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Purpose: We reported in a retrospective study that the presence of micrometastasis in lymph nodes, when assessed by carcinoembryonic antigen (CEA)-specific RT-PCR, is a significant prognostic factor in stage II colorectal cancer. The aim of this study was to clarify the clinical value of micrometastasis in a prospective multicenter trial.Experimental Design: From November 2001 to December 2005, a total of 419 colorectal cancer cases were preoperatively registered at a central data center. Of them, 315 node-negative stage II colorectal cancer cases were enrolled. After RNA quality check, 304 colorectal cancer cases were analyzed for CEA mRNA in lymph nodes by both conventional RT-PCR (a band method) and quantitative RT-PCR. Long-term prognosis of the patients was determined by each method.Results: A positive band for CEA mRNA was detected in 73 (24.0%) of 304 patients. Postoperative adjuvant chemotherapy was applied in 31 CEA band-positive cases with an oral 5-fluorouracil derivative HCFU (1-hexylcarbamoyl-5-fluorouracil) for 1 year, whereas chemotherapy was not administered to CEA band-negative group. Multivariate Cox regression analyses revealed that a high micrometastasis volume (high MMV, n = 95) was an independent poor prognostic factor for 5-year disease-free survival (DFS; P = 0.001) and 5-year overall survival (OS; P = 0.016).Conclusions: This prospective clinical trial demonstrates that micrometastasis volume is a useful marker in identifying patients who are at high or low risk for recurrence of stage II colorectal cancer. Clin Cancer Res; 22(13); 3201–8. ©2016 AACR.

LNs were collected within 3 hours after resection of the specimens with a disposable LN sampling kit that was prepared in a RNase-free state. In addition to routine pathological examination of LNs, representative five pericolic nodes adjacent to the tumor were cut into halves and stored in RNA laterTM at -20{degree sign}C. Immediately after pathological tests reported node-negative stage II CRC, RNA was extracted from LNs, checked for RNA quality, and then subjected to conventional RT-PCR for the CEA band and qRT-PCR for CEA mRNA value by the Light CyclerTM. Among seven CRC cases tested, Case No. 3, 4, and 6 were judged positive (Lower panel). Positivity of the CEA band was judged consistently by reference of the simultaneously produced control panel. One microgram of RNA from gastric cancer MKN45 cells and colon cancer LoVo cells was subjected to the RT reaction. Each cDNA was serially diluted at 1x10-1 to 1x10-5. PCR was performed using CEA primers and PBGD primers. A positive CEA band was visible at a 1x10-4 dilution in the MKN45 cells and at a 1x10-3 dilution in the LoVo cells (Upper panel).

The standard curves were plotted using the serial dilution of cDNA from MKN45. We confirmed that the CEA value was reproducibly measured in the range of 1.0x10-1 to 1.0x10-4 with standard deviation < 10% in each dilution.

Of 55 node-negative CRCs (9 stage I and 46 stage II), Micrometastais was positive in 59 of 373 LNs (15.8%) at level 1, 16 of 193 LNs (8.3%) at level 2 and 4 of 86 LNs (4.7%) at level 3 through 5 slides inspection by immunostaining using pan-cytokeratin AE1/AE3 antibody (Dako). As results, 27 CRC cases were positive for micrometastasis in LNs. Micromstastasis was found at pericolic nodes adjacent to the tumor (level 1) in 26 cases of 27 CRCs (96.3%). On the other hand, micrometastasis stayed at intermediate nodes along the course of the main blood vessel, e.g., inferior mesenteric artery (level 2) and at central nodes around the root of the main blood vessel (level 3) in 37.0% and 14.8%, respectively. Level 1, pericolic nodes adjacent to the tumor; Level 2, intermediate nodes along the course of the main blood vessel; Level 3, central nodes around the root of the main blood vessel. Level 1, pericolic nodes adjacent to the tumor; Level 2, intermediate nodes along the course of the main blood vessel; Level 3, central nodes around the root of the main blood vessel.

Figure S5: Impact of chemotherapy in High-MMV group. Post-operative chemotherapy was performed in 29 of 95 High-MMV cases and 2 of 201 Low-MMV cases. Irrespective of chemotherapy applied to High-MMV cases, High-MMV group consistently showed significantly worse 5-year DFS as compared to the Low-MMV group with no treatment (P= 0.009, 0.007). Similar results were observed in analyses for OS (P=0.003, 0.026).; Figure S6:Disease recurrence mode in stage II CRC. Among 296 patients, 51 developed disease recurrence after surgery. The recurrent organ site was 60 in all and are listed here. Like more advanced-stage patients, stage II patients had often hematogenous metastasis to liver and lung.

