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Background Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing. Methods Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided. Results Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P Conclusion Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.

Background: In patients with colorectal cancer, the rate of recurrence increases as the histologic stage progresses. However, the prediction of recurrence in individual patients is difficult. Many studies have reported on the relation between outcomes and tissue-infiltrating lymphocytes (TILs). The aim of our study was to clarify the relation between TILs and oncologic outcomes in patients with colon cancer using propensity score matching analysis. Methods: The study group comprised 513 patients with colon cancer who received curative resection. By using propensity score matching for sex, age, tumor location, T stage, N stage, histologic type, and adjuvant therapy as conventional prognostic factors, 61 patients with recurrence and 61 patients with no recurrence were selected. Hematoxylin-eosin staining and immunohistochemical staining using CD3, CD8, CD4, and FoxP3 were performed for lymphocytes in the primary tissue. The results were evaluated separately in the whole tumor, the central part, and the invasive margin. Results: The median follow-up period was 53 months. Among the 513 patients, 70 had recurrence and 443 had no recurrence. In the comparison of outcomes between the 61 patients with recurrence and the 61 patients with no recurrence, univariate analysis showed that the disease-free survival rate was significantly higher among the patients with positive TILs in the whole tumor and in the invasive margin (p = 0.016 and p = 0.012, respectively) and with CD8+ cells in the central part (p = 0.039) than among those with negative results. A multivariate analysis showed that TILs in the invasive margin (hazard ratio 1.81; 95% confidence interval, 1.03–3.05; p = 0.037) and CD8+ cell density in the central part (hazard ratio 1.76; 95% confidence interval, 1.07–2.93; p = 0.023) were prognostic factors that were independent from conventional prognostic factors. Conclusions: In patients with curatively resected colon cancer, TILs in the invasive margin and CD8+ cell density in the central part may be prognostic factors suggesting host antitumor immune response.

Background: Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision surgery is a standard treatment for locally advanced rectal cancer (LARC). Tumor-infiltrating lymphocytes (TILs) have been reported to be associated with tumor response; however, this remains to be established. We previously reported that histological changes on biopsy specimens obtained 7 days after starting nCRT are strong predictors of response to nCRT. Methods: The subjects were 208 patients with LARC who received nCRT. TILs on hematoxylin-eosin staining together with immunohistochemical staining of lymphocyte surface markers including CD3, CD4, CD8, and FoxP3 were performed both on the biopsy specimens before and 7 days after starting nCRT. Results: The proportions of patients with high densities of CD3+, CD4+, CD8+, and FoxP3+ cells 7 days after starting CRT were significantly lower than the respective values before starting nCRT (p < 0.0001, p < 0.0001, p = 0.0023, and p = 0.0046). In biopsy specimens obtained before treatment, high-density CD4+ cells and FOXP3+ cells were significantly associated with tumor shrinkage rate. High-density FOXP3+ cells were significantly associated with marked tumor regression. In biopsy specimens obtained 7 days after starting treatment, high-density CD4+ cells were significantly associated with marked tumor regression, tumor regression grade 1, and tumor shrinkage rate. High-density FoxP3+ cells were significantly associated with marked tumor regression and tumor shrinkage rate. Conclusions: In patients who received nCRT for LARC, the evaluations of immunohistochemical staining for CD4+ and FOXP3+ TILs were more intimately related to histological response to CRT and tumor shrinkage rates in biopsy specimens obtained 7 days after starting treatment than in biopsy specimens obtained before CRT.

Background Seprafilm did not decrease small bowel obstruction (SBO), but significantly decreased reoperation in patients with inflammatory bowel disease. However, the preventive effect in colon cancer remains unclear. Methods We conducted a randomized controlled trial in patients with colon cancer. The study group comprised 345 patients with colon cancer. In the seprafilm group (n = 166), two sheets of seprafilm were inserted under a midline incision. Patients who were admitted and required decompression were considered to have SBO. Results The median follow-up was 61.9 months. Patient characteristics were well balanced. There was no significant difference in the incidence of SBO between the seprafilm group (7.8%) and the control group (10.6%) (P = .46). In patients who underwent reoperation, SBO occurred in a midline incision in one patient and at other sites in four patients in the seprafilm group as compared with two patients and five patients, respectively, in the control group. Multivariate analysis showed that only a history of laparotomy was an independent risk factor for SBO. Conclusions Seprafilm did not decrease SBO or reoperation in colon cancer. The incidence of SBO caused by adhesion to the midline incision was relatively low as compared with that caused by adhesion to other sites.

Background/aim Immune checkpoint inhibitors are mainly used for right-sided, microsatellite instability-high colorectal tumors. In this study, the effects of oral uracil-tegafur plus leucovorin (UFT/LV) chemotherapy on the gene expressions of four immunotherapy targets and the amounts of tumor-infiltrating lymphocytes (TILs) were investigated. Patients and methods Data of 260 patients with stage II or stage III colorectal cancer were analyzed. Gene expression and amount of TILs were evaluated using real-time reverse transcription polymerase chain reaction (CRT-PCR) assay and immunohistochemical staining, respectively. Results Expression of CTLA4 and LAG3 in tumor tissues was significantly increased after UFT/LV chemotherapy, but only in left-sided tumors. The percentage of high-TIL, high-CD3 and high-FoxP3 patients in the UFT/LV group was significantly higher than that in the control group, only in left-sided tumors. Conclusion The increase in TILs count, especially of CD3+ T cells and FoxP3+ regulatory T cells, after UFT/LV chemotherapy were specific to left-sided colorectal cancers.

Background: Survival rate may be predicted by tumor-node-metastasis staging systems in colon cancer. In clinical practice, about 20 to 30 clinicopathological factors and blood test data have been used. Various predictive factors for recurrence have been advocated; however, the interactions are complex and remain to be established. We used artificial intelligence (AI) to examine predictive factors related to recurrence. Methods: The study group comprised 217 patients who underwent curative surgery for stage III colon cancer. Using a self-organizing map (SOM), an AI-based method, patients with only 23 clinicopathological factors, patients with 23 clinicopathological factors and 34 of preoperative blood test data (pre-data), and those with 23 clinicopathological factors and 31 of postoperative blood test data (post-data) were classified into several clusters with various rates of recurrence. Results: When only clinicopathological factors were used, the percentage of T4b disease, the percentage of N2 disease, and the number of metastatic lymph nodes were significantly higher in a cluster with a higher rate of recurrence. When clinicopathological factors and pre-data were used, three described pathological factors and the serum C-reactive protein (CRP) levels were significantly higher and the serum total protein (TP) levels, serum albumin levels, and the percentage of lymphocytes were significantly lower in a cluster with a higher rate of recurrence. When clinicopathological factors and post-data were used, three described pathological factors, serum CRP levels, and serum carcinoembryonic antigen levels were significantly higher and serum TP levels, serum albumin levels, and the percentage of lymphocytes were significantly lower in a cluster with a higher rate of recurrence. Conclusions: This AI-based analysis extracted several risk factors for recurrence from more than 50 pathological and blood test factors before and after surgery separately. This analysis may predict the risk of recurrence of a new patient by confirming which clusters this patient belongs to.

Background: FOLFIRI plus bevacizumab have been widely used as first-line treatment for metastatic colorectal cancer (mCRC). Pharmacokinetics and pharmacodynamics suggested a low dose of irinotecan given as a long-term infusion is expected to enhance antitumor activity. We conducted a randomized phase II study to compare oral S-1 with a 24-h infusion of irinotecan plus bevacizumab versus FOLFIRI plus bevacizumab. Methods: The subjects comprised 120 chemotherapy-naïve patients with mCRC. The study group received a 24-h infusion of irinotecan at a dose of 125 mg/m2 on days 1 and 15, combined with oral S-1 80 mg/m2 on days 1–14 (24h-SIRI/B). The FOLFIRI/B group received irinotecan at a dose of 150 mg/m2, 5-fluorouracil given at a dose of 400 mg/m2 as a bolus injection and at a dose of 2,400 mg/m2 as a 46-h infusion, and 200 mg/m2 leucovorin on days 1 and 15. Bevacizumab was given at a dose of 5.0 mg/kg on days 1 and 15 in both groups. Treatment was repeated every 4 weeks. The primary endpoint was 1-year progression-free survival (PFS). Secondary endpoints were PFS, response rates (RR), overall survival (OS), and adverse events (AEs). Results: From December 2013 through January 2018, 120 patients were randomly assigned, 61 patients to the 24h-SIRI/B and 59 patients to the FOLFIRI/B. The median follow-up period was 22.8 months. The 1-year PFS rate was 43.14% in the 24h-SIRI/B arm and 19.15% in the FOLFIRI/B arm (HR = 0.312 [95%CI 0.13–0.78], p = 0.01). The median PFS was 10.2 months (95%CI 8.8–14.3) and 10.0 months (95%CI 7.4–11.0), and the median OS was 29.7 months (95%CI 22.9–43.9) and 28.8 months (95%CI 18.4-ND), respectively (p = 0.3758, p = 0.8234). The overall RR was 86.3 and 61.7%, respectively (p = 0.0053). AEs were similar. Conclusions: Our results show that the 24h-SIRI/B regimen is an effective and reasonably well-tolerated regimen for the first-line treatment of mCRC.

