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Background: Microsatellite instability (MSI) is a clonal change in the number of repeated DNA nucleotide units in microsatellites. High-frequency MSI (MSI-H) colorectal cancers (CRCs) are known to have different clinicopathological features compared with microsatellite stable (MSS) CRCs. In addition, previous studies have shown that type2 diabetes mellitus (T2DM) is a risk factor for malignant tumors including CRCs. The aim of this study was to investigate the relationship between T2DM and MSI-H colorectal cancer., Methods: The study design is a single center, cross-sectional study. Data from a series of 936 patients with CRCs were collected and MSI status was assessed., Results: In total, 29 (3.1%) and 907 (96.9%) tumors were classified as having MSI-H and low-frequency microsatellite instability or being MSS (MSS), respectively. Of the 936 patients, 275 (29.6%) were associated with T2DM. One (3.4%) of the 29 MSI-H patients and 274 (30.2%) of the 907 MSS patients had T2DM. Thus, the incidence of T2DM was significantly less frequent in MSI-H compared with MSS patients (Fisher's exact test: p = 0.0007)., Conclusions: We conclude that MSS tumors are significantly more common than MSI-H tumors among individuals with T2DM., Competing Interests: The authors have declared that no competing interests exist.

Recent developments in techniques of metabologenomics have given a better understanding the association of gut microbiota with various diseases. Gut microbiota has a strong impact on host immunostasis and homeostasis of gut function for maintaining the health condition. Dysbiosis leads to an increase in bacterial populations that stimulate tumorigenesis, and contributes to epithelial carcinogenesis and tumor progression by altering metabolic properties(such as bile acid and butyric acid)and inflammatory process. Inflammation aid the bacterial translocation into the neoplastic tissue, which in turn promotes production of inflammatory cytokines subsequently leading to tumor growth. The colonic microbiota such as enterotoxigenic Bacteroides fragilis(ETBF)may also promote colorectal cancer by stimulating exaggerated immune responses via Th17 cells. Dysbiosis caused by a deficiency of the NLRP6 inflammasome promotes cancer development via interleukin-6(IL- 6)-induced epithelial proliferation. Emerging data suggest that certain groups of bacteria might promote whereas others might protect against colon cancer. Indeed, Fusobacteriumnucleatum (F. nucleatum)seems to play a central role in the tumor microenvironment as its abundance correlates with cancer progression as well as the dysbiotic tumor microbiota composition including Bacteroides and Prevotella species. Moreover, gut microbiota not only plays a key role in carcinogenesis but also influences the efficacy and toxicity of cancer immunotherapy, especially immune checkpoint inhibitors by targeting the programmed death receptor 1(PD-1)and the cytotoxic T lymphocyte antigen 4(CTLA-4).

Background: The aim of this study was to clarify clinicopathological features, frequencies of molecular biomarkers, and prognoses in Japanese colorectal cancer patients and compare them with right-sided colon cancer (RCC) and left-sided colorectal cancer (LCRC)., Methods: We consecutively selected 575 colorectal cancer patients who underwent surgical resection from 2008 to 2011. RCC was located from the cecum to the transverse colon, and LCRC was located from the splenic flexure to the rectum. Frequencies of KRAS gene mutation, BRAF gene mutation, microsatellite instability (MSI), l18qLOH and CpG island methylator phenotype (CIMP) were statistically analyzed between groups., Results: Tumors were located in the RCC in 26.3% of patients and in the LCRC in 73.7%. Elderly patients, females and advanced diseases were significantly more frequent in the RCC group than in the LCRC group. However, venous invasion was significantly more frequent in LCRC than in RCC. Between groups, BRAF mutant type, KRAS mutant type, MSI and CIMP+ were significantly more frequent in RCC, whereas 18qLOH was significantly more frequent in LCRC. In overall survival, RCC demonstrated poor prognosis compared with LCRC; however, age, gender, stage, lymphatic invasion, KRAS status and BRAF status rather than tumor location were independent prognostic factors. In addition, the independent prognostic factors in RCC were different from those in LCRC in each stage. However, the consistency between OS and DFS was not observed in this study, excluding lymphatic invasion in LCRC., Conclusion: Comparing RCC with LCRC, RCC is different from LCRC in clinicopathological features, molecular biomarkers and prognostic factors in Japanese colorectal cancer patients. Since the proportions of molecular biomarkers of CRC in this study are different from Western CRCs, further studies are required to clarify the clinicopathological differences between Japanese CRCs and Western CRCs.

