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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.

Constipation has been reported to be more common in patients with mental disorders than in the general population. However, its relationships with psychiatric diagnosis, medication, age, and sex have not been fully identified. A total of 875 patients from the outpatient department were included in the study. As a retrospective observational study, the psychiatric diagnoses and psychotropic medications were examined based on the medical charts. Fecal conditions, including problems with defecation, abdominal pain, sense of incomplete evacuation, use of laxatives, frequency of defecation, and stool characteristics according to the Bristol Scale, were investigated. The study included 368 males and 507 females, with median ages of 48 and 52 years, respectively. The most common psychiatric diagnoses were depressive disorders (33%), followed by anxiety disorders (19%). Females had significantly higher rates of problems with defecation and laxative use than males (P .001, P .0001, respectively). The frequency of laxative use increased significantly with age (P .0001). The multivariate analyses revealed the close relationship between hypnotics and problems of defecation and that between hypnotics, antipsychotics, and laxative use. In psychiatric outpatients, females had significantly higher rates of problems with defecation and laxative use than males. The use of laxatives significantly increased with age. Problems with defecation were significantly more common in patients taking hypnotics and laxative use was significantly more common in patients taking hypnotics and antipsychotics.

In the process of caner recovery, Huaier simultaneously promotes significant hair growth and restoration as a typical evidence of its efficacy on induced tissue regeneration and repair function. Hair growth after conventional chemotherapy was a first and significant observation, and that in dose-dependent manner. The molecular basis of hair growth was identified as the activation of Hedgehog signaling pathway and among various perturbed signal transfer network, which initiates systematic tissue repair not only in pathogenic lesions but also to skin problems and inter/intra neural signal transfer. The activation followed by the inhibition at 3-6 months interval resulted in the prevention of subsequent complications, such as recurrence and metastasis by transcriptional control in cancer stem cell production. This regulation was demonstrated to occur irrespectively to SMO (smoothhead) function. The present study thus provides a simple and clear proof of Huaier effects on tissue regeneration, additional to the reported cancer specific-cell death.

Introduction: Total mesorectal excision is the standard treatment for clinical T2 (cT2) rectal cancer; however, this procedure can result in postoperative dysfunction, decreased quality of life, and stoma creation in some patients. We investigated neoadjuvant chemoradiotherapy (nCRT) plus local excision (LE) as an alternative treatment strategy for patients with cT2N0 rectal cancer. Method: Fifty-six patients with cT2N0M0 rectal cancer who exhibited the following characteristics (an anal verge of ≤8 cm, tumor size of 2) or S-1 (tegafur/gimeracil/oteracil; 80 mg/m2). Results: Fifty-five patients (98%) completed nCRT as planned. Histologically, the excision margin was negative in all patients, and four patients with ypT3 disease underwent total mesorectal excision. Recurrence was observed in 15 patients (27%), local recurrence in 7 (13%), and distant recurrence in 10 (18%). The salvage surgery was possible for the local recurrence group. The 5-year disease-free and overall survival rates were 68.4% and 84.9%, respectively. Multivariate analysis showed that only the tumor regression grade (TRG) was an independent risk factor for recurrence (p = 0.025). Although 7 (26%) out of 27 patients with a TRG of 3 or 4 developed local recurrence and 6 (22%) had distant metastasis, 25 patients with a TRG of 1 or 2 did not exhibit local recurrence, and only 1 (4%) experienced distant metastasis. Conclusion: nCRT plus LE may be an alternative treatment for patients with cT2N0 rectal cancer who achieved a TRG of 1 or 2. However, additional treatment was required in patients who achieved a TRG of 3 or 4.

