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Background Current guidelines recommend the prescription of immune-enriched oral nutritional supplements for malnourished patients before major gastrointestinal surgery. However, the benefit of preoperative immunonutrition is still controversial. This randomized controlled trial aims to evaluate the effect of preoperative immunonutrition on the outcomes of surgery for colon cancer. Methods/design Patients with primary colon cancer will be included as study participants after screening. They will be randomly assigned (in a ratio of 1:1) to receive preoperative immunonutrition added to the normal diet (experimental arm) or consume normal diet alone (control arm). Patients in the experimental arm will receive oral supplementation (400 mL/day) with arginine and ω-3 fatty acids for 7 days before elective surgery. The primary endpoint is the rate of infectious complications, while the secondary endpoints are postoperative complication rate, change in body weight, length of hospital stay, and nature of fecal microbiome. The authors hypothesize that the rate of infectious complications would be 13% in the experimental arm and 30% in the control arm. With a two-sided alpha of 0.05 and a power of 0.8, the sample size is calculated as 176 patients (88 per arm). Discussion Although there have been many studies demonstrating significant benefits of preoperative immunonutrition, these were limited by a small sample size and potential publication bias. Despite the recommendation of immunonutrition before surgery in nutritional guidelines, its role in reduction of rate of infectious complications is still controversial. This trial is expected to provide evidence for the benefits of administration of preoperative immunonutrition in patients with colon cancer. Trial registration Clinical Research Information Service KCT0003770. Registered on 15 April 2019.

Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross‐talk between FGFR4 and EGFR, and the effect of anti‐EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab‐induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti‐EGFR therapy in colon cancer., Our study has characterized the cross‐talk between fibroblast growth factor receptor 4 (FGFR4) and epidermal growth factor receptor (EGFR)/ErbB3 signaling by the contribution of EGFR ligands secreted from FGFR4. These findings provide experimental evidence for combined treatment with FGFR4 inhibitor and anti‐EGFR therapy in colon cancer.

Summary: Background: Among rectal cancer patients, some of good responders after neoadjuvant chemoradiotherapy (nCRT) are considered for non-operative treatments to avoid postoperative morbidities and permanent stoma. However, oncologic feasibility of non-operative treatment has not been fully understood. Methods: From 2008 to 2017, we retrospectively reviewed patient's records who had lower or mid rectal cancer and diagnosed to clinical complete response by magnetic resonance imaging after nCRT. Clinical differences and oncologic outcomes were compared among Radical surgery (RS), Local excision (LE) and Wait-and-see (WS) group. Results: Number of 129, 25, 15 patients included to RS, LE, WS groups. Local recurrence was frequent type of recurrence in both of LE and WS group (RS; 31.3%, LE; 80%, WS; 66.7%), and many patients in WS group omitted salvage treatment (RS; 75%, LE; 100%, WS; 33.3%). 5-years local-recurrence/disease-free survival rate (LRFS, DFS) between RS and LE were similar between each group, but WS showed significantly inferior outcomes than that of RS (LRFS; p = 0.001, DFS; p = 0.001). In multivariate analysis, WS protocol (OR; 7.163, 95% CI; 1.995–25.715) and cT4 stage (OR; 8.206, 95% CI; 1.596–42.198) were independent factors for LRFS. Conclusions: Wait-and-see group showed high rate of rejection of salvage treatments for recurrence, and poor oncologic outcomes. However, recent low-level evidences reported favorable outcome of WS protocol when salvage treatment was followed after recurrence. It seems that the application of WS protocol should be postponed until the results of randomized-controlled trials are available. Local excision seems to be good alternative option to radical surgery when salvage treatment is followed. Keywords: Rectal cancer, Complete response, Local excision, Wait-and-see