Regorafenib and trifluridine/tipiracil (TAS-102) are novel antitumor agents for patients with refractory metastatic colorectal cancer. However, it is unclear which patients may derive a survival benefit from these drugs in real-life clinical practice. We evaluated retrospectively the efficacy and safety of regorafenib and TAS-102 at a single institution between June 2013 and November 2015. Cox regression analysis was carried out to obtain predictive scores (the nearest integers of hazard ratio) for survival benefit. Forty-four patients treated with regorafenib or TAS-102 were included in the analysis; among them, 17 received crossover treatment. The median overall survival (OS) was 9.1 months for regorafenib and 9.3 months for TAS-102, and the corresponding values after crossover were 7.1 and 5.3 months, respectively. OS was not correlated to relative dose intensity, but was proportional to the total administered dose of each drug. Adverse events were tolerable even after crossover. We identified three variables as significant for prediction of OS with good discrimination (C-statistic=0.70): Poor Eastern Cooperative Oncology Group performance status, time since diagnosis of metastatic disease ≤18 months, and previous chemotherapy continued ≥2 months beyond progression were all predictors of poor OS. Regorafenib and TAS-102 can be recommended for patients with better performance status and slow progression of metastatic disease. Optimal survival benefit was provided by prompt administration of either drug after failure of previous chemotherapy, with flexible titration to the optimal dose for each individual patient.

Background/aim The standard treatment for rectal cancer is neoadjuvant chemoradiotherapy (nCRT) followed by surgery. Mucinous carcinoma responds poorly to nCRT. In some patients, mucin lakes (MLs) are induced by nCRT. Identifying whether MLs are induced or originally present would be of great importance. Patients and methods We studied 20 patients with MLs (CRT-MC group) among 205 patients who received nCRT. Among 88 patients who did not receive nCRT, we studied 9 patients with mucinous carcinoma (non-CRT-MC group) and 18 patients with MLs in differentiated adenocarcinoma (non-CRT-AC group). Tumors were stained with high iron diamine-Alcian blue (HID-AB) and MUC1 staining. Results Rate of AB>HID staining of cancer cells was significantly higher in the CRT-MC group than in non-CRT-MC group (p=0.0004). Rate of MUC1 staining in MLs was significantly higher in the CRT-MC group (p=0.0254). Conclusion nCRT can induce qualitative changes in mucinous components, however, other methods are required to distinguish induced components from originally existing components.

Background Mucinous rectal carcinoma has been reported to have a lower survival rate and a poorer histologic response to chemoradiotherapy(CRT). Magnetic resonance imaging (MRI) can accurately evaluate the amount of mucin pools (MP) in primary cancer tissue. We compared the degree of MP on MRI before and after CRT with the histologic findings of resected specimens to investigate the predictors of response to CRT. Methods The study group comprised 205 patients with rectal adenocarcinoma who received preoperative CRT. MPs were measured on MRI before and after CRT and in resected specimens. The degree of MP was classified into five classes according to the MP area ratio: 0%, class I; 1 to 19%, class II; 20 to 49%, class III; and 50% or higher, class IV. Results The degree of MP on MRI was largely unchanged after CRT; however, the MP on MRI after CRT was underestimated in 26.3% of patients as compared with that in resected specimens. A pathological complete response was obtained in patients who initially had no MP or had an MP ratio of less than 20%. The tumor volume was significantly greater, and the rates of tumor shrinkage and T downstaging were significantly lower in patients who had an MP area ratio of 20% or higher before CRT than in those who had an MP area ratio of less than 20%. Conclusions The MP area ratio measured on MRI before treatment was closely associated with the response to CRT and is a potentially useful predictor of treatment response.

In rectal cancer who received chemoradiotherapy, the number of Lymph nodes (LNs) required remains unclear. We conducted a randomized controlled trial to determine whether preoperative tattooing increases the number of LNs and enhances the detection rate of metastatic LNs.Eighty patients with rectal cancer who received chemoradiotherapy were randomly assigned to receive no tattooing (C group) or to receive tattooing (T group).The number of LNs was significantly higher in the T group (13.3 ± 7.4, mean ± SD) than in the C group (8.8 ± 5.9, p 0.001), however, the number of positive LNs did not differ (0.5 ± 1.3 vs. 0.5 ± 1.1, p = 0.882). The long-axis diameter of LNs was significantly smaller in the T group than in the C group (3.4 ± 1.8 vs. 3.9 ± 2.3 mm, p 0.001), however, the long-axis diameter of positive LNs did not differ.Tattooing increased the number of retrieved LNs by 51%, however, there was no increase in the number of positive LNs.

BACKGROUND: Most previous reports to analyze risk factors for peritoneal recurrence in patients with colon cancer have been observational studies of a population-based cohort. OBJECTIVE: This study aimed to determine the risk factors for peritoneal recurrence in patients with stage II to III colon cancer who underwent curative resection. DESIGN: This was a pooled analysis using a combined database obtained from 3 large phase III randomized trials (N = 3714). SETTINGS: Individual patient data were collected from the Japanese Foundation for Multidisciplinary Treatment of Cancer clinical trials 7, 15, and 33, which evaluated the benefits of postoperative 5-fluorouracil–based adjuvant therapies in patients with locally advanced colorectal cancer. PATIENTS: We included patients who had stage II to III colon cancer and underwent curative resection with over D2 lymph node dissection. MAIN OUTCOME MEASURES: Main outcomes measured were risk factors for peritoneal recurrence without other organ metastasis after curative surgery. RESULTS: Peritoneal recurrence occurred in 2.3% (86/3714) of all patients undergoing curative resection. Mean duration from operation to peritoneal recurrence was 17.0 ± 10.3 months. Of these patients with peritoneal recurrence, 29 patients (34%) had recurrence in ≥1 other organ. Multivariate analysis showed that age (≥60 y: HR = 0.531; p = 0.0182), pathological T4 (HR = 3.802; p < 0.0001), lymph node involvement (HR = 3.491; p = 0.0002), and lymphadenectomy (D2: HR = 1.801; p = 0.0356) were independent predictors of peritoneal recurrence. The overall survival was lower in patients who developed peritoneal recurrence than in those with other recurrence (HR = 1.594; p = 0.002). LIMITATIONS: The regimens of adjuvant chemotherapy were limited to oral 5-fluorouracil. CONCLUSIONS: Our findings clarified the risk factors for peritoneal recurrence in patients who underwent curative resection for colon cancer. See Video Abstract at http://links.lww.com/DCR/A609.

Objective: The National Comprehensive Cancer Network (NCCN) guidelines recommend local excision and observation as standard treatment for selected patients with clinical T1N0M0 rectal cancer. In patients with pathological T1 (pT1) rectal cancer who received local excision, the local recurrence rate is at least 10%. We studied oncological outcomes in patients with pT1 rectal cancer who received chemoradiotherapy (CRT) after local excision. Methods: Local excision was performed in 65 patients with clinical T1N0M0 rectal cancer (≤8 cm from the anal verge, tumor size < 30 mm, well or moderately differentiated adenocarcinoma). The patients received CRT (40 or 45 Gy in 1.8–2.0 fractions with concurrent oral UFT [tegafur/uracil] or S-1 [tegafur/gimeracil/ote­racil]) after confirmation of pT1 and negative margins. Results: Patients who had pT2 cancer or who did not provide informed consent were excluded. The remaining 50 patients additionally received CRT. The CRT was completed in 48 patients (96%). The median follow-up period was 71 months. Local recurrence occurred in 1 patient (2%). Distant metastases occurred in 3 patients (6%). The 5-year disease-free survival rate was 86%, and the 5-year overall survival rate was 92%. Conclusions: Our study suggested that multidisciplinary treatment with local excision plus CRT can be used as a treatment option in selected patients with clinical T1N0M0 rectal cancer.

