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Background: It currently remains unclear whether the anatomical pattern of lymph node (LN) spread differs between young (≤ 45 years, Y) and elderly (≥ 80 years, E) patients with stage III colon cancer (CC).Materials and Methods: Two groups of patients (Y and E) with stage III CC who underwent extensive (D3) lymphadenectomy at Japanese centers were retrospectively analyzed. The primary endpoint was the proportion of positive central LN. The planned sample size was at least 210 (Y) based on an expected value of 9.1% and threshold of 5%, and 230 (E) based on an expected value of 2% and threshold of 5%.Results: Two-hundred and ten Y patients and 348 E patients were identified and compared. The total number of LN harvested and the total number of invaded LN were significantly higher in group Y (median of 31.5 (3-151) vs. 21 (3-116), P Conclusions: Young stage III colon cancer patients have a higher risk of central LN invasion, suggesting a more aggressive disease biology. The presence of central LN invasion is associated with a worse outcome.

We previously reported the feasibility and efficacy of neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer. Here, we report the results of a long-term follow-up study.This was a multi-institutional, prospective phase 2 study of patients with locally advanced rectal cancer. Patients received neoadjuvant chemotherapy with molecularly targeted agents before undergoing total mesorectal excision. Six cycles of modified FOLFOX (mFOLFOX6) with bevacizumab were administered to KRAS-mutant patients, and mFOLFOX6 with cetuximab was administered to KRAS-wild-type patients. Here, we report the secondary end points of overall survival, relapse-free survival, and local recurrence rate.Sixty patients were enrolled in this study. R0 resection was achieved in 98.3% (59/60) patients, and pathological complete response was achieved in 16.7% (10/60) patients. After a median follow-up of 5.4 years, the 5 year overall survival was 81.6%, the 5 year relapse-free survival was 71.7%, and the 5 year local recurrence rate was 12.6%. None of the patients who achieved pathological complete response developed recurrence within 5 years.The use of molecularly targeted agents in the neoadjuvant setting for locally advanced rectal cancer has an acceptable prognosis.

Anorectal malignant melanoma(AMM)is a relatively rare disease with an extremely poor prognosis. We experienced a case of this disease detected by colorectal cancer screening and report it here with a literature review. Our 67-year-old female patient was referred to the Department of Gastroenterology at our hospital for a thorough examination of the gastrointestinal tract after an abnormal fecal occult blood count(+/+ on 2 occasions)was noted during a colorectal cancer screening. Lower gastrointestinal endoscopy revealed a small easily bleeding lesion near the anal verge for which endoscopic mucosal resection was performed. A histopathological examination revealed a primary malignant melanoma of the rectum, and the patient underwent abdominoperineal rectal amputation. According to the rules for the treatment of T1b (1,200 μm), N0, P0, H0, M(-), StageⅠ, Cur A colorectal cancer. A histopathological examination of the resected specimen showed no remnant tumor cells. About 2 years have passed since the surgery, and the patient is still alive without recurrence. Considering its characteristics, patients with AMM will require further careful follow-up. Here we summarize our experience diagnosing and treating a case of early-stage AMM.

BACKGROUND/PURPOSE To investigate the long-term outcome and entire treatment course of patients with technically unresectable CRLM who underwent conversion hepatectomy and to examine factors associated with conversion to hepatectomy. METHODS Recurrence and survival data with long-term follow-up were analyzed in the cohort of a multi-institutional phase II trial for technically unresectable colorectal liver metastases (the BECK study). RESULTS A total of 22/12 patients with K-RAS wild-type/mutant tumors were treated with mFOLFOX6 + cetuximab/bevacizumab. The conversion R0/1 hepatectomy rate was significantly higher in left-sided primary tumors than in right-sided tumors (75.0% vs 30.0%, P = .022). The median follow-up was 72.6 months. The 5-year overall survival (OS) rate in the entire cohort was 48.1%. In patients who underwent R0/1 hepatectomy (n = 21), the 5-year RFS rate and OS rate were 19.1% and 66.3%, respectively. At the final follow-up, seven patients had no evidence of disease, five were alive with disease, and 20 had died from their original cancer. All 16 patients who achieved 5-year survival underwent conversion hepatectomy, and 11 of them underwent further resection for other recurrences (median: 2, range: 1-4). CONCLUSIONS Conversion hepatectomy achieved a similar long-term survival to the results of previous studies in initially resectable patients, although many of them experienced several post-hepatectomy recurrences. Left-sided primary was found to be the predictor for conversion hepatectomy.

Chemotherapy in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy is under debate. REACT study aimed to investigate the efficacy of reintroducing modified FOLFOX6 (mFOLFOX6) or CAPOX with or without bevacizumab in recurrent colorectal cancer patients after oxaliplatin adjuvant chemotherapy. Patients that participated in this trial had a medical history of adjuvant chemotherapy, including oxaliplatin with a cumulative dose greater than 400 mg/m2, and recurrence that was diagnosed more six months post adjuvant chemotherapy. Primary endpoints were response rate (RR) and disease control rate (DCR), while key secondary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety. A total of 31 patients were enrolled between October 2012 and October 2016. Of the 29 eligible patients, 7 received mFOLFOX6 and 22 received CAPOX. The RR was 62.1% (95% confidence interval 42.3–79.3) and the DCR was 82.8% (95% confidence interval 64.2–94.2). The RR for oxaliplatin-free interval was 100.0% in months 6–12 and 56.0% after 12 months. Median TTF, PFS, and OS were 6.3, 10.8, and 28.7 months, respectively. Grade 3 or worse peripheral sensory neuropathy developed in 6.5%. Allergic reactions occurred in 12.9% of the patients, with one (3.2%) grade 3 episode. There were no other severe treatment-related adverse events. Reintroduction of oxaliplatin was feasible and achieved high RR or DCR in patients after more than 6 months post oxaliplatin adjuvant chemotherapy.