Figure S8: Survival analyses of the entire CEA　band-positive group.　 Of the entire CEA band-positive cases, 31 cases eventually received post-operative chemotherapy using HCFU for one year, whereas 41 cases had no treatment. There was no significant difference in 5-year DFS and 5-year OS between the two groups.; Figure S9. Survival curves stratified by High CK19 expression and Low CK19 expression. Survival analyses indicated that the High CK19 group (n=96) had a significantly (A) worse 5-year DFS (P= 0.001), (B) 5-year OS (P= 0.020), and (C) OS (P= 0.014) as compared to the Low CK19 group (n=193). A total of 289 cases with residual preserved RNA were analyzed.

MM-free CRC group (group a, n=90) had a considerably favorable prognosis. (A) 5-year DFS: 5-year DSF was 93.3, 86.5, and 74.7% in group a, group b and group c+d (High-MMV), respectively. (B) 5-year OS: 5-year OS was 97.8, 95.5, and 89.5 % in group a, group b, and group c+d (High-MMV), respectively. (C) Final OS: final OS was 97.8, 93.7, and 86.3% in group a, group b, and group c+d (High-MMV), respectively.

Background Fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) plus panitumumab therapy is a commonly used first-line chemotherapy for metastatic colorectal cancer (mCRC). However, the long-term administration of oxaliplatin is associated with peripheral neuropathy (PN). We investigated whether the planned discontinuation of oxaliplatin after FOLFOX plus panitumumab therapy can maintain efficacy and reduce PN incidence. Patients and methods Chemotherapy-naive patients with RAS wild-type mCRC, aged ≥20 years, were enrolled and received six cycles of modified FOLFOX6 (mFOLFOX6) plus panitumumab as induction therapy. Patients who completed induction therapy without progression were randomised to mFOLFOX6 plus panitumumab (group A) or to 5-FU/LV plus panitumumab (group B). The primary end-point was the progression-free survival (PFS) rate at 9 months after randomisation. The secondary end-points were PFS, overall survival (OS), time to treatment failure (TTF), response rate (RR) and safety. Results In total, 164 patients were enrolled; of whom, 113 patients were then randomised (group A, n = 56; group B, n = 57). The median follow-up after randomisation was 19.6 months. The PFS rates at 9 months and median PFS were 46.4% (80% confidence interval [CI], 38.1–54.9) and 9.1 months (95% CI, 8.6–11.1) in group A, compared with 47.4% (80% CI, 39.1–55.8) and 9.3 months (95% CI, 6.0–13.0) in group B, respectively. RR, OS and TTF were also similar in both groups. Grade ≥2 PN incidence was lower in group B (9.3%) than in group A (35.7%). Conclusion Planned discontinuation of oxaliplatin after six cycles of mFOLFOX6 plus panitumumab is a potential treatment option in patients with mCRC, achieving similar efficacy while reducing oxaliplatin-associated PN compared with mFOLFOX6 plus panitumumab. Trial registration number NCT02337946

Oxaliplatin-based adjuvant chemotherapy may be associated with debilitating peripheral sensory neuropathy (PSN) in patients with high-risk stage II colon cancer. This open-label, multicenter, randomized phase III trial was conducted as a prospective pooled analysis to investigate the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy.From 12 February 2014 to 31 January 2017, 525 Asian patients with high-risk stage II colon cancer were randomly assigned to 3- and 6-month treatment arms. The treatment consisted of either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine combined with oxaliplatin (CAPOX). The primary end point was disease-free survival (DFS). The secondary end points were treatment compliance and safety.Of the 525 randomized patients, 11 were not treated. Among the 514 participating patients (255 in the 3-month arm; 259 in the 6-month arm), 432 (84%) received CAPOX, and 184 (36%) presented with T4 as a high-risk factor for recurrence. The 3-year DFS rate was 88.2% in the 3-month arm and 87.9% in the 6-month arm [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.67-1.87]. With CAPOX, the 3-year DFS rate was 88.2% in the 3-month arm and 88.4% in the 6-month arm (HR, 1.13; 95% CI, 0.65-1.96). The discontinuation rate in the 3- and 6-month arms was 10% and 31% for mFOLFOX6 (P = 0.0193), and 15% and 35% for CAPOX (P0.0001), respectively. The incidence of grade ≥2 PSN was significantly lower in the 3-month arm than in the 6-month arm (16% and 43%, respectively, P0.0001).Three months of combination therapy presented significantly less grade ≥2 PSN than the respective 6-month regimen. The shortened therapy duration did not affect the 3-year DFS rate, suggesting that a 3-month course of CAPOX can be an effective treatment option.UMIN Clinical Trials Registry, UMIN000013036 and Japan Registry of Clinical Trials, jRCTs031180128.