Objectives: The histologic response to neoadjuvant chemoradiotherapy (nCRT) has been intimately related to outcomes in locally advanced rectal cancer. Serum carcinoembryonic antigen (CEA) levels change after nCRT and after surgery as compared with before nCRT. Methods: The subjects were 149 patients with locally advanced rectal cancer who received nCRT between 2005 and 2013. The patients were divided into 4 groups according to the serum CEA levels: group 1, 55 patients with negative serum CEA levels before nCRT; group 2, 41 patients with positive serum CEA levels before nCRT that became negative after nCRT; group 3, 37 patients with positive serum CEA levels after nCRT that became negative after surgery; and group 4, 16 patients with positive serum CEA levels after nCRT as well as after surgery. Results: Pathological complete response, T downstaging, and tumor shrinkage were significantly higher in group 1 than in other groups. Disease-free survival was significantly poorer in group 4. The lack of a decrease in the serum CEA level in group 4 was most likely attributed to the persistence of micrometastases outside the resection field. Conclusions: Changes in serum CEA levels measured before nCRT, after nCRT, and after surgery can be used to reliably predict the histologic response to nCRT and outcomes.

This study assessed the impact of postoperative complications on the colorectal cancer survival and recurrence after curative surgery using pooled individual patients’ data from three large phase III randomized trials. In total, 5530 patients were included in this study. The patients were classified as those with postoperative complications (C group) and those without postoperative complications (NC group). The risk factors for the overall survival (OS) and the disease‐free survival (DFS) were analyzed. Postoperative complications were found in 861 (15.6%) of the 5530 patients. The OS and DFS rates at 5 years after surgery were 68.9% and 74.8%, respectively, in the C group and 75.8% and 82.2%, respectively, in the NC group, values that were significantly different between the two groups (P

In recent years, the use of laparoscopic surgery has been expanded to include radical curative resection. In a previous study, 212 patients with primary colorectal cancer (stages I–III) underwent radical curative resection by hand-assisted laparoscopic surgery (HALS) (n=98) or conventional laparotomy (CL) (n=114) and were compared with respect to 3-year relapse-free survival (3Y-RFS) and 3-year overall survival (3Y-OS). The study included 210/212 patients who were followed up to 5 years, including 96 patients who underwent HALS and 114 treated with CL. The two groups were matched for stage, clinical background, and postoperative management. Patient characteristics were compared and the 5Y-RFS and 5Y-OS were determined. The 5-year follow-up rate was 97.6%. In stage I–III patients, 5Y-RFS and 5Y-OS showed no significant differences between HALS and CL. The patients with stage I disease accounted for 41.7% (40/96) of the patients undergoing HALS, while stage I patients only accounted for 23.7% (27/114) of the patients undergoing CL, and the difference was significant (P=0.005). Stage II patients undergoing CL were older than those treated with HALS (P=0.017). However, there were no differences in the characteristics of stage III patients undergoing HALS or CL. In conclusion, HALS achieved a similar survival to CL in patients with stage I to III colorectal cancer. Compared with CL, HALS was performed more safely and achieved superior cosmetic results.

Rectal washout is performed in rectal cancer surgery to eliminate exfoliated cancer cells. Before rectal washout, a cross-clamp should generally be placed distal to the tumor. In some patients with lower rectal cancer, however, the tumor cannot be adequately isolated. We, therefore, hypothesized that neoadjuvant chemoradiotherapy (nCRT) can decrease the number of exfoliated cancer cells even after the rectal washout including tumors. We prospectively studied 86 patients with rectal cancer who underwent proctectomy after nCRT. A cross-clamp was applied proximal to the tumor, and the rectum was washed with 2000 mL of physiological saline solution. The initial 100 mL used to wash the rectum was collected as a pre-washout sample. After the rectum was washed with the remaining 1900 mL, the solution remaining in the rectum was collected as a post-washout sample. Cells classified as class IV or higher according to the papanicolaou classification were considered to indicate a positive diagnosis. The cytological diagnosis was positive in pre-washout samples in 21 patients (24%) and post-washout samples in two patients (2%). In patients with rectal cancer, nCRT may decrease the number of exfoliated cancer cells in the rectum, and rectal washout including the tumor may be oncologically acceptable.

Background: Colorectal neuroendocrine carcinoma (NEC) is a rare disease, and mixed cases with colorectal adenocarcinoma also exist. The histogenesis of this disease remains unclear. We studied the numbers of neuroendocrine marker-positive cells in adenocarcinoma tissue and in normal ­mucosal tissue to investigate the relation between adenocarcinoma and NEC and to discuss the histogenesis of NEC. Methods: We studied a total of 354 curatively resected cases of stage II or III colon cancer and 36 cases of rectal cancer treated at the Tokai University Hospital between 2007 and 2012. Adenocarcinoma tissue and normal mucosal tissue were immunohistochemically stained with chromogranin A, synaptophysin, and CD56. Cases in which neuroendocrine marker-positive cells were found in cancer tissue were defined as positive. In normal mucosa, the numbers of positive cells per 15 high-power fields (HPF) were counted. Results: Among the 390 cases, 181 cases had right sided colon cancer, 173 cases had left sided colon cancer, and 36 cases had rectal cancer. The rates of positive staining for chromogranin A, synaptophysin, and CD56 were significantly higher in the right sided colon than in the left sided colon, consistent with the preferred sites of NEC as reported previously. Cells positive for chromogranin A and synaptophysin in normal mucosa were significantly more common in the rectum and the left sided colon than in the right sided colon. No site-specific differences were found for CD56. Conclusions: Neuroendocrine marker-positive cells in colorectal cancer tissue are more common in the right sided colon, whereas neuroendocrine marker-positive cells in normal mucosa are more common in the rectum. These results suggest that NEC may arise from preceding adenocarcinomas.

Background Six months of adjuvant chemotherapy is regarded as the standard of care for patients with stage III colon cancer. However, whether longer treatment can improve prognosis has not been fully investigated. We conducted a phase III study comparing 6 and 12 months of adjuvant capecitabine chemotherapy for stage III colon cancer, and report here the results of our preplanned safety analysis. Methods Patients aged 20–79 years with curatively resected stage III colon cancer were randomly assigned to receive 8 cycles (6 months) or 16 cycles (12 months) of capecitabine (2500 mg/m2/day on days 1–14 of each 21-day cycle). Treatment exposure and adverse events (AEs) were evaluated. Results A total of 1304 patients (642 and 636 in the 6-month and 12-month groups, respectively) were analyzed. The most common AE was hand-foot syndrome (HFS). HFS, leukocytopenia, neutropenia, and hyperbilirubinemia (any grade) occurred more frequently in the 12-month group than in the 6-month group. HFS was the only grade ≥3 AE to have a significantly higher incidence in the 12-month group (23 vs 17%, p = 0.011). The completion rate for 8 cycles was 72% in both groups, while that for 16 cycles was 46% in the 12-month group. HFS was the most common AE requiring dose reduction and treatment discontinuation. Conclusions Twelve months of adjuvant capecitabine demonstrated a higher cumulative incidence of HFS compared to the standard 6-month treatment period, while toxicities after 12 months of capecitabine were clinically acceptable. Trial registration UMIN-CTR, UMIN000001367.