3518 Background: Rechallenge with anti-EGFR monoclonal antibody (EGFR mAb) showed certain activities in patients (pts) with RAS/ BRAF V600E wild-type (wt) metastatic colorectal cancer (mCRC), particularly in pts with negative plasma RAS (p RAS) mutation by circulating-tumor DNA (ctDNA) assay at ‘just before’ the rechallenge therapy. However, the efficacy is unknown in pts with RAS/ BRAF wt mCRC whose p RAS was converted to positive once during or after EGFR mAb. Therefore, we conducted REMARRY, a prospective longitudinal study to investigate the p RAS dynamics, and PURSUIT trials, a phase II trial to investigate the efficacy of EGFR mAb rechallenge in pts with p RAS wt just before rechallenge therapy. Methods: The eligibility criteria of REMARRY trial included RAS/ BRAF V600E wt mCRC; ECOG PS 0-1; CR or PR during EGFR mAb; and a refractory ≤ 2 months from the last administration of EGFR mAb. p RAS status by the BEAMing method was prospectively monitored at timepoints of progression on EGFR mAb and each subsequent therapy. The eligibility criteria of PURSUIT trial included enrollment in the REMARRY trial with confirmed p RAS wt prior to enrollment in PURSUIT trial; being refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; and ≥ 4 months of EGFR mAb-free interval. Study treatment was rechallenge with panitumumab + irinotecan (6 mg/kg + 150 mg/m2 q2wks). Primary endpoint was a confirmed objective response rate (ORR) according to RECIST v1.1. The required number of pts was 45, with a null ORR of 10%, an expected ORR of 25%, power of 85%, and one-sided α of 0.05. Results: Between May 2019 and May 2021, 183 pts with 343 timepoints (median, 2) were enrolled in REMARRY trial from 27 institutions, and 50 pts were enrolled in PURSUIT trial; median age, 68 years; left-sided primary, 44 pts; prior EGFR mAb, 1st/2nd/≥3rd lines was 28/6/16 pts; and p RAS status at progression on prior EGFR mAb, wt/mutant (mt)/unknown in 31/7/12 pts. Confirmed ORR and disease control rate were 14% (90% CI, 7.8%–23.9%) and 80% (95% CI, 67.0%–88.8%), respectively. In addition, 4 pts showed an unconfirmed PR. With a median follow-up time of 8.7 months, median progression-free survival was 3.6 months (95% CI, 3.0 – 4.7 months). The subgroup analysis showed a significantly higher confirmed ORR in pts with a longer EGFR mAb-free interval than a shorter one (> vs. < 365 days, 44.4% vs. 7.3%, p = 0.0037). Without any unexpected safety signals, 58.5% of pts had ≥ grade 3 adverse events. Of 31 patients with wt p RAS at progression on prior EGFR mAb, 5 had a confirmed response (ORR, 16%), whereas no response was observed in patients with 7 p RAS mt (ORR, 0%) (p = 0.25). Conclusions: The primary endpoint of confirmed ORR was not met; however, pts with p RAS wt at progression on prior EGFR mAb may benefit from rechallenge with, implying a lack of or worse response if p RAS becomes positive even once during or after EGFR mAb. Clinical trial information: REMARRY: UMIN000036424 PURSUIT: jRCTs031190096.

The anatomical spread of lymph node (LN) metastasis is of practical importance in the surgical management of colon cancer (CC). We examined the effect of KRAS, BRAF, and microsatellite instability (MSI) on LN count and anatomical spread pattern in stage III CC. We determined KRAS, BRAF, and MSI status from stage III CC patients. Biomarker status was correlated with LN count and anatomical spread pattern, which was classified as sequential or skipped. Relapse‐free survival (RFS) was estimated using Kaplan‐Meier method, and correlations were assessed using log‐rank and Cox regression analyses. We analyzed 369 stage III CC patients. The proportion of KRAS mutant (mt), BRAF mt, and MSI‐high (H) were 44.2% (163/344), 6.8% (25/344), and 6.8% (25/344), respectively. The mean number of metastatic LN was higher in microsatellite‐stable (MSS) compared with MSI patients (3.5 vs. 2.7, P = .0406), although no differences were observed in accordance with KRAS or BRAF status. Interestingly, patients with BRAF mt and MSI‐H were less likely to harbor skipped metastatic LN (9.3% vs 20% and 4% vs 10.5% compared with BRAF wild‐type (wt) and MSS, respectively), but KRAS status did not predict anatomical spread pattern. Patients with KRAS wt and MSI‐H showed superior RFS compared with KRAS mt and MSS patients, respectively, whereas BRAF status did not affect RFS. Differences exist in the anatomical pattern of invaded LN in accordance with the molecular status of stage III CC. Patients with MSI‐H CC have less invaded and skipped LN, suggesting that a tailored surgical approach is possible., The association of KRAS/BRAF/MSI with invaded lymphatic spread pattern in colon cancer was assessed. The anatomical pattern of invaded LN varies in accordance with the molecular status, which may affect the outcome in stage III colon cancer.

