon lines. The primary line SW480 was negative while its metastasis from the same patient (SW620) was positive, suggesting that CNN3 was associated with metastasis. The CNN3 silencing was >98% efficient in the metastatic cell line SW620. Silenced cells were less invasive compared to the control and showed loss of mesenchymal markers and acquisition of epithelial markers. CNN3 partially restored the colon cancer cell sensitivity to 5FU. CNN3 was expressed in 20/56 (39%) of FFPE colon cancer by immunohistochemistry and it was not related to p53 stabilisation consistent with our cell line findings.ConclusionThe results suggested involvement of CNN3 in EMT and hence metastasis and also in resistance to standard chemotherapy in colon cancer. These data deserves further exploration in vivo and in clinical studies to validate the potential clinical applications of CNN3 in cancer treatment and prognosis.

27 Visualise cancer cell dynamics of colorectal cancer progressionhj snippertsa rosenberg

IntroductionCalponin 3 (CNN3) is one of the three isoforms in the Calponin family of actin-binding proteins. It is expressed in smooth muscle cells and non-smooth muscle cells and is required for cytoskeletal rearrangement and wound healing. Epithelial to Mesenchymal Transition (EMT) is important step in the development of epithelial cancers during which the cancer cell exploit the preexisting wound healing program. Therefore, it is expected that CNN3 plays a role in EMT. The few available data on the role of CNN3 in cancer shows that CNN3 is expressed in mammary cells in response to ErbB2-overexpression and in Duke’s stage C of colon cancer, but there is no comprehensive analysis of its role in cancer which is the aim of this study.Material and methodsTotal of 21 cell lines were included in this study (8 from breast cancer, 12 from colon cancer, and a cervical cancer cell (HeLa) as a positive control for EMT). CNN3 expression was examined by Western blotting, followed by siRNA silencing in the metastatic cell line SW620. The influence of CNN3 silencing on EMT was detected by EMT markers expression by Western blot and collagen invasion assay. Cell viability was performed after exposure to 5 Fluorouracil (5FU) using Sulforhodamine B (SRB) assay. Furthermore CNN3 expression was examined by immunohistochemistry in 56 formalin-fixed paraffin-embedded (FFPE) colon cancer tissue samples.Results and discussionsCNN3 showed positive expression in 6/8 breast lines and 7/12 colon lines. The primary line SW480 was negative while its metastasis from the same patient (SW620) was positive, suggesting that CNN3 was associated with metastasis. The CNN3 silencing was >98% efficient in the metastatic cell line SW620. Silenced cells were less invasive compared to the control and showed loss of mesenchymal markers and acquisition of epithelial markers. CNN3 partially restored the colon cancer cell sensitivity to 5FU. CNN3 was expressed in 20/56 (39%) of FFPE colon cancer by immunohistochemistry and it was not related to p53 stabilisation consistent with our cell line findings.ConclusionThe results suggested involvement of CNN3 in EMT and hence metastasis and also in resistance to standard chemotherapy in colon cancer. These data deserves further exploration in vivo and in clinical studies to validate the potential clinical applications of CNN3 in cancer treatment and prognosis.

PO-206 Calponin 3 (CNN3) promotes epithelial to mesenchymal transition and drug resistance of colon cancer cells

IntroductionCalponin 3 (CNN3) is one of the three isoforms in the Calponin family of actin-binding proteins. It is expressed in smooth muscle cells and non-smooth muscle cells and is required for cytoskeletal rearrangement and wound healing. Epithelial to Mesenchymal Transition (EMT) is important step in the development of epithelial cancers during which the cancer cell exploit the preexisting wound healing program. Therefore, it is expected that CNN3 plays a role in EMT. The few available data on the role of CNN3 in cancer shows that CNN3 is expressed in mammary cells in response to ErbB2-overexpression and in Duke’s stage C of colon cancer, but there is no comprehensive analysis of its role in cancer which is the aim of this study.Material and methodsTotal of 21 cell lines were included in this study (8 from breast cancer, 12 from colon cancer, and a cervical cancer cell (HeLa) as a positive control for EMT). CNN3 expression was examined by Western blotting, followed by siRNA silencing in the metastatic cell line SW620. The influence of CNN3 silencing on EMT was detected by EMT markers expression by Western blot and collagen invasion assay. Cell viability was performed after exposure to 5 Fluorouracil (5FU) using Sulforhodamine B (SRB) assay. Furthermore CNN3 expression was examined by immunohistochemistry in 56 formalin-fixed paraffin-embedded (FFPE) colon cancer tissue samples.Results and discussionsCNN3 showed positive expression in 6/8 breast lines and 7/12 colon lines. The primary line SW480 was negative while its metastasis from the same patient (SW620) was positive, suggesting that CNN3 was associated with metastasis. The CNN3 silencing was >98% efficient in the metastatic cell line SW620. Silenced cells were less invasive compared to the control and showed loss of mesenchymal markers and acquisition of epithelial markers. CNN3 partially restored the colon cancer cell sensitivity to 5FU. CNN3 was expressed in 20/56 (39%) of FFPE colon cancer by immunohistochemistry and it was not related to p53 stabilisation consistent with our cell line findings.ConclusionThe results suggested involvement of CNN3 in EMT and hence metastasis and also in resistance to standard chemotherapy in colon cancer. These data deserves further exploration in vivo and in clinical studies to validate the potential clinical applications of CNN3 in cancer treatment and prognosis.