Purpose: Reliable risk estimates of recurrence are necessary to establish optimal postoperative surveillance strategies. The purpose of the present study was to clarify changes in the hazard rate (HR) for tumor recurrence over time in Japanese patients with colon cancer. Methods: Data for 3984 patients from three clinical trials evaluating the benefit of adjuvant chemotherapy for colon cancer were analyzed. Estimated HRs were plotted over time for the entire cohort, as well as for node-positive and node-negative patients separately. The changes in risk were further analyzed according to eight clinical variables, and factors predictive of early (3 years) recurrence were explored using Cox's regression analysis. Results: In node-positive patients, there was a prominent HR peak 0.6 years after surgery, whereas HR remained at consistently low levels in node-negative patients. In node-positive patients, HR decreased steadily until 3 years, after which the decline in HR plateaued. Those with T4 tumors had a prominent HR peak around 1 year, including node-negative patients. The HR for T1/T2 Stage III colon cancers showed a similar pattern as that for T1-T3 node-negative colon cancers. Cox regression analysis revealed that a lack of adjuvant chemotherapy, positive node status, T3/T4 factors, and male gender predict early recurrence, whereas patients with lymph node metastasis, T4 tumors, and a lesser extent of lymph node removal have a higher risk of recurrence 3-4 years after surgery (P

Background: To prevent surgical site infection (SSI) in colorectal surgery, the combination of mechanical bowel preparation (MBP), oral antibiotic bowel preparation (OABP), and the intravenous antibiotics have been proposed as standard treatment. We conducted an RCT comparing the incidence of SSI between MBP + OABP and OABP alone after receiving a single dose of intravenous antibiotics. Methods: The study group comprised 254 patients who underwent elective surgery for colon cancer. Patients were randomly assigned to receive MBP + OABP and intravenous antibiotics (MBP + OABP group) or to receive OABP and intravenous antibiotics (OABP alone group). Results: Overall, 125 patients in MBP + OABP group and 126 patients in OABP alone group were eligible. Incisional SSI occurred in 3 patients (2.4%) in MBP + OABP group, and 8 patients (6.3%) in the OABP-alone group. Organ/space SSI developed in 0 patients (0%) and in 4 patients (3.2%) in each group respectively. The OABP-alone group was thus not shown to be noninferior to the MBP + OABP group in the incidences of incisional SSI or organ/space SSI. Other infectious complications developed in 7 patients (5.6%) and in 6 patients (4.8%) in each group, indicating the non-inferiority of OABP alone to MBP + OABP. Conclusions: MBP combined with oral antibiotics and intravenous antibiotics remains standard in elective colon cancer surgery.

Background Although colorectal cancer comprises several histological subtypes, the influences of histological subtypes on disease progression and treatment responses remain controversial. Objective We sought to evaluate the prognostic relevance of mucinous and poorly differentiated histological subtypes of colorectal cancer by the propensity score weighting analysis of prospectively collected data from multi-institute phase III trials. Design Independent patient data analysis of a pooled database from 3 phase III trials was performed. Settings An integrated database of 3 multicenter prospective clinical trials (the Japanese Foundation for Multidisciplinary Treatment of Cancer 7, 15, and 33) was the source of study data. Interventions Surgery alone or postoperative adjuvant chemotherapy was offered in patients with resectable colorectal cancer. Main outcome measures To balance essential variables more strictly for the comparison analyses, propensity score weighting was conducted with the use of a multinomial logistic regression model. We evaluated the clinical signatures of mucinous and poorly differentiated subtypes with regard to postoperative survival, recurrence, and chemosensitivity. Results Of 5489 patients, 136 (2.5%) and 155 (2.8%) were pathologically diagnosed with poorly differentiated and mucinous subtypes. The poorly differentiated subtypes were associated with a poorer prognosis than the "others" group (HR, 1.69; 95% CI, 1.00-2.87; p = 0.051), particularly in the patient subgroup of adjuvant chemotherapy (HR, 2.16). Although the mucinous subtype had a marginal prognostic impact among patients with stage I to III colorectal cancer (HR, 1.33; 95% CI, 0.90-1.96), it was found to be an independent prognostic factor in the subpopulation of patients with stage II disease, being associated with a higher prevalence of peritoneal recurrence. Limitations The treatment regimens of postoperative chemotherapy are now somewhat outdated. Conclusions Both mucinous and poorly differentiated subtypes have distinct clinical characteristics. Patients with the mucinous subtype require special attention during follow-up, even for stage II disease, because of the risk of peritoneal or local recurrence. See Video Abstract at http://links.lww.com/DCR/A531.

Background The usefulness of adjuvant chemotherapy for stage II colon cancer has not been established. Meanwhile, the presence of stage II colon cancer with high-risk factors for recurrence has been reported. To our knowledge, no prospective study of adjuvant chemotherapy for stage II colon cancer with high-risk factors has been implemented to date. Patients and Methods This study is a prospective nonrandomized controlled study based on patients' selection of treatment option, including randomized therapeutic decision-making, to evaluate the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) with leucovorin (LV) for stage II colon cancer with high-risk factors for recurrence, compared with surgery alone. Five courses of UFT/LV therapy will be given as follows: UFT (300 mg/m2/d) with LV (75 mg/d) will be orally administered in 3 doses per day. Treatment will be received daily for 28 days, followed by a 7-day rest or will be received daily for 5 days, followed by a 2-day rest. For both regimens, 1 course will last 5 weeks, and 5 courses will be given. The primary end point is disease-free survival. A propensity score matching will be conducted based on 7 variables that represent risk factors to minimize selection bias in a comparison between the nonrandomized arms. For this nonrandomized comparison, a target sample size is set at 1200 (400 and 800 patients for the surgery alone and UFT/LV groups, respectively) and 1720 patients will be enrolled. In this study we aim to evaluate the therapeutic usefulness of adjuvant chemotherapy with UFT/LV for stage II colorectal cancer with risk factors for recurrence.

While adjuvant chemotherapy is preferable for colon cancer, treatment duration is controversial. This phase III trial is investigated optimal duration of adjuvant chemotherapy for Stage IIB/III colon cancer. Eighteen-month treatment with UFT/LV did not improve DFS compared with 6-month UFT/LV treatment. This study suggests that 6 months treatment duration is enough for Stage IIB/III colon cancer., Background While adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer. Patients and methods Patients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety. Result A total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group. Conclusion Eighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer. Clinical trial number UMIN-CTR C000000245.

Preoperative chemoradiotherapy (CRT) significantly decreases local recurrence in patients with rectal cancer. Although various biomarkers in biopsy specimens obtained before starting CRT have been examined, reliable prognostic factors have yet to be established. We tested the hypothesis that biopsy specimens obtained soon after the start of CRT can be used as prognostic factors. Preoperative CRT was given to 70 consecutive patients with rectal cancer. Biopsies were taken before and about 7 days after starting CRT. The specimens were stained with hematoxylin and eosin (HE), and the expressions of Ki67, p53, and p21 and apoptosis were evaluated immunohistochemically. The expressions of Ki67, p53, and p21 and apoptosis before treatment were not significantly related to histologic response or tumor shrinkage. In specimens obtained about 7 days after CRT began, marked histologic regression was significantly higher in p21-positive, apoptosis-positive cases, and in cases with moderate changes on HE specimens (p = 0.017, p = 0.010, and p = 0.004, respectively). The tumor shrinkage was significantly higher in apoptosis-positive cases and cases with moderate changes on HE specimens (p = 0.002 and p

Minimally invasive laparoscopic surgery has become widespread and the indications for such surgery have recently been extended to various conditions, including rectal cancer. The objective of this study was to compare the clinical outcome of hand-assisted laparoscopic surgery (HALS) and conventional laparotomy (CL) in patients with rectal cancer. Patients who underwent radical resection of stage I–III primary rectal cancer (n=111) were classified into those receiving HALS (n=57) and those receiving CL (n=54); the two groups were matched for stage and postoperative treatment. The 3-year relapse-free survival (3Y-RFS) and 3-year overall survival (3Y-OS) were calculated and compared between the two groups. Intraoperative blood loss, operating time, postoperative hospital stay and complications were also compared between the two groups. There were no significant differenceS in 3Y-RFS or 3Y-OS between the HALS and CL groups for patients with all-stage (I, II and III) rectal cancer. The mean (median) intraoperative blood loss was 344.0 (247.0) ML in the HALS group vs. 807.5 (555.5) ML in the CL group (P