Introduction Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse events that can limit a patient's quality of life during/after chemotherapy. However, no appropriate methods have been established yet for monitoring the risk of progression of OIPN. Methods A simple assessment tool using gem clips, the CLIP test, was established and its performance in predicting the risk of progression to ≥grade 2 peripheral sensory neuropathy (CTCAE ver. 4.0) was investigated in patients receiving chemotherapy with oxaliplatin. Results Among 101 patients included in this study, 71 patients developed CTCAE ≥grade 1 peripheral neuropathy (grade 1, n = 67; grade 2, n = 4) at a median of 63 (range, 14-259) days after the start of treatment. Of the 67 patients with grade 1 peripheral neuropathy, 17 showed progression to ≥grade 2 neuropathy after a median interval of 84 (range, 21-246) days. Of these patients, 27 showed a positive result of the CLIP test at a median of 91 (range, 14-224) days, excluding one patient who already showed a positive result of the test at the baseline. Therefore, the risk ratio for the development of CTCAE ≥grade 2 peripheral neuropathy was 8.3 in the patients who showed a positive result on the CLIP test. Multivariate analysis confirmed that a positive results on the CLIP test was significantly correlated with the risk of future development of CTCAE ≥grade 2 peripheral neuropathy (odds ratio, 9.37; P = 0.002). Conclusion A positive result on the CLIP test predict is predictive of the risk of progression of OIPN during chemotherapy with oxaliplatin.

Background and objectives This prospective study aimed to identify long-term changes in sexual function of men with rectal cancer from point of diagnosis to 24 months postoperatively. Methods Male patients undergoing laparoscopic rectal cancer surgery were prospectively enrolled. International Index of Erectile Function (IIEF) Questionnaire scores were collected at diagnosis; first follow-up; and 6, 12, and 24 months postoperatively. Missing values were managed via multiple imputations using the propensity score method. Paired t tests were applied to examine changes in IIEF scores over time. Results This study analyzed 115 patients. For erectile function, there were no significant changes in scores from the point of diagnosis to first treatment (9.4 vs. 9.8 as mean scores; p = .227). Scores deteriorated postoperatively and recovered until 12 months post-surgery, but did not improve significantly from 12 months to 24 months post-surgery (8.7 vs. 8.2 as mean scores; p = .440). This pattern of change was observed in all other domains: orgasmic function, sexual desire, orgasmic satisfaction, and overall satisfaction. Conclusions Sexual function was not influenced by a rectal cancer diagnosis. Sexual function deteriorated following surgery and recovered until 12 months post-surgery; however, it did not significantly improve from 12 months to 24 months postoperatively.

168 Background: Identifying molecular residual disease (MRD) using circulating tumor DNA (ctDNA) analysis after curative surgery can potentially stratify the recurrence risk and facilitate personalization of adjuvant treatment in patients with colorectal cancer (CRC). We conducted a prospective study “COSMOS-CRC-01” to evaluate the utility of a plasma-only ctDNA assay integrating genomic and epigenomic signatures. Methods: Patients with resectable clinical stage 0–III colorectal cancer were eligible. Plasma samples were collected at structured pre- and post-surgical timepoints and analyzed using Guardant Reveal, a plasma-only ctDNA assay that detects the presence of MRD by identifying somatic alterations and methylation signatures of cell-free DNA associated with colorectal cancer. Results: As of April 2021, 501 patients were enrolled in the COSMOS-CRC-01, of which 496 patients had their post-operative 4-week ctDNA status. In this analysis, we included the first 100 patients enrolled with clinical stage II or more CRC. Seven patients were excluded due to non-curative resection or pathological stage (pStage) IV. The assay was able to produce a result for all 93 samples analyzed (failure rate of 0%). MRD was detected in 23 (25%) patients 4 weeks after surgery. The MRD detection rate was 20% in pStage II disease and 29% in pStage III disease. Patients with positive MRD were older than those with negative MRD ( p = 0.0001). Across all MRD positive samples, 30%, 9%, and 61% were positive by both genomic and epigenomic, only genomic, and only epigenomic calls. Genomic signatures included APC, BRAF, KRAS, and TP53 mutations with the lowest variant allelic fraction of 0.04%. With a median follow-up time of 12.2 months (range 8-18 months), 9 of 93 patients recurred (9.7%). ctDNA was detected from a single 4-week post-surgical sample in 55% of patients who recurred (5 of 9). 1-year disease-free survival was 81.2% in patients with positive MRD and 93.9% in those with negative MRD (hazard ratio 3.49, 95% CI 0.93–13.10, p = 0.049). Multivariate analysis including baseline characteristics associated with recurrence risk showed that MRD status had the strongest association with the recurrence. Post-operative 4-week serum CEA level was not associated with risk for recurrence. Conclusions: While follow-up in this cohort is currently limited, the results suggest that a single post-surgery sample run on a plasma-only assay that integrates genomic and epigenomic signatures can more accurately stratify patients with CRC by recurrence risk than previously known clinical factors. Data from baseline and longitudinal timepoints will be reported as available along with longer term clinical follow-up. Clinical trial information: UMIN000037765.

TPS215 Background: Circulating tumor DNA (ctDNA) can be used to predict the risk of recurrence by detecting molecular residual disease (MRD) in patients with colorectal cancer (CRC). Although patients with MRD positive status have extremely high risk of relapse, no standard treatment has been established for these patients after adjuvant chemotherapy. Trifluridine/tipiracil hydrochloride (FTD/TPI) is an oral anti-tumor agent combining thymidine-based nucleoside analogue with a thymidine phosphorylase inhibitor, which presents improved survival in patients with metastatic CRC refractory to fluoropyrimidines. Methods: The ALTAIR trial is a randomized, double-blind, phase III study designed to establish the superiority of FTD/TPI as compared with placebo in patients with resected CRC who show MRD positive status at any time after curative resection. ctDNA testing for screening patients with MRD positive is performed in the observational GALAXY study (UMIN000039205) that is a prospectively conducted large-scale nationwide registry designed to monitor ctDNA status for patient who can undergo curative resection. A personalized tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay) is used for the detection and quantification of ctDNA-based postsurgical MRD. Key eligibility criteria are (a) having undergone radical resection of primary and/or metastatic tumors, (b) a history of standard adjuvant chemotherapy, (c) positive ctDNA status within the previous 3 months at any time postoperatively, and (d) no obvious relapse confirmed by chest, abdominal, and pelvic CT scans. Patients will be randomly assigned in a 1:1 ratio to receive either 6 months of oral FTD/TPI or a matching course of placebo. Randomization is stratified by age (