Small-bowel obstruction (SBO) during pregnancy is uncommon and can be difficult to diagnose. Therefore, the condition is associated with significant maternal and fetal mortality. We report a case of successful laparoscopic treatment of SBO in early pregnancy. A 37-year-old woman presented with diffuse abdominal pain and vomiting at 8 weeks of gestation. She had a history of abdominal surgery. Exploratory laparoscopy was performed by a gastrointestinal surgeon because SBO, and specifically strangulated ileus, was strongly suspected. On entry into the abdomen, dilated small bowel was visible in the pelvis; this was attached to the pelvic wall and twisted near the right adnexa. The small bowel initially appeared dark and congested, but after releasing the adhesions, it regained its normal color, was viable, and peristalsis was observed. Therefore, bowel resection was not required. No recurrence was observed after food ingestion, and the patient was discharged 12 days after surgery.

Background The IDEA collaboration, a prospective pooled analysis of four concurrently conducted randomized phase III trials (SCOT, TOSCA, ACHIEVE-2, and HORG) for pts with high-risk stage II CC investigating duration of adj oxaliplatin-based therapy, were presented at ASCO 2019. The results of ACHIEVE-2 trial, the only investigation in Asia, are presented here. Methods ACHIEVE-2 was an open-label, multicenter trial randomizing pts with high-risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation or vascular invasion) to receive 3 months (m) or 6m of mFOLFOX6/CAPOX after curative surgery. Choice of regimen was declared before randomization by a site investigator. Primary endpoint was disease-free survival (DFS). No formal hypothesis testing for non-inferiority (NI) was planned in this trial. Results Between Feb 2014 and Jan 2017, 525 pts were randomized. The primary analysis included 514 randomized pts of which 82 had mFOLFOX6 (16.0%) and 432 had CAPOX (84.0%). High-risk features included 35.8% of T4, 12.8% of inadequate nodal harvest, 11.5% of poorly differentiated, 19.3% of obstruction, 6.4% of perforation and 87.5% of vascular invasion. There was significantly less grade 3-5 toxicity with 3m treatment (p = 0.0003). Grade 2 or higher neurotoxicity in 3m was significantly lower than that in 6m (16.5% vs. 42.9%, p Conclusions Shorter duration significantly decreased overall toxicities including neurotoxicity. Our results need to be interpreted within the IDEA combined analysis as well as in terms of the reproducibility of results across all trials. Clinical trial identification UMIN000013036. Legal entity responsible for the study The authors. Funding Japanese Foundation for Multidisciplinary Treatment of Cancer under the contract with Yakult Honsha. Disclosure T. Yoshino: Research grant / Funding (institution): Novartis Pharma K.K; Research grant / Funding (institution): MSD.K.K.; Research grant / Funding (institution): Sumitomo Dainippon Pharma Co., Ltd.; Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Sanofi K.K.; Research grant / Funding (institution): Daiichi Sankyo Company, Limited; Research grant / Funding (institution): Parexel International Inc.; Research grant / Funding (institution): Ono Pharmaceutical Co., Ltd. T. Yamanaka: Honoraria (self), Research grant / Funding (institution): Chugai; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self), Research grant / Funding (institution): Boehringer-Ingelheim; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): Pfizer; Advisory / Consultancy: Gilead Sciences; Advisory / Consultancy, Research grant / Funding (institution): Daiichi-Sankyo; Advisory / Consultancy: Sysmex; Advisory / Consultancy: Huya Biosciences; Research grant / Funding (institution): Ono; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Eli Lilly. M. Kotaka: Honoraria (self): Yakult Honsha; Honoraria (self): Chugai pharmaceutical. M. Gamoh: Honoraria (self): Taiho; Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self): Ono; Honoraria (self): Shionogi; Honoraria (self): Sanofi; Honoraria (self): Asahikasei; Honoraria (self): Chugai; Honoraria (self): Takeda; Honoraria (self): Daiichisankyo; Honoraria (self): Merck; Honoraria (self): Nipponkayaku; Honoraria (self): Eli Lilly Japan. A. Makiyama: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lily Pharmaceutical; Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Takeda. K. Shitara: Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Ono; Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Medi Science; Honoraria (self): Novartis; Honoraria (self): AbbVie; Honoraria (self): Yakult. K. Yamazaki: Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: Yakult. A. Ohtsu: Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self): Ono; Honoraria (self): Eisai. Y. Maehara: Research grant / Funding (institution): Yakult; Research grant / Funding (institution): Chugai. All other authors have declared no conflicts of interest.

Purpose Oxaliplatin-induced peripheral neurotoxicity (OPN) is frequent and potentially severe, but successful treatment of this condition is still an unmet clinical need. We aimed to determine whether treatment with goshajinkigan (TJ-107), a traditional Japanese medicine, is better than placebo in preventing OPN in patients with advanced or recurrent colorectal cancer patients treated with standard FOLFOX regimens. Methods In this phase 2, randomized, double-blind, placebo-controlled study, patients undergoing oxaliplatin-based chemotherapy were randomized to receive either oral TJ-107 (7.5 g) or matching placebo daily. The severity of OPN was assessed according to the Common Toxicity Criteria for Adverse Events at baseline, every 2 weeks until the 8th cycle, and every 4 weeks thereafter until the 26th week. The primary endpoint was the incidence of grade 2 or greater OPN until the 8th cycle of chemotherapy. Results Analyses were done by intention to treat. Eighty-nine patients were randomly assigned to receive either TJ-107 (n = 44) or placebo (n = 45) between May 2009 and March 2010. The incidence of grade 2 or greater OPN until the 8th cycle was 39 and 51 % in the TJ-107 and placebo groups, respectively (relative risk (RR), 0.76; 95 % CI, 0.47–1.21). The incidence of grade 3 OPN was 7 % (TJ-107) vs. 13 % (placebo) (0.51, 0.14–1.92). No concerns regarding toxicity emerged with TJ-107 treatment. Conclusions TJ-107 appears to have an acceptable safety margin and a promising effect in delaying the onset of grade 2 or greater OPN without impairing FOLFOX efficacy.