Although striking effects of vaccination strategy against COVID-19 world-wide, a long-term influence by sequential viral mRNA injections are unknown. We analysed biological alterations by total RNA sequencing in Pfizer-BioNTech vaccinated normal healthy volunteers and cancer patients, with or without adjuvant Huaier therapy. A significant destruction in ribosomal RNA structures was identified, enhanced by serial shots. Unlike the destruction caused by chemotherapy with platinum (II) complex, progressive destruction in 18S ribosome was identified even at 6 months after vaccination. The influence resulted in massive inhibition of translation and transcription, significantly in intra/inter neural signaling transfer and in lipid metabolism, related to ageing process. Huaier compensated these dysfunctions by miRNA-mediated transcriptional control, by typical activation in PI3K/AKT signaling pathway. Gene Ontology analysis revealed spontaneous virion production in number even after 3 months of the first vaccination. Present study indicated that the adjuvant therapy like Huaier compensates accelerated ageing process by mRNA vaccination.

117 Background: The usefulness of adjuvant chemotherapy for stage II colon cancer with high-risk factors for recurrence has not been established. Methods: This was a prospective, non-randomized controlled study based on patients’ selection of treatment options, including randomized therapeutic decision-making. High-risk factors were defined as having at least one of the following factors: T4, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, and < 12 dissected lymph nodes. UFT (300 mg/m2/day) plus LV (75 mg/day) were orally administered for 6 months after surgery. The primary endpoint was disease-free survival (DFS) after adjusting for risk factors using propensity sore matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm. The secondary endpoints were overall survival (OS) and safety. Results: 1902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively between May 2012 and April 2016. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Eligible patients were divided into two groups: A, patients who selected surgery alone (n = 641); B, patients who selected UFT/LV treatment (n = 1239). Of the eligible patients, 402 in group A and 804 in group B were propensity score-matched. The 5-year DFS rate (95% confidence interval) was significantly higher in group B (76.3% [73.1-79.1]) than in group A (68.8% [63.9-73.2]) {hazard ratio [HR] 0.66 [0.51–0.84, P = 0.0008]}. The 5-year OS rates were not significantly different between group B and group A [HR 0.74 (95% CI 0.50–1.10, P = 0.1391)]. Using IPTW, significantly higher 5-year DFS [HR 0.71 (95% CI 0.59–0.86, P = 0.0006)] and overall survival [HR 0.66 (95% CI 0.49–0.90, P = 0.0122)] rates were observed in group B compared with group A. Multivariate analysis revealed that male sex, over 70 years old, T4, < 12 dissected lymph nodes, and no adjuvant chemotherapy were significant risk factors for recurrence. Conclusions: Adjuvant chemotherapy with UFT/LV significantly improves DFS. Oral UFT/LV as adjuvant chemotherapy shows efficacy with an acceptable safety profile for stage II colon cancer with risk factors. Clinical trial information: UMIN000007783 .

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 Up to 6-months oxaliplatin-containing regimen is now widely accepted as a standard adjuvant chemotherapy for stage III colorectal cancer (CRC). However, oral fluoropyrimidine monotherapy is used for some part of patients, especially in Asian countries including Japan, and its optimal duration is yet to be fully investigated. Methods A total of 1306 patients with curatively-resected stage III CRC were randomly assigned to receive capecitabine (2500 mg/m2/day) for 14 out of 21 days for 6 (n = 654) or 12 (n = 650) months. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were relapse-free survival (RFS), overall survival (OS), and adverse events. Results The 3- and 5-year DFS were 70.0% and 65.3% in the 6M group and 75.3% and 68.7% in the 12M group, respectively (p = 0.0549, HR = 0.858, 90% CI: 0.732–1.004). The 5-year RFS was 69.3% and 74.1% in the 6M and 12M groups, respectively (p = 0.0143, HR = 0.796, 90% CI: 0.670–0.945). The 5-year OS was 83.2% and 87.6%, respectively (p = 0.0124, HR = 0.727, 90% CI: 0.575–0.919). The incidence of overall grade 3–4 adverse events was almost comparable in both groups. Conclusions Although 12-month adjuvant capecitabine did not demonstrate superior DFS to that of 6-month, the observed better RFS and OS in the 12-month treatment period could be of value in selected cases.

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.