Purpose: The aim of this study was to assess oncological outcomes of postoperative radiotherapy plus chemotherapy (CRT) versus chemotherapy alone (CTx) in stage II or III upper rectal cancer patients who underwent curative surgery.Methods: We retrospectively reviewed 263 consecutive patients with pathologic stage II or III upper rectal cancer who underwent primary curative resection with postoperative CRT or CTx from January 2008 to December 2014 at Chonnam National University Hwasun Hospital. Multivariate and propensity score matching analyses were used to reduce selection bias.Results: Median follow-up was 48.1 months for the entire cohort and 53.5 months for the matched cohort. In subgroup analysis of the propensity score matched cohort, the 3-year local recurrence-free survival was 94.1% (95% confidence interval [CI], 87.8%–100%) in the CRT group and 90.1% (95% CI, 82.8%–97.9%) in the CTx group (P = 0.370). No significant difference in disease-free survival was observed according to treatment type. On multivariate analysis, circumferential resection margin involvement (hazard ratio [HR], 2.386; 95% CI, 1.190–7.599; P = 0.032), N stage (HR, 6.262; 95% CI, 1.843–21.278, P = 0.003), and T stage (HR, 5.896, 95% CI, 1.298–6.780, P = 0.021) were identified as independent risk factors for local recurrence of tumors of the upper rectum.Conclusion: Omission of radiotherapy in an adjuvant treatment setting may not jeopardize oncologic outcomes in stages II and III upper rectal cancer.

Background: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. Methods: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). Results: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03–1.13; OR: 3.33, 95% CI, 2.46–4.50; and OR: 1.15, 95% CI, 1.02–1.29, respectively). Conclusions: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (TCGA, n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10(−6), including genes in four novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In nine known GWAS-identified loci, we uncovered nine genes that have not been previously reported, whereas four genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < 0.01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSION: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

We aimed to assess the survival benefits of primary tumor resection (PTR) followed by chemotherapy in patients with asymptomatic stage IV colorectal cancer with asymptomatic, synchronous, unresectable metastases compared to those of upfront chemotherapy alone. This was an open-label, prospective, randomized controlled trial (ClnicalTrials.gov Identifier: NCT01978249). From May 2013 to April 2016, 48 patients (PTR, n = 26, upfront chemotherapy, n = 22) diagnosed with asymptomatic colorectal cancer with unresectable metastases in 12 tertiary hospitals were randomized (1:1). The primary endpoint was two-year overall survival. The secondary endpoints were primary tumor-related complications, PTR-related complications, and rate of conversion to resectable status. The two-year cancer-specific survival was significantly higher in the PTR group than in the upfront chemotherapy group (72.3% vs. 47.1%, p = 0.049). However, the two-year overall survival rate was not significantly different between the PTR and upfront chemotherapy groups (69.5% vs. 44.8%, p = 0.058). The primary tumor-related complication rate was 22.7%. The PTR-related complication rate was 19.2%, with a major complication rate of 3.8%. The rates of conversion to resectable status were 15.3% and 18.2% in the PTR and upfront chemotherapy groups. While PTR followed by chemotherapy resulted in better two-year cancer-specific survival than upfront chemotherapy, the improvement in the two-year overall survival was not significant.

Primary tumor resection (PTR) for unresectable metastatic colorectal cancer (mCRC) patients has been documented to be associated with postoperative hyper-neovascularization and enhanced growth of metastases, which may be prevented by bevacizumab. This study aimed to investigate the survival outcome of PTR in patients who received palliative bevacizumab-containing chemotherapy (BCT). From January 2006 to December 2018, medical records of 240 mCRC patients who received palliative BCT at a single tertiary colorectal cancer center were retrospectively reviewed. Patients were classified into three groups: PTR-a (PTR before BCT, n = 60), PTR-b (PTR during BCT, n = 17), and BCT-only group (n = 163). Resectable mCRCs or recurrent diseases were excluded, and the end-point was overall survival (OS) rate. Three groups had similar age, cell differentiation, location of the primary tumor, and the number of metastatic organs. More than two-thirds of patients who received PTR experienced disease-progressions (PD) during their postoperative chemotherapy-free time (PTR-a vs PTR-b; 66.7% vs 76.5%, P = .170), but OS was not inferior to the BCT-only group (PTR-a vs BCT-only; HR 0.477 [95% CI 0.302–0.754], P = .002/PTR-b vs BCT-only; HR 0.77 [95% CI 0.406–1.462], P = .425). The postoperative chemotherapy-free time was similar between PTR-a and PTR-b (median 32.0 [14–98] days vs 41.0 [18–71] days, P = .142), but non-obstructive indications (perforation, bleeding, pain) were the more frequent in the PTR-b than PTR-a. Young age, the number of BCT, and PTR-a were the independent factors for OS. The efficacy of the PTR for unresectable mCRC has been controversial, but this study demonstrated that PTR should be considered for the unresectable mCRC patients regardless before and during BCT.