// Michitaka Honda 1, * , Koji Oba 2, * , Takashi Akiyoshi 3 , Hiromichi Maeda 4 , Kosuke Kashiwabara 2 , Mitsuro Kanda 5 , Shuhei Mayanagi 6 , Toru Aoyama 7 , Chikuma Hamada 8 , Sotaro Sadahiro 9 , Yosuke Fukunaga 3 , Masashi Ueno 3 , Junichi Sakamoto 10, 11 , Shigetoyo Saji 11 and Takaki Yoshikawa 12 1 Department of Minimally Invasive Surgical and Medical Oncology, Fukushima Medical University, Fukushima, Japan 2 Department of Biostatistics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 3 Department of Gastroenterological Surgery, Gastroenterological Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan 4 Cancer Treatment Center, Kochi Medical School Hospital, Kochi University, Nankoku, Japan 5 Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan 6 Department of Surgery, Keio University, Tokyo, Japan 7 Department of Surgery, Yokohama City University, Yokohama, Japan 8 Faculty of Engineering, Tokyo University of Science, Tokyo, Japan 9 Department of Surgery, Tokai University, Isehara, Japan 10 Tokai Central Hospital, Kakamigahara, Japan 11 Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan 12 Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan * These authors contributed equally to this work Correspondence to: Michitaka Honda, email: mhonda@fukushimamed.com Takaki Yoshikawa, email: yoshikawat@kcch.jp Keywords: prognostic nomogram, prediction model, colorectal cancer, overall survival, disease free survival Received: August 14, 2017 Accepted: September 21, 2017 Published: October 12, 2017 ABSTRACT Background: Few prediction models have so far been developed and assessed for the prognosis of patients who undergo curative resection for colorectal cancer (CRC). Materials and Methods: We prepared a clinical dataset including 5,530 patients who participated in three major randomized controlled trials as a training dataset and 2,263 consecutive patients who were treated at a cancer-specialized hospital as a validation dataset. All subjects underwent radical resection for CRC which was histologically diagnosed to be adenocarcinoma. The main outcomes that were predicted were the overall survival (OS) and disease free survival (DFS). The identification of the variables in this nomogram was based on a Cox regression analysis and the model performance was evaluated by Harrell’s c-index. The calibration plot and its slope were also studied. For the external validation assessment, risk group stratification was employed. Results: The multivariate Cox model identified variables; sex, age, pathological T and N factor, tumor location, size, lymphnode dissection, postoperative complications and adjuvant chemotherapy. The c-index was 0.72 (95% confidence interval [CI] 0.66-0.77) for the OS and 0.74 (95% CI 0.69-0.78) for the DFS. The proposed stratification in the risk groups demonstrated a significant distinction between the Kaplan–Meier curves for OS and DFS in the external validation dataset. Conclusions: We established a clinically reliable nomogram to predict the OS and DFS in patients with CRC using large scale and reliable independent patient data from phase III randomized controlled trials. The external validity was also confirmed on the practical dataset.

Objective: The histologic response to neoadjuvant chemoradiotherapy (CRT) has been intimately related to outcomes in locally advanced rectal cancer. However, reliable prognostic factors have yet to be established. Subjects and Methods: The study group comprised 198 patients with locally advanced rectal cancer who received CRT. A modified classification based on the combination of ypStage and tumor regression grade (TRG) was developed. ypStage II with TRG 2 was classified as ypTRGstage IIA, and ypStage II with TRG 3 or 4 was classified as ypTRGstage IIB. ypStage 0 and ypStage I were classified as ypTRGstage I, and ypStage III was classified as ypTRGstage III. Results: The 5-year disease-free survival (DFS) was 83% in ypTRGstage I, 86% in ypTRGstage IIA, 57% in ypTRGstage IIB, and 60% in ypTRGstage III (p = 0.0001). The 5-year DFS in ypTRGstage IIA did not differ significantly from that in ypStage 0 (p = 0.865) or ypStage I (p = 0.585). The 5-year DFS in ypStage IIB did not differ from that in ypStage III (p = 0.912). Multivariate analysis showed that ypTRGstage was an independent risk factor for DFS. Conclusion: A modified classification allows patients with ypStage II locally advanced rectal cancer to be clearly divided into two groups: responders and nonresponders.

The aim of the present study was to determine whether or not the overall survival (OS) and disease‐free survival (DFS) were affected by the tumor location in patients who underwent curative resection for colon cancer in a pooled analysis of three large phase III studies performed in Japan. In total, 4029 patients were included in the present study. Patients were classified as having right‐side colon cancer (RC) if the primary tumor was located in the cecum, ascending colon, hepatic flexure or transverse colon, and left‐side colon cancer (LCC) if the tumor site was within the splenic flexure, descending colon, sigmoid colon or recto sigmoid junction. The risk factors for the OS and DFS were analyzed. In the present study, 1449 patients were RC, and 2580 were LCC. The OS rates at 3 and 5 years after surgery were 87.6% and 81.6% in the RC group and 91.5% and 84.5% in the LCC group, respectively. Uni‐ and multivariate analyses showed that RRC increased the risk of death by 19.7% (adjusted hazard ratio = 1.197; 95% confidence interval, 1.020–1.408; P = 0.0272). In contrast, the DFS was similar between the two locations. The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.

The present study aimed to compare the results of hand-assisted laparoscopic surgery (HALS) and conventional laparotomy (CL) at a single institution in Japan. Of the 212 patients with stage I/II/III colorectal cancer who received a curative resection, 98 patients underwent HALS and 114 patients underwent CL. The clinical background and post-operative management did not differ between the two groups. There were no significant differences in the 3-year relapse-free and 3-year overall survival rates between the HALS and CL groups for the patients in any stage. Blood loss during surgery was 250.1 and 135.5 ml (mean and median; the same hereafter) in stage I patients receiving HALS versus 608.2 and 315.5 ml in stage I CL patients (P=0.006), while it was 277.6 and 146 ml in stage II patients receiving HALS versus 548.6 and 347 ml in stage II CL patients (P=0.004). Post-operative hospital stay was recorded at 16.8 and 15 days in stage III patients receiving HALS versus 23.1 and 21 days in stage III CL patients (P=0.001). There were no significant differences in the operating time or complications between the two groups. These results indicate that the survival rate was comparable for HALS and CL, while HALS caused less surgical stress and achieved a better cosmetic outcome. The results of the final analysis of this cohort are awaited.

613 Background: FOLFOX or FOLFIRI plus Bev is a first-line treatment for MCRC. Recent studies have confirmed that oral S-1 combined with Iri and Bev is equivalent to FOLFIRI plus Bev. Iri is usually administered as a short-term 90-min. infusion. However, the cytocidal activity is S-phase specific, and carboxylesterases, that convert Iri into SN-38, are less likely to become saturated when Iri is given as a long-term infusion. Therefore, a low dose of Iri given as a long-term infusion is expected to enhance antitumor activity. We conducted a randomized phase II study to compare this regimen with FOLFIRI plus Bev. Methods: The subjects comprised 120 chemotherapy-naïve patients with MCRC. The study group received 24-hr infusion of Iri at a dose of 125 mg/m2 on days 1 and 15, combined with oral S-1 80 mg/m2 on days 1 to 14. The FOLFIRI group received Iri at a dose of 150 mg/m2, 5-FU given at a dose of 400 mg/m2 as a bolus injection and at a dose of 2400 mg/m2 as a 46 hr-infusion, 200 mg/m2 of leucovorin on days 1 and 15. Bev was given at a dose of 5.0 mg/kg on days 1 and 15 in both groups. Treatment was repeated every 4 weeks. The primary endpoint was the 1 y progression-free survival (PFS). Secondary endpoints were PFS, response rates (RR), overall survival (OS), and adverse events (AEs). Results: From October 2013 through December 2017, a total of 61 patients assigned to receive IRIS plus Bev (the A group) and 59 patients assigned to receive FOLFIRI plus Bev (the B group) were included in the analysis. The 1y RFS was 37.3% in the A group and 17.0% in the B group (p = 0.0281). The PFS was 10.2 mon in the A group and 10.0 mon in the B group, and the median OS was 27.0 mon and 28.6 mon, respectively (p = 0.26, p = 0.68). RR was significantly higher in the A group (87.0%) than in the B group (61.7%) (p = 0.005). The main grade 3 or 4 AEs were neutropenia (27.8%) and diarrhea (11.1%) in the A group and neutropenia (23.4%) and leukopenia (6.4%) in the B group. Conclusions: Our results showed that Iri, given biweekly as a 24-hour infusion in combination with oral S-1 and Bev, is a highly effective and well-tolerated regimen for the first-line treatment of MCRC. Clinical trial information: UMIN000014664.