Patients’ preferences for 3 months versus 6 months of adjuvant chemotherapy (ACT) for colon cancer in the SCOT trial: what survival benefits make longer chemotherapy worthwhile?

3602Background: The optimal duration of ACT following surgery for colon cancer remains controversial. SCOT is an international, randomised trial that compared 3 months versus 6 months of ACT in thi...

Association of sex and adverse events (AEs) of adjuvant chemotherapy (ACT) in early stage colon cancer (CC): A pooled analysis of 28,636 patients (pts) in the ACCENT database.

3603Background: Sex is one of several factors known to affect drug efficacy and toxicity. Preliminary data in different types of cancers suggest a higher toxicity of chemotherapy in women. Aim of t...

Chemotherapy for metastatic colon cancer: No effect on survival when the dose is reduced due to side effects

Background5-Fluorouracil (5FU), Folinic acid (FA), and Oxaliplatin (FOLFOX) or 5FU, FA, and Irinotecan (FOLFIRI) are standard regimens for palliative chemotherapy of metastatic colon cancer. Since data showing the influence of dose reduction in palliative treatment are rare, the objective of this single center, retrospective study was to further characterize the influence of dose reduction on efficacy of these therapeutic regimens.MethodsOne hundred nine patients, diagnosed with stage IV colon cancer between 2004 and 2012 and receiving palliative first-line chemotherapy with either FOLFOX or FOLFIRI regimens in our outpatient clinic were analyzed for treatment efficacy. Patients who received dose reductions due to side effects usually received doses of 80% or lower of per protocol dose. Survival data were obtained from the Regensburg Tumor Registry. Survival analysis was performed using Kaplan-Meier statistical analysis and multivariable analysis.ResultsA dose reduction due to side effects was necessary in 46 (42%) patients. Dose reduction was independent of age. Major reasons for dose reduction were neutropenia (30%) followed by polyneuropathy (16%) and diarrhea (14%). Dosage was more often reduced in patients receiving FOLFOX based therapy. Comparison of patients with dose reduction versus patients with full dosage showed no significant difference on overall survival (p = 0.430). Subgroup analysis revealed dose reduction in patients with N2 stage disease was associated with improved survival. Patients who underwent dose reduction received more cycles of chemotherapy (13.7 vs. 10.8 cycles) and cumulative dosage was similar in both groups.ConclusionContrary to our expectations, the need to reduce chemotherapy dosage due to side effects does not indicate a worse prognosis in our retrospective analysis. We believe this can in part be explained by better adaption to interindividual pharmacokinetics and longer time of treatment.

Polymorphisms in the ICOS/CD28-ICOSL pathway are related to capecitabine-based chemotherapy response in advanced colon cancer patients

Polymorphisms within a gene’s 3′-UTR may modulate posttranscriptional regulation of gene expression, and may explain individual sensitivity of chemotherapy. To investigate the correlation between single nucleotide polymorphisms (SNPs) in 3′-UTRs of B7/CD28 family genes and the response of capecitabine-based chemotherapy in colon cancer, 16 SNPs were identified in 274 advanced colon cancer patients. Statistical analysis indicated that ICOS rs1559931, rs4404254, and rs4675379 were in complete linkage disequilibrium and significantly associated with chemotherapy response. Heterozygous patients with rs1559931 G/A (31.34% vs 48.29%; P = 0.016), rs4404254 T/C (30.43% vs 48.77%; P = 0.011), or rs4675379 G/C (28.13% vs 49.04%; P = 0.004) genotypes showed poorer response to chemotherapy compared to wildtype patients. Moreover, three SNPs, including ICOSL rs15927, ICOSL rs3804033 and CD28 rs3181113, were significantly associated with the occurrence of side effects of chemotherapy. In addition, patients with ICOSL rs15927 G/G (78.26%), ICOSL rs3804033 G/G (76.00%), or CD28 rs3181113 T/T (82.05%) were more prone to enduring adverse events compared to patients bearing other polymorphisms. Taken together, our findings demonstrated that polymorphisms in the 3′-UTRs of genes in the ICOS/CD28-ICOSL pathway may influence the efficacy and occurrence of adverse events of capecitabine-based chemotherapy in advanced colon cancer patients.

Time to adjuvant chemotherapy in CEA-positive colon cancer: An NCDB analysis.