Objective: We previously reported that the largest diameter of retrieved lymph nodes (LNs) correlates with the number of LNs and is a prognostic factor in stage II colon cancer. We examine whether T, B, and natural killer (NK) cells in LNs are related to the number of LNs and survival. Methods: The subjects comprised 320 patients with stage II colon cancer. An LN with the largest diameter was selected in each patient. The positive area ratios of cells that stained for CD3 and CD20, and the numbers of CD56-positive cells were measured. Results: The CD3-positive area ratio was 0.39 ± 0.08 and CD20-positive area ratio was 0.42 ± 0.10. The mean number of CD56-positive cells was 19.3 ± 22.7. The area ratios of B cells and T cells and the number of NK cells were significantly related to the sizes of the largest diameter LNs. The number of NK cells significantly correlated with the number of LNs and was an independent prognostic factor. On multivariate analysis, pathological T stage (T4 or T3; HR 4.71; p < 0.001) and the number of CD56-positive cells (high or low; HR 0.22; p < 0.001) were found to be independent prognostic factors. Conclusions: The number of NK cells in the largest diameter LNs can most likely be used as a predictor of recurrence.

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.

In addition to their major targets, clinically effective drugs may have unknown off-targets. By identifying such off-targets it may be possible to repurpose approved drugs for new indications. We are interested in the Golgi apparatus as a novel target for cancer therapy, but there is a paucity of candidate Golgi-disrupting drugs. Here, we aimed to identify Golgi-disrupting compounds from a panel of 34 approved anticancer drugs by using HBC-4 human breast cancer cells and immunofluorescence microscopy to visualize the Golgi apparatus. The screen identified five drugs having Golgi-disrupting activity. Four of them were vinca alkaloids (vinorelbine, vindesine, vincristine and vinblastine), and the fifth drug was eribulin. This is the first study to demonstrate that vinorelbine, vindesine and eribulin possess Golgi-disrupting activity. The 5 drugs are known to inhibit tubulin polymerization and to induce microtubule depolymerization. Interestingly, a microtubule-stabilizer paclitaxel did not induce Golgi-disruption, suggesting that the three-dimensionally preserved microtubules are partly responsible for maintaining the Golgi complex. Concerning eribulin, a noteworthy drug because of its high clinical efficacy against advanced breast cancer, we further confirmed its Golgi-disrupting activity in 3 different human breast cancer cell lines, BSY-1, MDA-MB-231 and MCF-7. Golgi-disruption may contribute to anticancer efficacy of eribulin. In conclusion, the present study revealed that 4 vinca alkaloids and eribulin possessed potential Golgi-disrupting activity among a panel of 34 approved anticancer drugs. Other drugs covering various molecular-targeted drugs and classical DNA-damaging drugs showed no Golgi-disrupting effect. These results suggest that tubulin polymerization-inhibitors might be promising candidate drugs with Golgi-disrupting activity.

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: Among historical nature remedies in Eastern Asia, Huaier (Trametes robiniophila murr) has long been reported for its significant efficacy on longevity and health maintenance, and more importantly, on cancer. The target cancers of Huaier show the almost complete overlap with those strongly influenced by the Hippo pathway function, which is also well known as a tumor suppressor mechanism. Objective: We have initiated the present study in order to prove the hypothesis that the Hippo signaling pathway is a main molecular mechanism of Huaier effects on cancer and on multiple physiological disorders. Methods: We performed in vivo study using Drosophila flies genetically disrupted transcriptional control in the Hippo pathway with overexpressing non-phosphorylatable Yorkie (Yki:V5S168A) as a cancer model. In addition, metabolome analysis was performed using those cancer-model mutants with a comparison to healthy controls. Results: The administration of Huaier clearly resulted in the recovery of rough eye formation of the mutants, indicating the rescue of tumor suppressor mechanism disrupted by the genetically inoculated overabundant transcriptional activators. These improvements occurred in a dose-dependent manner, just as shown in clinical observations. Simultaneously, the GC/MS-based metabolome analysis revealed that Huaier uptake lead the metabolic profile of the mutant flies strongly shifted to that of the early developmental stage. Conclusion: The present study emphasizes that a broad spectrum of Huaier effects was based on the rescue of the disrupted Hippo signaling pathway control, especially on the recovery in transcriptional dysregulation. The metabolome profile shift would explain the molecular basis of the tissue recovery after a long course of Huaier treatment, by the potential to modulate the cell fate through the embryogenesis and subsequent normal specification of the cells in the damaged tissues.