Background FOLFOXIRI (Fluorouracil, folinate, oxaliplatin, and irinotecan) plus bevacizumab improved progression-free survival (PFS) and overall survival in patients with metastatic colorectal cancer (mCRC), compared with FOLFIRI (fluorouracil, folinate, and irinotecan) plus bevacizumab, but significantly increased the incidences of adverse events. The efficacy and safety profiles of FOLFOXIRI plus bevacizumab in ethnic Asian patients have not been established yet. Patients and Methods This study was an open-label, single-arm, multi-centered phase II prospective clinical trial in patients with mCRC who received FOLFOXIRI plus bevacizumab. The primary endpoint was the PFS rate at 10 months. Secondary endpoints included overall survival, response rate, and safety. Results A total of 69 patients received FOLFOXIRI plus bevacizumab as induction therapy and were assessed for efficacy and safety. The PFS rate at 10 months was 75.2% and the median PFS was 13.3 months. Complete response and partial response were achieved in 2 (2.9%) and 47 patients (69.1%), respectively. Grade 3 and 4 adverse events with incidence rates exceeding 20% were neutropenia (72.5%), hypertension (34.8%), leucopenia (33.3%), and febrile neutropenia (21.7%). Significantly more patients with grade 4 neutropenia had single-heterozygous UGT1A1*1/*6 or *1/*28 (46.2%) than UGT1A1 wild-type genotype (*1/*1) (13.3%) (P = .004). Conclusions FOLFOXIRI plus bevacizumab is considered an effective first-line regimen that improves the outcome of patients with mCRC regardless of ethnicity. In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered.

Liver ischemia–reperfusion injury (IRI) is an important problem in liver transplantation. Thrombomodulin (TM), an effective drug for disseminated intravascular coagulation, is also known to exhibit anti-inflammatory effect through binding to high mobility box-1 protein (HMGB-1) known as a pro-inflammatory mediator. Here we examined the effect of recombinant human TM (rTM) on partial warm hepatic IRI model in WT and toll-like receptor-4 (TLR-4) KO mice focusing on HMGB-1/TLR-4 axis. As in vitro experiments, peritoneal macrophages were stimulated with recombinant HMGB-1 protein. rTM showed a protective effect on liver IRI. rTM diminished the down-stream signals of TLR-4 and also HMGB-1 expression in liver cells as well as its release from liver. Interestingly, neither rTM treatment in vivo nor HMGB-1 treatment in vitro showed any effect on TLR-4 KO mice. Parallel in vitro studies have confirmed that rTM interfered interaction between HMGB-1 and TLR-4. Furthermore, the recombinant N-terminal lectin-like domain-1 (D1) subunit of TM (rTMD1) also ameliorated liver IRI to the same extent as whole rTM. Not only rTM but also rTMD1 might be a novel and useful medicine for liver transplantation. This is the first report clarifying that rTM ameliorates inflammation such as IRI in the TLR-4 pathway dependent manner. This article is protected by copyright. All rights reserved.

A 69-year-old female was introduced to our department for a retroperitoneal mass, 25 mm in diameter, in the right perirenal space indicated by computed tomography (CT). On the basis of magnetic resonance imaging (MRI), retroperitoneal soft tissue sarcoma was suspected. Because she rejected surgical treatment, we continued imaging surveillance. Subsequently, the mass grew larger, but her intention did not change. At 21 months after initial consultation, CT revealed further increase of the above mass and a new lesion with calcification. Ultimately, she underwent mass resection with concomitant resection of the right kidney. Histological examination showed dedifferentiated liposarcoma with metaplastic bone formation and positive surgical margin, but she refused adjuvant chemotherapy. She has survived 7 months since the operation with no evidence of recurrence.

3529 Background: No predictive biomarkers have been validated to determine which patients (pts) with metastatic colorectal cancer (mCRC) benefit the most from angiogenesis inhibitors. Recent studies suggest that plasma angiogenesis factors and their dynamics may have some prognostic or predictive value. Methods: In this prospective longitudinal study, serial plasma sample collections were done at the time points of pre- and post-treatments in mCRC pts receiving biologics in either first- or second-line chemotherapy (chemo). Comprehensive measurements of 17 factors were performed by the multiplex assay with Luminex technology. Statistical analyses were conducted by using the Brunner-Munzel and Jonckheere-Terpstra test. Results: From Sep 2017 to Dec 2020, 789 plasma samples were collected from 498 enrolled pts [first-line chemo plus bevacizumab (BEV, n=102), first-line chemo plus anti-EGFR antibody (aEGFR, n=100), second-line chemo plus BEV (n=100), second-line FOLFIRI plus ramucirumab (RAM, n=99), second-line FOLFIRI plus aflibercept (AFL, n=85) and other treatment (n=7)]. 789 samples were evaluable for this analysis. In the analysis of first-line, level of VEGF-D was significantly higher in both post-BEV and post-aEGFR comparing with pre-first-line [pre-first-line; 264 pg/ml, post-first-line BEV; 354 pg/ml (p