Objective: This is a feasibility trial of oral uracil/tegafur (UFT)/oral leucovorin (LV) and irinotecan (TEGAFIRI) with maximum dose confirmed in Japan. To document the toxicity and define the objective response rate (RR); and determine progression-free and overall survival. Methods: Patients with advanced or metastatic colorectal cancer (CRC) received: UFT 300 mg/m 2 , LV 75 mg/body and CPT-11 150 mg/m 2 (UFT and LV given on days 1 –1 4, and CPT-11 on day 1, every 3 weeks). Eligibility: ECOG performance status (PS) 0–1, adequate bone marrow/liver function and serum creatinine level less than institutional normal value. Results: Eighteen patients enrolled, 17 evaluable for toxicity and response and 1 patients recalled chemotherapy upon registration. Characteristics: 61% male, median age 63.5 years (51–71). Seventy-two per cent PS 0, 50% first line. One hundred and eighty-six cycles have been delivered. The common Grade 3 –4 toxicities were neutropenia (35.3%), leukopenia (29.4%), diarrhea (5.9%), anorexia (5.9%), vomiting (5.9%) and dizziness (5.9%). There was no episode of febrile neutropenia. No death occurred on treatment: Overall RR was 41.2% [7/ 17: 1 complete response (CR) þ 6 partial response (PR)]. Progression-free survival (PFS) is 6.9 months, median survival time (MST) is 25.1 months and 1-year survival rate is 70.6%, whereas PFS 15.0 months, MST 43.6þ months and 1-year survival rate 100% in cases with CR or PR. Conclusions: Approved dose of CPT-11 is 150 mg/m 2 in Japan. As is lower dose with CPT11, TEGAFIRI for patients with advanced or metastatic CRC in Japan seems to have the similar effect with that reported in aboard and indicates prolonged PFS and MST in cases with CR or PR.

症例は56歳男性．大腸疾患の家族歴はない．健診で貧血を指摘され近医を受診し，注腸造影検査で多発性ポリープおよび横行結腸腫瘍を指摘され，当院外科に紹介受診となった．大腸内視鏡検査を行い上行結腸と直腸からS状結腸にかけて有茎性ポリープを認め，その一部を内視鏡的切除した．また，CTにて横行結腸に径4cmの腫瘍性病変を認めた．治療方針としては，上行結腸·横行結腸·S状結腸から直腸の3カ所に病変が存在したため大腸全摘術を選択した．摘出標本の病理診断は（1）上行結腸·S状結腸から直腸の有茎性ポリープは若年性ポリープ（2）横行結腸の亜有茎性腫瘍は高度異型腺腫の診断であった． 若年性ポリポーシスは，過誤腫のために腺腫性ポリポーシスと比較して悪性腫瘍との関連性が低いとされてきたが，最近では前癌状態であることを示唆する報告もある．今回，若年性ポリポーシスと同時性高度異型腺腫の切除症例を経験したので文献的考察も加えて報告する．

Objective: No salvage treatment had been established for metastatic colorectal cancer (mCRC) with mutated KRAS before the emergence of the new drugs regorafenib and TAS-102. We performed a phase II study of third-line chemotherapy with combined bevacizumab and S-1 for mCRC. Methods: Subjects were mCRC patients with mutated KRAS who showed disease aggravation even after two regimens with oxaliplatin and irinotecan. Bevacizumab was given intravenously every 2 weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary endpoint was disease control rate (DCR). Results: In total, 31 subjects were enrolled between August 2009 and June 2011. Three subjects in whom antitumor effects could not be evaluated were excluded. The median follow-up period was 8.6 months. The DCR was 67.9%, the response rate 0%, median progression-free survival 3.7 months, and overall survival 8.6 months. In 30 subjects evaluated for safety, there was no treatment-related death. The most common adverse events were anorexia (grade ≥3, 20%), diarrhea (grade 3, 10%), and decreased hemoglobin (grade ≥3, 17%). Conclusions: The results suggest that third-line chemotherapy with combined bevacizumab and S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS.