PURPOSE The aim of this study was to compare the outcomes between patients under 60 years of age and older patients over 80 years of age who underwent laparoscopic colorectal surgery with colorectal cancer. METHODS A retrospective analysis of 519 colorectal patients who underwent laparoscopic colorectal surgery for colorectal adenocarcinoma between January 2007 and December 2012 was collected and categorized into 2 groups of patients, those under 60 years of age (n = 404) and those over 80 years of age (n = 115). RESULTS The group of patients over 80 years of age had a significantly higher ASA physical status classification (P < 0.001), more preoperative comorbidities (P < 0.001), had a tendency towards more tumors in a colonic location (P = 0.034), and more advanced American Joint Committee on Cancer TNM stage (P = 0.001). A higher proportion of right hemicolectomy and abdominoperineal resection was performed and more transfusions were required in the group of patients over 80 years of age (P = 0.002 and P = 0.001, respectively). There were no significant differences in operative time, conversion rate, resection margins, and numbers of harvested lymph nodes, hospital stay, and morbidity between the 2 groups. No postoperative mortality was found in the present study. The 3-year DFS for over 80 years age group and under 60 years age group were 73.5% and 73.9%, respectively (P = 0.770). CONCLUSION Laparoscopic colorectal surgery was effective and safe for elderly patients over 80 years of age and resulted in postoperative outcomes similar to those in younger patients. The postoperative morbidity after laparoscopic colorectal cancer surgery was not increased in over 80 years of age.

Purpose The aim of this retrospective study was to evaluate the feasibility of single incision laparoscopic surgery (SILS), and to compare the short-term surgical outcomes with those of conventional laparoscopic surgery for colorectal cancer. Methods Forty-four patients who underwent SILS were compared with 263 patients who underwent conventional laparoscopic surgery for colorectal adenocarcinoma between November 2011 and September 2012. Results In the SILS group, eleven cases (25.0%) of right hemicolectomy, 15 (34.1%) anterior resections, and 18 (40.9%) low anterior resections were performed. Additional ports were required in 10 rectal patients during SILS operation. In the 32 patients with rectosigmoid and rectal cancer in the SILS group, patients with mid and lower rectal cancers had a tendency to require a longer operation time (168.2 minutes vs. 223.8 minutes, P = 0.002), additional ports or multiport conversion (P = 0.007), than those with rectosigmoid and upper rectal cancer. Both SILS and conventional groups had similar perioperative outcomes. Operation time was longer in the SILS group than in the conventional laparoscopic surgery group (185.0 minutes vs. 139.2 minutes, P < 0.001). More diverting stoma were performed in the SILS group (64.7% vs. 24.2%, P = 0.011). Multivariate analysis showed that tumor location in the rectum (95% confidence interval [CI], 1.858-10.560; P = 0.001), SILS (95% CI, 3.450-20.233; P < 0.001), diverting stoma (95% CI, 1.606-9.288; P = 0.003), and transfusion (95% CI, 1.092-7.854; P = 0.033) were independent risk factors for long operation time (>180 minutes). Conclusion SILS is a feasible, not inferior treatment option for colorectal cancer, and appears to have similar results as standard conventional multiport laparoscopic colectomy, despite the longer operative time.