617 Background: Neuroendocrine carcinoma (NEC) is a rare disease and has been reported to most frequently arise in the right side of the colon. In the 2010 WHO classification, mixed adenoneuroendocrine carcinoma (MANEC) was defined as a neoplasm consisting of NEC and adenocarcinoma components. To clarify the histogenesis of NEC, we attempted to detect neuroendocrine marker-positive cells in cancer tissue and in the adjacent mucosa in patients with adenocarcinoma. Methods: The study group comprised 390 patients with Stage II or III colorectal adenocarcinoma between 2007 and 2012. Immunostaining was performed with anti chromogranin A, synaptophysin, and CD56 antibodies. Cases with positively stained cells in cancer tissue were defined as positive. In the adjacent mucosa, at least 5 cm from the tumor, the numbers of positive cells per 15 HPF were measured. Results: Tumor location was right side in 181 patients, left side in 173, and the rectum in 36 patients. Positive rates of Chromogranin A in cancer tissues were 23.7% in the right colon, 13.2% in the left colon, and 19.4% in the rectum. Those of synaptopysin were 35.3%, 21.9%, and 30.6%, respectively. Those of CD56 were 22.6%, 8.0%, and 16.7%, respectively. Positive rates of these three markers in right colon were significantly higher than those in left colon and rectum. (p = 0.0115, p = 0.0054, p = 0.0062). In the adjacent mucosa, the mean numbers of positive cells for chromogranin A were 62.2 ± 20.5 in the right colon, 131.9 ± 44.7 in the left colon, and 243.7 ± 60.2 in the rectum (p < 0.001). Those for synaptophysin were 47.7 ± 23.5, 95.3 ± 35.1, and 156.9 ± 56.8, respectively. (p < 0.001). There were no significant differences in the number of positive cells for CD56 among the sites (p = 0.295). Conclusions: In cancer tissue, the rate of positive staining for neuroendocrine marker-positive cells was higher in the right side of the colon, whereas in normal mucosa the rates of positive staining for these cells were higher in the sigmoid colon and the rectum. These results suggest that neuroendocrine marker-positive cells are an acquired characteristic of cancer tissue.

494 Background: In colon cancer, retrieval of less than 12 lymph nodes is a risk factor for recurrence. We previously reported that the long-axis diameter of the largest LNs (maximum LNs) is associated with a higher number of retrieved LNs and better outcomes in stage II disease (Int J Colorectal Dis 2015). Furthermore, the number of natural killer cells in the maximum LNs is associated with the number of retrieved LNs and lymph node size, and is an independent prognostic factor (Oncology 2018). We examined whether the long-axis diameter of maximum LNs with and without metastasis is a prognostic factor in stage III colon cancer. Methods: The study group comprised 190 patients with stage III colon cancer from 2005 to 2014. For each patient, one negative LN and one positive LN with the greatest long-axis diameter were selected, and the diameter was measured on H-E stained specimens. The endpoint of survival analysis was relapse free survival (RFS). The cut-off value (COV) was determined by using receiver operating characteristic curves. Results: The mean long-axis diameter of maximum negative and positive LNs were 8.5 ± 3.7 and 9.9 ± 4.9 mm, respectively. Factors related to the number of retrieved LNs were the tumor size (less than 4.3 cm, 13.5 ± 6.4; 4.3 cm or more, 16.6 ± 7.3; p = 0.004) and the long axis diameter of maximum negative LNs (< 8.1 mm, 13.4 ± 6.9; ≥ 8.1 mm, 17.6 ± 6.6; p < 0.001). Maximum negative LNs with a diameter of ≥ 8.1 mm was associated with significantly better RFS than maximum negative LNs with a diameter of < 8.1 mm (p = 0.020). The diameter of maximum positive LNs was not a prognostic factor. On multivariate analysis, the tumor size (≥ 4.3 cm/< 4.3 cm, HR 3.02; p < 0.001), venous invasion (absent/present, HR 0.41; p = 0.017), the number of LNs (≥ 12/< 12, HR 0.56; p = 0.043), and the diameter of maximum negative LNs (≥ 8.1 mm/< 8.1 mm, HR 0.45; p = 0.008) were independent prognostic factors. Conclusions: In stage III colon cancer, the long-axis diameter of negative maximum LNs was a prognostic factor. Enlarged negative LNs are caused by hyperplasia of cell components in LNs. The size of negative maximum LNs might reflect the tumor immunity of the host.

Background Preoperative chemoradiotherapy (CRT) significantly decreases local recurrence in advanced rectal cancer. We studied whether the degree of tumor shrinkage can be used as a predictor of histologic response. Methods The subjects were 114 patients with locally advanced rectal cancer who underwent total mesorectal excision after receiving radiotherapy combined with uracil/tegafur (UFT) or S-1. The degree of tumor shrinkage based on barium enema examination and magnetic resonance imaging (MRI) were assessed before CRT and immediately before surgery. Results A histologic complete response (ypCR), histologic marked regression, T and N downstaging were associated with significantly higher tumor-shrinkage rates on barium enema (P

Purpose Preoperative chemoradiotherapy (CRT) using 5-fluorouracil (5-FU)-based chemotherapy is the standard of care for rectal cancer. The effect of additional chemotherapy during the period between the completion of radiotherapy and surgery remains unclear. Predictive factors for CRT may differ between combination chemotherapy with S-1 and with tegafur-uracil/leucovorin (UFT/LV). Methods The subjects were 54 patients with locally advanced rectal cancer who received preoperative CRT with S-1 or UFT/LV. The pathological tumor response was assessed according to the tumor regression grade (TRG). The expression levels of 18 CRT-related genes were determined using RT-PCR assay. Results A pathological response (TRG 1-2) was observed in 23 patients (42.6%). In a multivariate logistic regression analysis for pathological response, the overall expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, were significant, and the accuracy rate of the predictive model was 83.3%. The effects of the gene expression levels of GGH on the response differed significantly according to the treatment regimen. The total pathological response rate of both high-GGH patients in the S-1 group and low-GGH patients in the UFT/LV group was 58.3%. Conclusion Additional treatment with 5-FU-based chemotherapy during the interval between radiotherapy and surgery is not beneficial in patients who have received 5-FU-based CRT. The expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, in tumor tissues can predict the response to preoperative CRT including either S-1 or UFT/LV. In particular, the gene expression level of GGH in tumor tissues may be a useful biomarker for the appropriate use of S-1 and UFT/LV in CRT.

Objectives: Serum carcinoembryonic antigen (CEA) has been widely used for postoperative surveillance for colorectal cancer. However, serum CEA has a poor diagnostic accuracy for detecting recurrence. We tested the hypothesis that determining cutoff values according to the preoperative serum CEA levels would enhance the diagnostic accuracy. Methods: Serum CEA was measured before and 1-6 months after surgery in 783 patients with curatively resected colon cancer from 2005 through 2013. The cutoff values during surveillance were determined separately according to preoperative serum CEA levels. Results: In patients with negative preoperative serum CEA, the diagnostic accuracy for recurrence was 89.1% when a postoperative cutoff value was set at 5 ng/mL. However, in patients with positive preoperative serum CEA, the diagnostic accuracy was 58.4% when a postoperative cutoff value was set at 5 ng/mL, and was 75.6% when a cutoff value was set at 8 ng/mL. Among patients with positive preoperative serum CEA, the recurrence-free survival rate was significantly lower in patients with a serum CEA of ≥8 ng/mL than those with a serum CEA of p = 0.0018). Conclusions: The diagnostic accuracy of serum CEA for recurrence is enhanced by separately setting cutoff values according to preoperative serum CEA.

Background Rectal cancer is associated with a higher rate of surgical complications. The ability to predict the risk of complications before treatment would facilitate the design of personalized treatment strategies optimally suited for each patient. Methods We retrospectively studied 260 patients with rectal cancer who underwent radical surgery to examine the relations between complications and 5 types of risk scores. Results Complications developed in 56 patients (21.5%). Nineteen patients had infectious complications, 16 had intestinal obstruction, and 12 had other complications. Twelve patients out of 187 patients who received low anterior resection had anastomotic leakage. Estimation of Physiologic Ability and Surgical Stress Comprehensive Risk Score (E-PASS CRS) and Neutrophil-to-lymphocyte Ratio (NLR) were significantly related to all complications, infectious complications, and anastomotic leakage. Surgical Apgar Score was significantly related to infectious complications. Prognostic Nutritional Index was significantly related to all complications and intestinal obstruction. Colorectal Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity was significantly related to all complications, and infectious complications. A multivariate analysis showed that body-mass index, E-PASS CRS, and NLR were independent risk factors for anastomotic leakage. In particular, NLR was the only score that could be evaluated before surgery. Conclusions Five types of risk scores were useful methods for evaluating the risks of complications in patients with rectal cancer. NLR is a score that can be evaluated before surgery and predicted the risk of anastomotic leakage, suggesting that it is useful for assessing the need for a diverting colostomy.