Background The clinical benefit of cetuximab combined with oxaliplatin-based chemotherapy remains under debate. The aim of the present multicenter open-label Phase II study was to explore the efficacy and safety of biweekly administration of cetuximab and mFOLFOX-6 or XELOX as first-line chemotherapy in patients with metastatic colorectal cancer. Methods Sixty-two patients with previously untreated KRAS/BRAF wild-type metastatic colorectal cancer were recruited to the study between April 2010 and May 2011. Patients received one of two treatment regimens, either cetuximab plus mFOLFOX-6 (FOLFOX + Cmab) or cetuximab plus biweekly XELOX (XELOX + Cmab), according to their own preference. Treatment was continued until disease progression or the appearance of intolerable toxicities. The primary endpoint was response rate; secondary endpoints were progression-free survival, overall survival, disease control rate, dose intensity, conversion rate to surgical resection, and safety. Results The response rates in the FOLFOX + Cmab (n = 37) and XELOX + Cmab (n = 25) groups were 64.9 % (24/37) and 72.0 % (18/25), respectively. The median PFS in the FOLFOX + Cmab and XELOX + Cmab groups was 13.1 months (95 % confidence interval [CI] 12.1–17.5) and 13.4 months (95 % CI 10.1–17.9), respectively. Neutropenia was the most frequent grade 3/4 adverse event in both groups (33.9 %), followed by anorexia, acneiform eruption, skin fissure and paronychia. A waterfall plot of tumor diameter showed prominent shrinkage of the tumors in 88.7 % of patients. Conclusions The results of the present study indicate that biweekly cetuximab plus mFOLFOX-6/XELOX is an effective and tolerable treatment regimen. Biweekly administration of cetuximab requires only one hospital visit every 2 weeks, and may become a convenient treatment option for patients with KRAS/BRAF wild-type metastatic colorectal cancer. Trial registration This study is registered with University Hospital Medical Information Network (UMIN 000003253). Registration date is 02/24/2010. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1685-z) contains supplementary material, which is available to authorized users.

Background Although number of elderly patients with metastatic colorectal cancer (mCRC) is rapidly increasing, this population is often underrepresented in clinical trials. Recently, a phase II trial demonstrated that capecitabine and oxaliplatin (XELOX) combined with bevacizumab XELOX plus bevacizumab was effective and well tolerated by elderly patients with mCRC who reside in Western countries. The aim of this study was to evaluate the safety and efficacy of XELOX plus bevacizumab for Japanese patients aged ≥75 years with mCRC. Methods This prospective, open-label phase II trial recruited patients aged ≥75 years with previously untreated mCRC between March 2010 and January 2012. Treatment consisted of 7.5 mg/kg of intravenous bevacizumab and 130 mg/m2 of oxaliplatin on day 1 of each cycle combined with 2000 mg/m2 of oral capecitabine per day on days 1–14 of each cycle. Treatment was repeated every 3 weeks until disease progression or termination of the study. The primary endpoint was progression-free survival; the secondary endpoints were toxicity, overall response rate, time-to-treatment failure, and overall survival. Results Thirty-six patients (male 58 %; median age 78 years; colon cancer 67 %) met all eligibility criteria and received at least one course of the planned treatment. The median time-to-treatment failure was 7.0 months. Twelve patients (33.3 %) experienced adverse effects (AEs) ≥ grade 3 and frequent AEs ≥ grade 3, including neutropenia (22.2 %) and neuropathy (13.9 %). Hypertension was the most frequent AE ≥ grade 3 associated with bevacizumab (11.1 %). Low baseline creatinine clearance associated significantly with the incidence of AEs ≥ grade 3. Response and disease control rates were 55.6 and 91.7 %, respectively. Median progression-free and overall survival times were 11.7 months (95 % confidence interval, 8.0–13.4 months) and 22.9 months, respectively. Conclusion XELOX combined with bevacizumab was well tolerated by selected Japanese patients aged ≥75 years with mCRC patients, and controlled clinical trials are now required to determine the survival benefit. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1712-0) contains supplementary material, which is available to authorized users.

Purpose: We reported in a retrospective study that the presence of micrometastasis in lymph nodes, when assessed by carcinoembryonic antigen (CEA)-specific RT-PCR, is a significant prognostic factor in stage II colorectal cancer. The aim of this study was to clarify the clinical value of micrometastasis in a prospective multicenter trial. Experimental Design: From November 2001 to December 2005, a total of 419 colorectal cancer cases were preoperatively registered at a central data center. Of them, 315 node-negative stage II colorectal cancer cases were enrolled. After RNA quality check, 304 colorectal cancer cases were analyzed for CEA mRNA in lymph nodes by both conventional RT-PCR (a band method) and quantitative RT-PCR. Long-term prognosis of the patients was determined by each method. Results: A positive band for CEA mRNA was detected in 73 (24.0%) of 304 patients. Postoperative adjuvant chemotherapy was applied in 31 CEA band-positive cases with an oral 5-fluorouracil derivative HCFU (1-hexylcarbamoyl-5-fluorouracil) for 1 year, whereas chemotherapy was not administered to CEA band-negative group. Multivariate Cox regression analyses revealed that a high micrometastasis volume (high MMV, n = 95) was an independent poor prognostic factor for 5-year disease-free survival (DFS; P = 0.001) and 5-year overall survival (OS; P = 0.016). Conclusions: This prospective clinical trial demonstrates that micrometastasis volume is a useful marker in identifying patients who are at high or low risk for recurrence of stage II colorectal cancer. Clin Cancer Res; 22(13); 3201–8. ©2016 AACR.