Purpose Preoperative chemoradiotherapy is now widely accepted to treat rectal cancer; however, the prognosis for rectal cancer patients during and after chemoradiotherapy must be determined. The aim of this study was to evaluate the serial serum carcinoembryonic antigen (s-CEA) samples in patients with rectal cancer who underwent radical surgery after concurrent chemoradiotherapy (CRT). Methods This study evaluated 236 patients with rectal cancer who received preoperative CRT followed by curative surgery between June 2005 and June 2010. We measured the patient's s-CEA levels pre-CRT, post-CRT and post-surgery. Patients were classified into four groups according to their s-CEA concentrations (group 1, high, high, high; group 2, high, high, normal; group 3, high, normal, normal; group 4, normal, normal, normal). We analyzed the clinicopathologic factors and the outcomes among these groups. Results Of the 236 patients, 12 were in group 1, 31 were in group 2, 67 were in group 3, and 126 were in group 4. The 3-year disease-free survival rate in group 1 was poorer than those in group 3 (P = 0.007) and group 4 (P < 0.001). In a univariate analysis, type of surgery, clinical N stage, pathologic T or N stage, lymphovascular invasion, perineural invasion, and CEA group were prognostic factors. A multivariate analysis revealed that type of surgery, pathologic T stage, and lymphovascular invasion were independent prognostic factors; however, no statistical significance was associated with the CEA group. Conclusion High pre-CRT, post-CRT, and post-surgery s-CEA levels in patients with rectal cancer were associated with high rates of systemic recurrence and poor survival. Therefore, patients with sustained high s-CEA levels during CRT require careful monitoring after surgery.

Purpose: Neoadjuvant chemoradiotherapy applied to the locally advanced rectal cancer reduces local recurrence and improves survival. We assessed tumor regression grade (TRG) and its influence on survival in rectal cancer patients treated with chemoradiotherapy followed by surgical resection. Methods: We studied 108 patients that were seen at our hospital between August 2004 and December 2008. Patients received preoperative chemoradiotherapy consisting of 5-fluorouracil and leucovorin by continous infusion during the first and fifth week, delivered with concurrent pelvic radiation of 50.4 Gy, followed by radical surgery at 6-8 weeks. The TRG was determined by the amount of fibrosis in the tumor embedding area and was divided into 5 grades based on the relative amount of fibrosis. We analyzed all preoperative clinicopathologic factors, postoperative pathologic stages, TRG and prognosis, retrospectively. Results: Downstaging of rectal cancer through neoadjuvant chemoradiotherapy occurred in 64 (59%) patients. The numbers of total regressions (TRG4), good regressions (TRG3), moderate regressions (TRG2), minor regressions (TRG1), and no regression (TRG0) were 19 (18%), 65 (60%), 17 (16%), 6 (5%), and 1 (1%) respectively. The TRG was inversely correlated with perineural invasion and lymphovascular invasion (P = 0.008, P = 0.032). The local recurrence rate declined as the tumor regression grade increased (P = 0.032). The 19 patients with TRG4 had a better three-year disease free survival than the 89 patients with TRG0-3 (P = 0.034). The 16 patients with pathologic complete remission (pCR) had a better three-year disease free survival than the 92 patients with non-pCR (P = 0.025). Conclusion: Higher TRG after preoperative chemoradiotherapy for rectal cancer closely correlates with better survival and low local recurrence. The TRG is considered to be a significant prognostic factor.

Situs inversus totalis is a rare anomaly in which the abdominal and thoracic cavity structures are opposite their usual positions. A 41-yr-old woman, who had an ulcerating cancer on the rectum, was found as a case of situs inversus totalis. We present an overview of the operative technique for the first documented laparoscopic total mesorectal excision of a rectal cancer in the patient with situs inversus totalis. Careful consideration of the mirror-image anatomy permitted a safe operation using techniques not otherwise different from those used for the general population. Therefore, curative laparoscopic surgery for rectal cancer in this patient is feasible and safe.