Introduction : During laparoscopic abdominoperineal resection (APR) for low rectal cancer, it is difficult to resect the levator muscles and remove a cylindrical specimen without venturing close to the rectal wall to ensure negative circumferential resection margins (CRM). To solve this problem, we developed a needle-guided, laparoscopic, abdominoperineal resection (LAPR) technique. Aim: To present the safety and superiority of our technique, “needle-guided LAPR”. Material and methods: In 2015, we performed needle-guided LAPR in 5 patients. In brief, the procedure is performed as follows. After total mesorectum excision to the level of the levator muscles, a needle is inserted through the perineum from the dorsal side of the internal aspect of the anus toward the sacral tip. The levator muscles and fat tissue are resected laparoscopically by following the needle. After the levator muscles have been resected, the needle is followed in a similar manner to resect the specimen from the perineum, enabling easy access to the intra-abdominal space and removal of the specimen. No position change is required during the perineal operation or pelvic floor reconstruction. Results : Mean age was 68 years and 3 patients were male. There were no intraoperative complications or conversions to open surgery. The mean operation time and intraoperative blood loss were 319 min and 131 ml, respectively. All specimens were cylindrical in shape and had negative CRM. There were no postoperative complications. Conclusions : Needle-guided LAPR was easily and safely performed to achieve accurate resection of the levator muscles. This technique could contribute to standardization of LAPR.

Background Validation studies demonstrated that the 12-RS assay, known as Oncotype DX Colon Cancer Assay, can identify a wide range of recurrence risk in stage II/III colon cancer (CC). The objective of this prospective study was to evaluate the decision impact of the 12-RS assay on adjuvant chemotherapy recommendation for stage II/III CC patients (UMIN000028784). Method Patients who had curatively resected stage II, IIIA or IIIB CC were eligible. Physicians formulated a treatment recommendation and completed a pre-assay questionnaire, and then the 12-RS assay was performed. Following receipt of the 12-RS result, the treatment recommendation was revised in a post-assay questionnaire. The primary endpoint was the proportion of changes in a treatment recommendation between pre- and post- assay. The threshold value for the proportion of changes was assumed 20%. The target enrollment was 300 patients (100 stage II and 200 stage III CC). Results Between November 2017 and January 2019, 305 patients were registered from 14 centers. Of 275 who were evaluable, stage II/III was 97/178 patients. The RS Conclusions This is the first study to evaluate the impact of the 12-RS assay on adjuvant treatment recommendations for stage III CC. The 12-RS results significantly influenced treatment recommendations.

Background Patients with colorectal liver metastasis (CRLM) might be down-staged by chemotherapy from an initially unresectable stage to a resectable stage. Because the tumor response to preoperative chemotherapy has been correlated with resection rate, the improved efficacy from the concept that only the patients without K-ras mutations receive an anti-EGFR antibody might be expected to increase the conversion rate. The purpose of this study is to evaluate the conversion rate from unresectable CRLM to complete resection. Methods We conducted a multi-institutional phase II trial for unresectable CRLM. Patients received mFOLFOX6 with either bevacizumab (bev) or cetuximab (cet) based on K-ras status (UMIN000004310). Planned treatment was for six cycles during which tumors were assessed for resectability every three cycles. Patients whose disease was unresectable after six cycles switched their chemotherapy regimen from mFOLFOX6 to FOLFIRI. The primary endpoint was R0 resection rate. Results Thirty-five patients with unresectable CRLM were enrolled. A total of 22/12 patients with K-ras wild-type/mutant (wt/mt) were treated with mFOLFOX6 plus cet/bev, respectively. The overall response rate was 64.7% (wt/mt; 77.3%/41.7%, P = 0.04). In 20 patients (58.8%), hepatectomy was performed according to protocol treatment, and the conversion rate was 72.7%/33.3% in wt/mt patients, respectively (P = 0.03). Finally, 23 patients (67.6%) underwent hepatectomy, and the conversion rate was 77.2%/50.0% in wt/mt patients (P = 0.09). The overall R0 resection rate was 47.1% (wt/mt; 50.0%/41.7%, P = 0.36). Conclusions This prospective study showed that combined chemotherapy based on K-ras status can facilitate conversion to resection in patients with unresectable CRLM.

Backgrounds The prognostic value of biomarkers in metastatic colorectal cancer (mCRC) patients with liver metastases remains unclear. We assessed the difference of expression of biomarkers between primary tumors and liver metastases treated with chemotherapy in mCRC patients, as well as the prognostic value of these markers. Methods Forty-three mCRC patients with liver-limited disease from January 2007–November 2011 were analyzed. They all received resection of primary tumors followed by oxaliplatin-based chemotherapy. After chemotherapy, they all received hepatic resection. Forty-three paired primary and metastatic tumor specimens were collected to measure the messenger RNA expression of six biomarkers by the Danenberg tumor profile method (thymidylate synthase, dihydropyrimidine dehydrogenase [DPD], excision repair cross-complementing gene1, thymidine phosphorylase [TP], folylpolyglutamate synthase, and regenerating islet-derived family, member 4). Results Thirty-six patients' messenger RNA was used for analysis. All markers showed similar expression between primary and metastatic sites. The low-expression group of Danenberg tumor profile and TP in the primary tumor showed significantly higher overall survival than the high-expression group ( P P = 0.033), but for DPD and TP in liver metastases, there were no significant differences of overall survival between the two groups. The ratios of marker expression in liver metastatic site to that in primary site of DPD and TP were significantly higher in chemo-responders than in non-chemo-responders ( P = 0.034 and P = 0.022). Conclusions Biomarkers' expressions in liver metastases were similar to those in the primary tumor. DPD and TP in the primary lesion may be a prognostic factor in chemotherapy-naive mCRC patients with liver-limited disease, but those in liver tumor were not. Further validated analysis to our results would be warranted.