Hereditary non-polyposis colorectal cancer (HNPCC) is a very important clinical entity in oncology. In order to identify HNPCC, the international diagnostic criteria, named 'Amsterdam criteria', has been used. In this report, we present a patient with HNPCC who completely lacks a family history of cancer, thus does not meet the revised Amsterdam criteria and was finally confirmed as HNPCC by genetic testing which revealed a novel germline mutation of the hMLH1 gene. The proband was a 52-year-old Japanese female with a diagnosis of advanced ascending colon cancer. She had a past history of Miles' operation for rectal cancer at the age of 40. A subtotal colectomy was performed and the subsequent microsatellite instability (MSI) analysis revealed high MSI in the resected tumor tissue. PCR/direct sequencing analysis of the genomic DNA revealed the base deletion 2006delAAAAG at codon 669 in exon 18 of the hMLH1 gene, which was considered to be a pathogenic mutation. According to the Human Mutation Database and International Collaborative Group on HNPCC (ICG-HNPCC) Database, this is the first report of this type of deletion mutation in the hMLH1 gene.

Hereditary non-polyposis colorectal cancer (HNPCC) is a very important clinical entity in oncology. In order to identify HNPCC, the international diagnostic criteria named "Amsterdam criteria" have been used. In this report, we present a case of an HNPCC patient who met the revised Amsterdam criteria after the sequential history taking in which a novel germline mutation of hMSH2 gene was detected by genetic testing. The proband was a 69-year-old Japanese female who was admitted to our hospital with a diagnosis of advanced ascending colon cancer. Microsatellite instability (MSI) analysis revealed high MSI in the resected tumor tissue. PCR/direct sequencing analysis of the genomic DNA revealed the TTG(Leu) to TAG(Stop) nonsense mutation at codon 302 in exon 5 of the hMSH2 gene, which was considered to be a pathogenic mutation. According to the Human Mutation Database and International Collaborative Group on HNPCC (ICG-HNPCC) Database, this type of nonsense mutation is the first report in the hMSH2 gene.

This study was the first multicenter phase II study of cetuximab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) in KRAS wild-type mCRC as a second-line treatment in Japan including BRAF and PIK3CA genotyping.Tumors of 112 pre-registered patients were genotyped for KRAS, BRAF, and PIK3CA. The primary study end-point was response rate, and secondary end-points were progression-free survival (PFS), overall survival (OS), and safety.Sixty-seven patients (59.8%) were EGFR-positive and KRAS wild-type. The mean age of the enrolled patients (n=60) was 62.6 years (range=37-82 years). The response rate was 31.7% and stable disease was observed in 53.3%. No objective response was observed in patients with BRAF or PIK3CA mutations. The median PFS and OS were 7.4 and 18.2 months, respectively. Grade-3/4 adverse events were leucopenia (26.7%), neutropenia (43.3%), paronychia (10.0%), fissure (10.0%) and acne-like rash (5.0%).Second-line cetuximab plus FOLFIRI was effective and well-tolerated.

So far we are obliged to perform colostomy temporarily for rectal stenosis due to Schnitzler metastasis from gastric cancer. This time we were able to manage a case of the disease by placement of an expandable metallic stent (EMS).A 64-year-old woman who had been followed clinical course after the operation for gastric cancer was admitted to the hospital because of abdominal distension and general fatigue. Intestinal obstruction due to rectal stenosis was suspected. Fluoroscopy of the rectum revealed a stenosis at the RS of the rectum. One year and 4 months after the operation, an EMS was placed at the same site. Thereafter gradual symptomatic remission was attained. The patient started to eat and was discharged from the hospital.This EMS method can be easily and safely performed and appears to be very helpful to improve the quality of the patient.