Objectives: Carcinoembryonic antigen (CEA) is widely used for postoperative surveillance of colon cancer. Even if serum CEA is negative at initial surgery, it may turn positive at recurrence. We investigated the relation between serum CEA levels and the immunohistochemical staining status of CEA in the primary and resected metastatic tissues. Methods: Out of 224 patients with recurrent colon cancer between 1998 and 2012, we studied 46 patients in whom serum CEA levels were measured and immunohistochemical staining for CEA was possible in the primary and metastatic tissues. Results: The positive rate of serum CEA did not differ between initial surgery and recurrence, regardless of whether the cutoff value was set at 5 or 10 ng/ml (p = 0.829, p = 0.671). There was no relation between the CEA staining status and serum CEA level at initial surgery. However, the CEA staining status of metastatic tissue was significantly related to the serum CEA level at recurrence (p = 0.0046 and p = 0.0026). Conclusions: The immunohistochemical staining status of CEA in metastatic tissue is closely related to the serum CEA level. This finding suggests that serum CEA levels are influenced not only by the CEA production capacity of cancer cells but also by the ability of the surrounding tissue to release CEA into the blood.

To identify useful predictive factors for the response to 5-fluorouracil (5-FU)/leucovorin (LV) and oral uracil and tegafur (UFT)/LV chemotherapy among patients with colorectal cancer, we investigated the association between the gene expression levels of pyrimidine and folate metabolism-related enzymes in colorectal cancer (CRC) tissues and the response to UFT/LV neoadjuvant chemotherapy. The subjects were 76 CRC patients who were scheduled to undergo surgery. UFT (300 mg/m2/day) and LV (75 mg/body/day) were administered for 2 weeks before surgery. Biopsy samples were endoscopically obtained before drug administration. The gene expression levels of 14 genes in the biopsy samples were quantitatively evaluated using a real-time polymerase chain reaction (RT-PCR) assay. Fifteen patients (19.7 %) with marked pathological regression were judged to be responders. Thymidine phosphorylase (TP) gene expression levels among the responders were significantly higher than those among the non-responders. Right-sided tumors with high TP gene expression levels were associated with a significantly higher response rate to UFT/LV chemotherapy than left-sided tumors. TP gene expression levels in primary CRC tissues and the primary tumor site may be useful predictors of the efficacy of oral UFT/LV chemotherapy.

790 Background: Neoadjuvant chemoradiotherapy (nCRT) is a standard of care for LARC. The serum CEA level is a predictor of the response to nCRT; however, the relation between CEA production immunohistochemically evaluated in cancer tissue and treatment response remains unclear. Methods: The study group comprised 145 patients with clinical Stage II/III rectal cancer who received nCRT followed by surgery from 2005 through 2013. The radiation dose was 40 to 45 Gy. UFT- or S-1-based chemotherapy was given concurrently. Surgery was performed 6 to 8 weeks after the completion of radiotherapy. Immunohistological CEA staining patterns in biopsy tissue obtained before nCRT were evaluated. Specimens in which the luminal cell membrane or the cytoplasm was strongly stained were defined as staining positive. The histologic response was evaluated on the basis of the pathological complete response (ypCR) rate, T downstaging, tumor regression grade (TRG), and tumor shrinkage rate on MRI. Results: CEA staining in biopsy specimens and serum CEA levels were both negative in 17 patients (11.7%) and both positive in 72 patients (49.7%). There was no relation between the groups (p = 0.174). In patients with negative CEA staining, the rates of ypCR, T downstaging, marked regression, and mean tumor shrinkage were 24.3%, 51.4%, 45.9%, and 72.3%, respectively. In patients with positive CEA staining, these rates were 11.1%, 48.1%, 37.0%, and 72.8%, respectively. CEA staining of cancer tissue was not significantly related to the ypCR rate, T downstaging, a marked regression rate, or the tumor shrinkage rate on MRI (p = 0.060, p = 0.849, p = 0.436, and p = 0.874, respectively). Patients with negative serum CEA levels before nCRT had significantly higher rates of ypCR, T downstaging, marked regression, and tumor shrinkage on MRI than did patients with positive serum CEA levels (p = 0.014, p = 0.006, p = 0.002, and p = 0.014, respectively). Conclusions: Serum CEA levels before nCRT were a significant predictor of the histologic response to nCRT; in contrast, tissue CEA staining before nCRT was unrelated to the histologic response to nCRT.

768 Background: Mucinous carcinoma has been reported to have a lower survival rate, a poorer histologic response to preoperative chemoradiotherapy (CRT) than non-mucinous differentiated adenocarcinoma. Mucinous carcinoma was difficult to diagnose on biopsy because mucinous components are mainly located inside the tumor. We therefore compared MRI findings before and after CRT with histologic findings of resected specimens to investigate the predictive factor of response to CRT. Methods: The study group comprised 205 patients with locally advanced rectal cancer (LARC) who received CRT (40 to 45 Gy) from January 2006 through December 2014. T2-weighted fast-spin echo MRI was used to show the area ratio of mucin lakes (ML) to the maximum cut surface of the primary tissue. The presence or absence of ML and the area ratio of ML on the maximum cut surface were evaluated. Results: The histologic type on preoperative biopsy was well-differentiated or moderately differentiated adenocarcinomas in 202 patients (98.5%), poorly differentiated adenocarcinoma in 2 patients (1.0%), and mucinous carcinoma in only 1 patient (0.5%). ML area ratio on MRI before treatment was less than 20% in 194 patients (94.6%), 20% to 50% in 4 patients (2.0%), 50% or more in 7 patients (3.4%). In 11 patients with ML area ratio of 50% or more in resected specimen, mucinous carcinoma was diagnosed in only one patient (14.3%). The tumor shrinkage rate was 74% in patients with ML area ratio of less than 20%, 54.5% with ML area ration of 20% to 50%, and 56.4% with ML area ratio of 50% or more. (p = 0.002) The rate of T-downstaging was significantly greater in patients with ML area ratio of less than 20% than those with ML area ratio of 20% or more. (58% vs. 27%, p = 0.047) The rates of pCR were 13% and 0%, however, the difference was not significant. (p = 0.21) Conclusions: Mucinous carcinoma is difficult to diagnose on biopsy before chemoradiotherapy. The diagnosis of mucin lakes on MRI before treatment may be useful for predicting the response to CRT.

Background: To evaluate the efficacy and safety of irinotecan combined with UFT for untreated and pretreated metastatic colorectal cancer. Methods: Escalating doses of irinotecan (80–110 mg/m2) were administered by 24-hour infusion on day 1. UFT was administered orally at 400 mg/m2/day on days 3–7 and 10–14. The treatment cycles were repeated every 2 weeks. Results: In the phase I study, the maximum tolerated dose of irinotecan was 110 mg/m2 and the recommended dose for the phase II study was determined to be 100 mg/m2. Thirty-five patients including 3 patients at the recommended dose in the phase I study were evaluated in the phase II study. The grade 3/4 toxicities observed were leukopenia, neutropenia, thrombocytopenia and anemia. No grade 3 or more severe nonhematological toxicities were noted. The response rate was 62.9% and the median overall survival 16.7 months. Conclusions: A 24-hour infusion of irinotecan combined with UFT is feasible and active for metastatic colorectal cancer.

In order to develop a model of liver metastasis of human gastrointestinal cancer cells, we examined the potential of 10 human colon and stomach cancer cell lines (HT-29, WiDr, HCT-116, HCT-15, HCC-2998, MKN7, MKN28, MKN45, MKN74 and St-4) to form liver metastases in nude mice. Among the cell lines, HCT-116 cells consistently formed gross liver metastases when injected into the spleens of nude mice. In contrast, other human colon and stomach cancer cells produced little or no liver metastasis. In order to analyze the high metastatic potential of HCT-116 cells, the adhesion potential was compared between HCT-116 cells and the other colon cancer cell lines. HCT-116 cells showed more efficient adhesion to fibronectin (FN) than other cells. Furthermore, FN enhanced haptotaxis of HCT-116 cells, but not of other colon cancer cells. The high adhesion potential to FN and enhanced haptotaxis may contribute, at least in part, to the high metastatic potential of HCT-116. To assess the value of this newly developed model of liver metastasis, we compared the ability of four anticancer drugs (fluorouracil, doxifluridine, paclitaxel and irinotecan) to inhibit the formation of liver metastases. Paclitaxel and irinotecan showed strong inhibition of liver metastasis but fluorouracil and doxifluridine showed only slight inhibition. Therefore, this model of metastasis may be useful for screening anti-liver metastatic reagents. These results indicate that the HCT-116 liver-metastasis model should be useful for analyzing the molecular mechanism of liver metastasis and for evaluating new anti-liver metastatic drugs.