Background: This study evaluated the tolerability and efficacy of intermittent oxaliplatin treatment based on mFOLFOX6 using oral uracil-tegafur(UFT) and leucovorin(LV) maintenance therapy in the treatment of elderly patients with advanced colorectal cancer. Methods: Ten non-elderly patients (70 years) with advanced/recurrent colorectal cancer were enrolled in this prospective, multicenter cooperative group clinical trial. The mFOLFOX6 regimen was administered for eight cycles with maintenance therapy with oral UFT/LV treatment until progression. In cases with disease progression, mFOLFOX6 was reintroduced. Results: Grade 2 peripheral neuropathy was noted in 30.0% and 25.0% of the elderly and non-elderly patients, respectively. The observed time to treatment failure (TTF) was 6.3 months in the elderly patients and 6.4 months in the non-elderly patients. The disease control rate was 83.3% in each group. Conclusion: Our new stop-and-go strategy using oral UFT/LV is well-tolerated and effective even in elderly patients.

Backgrounds In ATTRACTION-2 trial, nivolumab (NIVO) showed better outcome compared with best supportive care in advanced gastric cancer (AGC) patients (pts) at least two previous regimens. (NIVO has changed the treatment of AGC in Japan.) Methods: From Nov 2017 to Feb 2019, we retrospectively investigated 25 pts with AGC who received NIVO. Results: The patient demographics were as follows: median age, 67 (range, 39-82); male/female ratio, 18:7; performance status (PS) 0/1/2, 9/14/2; unresectable /recurrent, 20 /5; HER2 positive, 3; deep vein thrombosis, 3; intestinal type /diffuse type, 13 /12; primary site EGJ/UML/UM/ML/U/M/L, 2/2/1/3/5/4/8; site of metastases lymph node /liver /peritoneum /ovary, 13 /8 /9 /1; and previous treatment regimens 2 regimens /3 regimens /≥4 regimens, 9 /10 /6. Response rate (RR) was 12% and disease control rate (DCR) was 28%. The median progression free survival (PFS) was 4.1 months (95% confidence interval [CI], 2.8-NA) and the median overall survival (OS) was 11.8 months (95% CI, 8.2-12.8). In histologic subtypes and PS, there were no difference in PFS and OS between pts with intestinal type and diffuse type as well as between those with PS of 0 and 1-2. As for the number of previous treatment regimens, there was no difference in PFS between pts who received ≥3 regimens and pts who received 2 regimens. However, the former had significantly longer OS compared with the latter. Ten patients (40%) developed immune-related adverse event (ir-AE) and four (16%) did severe ir-AE (≥grade 3). Conclusions: The current study showed better results and longer OS for AGC pts who received NIVO with acceptable toxicities. The limitation is a small number of patients accompanied by a potential of selection with retrospective manner, thus warrants a further studies.

634 Background: Chemotherapy in relapsed colon cancer patients (pts) treated with oxaliplatin as adjuvant chemotherapy is under debate. REACT study aimed to investigate the efficacy of re-introducing FOLFOX or XELOX ± bevacizumab therapy for recurrent colorectal cancer pts after adjuvant chemotherapy including oxaliplatin. Methods: Pts with past history of adjuvant chemotherapy including oxaliplatin (FOLFOX, XELOX or SOX) with a cumulative dose of more than 400 mg/m2, and recurrence observed by imaging after more than 6 months post adjuvant chemotherapy participated in this trial. Primary endpoints were response rate (RR) and disease control rate (DCR). Key secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. Results: A total of 31 pts were enrolled between Oct 2012 and Oct 2016. Of 29 eligible pts, 7 received FOLFOX ± bevacizumab, and 22 received XELOX ± bevacizumab. 28 of the pts received bevacizumab. The RR was 66.7% (95% CI, 46.0-83.5) and the DCR was 88.9% (95% CI, 70.8-97.6). The RR for oxaliplatin free-interval was 100.0% (n = 4, 95% CI, 39.8-100.0) in 6 to 12 months, 60.9% (n = 25, 95% CI, 38.5-80.3%) over 12 month, respectively. Median PFS, TTF and OS were 10.9 months (95% CI, 7.0-19.0), 6.3 months (95% CI, 2.8-8.0) and 29.1 months (95% CI, 20.3-53.3). The most common grade 3 or 4 adverse event was hypertension (19.4%). Grade 3 or worse peripheral sensory neuropathy developed only two pts (6.5%). Allergic reactions occurred in 12.9% of the pts, with one (3.2%) grade 3 episode. There were no other severe treatment-related adverse events. Conclusions: Re-introduction of oxaliplatin was feasible and achieved high RR or DCR in after more than 6 months post adjuvant chemotherapy including oxaliplatin. Clinical trial information: UMIN000006523.

501 Background: Oxaliplatin (l-OHP) is a key drug commonly used in primary and metastatic colorectal cancer treatment. However, l-OHP is associated with non-hematological adverse effects, including peripheral neuropathy (PN). About 90% of patients who received l-OHP experience PN after single dose of l-OHP and PN is likely to be negatively associated with quality of life. There is no established effective prophylactic management for chemotherapy induced PN according to the 2014 American Society of Clinical Oncology (ASCO) guideline. Recently, compression of hands during injection of drugs has been reported to be effective for chemotherapy induced PN. We developed new gloves for compression therapy which are reusable and low cost. We prospectively analyzed the safety of the gloves. Methods: Patients who received l-OHP were eligible for this phase Ⅰ study. Wrist and hand size were measured and appropriate size of gloves were selected. The pressure of hands is estimated as 20-33 hPa. Patients start to wear the gloves on both hands, from 30 min before the injection of l-OHP until 30 min after the injection. Peripheral neuropathy was evaluated at each treatment cycle using common terminology criteria for adverse events (CTCAE) version 4.0. Results: Between October 2017 and August 2018, fourteen patients (median age 66 years [range 39– 79years], 7 male and 7 female) were enrolled and were evaluated. No patients withdrew from this study. No safety concerns were identified for any safety variables assessed during the trial. CTCAE grade 2 or higher sensory PN was observed in four (28.6%) patients. The average time until grade 1 or more neuropathy appeared was 27.8 days and average dose of l-OHP was 225mg. Conclusions: Compression therapy by the new gloves had no safety concerns, demonstrating a profile favorable for further development for prevention of oxaliplatin induced PN. Clinical trial information: 000029671.