We recently showed that liver metastatic tissue from patients with colorectal cancer (CRC) was a useful model for identifying novel, hypoxia-inducible genes and prognostic markers. We showed that the expression of secretoglobin, family 2A, member 1 (SCGB2A1) was a potential prognostic factor for CRC. Here, we further evaluated the prognostic impact and function of SCGB2A1 in 222 patients with CRC. The impact of SCGB2A1 expression on disease-free survival (DFS) and overall survival (OS) was assessed with mRNA expression profiling. The function of SCGB2A1 was analyzed by evaluating mRNA expression profiles in cells derived from patients with CRC and by testing the effects of transfecting SCGB2A1 into different CRC-derived cell lines. We evaluated the effects of SCGB2A1 on proliferation, chemosensitivity, radiation sensitivity and sphere formation. Univariate and multivariate analyses indicated that the expression of SCGB2A1 was an independent prognostic factor for CRC (p

The retinoblastoma gene (Rb gene) is a tumour-suppressor gene and its product (pRB) is known to act as a negative regulator of the cell cycle. Although lack of pRB expression resulting from gene alterations is considered to be responsible for the genesis of several human malignancies, increased expression of pRB has been demonstrated in a majority of colorectal cancer cases. In the present study, we investigated the expression of pRB as well as that of its related kinases, cdk2 and cdc2, in colorectal cancer, since these kinases have been reported to phosphorylate and inactivate pRB. Western blot analysis revealed that colorectal cancer expressed higher levels of cdk2 and cdc2 than did normal mucosa and that the ratio of the hyperphosphorylated form of pRB was higher in colorectal cancer. Furthermore, immunohistochemical studies showed that cdk2/cdc2 was expressed exclusively in the cancer cells positive for pRB. These results suggest that an increase in the expression of cdk2/cdc2 in colorectal cancer may have prevented pRB from braking the cell cycle through phosphorylation. Images Figure 1 Figure 2 Figure 3 Figure 4

A 59-year-old male developed a cutaneous fistula in the right iliac region. Barium enema and computed tomography revealed that this fistula was originated from a retroperitoneal abscess due to penetration of an advanced cancer of the ascending colon. Extended radical operation comprising of right hemicolectomy with partial resection of the right abdominal wall and reconstruction with recto-abdominal musculo-cutaneous flap was performed. Postoperative clinical course was uneventful, and the patient restored a good QOL (quality of life) and acceptable social activity. In general, colonic cancer is biologically characterized by local growth rather than distant metastasis except in the late stage. There have been many reports which describe a good prognosis on the cases of colonic cancer undergoing the extended resection. Consequently, we should consider to indicate the extended radical operation, for the advanced colonic cancer with invasion to the other organs, if the tumor still remains locally. In this paper, we present a case of advanced colonic cancer with a cutaneous fistula and also discuss the usefulness of the extended radical operation against the advanced colonic cancer with a review of the literature.

A case of gangrenous type ischemic colitis is described. The patient was a 48-year-old woman. There was a previous history of undergoing abdominal surgery three times. After the constipation for 5 days, abdominal pain with rebound tenderness, diarrhea and bloody stool was observed. CT scan revealed a remarkable thickening of the colon, and signs of in flammation continued. Left hemicolectomy was performed. Although the mortality of gangrenous type ischemic colotis is high, the immediate operation successfully saved the life of this patient. In case of gangrenous type of ischemic colitis, early diagnosis and immediate surgery should be performed.

Postoperative endocrine and exocrine insufficiencies following traditional pancreatectomies might cause a deterioration of the quality of life and surgical outcome. Parenchyma-sparing pancreatectomies have been utilized in benign lesions and low-grade malignancies.A 67-year-old female with a past history of right nephrectomy for renal cell carcinoma 20 years earlier was referred to our institute with obstructive jaundice and multiple nodules in the pancreas. Computed tomography demonstrated five well-demarcated, strongly enhanced nodules with diameters of 5.5 cm in the head, 2.0 and 1.8 cm in the body, and 1.2 and 1.0 cm in the tail. Fluorine-18 fluorodeoxyglucose positron emission tomography did not demonstrate any extrapancreatic uptake. A middle-preserving pancreatectomy was performed after ultrasonography had confirmed arterial perfusion in the middle segment. A histological study demonstrated metastatic clear cell renal carcinoma. To date, the patient has remained without recurrence for two and a half years since surgery. A minimal administration of insulin has been necessary; however, C-peptide is detectable and nutritional status is comparatively good.A middle-preserving pancreatectomy is a useful procedure in a parenchyma-sparing pancreatectomy for resecting multifocal lesions in the head, body and tail of the pancreas.

We have previously reported that abnormal accumulation of p53, an onco-suppressor gene product, is immunohistologically demonstrable in microwave (MW)-fixed, paraffin-embedded sections of colorectal tumors with the use of a monoclonal antibody, PAb1801 (Am. J. Clin. Pathol., 97: 244-249, 1992). This monoclonal antibody targets the human specific epitope of p53 molecule but cannot distinguish the mutant form from wild-type p53, and no immunoreactivity of a mutant-specific monoclonal antibody, PAb240, could be observed in MW-fixed sections. In the present paper, we have executed a comparative immunohistochemical study on p53 and 70Kd heat shock proteins (HSP70) in MW-fixed sections of 20 colorectal carcinomas and 20 adenomas because mutant p53 has been reported to form a stable complex with HSP70. The use of PAb1801 resulted in nuclear p53 being detected in 11 out of 20 carcinomas and p53 being expressed focally in five out of 20 adenomas. In the adjacent sections, the majority of p53-positive carcinomas and adenomas also expressed HSP70 in the nucleus as well as in the cytoplasm. Coincident expression of p53 and HSP70 in the nuclei of colorectal tumor cells implies that the p53 detected with PAb1801 may be the mutated protein that forms stable complexes with HSP70.