Colorectal cancer cells frequently have low levels of microsatellite instability (MSI-L) and elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), but little is known about the clinicopathologic significance of these features. We observed that patients with stage II or III colorectal cancer with MSI-L and/or EMAST had shorter times of recurrence-free survival than patients with high levels of MSI ( P = .0084) or with highly stable microsatellites P = .0415), based on Kaplan–Meier analysis. MSI-L and/or EMAST were independent predictors of recurrent distant metastasis from primary stage II or III colorectal tumors (Cox proportional hazard analysis: hazard ratio, 1.83; 95% confidence interval, 1.06–3.15; P = .0301).

Dendritic cells (DCs) play a role in natural killer (NK) cell activation, while NK cells are also able to activate and mature DCs. Toll-like receptors (TLRs) on the surface of DCs and NK cells induce the maturation and activation of these cells when engaged with their cognate ligand. We investigated to generate potent DCs by maturation with NK cells in the presence of TLR agonist in vitro and tested the efficacy of these DC vaccinations in mouse colon cancer model. The optimal ratios of DCs versus NK cells were 1:1 to 1:2. Immature DCs were mature with NK cells in the presence of lipopolysaccharide, which is TLR4 agonist, and further addition of IL-2 induced phenotypically and functionally mature bone marrow-derived DCs. These potent DCs exhibited not only high expression of several costimulatory molecules and high production of IL-12p40 and IL-12p70, but also high allogeneic T cells stimulatory capacity, and the induction of the high activities to generate tumor-specific CTLs. Consistently, vaccination with these DCs efficiently inhibited CT-26 tumor growth in mouse colon cancer model when compared to other vaccination strategies. Interestingly, combination therapy of these DC-based vaccines and with low-dose cyclophosphamide showed dramatic inhibition effects of tumor growth. These results suggest that the DCs maturated with NK cells in the presence of TLR agonist are potent inducer of antitumor immune responses in mouse model and may provide a new source of DC-based vaccines for the development of immunotherapy against colon cancer.

The present study evaluated the expression of p53, pRb, hMLH1 and MDM2 prior to preoperative chemoradiotherapy (CRT) in patients with rectal cancer, and attempted to determine any correlation with treatment outcome. Forty-five patients with available pretreatment biopsy tissues and who received preoperative CRT were enrolled in this study. Preoperative CRT consisted of a median 50.4 Gy and 2 cycles of concurrent administration of 5-fluorouracil + leucovorin. Surgery was performed approximately seven weeks after CRT. Protein expression in formalin-fixed paraffin-embedded biopsy specimens was assessed by immunohistochemistry. A positive expression of p53, pRb, hMLH1 and MDM2 was found in 40, 46.7, 40 and 66.7% of the tissue specimens, respectively. The 5-year overall (OS), disease-free (DFS) and locoregional recurrence-free survival (LRFS) rates for patients included in the study were 71.3, 66.1 and 60.9%, respectively. p53 expression presented a significantly different OS (positive vs. negative, 45.8 vs. 86.2%; p=0.02). However, the expression of pRb, hMLH1 and MDM2 was not significant for OS. The expression of p53 was a borderline significant prognostic factor for DFS and for LRFS. Age, p53 and MDM2 expression were significant factors in the multivariate analysis performed for OS with 12 covariates, including 8 clinicopathological parameters and 4 proteins. No significant factor affected DFS or LRFS in the multivariate analysis. We suggest that the expression of p53 is a potential marker of survival. Determinations of this protein expression may be useful for selecting candidates from rectal cancer patients for more tailored treatment.