603 Background: It is well accepted that positive serum carcinoembryonic antigen (CEA) levels are associated with inferior survival in patients with advanced non-metastatic colon cancer; however, it is not fully elucidated whether this prognostic factor can inform clinical decisions, specifically for the optimal timing of adjuvant chemotherapy after definitive surgical treatment. This study was aimed to determine the relationship between onset of adjuvant chemotherapy and rate of survival in stage III colon cancer patients who tested CEA-positive, and thus, potentially identifying the optimal timing to increase survivorship. Methods: We identified 19,180 patients from the NCDB with TNM pathologic stage IIIB and IIIC adenocarcinoma of the colon who also had a recorded CEA test result and whom had received adjuvant chemotherapy. We examined unadjusted overall survival based on CEA status with the Kaplan-Meier method. A multivariable Cox regression model was estimated to determine the association of CEA status and overall survival after controlling for site, stage, days from surgery to chemotherapy, demographic background, and facility characteristics. All analyses were conducted with SAS version 9.4 (SAS Institute Inc., Cary, NC) with a statistical threshold of p < 0.05. Results: Based on the log-rank χ2 test, a positive CEA test result was significantly associated with worse survival. We adjusted for patient and facility level characteristics, and found a 49.7% increased risk of death for a patient with a positive CEA result (95% CI: 41.7% to 58.2%). We found a median number of 43 days from definitive surgery to initiation of chemotherapy; after adjusting for all other variables, we found for every ten-day delay in receiving adjuvant therapy after definitive surgical intervention, there was a 1.6% increased risk of death (95% CI: 1.0 to 2.2%). Conclusions: In this cohort of patients who tested CEA-positive, delays in receiving adjuvant chemotherapy had a negative linear association on survival. Adjuvant therapy should be considered as soon as patient’s clinical condition permits.

Adenocarcinoma Ex goblet cell: A retrospective experience.

847 Background: Adenocarcinoma ex goblet cell tumors (AGCC) represent rare appendiceal neoplasms with neuroendocrine and adenocarcinoma features. They represent the most aggressive subset of goblet cell carcinoids (Group B and C) and are often categorized as chemotherapy unresponsive [Am J SurgPathol.2008;32(10):1429-43]. Despite this, most patients with AGCC are treated with colon cancer chemotherapy regimens. We explored outcomes in patients treated at our institution with these regimens. Methods: We performed a single center retrospective analysis of 22 biopsy-proven AGCC patients (13 men, 9 women, median age at diagnosis 54.5) at Vanderbilt who had undergone treatment for local or metastatic disease. PFS and OS were determined for each patient and stratified by features listed on Table 1. Patients who were lost to follow up were censored based on their last recorded clinic date. Results: 16 patients received chemotherapy in the metastatic setting and all 16 had peritoneal involvement; of these patients 4 underwent HIPEC. Median PFS and OS in HIPEC treated patients was 17 months and 33 months respectively. 8 patients received adjuvant chemotherapy with FOLFOX; 6 in the local setting and 2 in the metastatic setting. Patients with metastatic AGCC had a median PFS of 21.5 months and a median OS of 32.9 months. Patients with local disease had a median PFS of 32.8 months and an OS that was not reached (median duration of follow up 12.4 months). Conclusions: AGCC have a predilection for peritoneal spread. Patients who received either adjuvant FOLFOX post definitive surgery or FOLFOX/FOLFIRI in the metastatic setting post optimal cytoreduction had prolonged periods of PFS and OS. [Table: see text]

The Level of TWIST1 expression determines the response of colon cancer cells to mitogen-activated protein kinases inhibitors.

Background/Aim:Currently, it has been proposed that combination of 5-fluorouracil (5FU) with inhibitors of the mitogen-activated protein kinases (MAPKs) signaling pathway might enhance the efficacy of 5FU-based chemotherapy in colon cancer. Our study aimed to investigate an impact of TWIST1 silencing on the sensitivity of cancer cells to 5FU and selected MAPK inhibitors.Materials and Methods:The suppression of TWIST1 expression in human colon cancer HT29 and HCT116 cell lines was achieved by transduction with lentiviral vector carrying the TWIST1 silencing sequence (pLL3.7-sh TWIST1). The statistical calculation was performed with analysis of variance or Dunnett's test for comparison to control group. Paired Student's t-test was performed when two groups were analyzed.Results:Suppression of TWIST1 reduced the proliferation rate of colon cancer cells and enhanced their sensitivity to 5FU and MAPKs inhibitors. The sensitivity of HT29 cells to examined compounds was more dependent on TWIST1 expression level compared to HCT116 cells. The most noticeable effect of TWIST1 suppression on sensitivity of both colon cancer cell lines to combined treatment of 5FU and the MAPKs inhibitors was observed for inhibitors of p38α/β and JNK1-3. We also noted that the suppression of TWIST1 significantly sensitized both cell lines to combined treatment of 5FU and Rac inhibitor.Conclusions:Our observations point to TWIST1 expression level as a marker of colon cancer sensitivity to combined treatment of 5FU and MAPKs inhibitors.