Background: Because bone metastasis from colorectal cancer is rare, there are little available data regarding such cases., Objective: The study aim was to identify the prognostic factors and characteristics associated with survival in colorectal cancer patients with bone metastasis., Design: This was a retrospective study from a prospectively collected database., Settings: The study took place in a multidisciplinary, high-volume tertiary cancer center in Japan., Patients: Examined were records from 104 consecutive patients treated between 2004 and 2015 for bone metastasis from colorectal cancer., Main Outcome Measures: The primary outcome measure was overall survival., Results: The spine was the most common site of bone metastasis from colorectal cancer. Right colon cancer correlated significantly with long bone metastasis (p = 0.046), whereas left colon cancer correlated significantly with spinal bone metastasis (p = 0.034). Liver metastasis was also significantly correlated with spinal bone metastasis (p = 0.036). The median interval between the primary therapy for colorectal cancer and the metachronous diagnosis of bone metastasis was 20.0 months (quartile 1 to quartile 3, 9.0-46.5 mo). The median survival time from diagnosis of bone metastasis from colorectal cancer was 5.0 months (95% CI, 4.0-9.0 mo), and the 1-year survival rate was 30.0% (95% CI, 21.1%-39.4%). Multivariate analysis revealed that ≥2 extra-bone metastatic organs, hypercalcemia, and pathologic fractures were independent poor prognostic factors (p < 0.001, 0.001, and 0.033). The number of extra-bone metastatic organs correlated with prognosis., Limitations: This study was limited by its retrospective, nonrandomized design, as well as selection bias and performance at a single institute., Conclusions: The location of colorectal cancer correlates significantly with the site of bone metastasis; the prognosis of patients with bone metastasis from colorectal cancer is very poor, and the significant prognostic factors are number of extra-bone metastatic organs, hypercalcemia, and pathologic fractures. See Video Abstract at http://links.lww.com/DCR/A589.

Objectives: The objective of this study was to assess prospectively the diagnostic accuracy of computer-assisted computed tomographic colonography (CTC) in the detection of polypoid (pedunculated or sessile) and nonpolypoid neoplasms and compare the accuracy between gastroenterologists and radiologists., Methods: This nationwide multicenter prospective controlled trial recruited 1,257 participants with average or high risk of colorectal cancer at 14 Japanese institutions. Participants had CTC and colonoscopy on the same day. CTC images were interpreted independently by trained gastroenterologists and radiologists. The main outcome was the accuracy of CTC in the detection of neoplasms ≥6 mm in diameter, with colonoscopy results as the reference standard. Detection sensitivities of polypoid vs. nonpolypoid lesions were also evaluated., Results: Of the 1,257 participants, 1,177 were included in the final analysis: 42 (3.6%) were at average risk of colorectal cancer, 456 (38.7%) were at elevated risk, and 679 (57.7%) had recent positive immunochemical fecal occult blood tests. The overall per-participant sensitivity, specificity, and positive and negative predictive values for neoplasms ≥6 mm in diameter were 0.90, 0.93, 0.83, and 0.96, respectively, among gastroenterologists and 0.86, 0.90, 0.76, and 0.95 among radiologists (P<0.05 for gastroenterologists vs. radiologists). The sensitivity and specificity for neoplasms ≥10 mm in diameter were 0.93 and 0.99 among gastroenterologists and 0.91 and 0.98 among radiologists (not significant for gastroenterologists vs. radiologists). The CTC interpretation time by radiologists was shorter than that by gastroenterologists (9.97 vs. 15.8 min, P<0.05). Sensitivities for pedunculated and sessile lesions exceeded those for flat elevated lesions ≥10 mm in diameter in both groups (gastroenterologists 0.95, 0.92, and 0.68; radiologists: 0.94, 0.87, and 0.61; P<0.05 for polypoid vs. nonpolypoid), although not significant (P>0.05) for gastroenterologists vs. radiologists., Conclusions: CTC interpretation by gastroenterologists and radiologists was accurate for detection of polypoid neoplasms, but less so for nonpolypoid neoplasms. Gastroenterologists had a higher accuracy in the detection of neoplasms ≥6 mm than did radiologists, although their interpretation time was longer than that of radiologists., Competing Interests: Guarantors of the article: Hiroyuki Yoshida, PhD, and Koichi Nagata, MD, PhD. Specific author contributions: Acquisition of data: Honda, Yasuda, Hirayama, Takahashi, Kato, Horita, Furuya, Kasai, Matsumoto, Kimura, Kato, Kondo, Abe, Yamano, Takeuchi, Saida, and Fukuda; analysis and interpretation of data: Nagata, Honda, Hirayama, Kato, Furuya, Matsumoto, Utano, Ryu, and Kasai; drafting of the manuscript: Nagata and Yoshida; critical revision of the manuscript for important intellectual content: all authors; statistical analysis: Yamamichi and Shimamoto; obtaining funding: Nagata and Yoshida; administrative, technical, or material support: Yoshida, Nagata, Endo, Näppi, Sugimoto, Yamada, Matsui, Doi, Yamano, Hanai, and Saida; study supervision: Yoshida and Nagata. All authors had access to the study data and reviewed and approved the final manuscript. Financial support: This study was in part supported by the Japanese CTC Society, Ajinomoto Pharmaceutical, and R01CA095279 (Principal Investigator: Yoshida) from the National Institutes of Health, Bethesda, Maryland. The Japanese CTC Society did have a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication. The industry sponsor, Ajinomoto Pharmaceutical, had no role in the above aspects of the study. The National Institutes of Health had no role in the above aspects of the study, but had a role in supporting the development of computer-aided diagnosis software for image interpretation used in the study through grant R01CA095279. Potential competing interests: Koichi Nagata reported that he is an inventor of PEG-C bowel preparation and holds a licensing agreement with Ajinomoto Pharmaceutical, without associated royalty, had a 1-year consulting agreement with Aze, during 2010–2011 with associated compensation, and was partially supported by the National Institutes of Health. Janne Näppi reported that he is a co-inventor of CAD software patents assigned to his home institution, without associated royalties, and was partially supported by the National Institutes of Health. Hiroyuki Yoshida reported that he is a co-inventor of CAD software patents assigned to his home institution, without associated royalties, had a 1-year consulting agreement with Aze, during 2010–2011 with associated compensation, and was partially supported by the National Institutes of Health. The remaining authors declare no conflict of interest.