This Japanese multicenter retrospective study evaluated short- and long-term outcomes of palliative laparoscopic procedures for symptomatic stage IV colorectal cancer compared with conventional open procedures.Of 968 eligible patients with stage IV colorectal cancer enrolled during January 2006-December 2007 from 41 participating surgical units (Japan Society of Laparoscopic Colorectal Surgery Group), we studied 409 patients who underwent palliative resection of symptomatic primary colorectal tumor.Data from patients with laparoscopic resection (n = 98) and open colorectal resection (n = 311) were analyzed. Eleven (11.2 %) laparoscopic operations were converted to an open procedure. Fewer complications were reported for laparoscopic resections than for open procedures (13.3 vs. 26.7 %; p = 0.0042). Postoperative hospital stay was significantly shorter in the laparoscopic vs. open resection group (median, 14 vs. 17 days; p = 0.0242). Postoperative chemotherapy treatment was administered to 245 (78.9 %) patients in the open and 78 (79.6 %) patients in the laparoscopic resection group. Time from surgery to start of postoperative chemotherapy was significantly shorter in the laparoscopic vs. open resection group (median, 32 vs. 27 days; p = 0.0487). Median survival time between the two groups was not significantly different (22.0 vs. 22.2 months; p = 0.948).Laparoscopic palliative resection results in reduced postoperative complications and earlier recovery with acceptable long-term outcomes comparable with open surgery. When performed by experienced surgeons in selected patients, it may be a safe and feasible option. Because of the potential of significant bias arising from the included studies, further randomized controlled trials should be undertaken to confirm this bias.

This prospective multicenter phase 2 study aimed to evaluate the feasibility and efficacy of neoadjuvant chemotherapy (NAC) without radiotherapy for locally advanced rectal cancer (LARC). Patients with LARC (cStage II and III) were included in the study. Those with cT4b tumor were excluded. Six cycles of modified FOLFOX6 (mFOLFOX6) plus either bevacizumab or cetuximab, depending on KRAS status, were administered before surgery. The primary end point of the study was the R0 resection rate. The secondary end points were adverse effect, rate of NAC completion, postoperative complications, and pathologic complete response (pCR) rate. The study enrolled 60 patients from eight institutions. For the study, mFOLFOX6 was administered with cetuximab to 40 patients who had wild-type KRAS and with bevacizumab to 20 patients who had KRAS mutations. The completion rate for NAC was 88.4%. Sphincter-preserving surgery was performed for 43 patients and abdominoperineal resection for 17 patients. The median operation time was 335 min, and the median blood loss was 40 g. The R0 resection rate was 98.3%, and the pCR rate was 16.7%. The overall postoperative complication rate (≥grade 2) was 21.7%. The complications included anastomotic leakage (11.6%), surgical-site infection (6.7%), and urinary dysfunction (3.3%). The patients with wild-type KRAS did not differ significantly from those with KRAS mutations in terms of response rate, postoperative complication rate, and pCR rate. The findings show that NAC is a feasible and promising treatment option for LARC (This study is registered with UMIN-CTR, UMIN000005654).

Although liver resection combined with preoperative chemotherapy is expected to improve outcomes of patients with resectable colorectal liver metastasis (CRLM), there is as yet insufficient clinical evidence supporting the efficacy of preoperative systemic chemotherapy. The aim of this phase II study was to assess the feasibility and efficacy of preoperative FOLFOX systemic chemotherapy for patients with initially resectable CRLM.A prospective multi-institutional phase II study was conducted to evaluate the feasibility and efficacy of preoperative chemotherapy for resectable CRLM (ClinicalTrials.gov identifier number NCT00594529). Patients were scheduled to receive 6 cycles of mFOLFOX6 therapy before liver surgery. The primary endpoint was the macroscopic curative resection rate.A total of 30 patients were included in this study. Two patients who were diagnosed with hepatocellular and intrahepatic cholangiocellular carcinoma based on pathology were excluded from the analysis. More than half of the patients (57 %) had solitary liver metastasis. The completion rate of preoperative chemotherapy was 64.3 % and the response rate was 53.6 %. Two patients were unable to proceed to liver resections due to disease progression and severe postoperative complications following primary tumor resection. Macroscopic curative resection was obtained in 89.3 % of eligible patients. Postoperative mortality and severe complication (≥Gr. 3) rates were 0 and 11 %, respectively. The 3-year overall and progression-free survival rates were 81.9 and 47.4 %, respectively.Our phase II study demonstrated the feasibility of liver resection combined with preoperative mFOLFOX6 therapy in patients with initially resectable CRLM. Further study is warranted to address the oncological effects of preoperative chemotherapy.