No consensus has been reached on whether cancer cells detected in blood during colorectal cancer (CRC) surgery may serve as a prognostic indicator.One hundred patients with CRC who underwent curative surgery were the subjects. Portal and peripheral blood were collected immediately after celiotomy and examined for carcinoembryonic antigen (CEA) messenger RNA (mRNA) by using competitive semi-nested reverse transcriptase-polymerase chain reaction. The median follow-up period was 59 months (range, 49-74 months).Until now, recurrence has been confirmed in 13 patients (13%). The 4-year recurrence rate was 6.7% (3 of 45) in patients with CEA mRNA-positive portal blood and 20.8% (10 of 48) in patients with CEA mRNA-negative portal blood (P = .09); it was 5.6% (2 of 36) and 19.3% (11 of 57) in patients with CEA mRNA-positive peripheral blood and CEA mRNA-negative blood, respectively (P = .12). There was no difference in disease-free survival between the CEA mRNA-positive and -negative groups. The multivariate analysis showed that the presence of tumor cells in portal or peripheral blood was a factor that reduced recurrence. The relative risks were .17 (P = .01) for the portal vein and .24 (P = .07) for the peripheral vein.The detection of cancer cells in blood taken during surgery is not considered to be a poor-prognostic factor in CRC.

In order to determine the reliable predictors of response to radiotherapy for rectal cancer, we assessed apoptosis, p53 and p21 in biopsy specimens collected before treatment, and investigated the relationships to the histological effect of irradiation and the degree of tumor shrinkage.Ninety-three patients with advanced rectal adenocarcinoma were treated with preoperative irradiation of 20 Gy in 10 fractions in combination with intraoperative electron beam irradiation of 15 Gy. We evaluated tumor grade, pathological tumor regression, biological markers associated with apoptosis and proliferation [apoptotic index (AI), p53, p21 and Ki67], and the degree of tumor shrinkage.Considering positivity of p21 and of apoptosis and negativity of p53 as favorable factors in tumor shrinkage, we compared the degree of shrinkage among the patients using the number of favorable factors as the score. The degree of shrinkage was 41.5 +/- 8.5% in patients with three favorable factors, 31.4 +/- 9.7% in patients with two favorable factors and 26.5 +/- 11.2% in patients with one favorable factor. However, there was no significant difference in the proportion of marked regression according to the number of favorable factors.Histological examination of apoptosis, p21 and p53 in biopsy specimens and scoring were considered to be useful predictive methods for assessing the efficacy of radiotherapy for rectal cancer.

Background: Hepatic intra-arterial infusion chemotherapy of 5-fluorouracil (5-FU) or fluorodeoxyuridine (FUDR) has been a treatment option for liver metastasis from colorectal cancer. However, an optimal administration schedule of 5-FU is still controversial. This study was conducted to evaluate a suitable schedule from the viewpoint of 5-FU metabolites and related enzymes. Methods: 5-FU was infused into the hepatic artery of rabbits having hepatic deposits of VX2 tumor cells in a daily dose of 1, 4, or 8 mg/kg using various schedules. 5-FU, Thymidylate synthase (TS), TS inhibition rate (TSIR), and the amount of fluoro-RNA (F-RNA) were measured. Results: A high concentration of 5-FU was detected in the tumors of the group that was administered a dose of 8 mg/kg. TSIR in the tumor was about two-fold higher in the rabbits that were administered a total dose of 8 mg/kg than in those that were administered doses of 4 mg/kg or less. F-RNA, ranging from 27 to 36 ng/mg RNA, was detected in the tumor of the rabbits that were administered a total dose of 8 mg/kg. No difference was observed between the short period and the continuous administration schedules of rabbits that were administered a dose of 8 mg/kg of 5-FU. However, DNA synthesis inhibition in normal hepatic tissue was more dependent on the administration schedule than on the total dose of 5-FU because TSIR was significantly higher with shorter periods of drug administration. Conclusion: Intermittent bolus administration of large doses of 5-FU might cause more severe hepatic impairment than continuous administration. These results suggest that hepatic intraarterial infusion of 5-FU should be administered continuously for liver metastasis, although further experiments including a longer administration period of 5-FU are required.

798 Background: Mucinous carcinoma (MC) has been defined as carcinoma with > 50% of tumor volume showing mucin pool (MP). The incidence of MC had been reported to be 4 to 12% of colorectal cancer and to be less effective for chemotherapy and CRT. The incidence of MC was 3 to 8% in rectal cancer treated with surgery alone and 13 to 24% in patients treated with CRT. These findings suggest that MP may be induced by CRT in some patients. We therefore compared the degree of MP in MRI findings before CRT, after CRT and in resected specimens. Methods: The study group comprised 205 patients with rectal cancer who received CRT (40 to 45 Gy) from 2006 through 2014. MPs on MRI were evaluated using T2-weighted fast-spin echo images, and the MP area ratios on maximum cross-section of the primary tumor were calculated. An MP area ratio of 0% was designated as class 0, 1 to 9% as class I, 10 to 29% as class II, 30 to 50% as class III, and 50% or higher as class IV. Results: On MRI before CRT, the MP area ratio was class 0 in 181 patients (88%), class I in 11 (5%), and class II or higher in 13 (6%). On MRI after CRT, the MP area ratio was class 0 in 186 patients (91%), class I in 4 (2%), and class II or higher in 15 (7%). The prevalence of MP classes did not change appreciably. The MP class evaluated on MRI before and after CRT changed by 2 or more levels in only 2 patients, both of whom had marked tumor shrinkage. Among 175 patients with an MP area ratio of class 0 or I in the resected specimens, the MRI findings after CRT were consistent with the findings of the resected specimens. However, the MP area ratio was underestimated by 2 or more levels on MRI in 14 (47%) of 30 patients who had an MP area ratio of class II or higher. A pathological complete response (pCR) was obtained in 24 patients (12%), all of whom had an MP area ratio of class 0 or I on MRI before CRT. No patient with an MP area ratio of class II or higher before CRT had a pCR. Conclusions: The degree of MP evaluated on MRI did not change during CRT. In patients who had an MP area ratio of > 10% in their resected specimens, the evaluation of MP on MRI was often underestimated. Patients with an MP area ratio of > 10% before CRT had a poor response to CRT, with no pCR.

804 Background: Multidisciplinary treatment had been a standard of care for locally advanced rectal cancer. Serum CEA had been reported as one of the predictive factors to CRT, however, serum CEA levels may change after CRT and surgery. We examined the relations of serum CEA before CRT, after CRT, and after surgery to histological response and outcomes. Methods: The subjects were 149 patients with cStage II or III adenocarcinoma of the rectum who underwent surgery after CRT from 2005 through 2013. A total dose of 40 to 45 Gy with concurrent oral UFT or S-1 was delivered. Surgery was performed 6 to 8 weeks after CRT. A serum CEA > 5 ng/mL was defined as positive. Patients with negative serum CEA before CRT were designated as group 1. Patients with positive serum CEA before CRT that became negative after CRT were designated as group 2. Patients with positive serum CEA after CRT that became negative after surgery were designated as group 3, and patients with positive serum CEA after CRT as well as after surgery were designated as group 4. The median follow-up period of the survivors was 60.4 months. Results: The numbers of patients in Groups 1, 2, 3, and 4 were 55 (37%), 41 (28%), 37 (25%), and 16 (11%), respectively. The incidences of pCR, T downstaging, and N downstaging did not differ significantly among the groups (p = 0.094, 0.060, and 0.346). Rates of marked regression (TRG Grade 1 or 2) were 55% in Group 1, 42% in Group 2, 16% in Group 3, 25% in group 4. The rates were significantly higher in groups 1 and 2 (p = 0.001).5y DFS was 76% in group 1, 75% in group 2, 77% in group 3, and 48% in group 4 and was significantly lower in group 4 (p = 0.024). 5y OS was 88% in group 1, 91% in group 2, 85% in group 3, and 68% in group 4 and was significantly lower in group 4 than that in groups 1 and 2 (p = 0.03, 0.019). Conclusions: In patients with rectal cancer who received CRT, changes in serum CEA levels before and after CRT and after surgery were intimately related to the histological response of the primary lesion. Patients who continued to have positive serum CEA levels after surgery had poor outcomes, strongly suggesting the presence of occult distant metastasis.