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.

The purpose of the present study was to evaluate the recent trend of diagnosing appendiceal diseases through the analysis of appendectomy materials, stressing the importance of their pathological examination. A clinicopathological assessment of patients undergoing an appendectomy was conducted, based on the pathological examination of resected appendiceal lesions. Using a pathological database of surgical specimens from patients who underwent an appendectomy between March 2002 and September 2014, a retrospective, single-center analysis was performed. Among the 803 patients identified, 752 with appendiceal disease were selected for clinicopathological analysis. The diagnosis was inflammation (i.e. appendicitis) in 97.7% (n=735) and appendiceal neoplasm in 2.3% (n=17) of the patients. The most frequent type of appendiceal neoplasm was an intramucosal neoplasm (23.5%, n=4). In conclusion, the incidence of appendiceal neoplasms has increased in recent years, potentially due to increased and earlier detection by newer imaging modalities.

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.

Purpose In stage II colon cancer, patients with many retrieved lymph nodes (LNs) have been reported to have better oncological outcomes. We tested the hypothesis that the greater number of retrieved LNs is related to a larger LN size. Methods The subjects comprised 320 patients with stage II colon cancer who underwent curative resection. All operations were elective and were performed by the same surgeons. The maximum long axis and short axis diameters of LNs were measured on hematoxylin-eosin-stained specimens. Results A total of 4,744 LNs were evaluated. The number of retrieved LNs was 14.8 ± 10.1 (mean ± SD). The long axis diameter was 4.8 ± 2.6 mm, with a median value of 4.3 mm, a maximum value of 20.4 mm, and a minimum value of 0.6 mm. The corresponding short axis diameters were 3.4 ± 1.7, 3.0, 15.1, and 0.5 mm, respectively. The highest correlation coefficient for the association with the number of LNs was obtained for the maximum value of the long axis diameter (0.59). Multivariate analysis revealed that age, tumor location, pathological T stage, and the maximum long axis diameter were independent prognostic factors. The number of LNs was not a significant factor. Patients with less than 12 LNs and a maximum long axis diameter of less than 10 mm had significantly poorer outcomes (p

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

Rigid proctoscopy is considered essential for rectal tumor localization, although the current gold standard for detection of colorectal cancers is colonoscopy. The European Society for Medical Oncology Guidelines indicate that rigid and flexible endoscopies afford essentially identical results, although little evidence is yet available to support this.The purpose of this study was to determine the accuracy of colonoscopy in identifying the location of rectal cancer and to compare the results with those of rigid proctoscopy and digital rectal examination.This was a retrospective analysis of a prospective database.The study was conducted at a single tertiary colorectal surgery referral center.A total of 173 patients scheduled for curative surgery for histologically verified rectal adenocarcinoma between December 2009 and February 2015 were entered into the study, after having given informed consent.The main study measure was the mean difference and limits of agreement in assessment of the height of the distal edge of rectal cancer from the anal verge, using the Bland and Altman method.The mean difference between rigid proctoscopy and flexible colonoscopy was -0.2 cm (95% CI, -2.0 to 1.6 cm). The mean difference between rigid proctoscopy and digital rectal examination was 0.3 cm (95% CI, 1.9 to 2.4 cm). Intermethod variability larger than the 95% CI between rigid and flexible endoscopes was correlated to the tumor height (OR, 4.27 (95% CI, 1.84-3.10); p = 0.021).This study was conducted in a single center.The limits of agreement (-2.0 and 1.6 cm) in identifying the height of rectal cancers from the anal verge are sufficiently small to support the view that flexible colonoscopy provides similar tumor locations to those measured by rigid proctoscopy, although the discrepancy occasionally exceeded 2 cm for tumors5 cm above the anal verge. See Video Abstract at http://links.lww.com/DCR/A405.