Background: Capecitabine and irinotecan combination therapy (XELIRI) has been examined at various dose levels to treat metastatic colorectal cancer (mCRC). Recently, in the Association of Medical Oncology of the German Cancer Society (AIO) 0604 trial, tri-weekly XELIRI plus bevacizumab, with reduced doses of irinotecan (200 mg/m 2 on day 1) and capecitabine (1600 mg/m 2 on days 1-14), repeated every 3 weeks, has shown favorable tolerability and efficacy which were comparable to those of capecitabine and oxaliplatin (XELOX) plus bevacizumab. The doses of capecitabine and irinotecan in the AIO trial are considered optimal. In a phase I/II study, XELIRI plus bevacizumab (BIX) as second-line chemotherapy was well tolerated and had promising efficacy in Japanese patients., Methods: The Asian XELIRI ProjecT (AXEPT) is an East Asian collaborative, open-labelled, randomized, phase III clinical trial which was designed to demonstrate the non-inferiority of XELIRI with or without bevacizumab versus standard FOLFIRI (5-fluorouracil, leucovorin, and irinotecan combination) with or without bevacizumab as second-line chemotherapy for patients with mCRC. Patients with 20 years of age or older, histologically confirmed mCRC, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and disease progression or intolerance of the first-line regimen will be eligible. Patients will be randomized (1:1) to receive standard FOLFIRI with or without bevacizumab (5 mg/kg on day 1), repeated every 2 weeks (FOLIRI arm) or XELIRI with or without bevacizumab (7.5 mg/kg on day 1), repeated every 3 weeks (XELIRI arm). A total of 464 events were estimated as necessary to show non-inferiority with a power of 80% at a one-sided α of 0.025, requiring a target sample size of 600 patients. The 95% confidence interval (CI) upper limit of the hazard ratio was pre-specified as less than 1.3., Conclusion: The Asian XELIRI ProjecT is a multinational phase III trial being conducted to provide evidence for XELIRI with or without bevacizumab as a second-line treatment option of mCRC. Trial registration ClinicalTrials.gov NCT01996306. UMIN000012263.