Purpose The 12-gene Recurrence Score assay has been validated in resected stage II colon cancer treated with or without chemotherapy and resected stage III disease treated with chemotherapy. This study evaluated the 12-gene Recurrence Score assay for stage II and III colon cancer without chemotherapy to reveal the natural course of recurrence risk in stage III disease. Methods A cohort-sampling design was used. From 1,487 consecutive patients with stage II to III disease who had surgery alone, 630 patients were sampled for inclusion with a 1:2 ratio of recurrence and nonrecurrence. Sampling was stratified by stage (II v III). The assay was performed on formalin-fixed, paraffin-embedded primary cancer tissue. Association of the Recurrence Score result with recurrence-free interval (RFI) was assessed by using weighted Cox proportional hazards regression. Results Overall, 597 of 630 patients were analyzable—247 patients had stage II, and 350 had stage III colon cancer. The continuous Recurrence Score was significantly associated with RFI after adjustment for disease stage (hazard ratio for a 25-unit increase in Recurrence Score, 2.05; 95% CI, 1.47 to 2.86; P < .001). With respect to prespecified subgroups, as defined by low (< 30), intermediate (30 to 40), and high (≥ 41) Recurrence Score risk groups, patients with stage II disease in the high-risk group had a 5-year risk of recurrence similar to patients with stage IIIA to IIIB disease in the low-risk group (19% v 20%), whereas patients with stage IIIA to IIIB disease in the high-risk group had a recurrence risk similar to that of patients with stage IIIC disease in the low-risk group (approximately 38%). Conclusion To our knowledge, this study provides the first validation of the 12-gene Recurrence Score assay in stage III colon cancer without chemotherapy and showed the heterogeneity of recurrence risks in stage III as well as in stage II colon cancer.

The aim of the present study was to examine the technical and oncological feasibility of laparoscopic surgery (LAP) in elderly patients with a history of abdominal surgery. We conducted a propensity score-matched case–control study of colorectal cancer (CRC) patients aged ≥80 years that were treated at 41 hospitals between 2003 and 2007. We included 601 patients who had a history of abdominal surgery and underwent curative and elective surgery for stage 0 to III CRC. After the matching procedure, 153 patients were included in each cohort. The surgical outcomes of LAP and open surgery (OS) were compared. P-values of

To investigate the hypothesis that laparoscopic primary tumor resection is safe and effective when compared with the open approach for colorectal cancer patients with incurable metastases.There are only a few reports with small numbers of patients on laparoscopic tumor resection for stage IV colorectal cancer.Data from consecutive patients who underwent palliative primary tumor resection for stage IV colorectal cancer between January 2006 and December 2007 were collected retrospectively from 41 institutions. Short- and long-term outcomes were compared between patients who underwent laparoscopic or open resection.A total of 904 patients (laparoscopic group: 226, open group: 678) with a median age of 64 years (range: 22-95) were included in the analysis. Conversion was required in 28 patients (12.4%) and the most common reasons for conversion (23/28: 82%) were bulky or invasive tumors. There was no 30-day postoperative mortality in either group. The complication rate (NCI-CTCAE grade 2-4) after laparoscopic surgery (17%) was significantly lower than that after open surgery (24%) (P = 0.02), and the difference was greater (4% vs 12%; P0.001) when we limited the analysis to severe (≥grade 3) complications. The median length of postoperative hospital stay in the laparoscopic group was significantly shorter than that in the open group (14 vs 17 days; P = 0.002). In univariate analysis, overall survival for the laparoscopic group was significantly better than that for open surgery (median survival time: 25.9 vs 22.3 months, P = 0.04), although no difference was apparent in multivariate analysis.Compared with open surgery, laparoscopic primary tumor resection has advantages in the short term and no disadvantages in the long term. It is a reasonable treatment option for certain stage IV colorectal cancer patients with incurable disease.

Background: Molecular targeted agents, such as bevacizumab and cetuximab, have been shown to improve the overall survival of metastatic colorectal cancer (mCRC) patients. However, we still do not know the best sequence in which to use the molecular targeted agents for mCRC, especially in K-ras wild-type cases. Methods: From July 2006 to November 2010, 63 chemotherapy-naive patients who were diagnosed with mCRC and received an oxaliplatin-based regimen as the first line, did not respond to a bevacizumab-containing regimen used as the first or second line, and received cetuximab or continued bevacizumab, were eligible for this analysis. Thirty-two patients received cetuximab as the third or fourth line chemotherapy due to the K-ras wild-type (Group A). Also, thirty-one patients continued a bevacizumab-containing regimen in spite of disease progression (Group B). Results: The difference in the rate of serious adverse events was not significant between the two groups, but the rate of overall adverse events tended to be higher in Group A than in Group B. The median overall survival (MST) was significantly higher in Group A than Group B (30.8 months and 23.13 months (95%CI: 15.80 - 30.47), respectively) (P = 0.031). Group A patients were all K-ras wild-type, and 21 of Group B were K-ras mutant type. Compared with Group B patients with the K-ras mutant type, MST of Group A patients was significantly longer (30.8 months and 25.73 months, respectively) (P = 0.025). Conclusion: Using cetuximab after progression with bevacizumab might be an effective sequence to improve the overall survival of K-ras wild-type mCRC patients. However, we need further prospective studies to identify the best sequence of chemotherapy for mCRC patients.

Crohn病（以下CD）に併発し穿孔性腹膜炎で発症した回腸癌の1例を報告する．症例は50歳代男性．11年前より小腸型CDと診断されていた．腹痛・発熱あり受診，腹腔内膿瘍と診断された．保存的治療にて軽快していたが約2カ月後腹痛・発熱が再燃し，小腸穿孔・汎発性腹膜炎と診断し開腹手術を施行した．膿性腹水および回腸の穿孔を認めたが明らかな腫瘤性病変は認めず，穿孔部および狭窄部を切除した．切除標本の精査にて，穿孔部の回腸に漿膜下に達する中分化管状腺癌を認めた．補助化学療法につき患者と相談し，術後は経過観察としたところ，再発のため術後21カ月目に死亡した．CDに併発した小腸癌は本邦では20例あまりの報告しかないが，CD患者の増加に伴って今後増加する可能性がある．CDの癌化リスクの疫学的評価，また有効な早期診断法の確立，また小腸癌の併発の可能性を念頭に置いたCDの経過観察・急性腹症の加療が必要と考えられる．