// 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.

Gastrointestinal neuroendocrine tumors (GI-NETs) often show hematogenous metastasis, with the liver being the most common metastatic site; however, metastasis to the pancreas is rare.We report a rare case of rectal NETs with pancreatic metastases in a 75-year-old man who presented with a chief complaint of constipation. Imaging and endoscopic findings revealed a rectal submucosal tumor, a pancreatic hypovascular mass, and multiple liver masses. The rectal lesion and pancreatic lesions were diagnosed as neuroendocrine tumors using biopsy and endoscopic ultrasound fine-needle aspiration, respectively. Synchronous rectal NET and pancreatic NET (P-NET) with liver metastasis of either of these two were preoperatively diagnosed. A two-stage surgery was performed, comprising abdominoperineal resection and distal pancreatectomy. Pre-operative imaging findings showed a solitary mass in the pancreas, although the resected specimen contained multiple lesions. Immunohistochemical staining of the resected rectal and pancreatic lesions showed that both were synaptophysin positive and chromogranin A (CgA) negative. Generally, rectal NET cells are positive for synaptophysin and negative for CgA, while the majority of P-NETs are positive for both. The final diagnosis was rectal NETs with pancreatic and liver metastases. Till date, there have been no reports on the outcomes in patients with pancreatic metastasis of GI-NETs.More case reports on metastatic NETs are needed to arrive at a consensus for a standardized treatment regimen.

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.

In recent years, there have been many reports about the efficacy of stenting for central bronchial stenosis. When central bronchial stenosis is due to metastasis of a malignant tumor to the trachea and/or bronchi (endobronchial metastasis: EM), it is classified as "narrow EM" and "broad EM." [1] We managed two patients in whom bilateral stent placement was required for narrow and broad EM arising from colorectal cancer. Case 1: In September 2011, a 66-year-old man underwent low anterior resection for advanced colorectal cancer associated with unresectable liver metastasis. The liver metastasis became resectable after chemotherapy, with two resection procedures and radiofrequency ablation (RFA) being performed. Thereafter, lung metastasis occurred and a tumor in the left lung was resected. In May 2015, he developed respiratory distress. CT identified multiple lesions protruding into the lumen of the trachea and the left and right main bronchi. There was no evidence of mediastinal relapse or local relapse at the resection margin, and tumors were only detected in the tracheobronchial walls. Accordingly, narrow EM was diagnosed. An expandable metallic stent (EMS) was placed on the right side where stenosis was more severe, and radiation therapy was conducted for the non-stented tumors. The patient died 8 months later. Case 2: A 69-year-old woman had undergone laparoscopic right hemicolectomy and adjuvant chemotherapy for Stage lllb cancer of the ascending colon. Due to subsequent elevation of tumor markers, PET-CT was conducted and abnormal uptake was seen in the apex of the right lung and right upper abdomen. Both lesions were resected, and omental and lung metastases were diagnosed. She received treatment with UFT / calcium folinate, but relapse occurred at the resection margin in the right lung. At 7 years and 5 months after initial surgery, she complained of respiratory distress at an outpatient visit. CT demonstrated displacement of the trachea and right main bronchus due to enlargement of upper mediastinal lymph nodes. There was also severe stenosis of the right main bronchus due to tumor infiltration. Because there was both infiltration from local recurrence after resection and upper mediastinal lymph node enlargement, broad EM was diagnosed. An EMS was placed at the site of severe stenosis in the right main bronchus. Similar to Case 1, radiation therapy was also conducted, but respiratory distress occurred after 3 months due to tumor re-growth at the stent margin. Accordingly, stent-in-stent placement was performed and her respiratory symptoms improved. However, superior vena cava syndrome occurred 1 month later and the patient died. We consider that placing an EMS is effective in patients with tracheal stenosis due to EM that is judged to be an oncological emergency.