A case of cancer of the colon associated with retrocaval ureter is reported. The case was a 47-year-old male who had a 7 cm colon cancer at the hepatic flexure of the transverse colon. There were inflammatory findings in the right flank caused by secondary infection around the colon cancer. The colon cancer existed near the right pelvic ureter to present with hydronephrosis, accordingly obstruction of ureter due to the cancer was suspected. However, CT-scan revealed a retrocaval segment and retrograde pyelography showed a sigmoid-shaped ureter, and it could be diagnosed preoperatively that hydronephrosis was caused by retrocaval ureter. Right hemicolectomy was carried out for the colon cancer and replacement of urinary tract with nephroplasty, for the retrocaval ureter.

大腸癌および大腸腺腫における癌抑制遺伝子産物p53の発現を免疫組織学的に調べた.組織の調整はマイクロウエーブ照射による迅速固定で行い,そのパラフィン切片に対して抗ヒトp53モノクローナル抗体(PAb1801)を1次抗体とするABC法を施行した.また,その隣接切片に対してp53との関連のあるheat shock protein(HSP72)およびproliferating cell nuclear antigen(PCNA)の染色をあわせて行った.p53は大腸癌98例中62例(63,2%)で癌細胞の核に検出されたが,その陽性率は癌の組織型・最大径・深達度などの臨床病理学的因子には影響されなかった.一方,腺腫では44個中4個(9%)でのみ腺腫細胞の核にp53がfocalに検出されたが,これらはいずれも異型度の低い腺腫であった.HSPは,癌および腺腫の核周囲細胞質に検出され,p53と複合体を形成しているという直接的証左はえられなかった.PCNA標識率からみると,p53陽性癌細胞の増殖能がとくに高いとは考えられなかったが,p53陽性腺腫細胞のそれは陰性の腺腫細胞に較べ明らかに高い標識率をしめした.

Objective: The primary objective of this study was to explore the efficacy and safety of combined chemotherapy with CPT-11 and UFT in patients with advanced/metastatic colorectal cancer. Methods: Twenty-two patients with metastatic colorectal cancer were enrolled in the phase I trial and 35 patients (including eight patients treated at level 4 during phase I) were evaluated in the phase II trial. Treatment consisted of two 35-day cycles of combination chemotherapy with CPT-11 and UFT. During phase I, CPT-11 was administered on days 1 and 15 as an intravenous infusion over 90 min at four different dose levels, starting from a dose of 80 mg/ m 2 (level 1). During phase II, the dose of CPT-11 was fixed at 150 mg/m 2 based on the results of the phase I study. UFT was administered orally at a fixed dose of 300 mg/m 2 on days 1‐28, followed by a 1-week drug holiday, during each course (35 days). Results: The maximum tolerated dose (MTD) of CPT-11 was determined to be 150 mg/m 2 during the phase I trial. The major toxicities detected during phase II in 35 patients receiving CPT-11 at this recommended dose were grade 3/4 neutropenia in nine patients (25.7%) and grade 3/4 anorexia in six patients (11.4%). No severe adverse events occurred. The overall response rate and the median overall survival time was 22.9% (8/35) and 23.9 months for all patients, respectively. For pre-treated patients they were 26.3% (5/19) and 25.1 months, respectively. Conclusion: This combination of CPT-11 and UFT is considered to be both feasible and relatively safe. The response rate of the patients receiving CPT-11 at a dose of 150 mg/m 2 was comparable to that reported previously for 5-FU-based regimens coupled with CPT-11, and this regimen can probably be beneficial for patients with pre-treated advanced colorectal cancer on an outpatient basis.

Treatment of metastatic colorectal cancer remains inadequate.In a multicentre Phase II study, irinotecan (100 mg/m2), 5-fluorouracil (5-FU) (500 mg/m2), and l-leucovorin (l-LV) (250 mg/m2) were administered on days 1, 8, and 15 of a five-week cycle. Forty-five patients were enrolled.The objective response rate was 26.7%. The median survival time was 21.8 months and the one-year survival rate was 73.3%. The median number of cycles was 4.0, with a median relative dose intensity of 83.3% for both irinotecan and 5-FU. Grade 3 or 4 haematological toxicities were anaemia in four patients, leukopaenia in six patients, and neutropaenia in 15 patients, while non-haematological toxicities were diarrhoea in three patients, and nausea, vomiting, anorexia and increased transaminases in two patients each. No treatment-related deaths occurred.Irinotecan plus 5-FU/l-LV can be used to treat metastatic colorectal cancer on an outpatient basis.