To evaluate the association of glutathione S-transferase mu (GSTM1) and glutathione S-transferase theta (GSTT1) null genotypes with the risk of gastric cancer (GC) and colorectal cancer (CRC) in a South Korean population.We conducted a population-based, large-scale case-control study including 2213 GCs, 1829 CRCs, and 1699 controls. Null and non-null genotypes of GSTM1 and GSTT1 were determined using real-time PCR.The null genotypes of GSTM1 and GSTT1 were not significantly associated with elevated risk of gastric (OR = 1.070, 95% CI = 0.935-1.224; OR = 1.101, 95% CI = 0.963-1.259, respectively) or colorectal cancer (OR = 1.065, 95% CI = 0.923-1.228; OR = 1.041, 95% CI = 0.903-1.200, respectively). The frequency of the combined null GST genotype was not different between the two cancer groups and controls. Moreover, smoking, drinking, and age did not modify the association between these genotypes and the risk of gastric or colorectal cancer.GSTM1 and GSTT1 null genotypes were not associated with increased risk of GC or CRC in Koreans.

AIM: To identify the clinicopathological characteristics of lymph node-negative gastric carcinoma, and also to evaluate outcome indicators in the lymph node-negative patients. METHODS: Of 2848 gastric carcinoma patients, 1524 (53.5%) were lymph node-negative. A statistical analysis was performed using the Cox model to estimate outcome indicators. RESULTS: There was a significant difference in the recurrence rate between lymph node-negative and lymph node-positive patients (14.4% vs 41.0%, P

Background This study was designed to investigate an association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer in the Korean population. Methods We conducted a population-based large-scale case-control study involving 2,213 patients with newly diagnosed gastric cancer, 1,829 patients with newly diagnosed colorectal cancer, and 1,700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. The statistical significance was estimated by logistic regression analysis. Results The MTHFR C677T frequencies of CC, CT, and TT genotypes were 35.2%, 47.5%, and 17.3% among stomach cancer, 34%, 50.5%, and 15.5% in colorectal cancer, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677TT genotype showed a weak opposite association with colorectal cancer compared to the homozygous CC genotype [adjusted age and sex odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.638-0.984, P = 0.035]. Subjects with the MTHFR 677CT showed a significantly reduced risk of gastric cancer compared whose with the 677CC genotype (age- and sex-adjusted OR = 0.810; 95% CI = 0.696-0.942, P = 0.006). We also observed no significant interactions between the MTHFR C677T polymorphism and smoking or drinking in the risk of gastric and colorectal cancer. Conclusions The T allele was found to provide a weak protective association with gastric cancer and colorectal cancer.

Approximately 20 % of all patients with colorectal cancer are diagnosed as having Stage IV cancer; 80 % of these present with unresectable metastatic lesions. It is controversial whether chemotherapy with or without primary tumor resection (PTR) is effective for the treatment of patients with colorectal cancer with unresectable metastasis. Primary tumor resection could prevent tumor-related complications such as intestinal obstruction, perforation, bleeding, or fistula. Moreover, it may be associated with an increase in overall survival. However, surgery delays the use of systemic chemotherapy and affects the systemic spread of malignancy. Patients with colon and upper rectal cancer patients with asymptomatic, synchronous, unresectable metastasis will be included after screening. They will be randomized and assigned to receive chemotherapy with or without PTR. The primary endpoint measure is 2-year overall survival rate and the secondary endpoint measures are primary tumor-related complications, quality of life, surgery-related morbidity and mortality, interventions with curative intent, chemotherapy-related toxicity, and total cost until death or study closing day. The authors hypothesize that the group receiving PTR following chemotherapy would show a 10 % improvement in 2-year overall survival, compared with the group receiving chemotherapy alone. The accrual period is 3 years and the follow-up period is 2 years. Based on the inequality design, a two-sided log-rank test with α-error of 0.05 and a power of 80 % was conducted. Allowing for a drop-out rate of 10 %, 480 patients (240 per group) will need to be recruited. Patients will be followed up at every 3 months for 3 years and then every 6 months for 2 years after the last patient has been randomized. This randomized controlled trial aims to investigate whether PTR with chemotherapy shows better overall survival than chemotherapy alone for patients with asymptomatic, synchronous unresectable metastasis. This trial is expected to provide evidence so support clear treatment guidelines for patients with colorectal cancer with asymptomatic, synchronous unresectable metastasis. Clinicaltrials.gov NCT01978249 .