Objective: BRAF D594G mutations in colorectal cancer patients are not clearly understood. We retrospectively investigated the clinicopathological features of colorectal cancers with BRAF D594G mutations., Methods: We selected 908 colorectal cancer patients who underwent surgical resection from January 2008 to January 2013, and assessed BRAF, KRAS, microsatellite instability, and CpG island methylator phenotype (CIMP)., Results: We detected BRAF D594G in 7 patients and BRAF V600E in 45 patients. The clinicopathological features of cancers with BRAF D594G mutation were similar to those with BRAF wild-type, but differed from those with BRAF V600E mutations. Regarding microsatellite instability status, 44.4% of cases with BRAF V600E mutations exhibited high microsatellite instability, compared to 14.3% of those with BRAF D594G mutations and 4.4% of those with BRAF wild-type. There were no CIMP-positive tumors in cancers with BRAF D594G mutations, whereas 67.8% of tumors with BRAF V600E mutations were CIMP-positive. In stage IV cancers, the survival rates of patients at 2 years were 8.5, 50.0, and 68.2% in the BRAF V600E mutation, BRAF D594G mutation, and BRAF wild-type groups, respectively., Conclusion: Colorectal cancers with BRAF D594G mutations exhibit similar clinicopathological features, microsatellite instability status, and prognosis as those with BRAF wild-type., (© 2016 S. Karger AG, Basel.)

Background: A Japanese multicenter study disclosed four prognostic indicators of colorectal cancer liver metastases: ≥5 hepatic tumors (HT), HT size > 5 cm, nodal status (N2) of primary cancer, and the presence of extrahepatic metastases (EM). The Japanese classification was then defined as Stage A, HT1 (≤4 lesions and ≤5 cm) and N0/1; Stage B, HT2 (≥5 lesions or >5 cm) and N0/1, or HT1 and N2; and Stage C, HT2 and N2, HT3 (≥5 lesions and >5 cm) with any N, or EM1 (presence of EM) with any HT/N. This study aimed to validate the prognostic reliability in a recent population and to develop a modified staging system that divided Stage C patients., Methods: A total of 1185 patients diagnosed with liver metastases between 2007 and 2008 were enrolled in the study. According to the classification, 358, 257, and 570 patients were categorized as Stages A, B, and C, respectively. Stage C was further divided into two groups: Stage C-I, HT3 and N0/1, HT2 and N2, or HT1 and EM1; and Stage C-II, HT3 and N2, or HT2/3 and EM1., Results: Cumulative overall survival curves for Stages A, B, and C were significantly different between each two stages (p < 0.0001, p < 0.0001). The modified system discriminated patients with a relatively better outcome (Stage C-I) from desperate patients (Stage C-II) (p < 0.0001)., Conclusions: The Japanese classification system was adequately validated in a recent population, and the modified system is useful in risk stratification of Stage C cases.

Purpose: S-1, a novel oral prodrug of 5-fluorouracil (5-FU), and irinotecan with or without bevacizumab is known to be effective in metastatic colorectal cancer (mCRC). However, it is not clear whether S-1 and irinotecan confers benefits compared to 5-FU and leucovorin plus oxaliplatin (FOLFOX) in patients with mCRC. Our aim was to compare the efficacy and safety of these regimens., Methods: We analyzed 187 patients with previously untreated mCRC who were enrolled in four phase II studies: SIR (S-1 and irinotecan, n = 40), SIRB (S-1 and irinotecan with bevacizumab, n = 51), FOLFOX (5-FU and leucovorin plus oxaliplatin, n = 46), and STOX (stop-and-go strategy of modified FOLFOX-6 with bevacizumab, n = 50). We evaluated efficacy and safety between SIR/SIRB and FOLFOX/STOX., Results: Baseline characteristics were similar in the two groups composed of SIR/SIRB (n = 91) and FOLFOX/STOX (n = 96). The overall response rates were not significantly different between the two groups (65% in SIR/SIRB vs. 52% in FOLFOX/STOX, p = 0.125). The median progression-free survival was 10.9 months in SIR/SIRB versus 12.1 months in FOLFOX/STOX (p = 0.59). The median overall survival was 27.3 months in SIR/SIRB versus 26.8 months in FOLFOX/STOX (p = 0.97). Gastrointestinal adverse events were the most common toxicities in SIR/SIRB, while neutropenia and sensory neuropathy were the most common toxicities in FOLFOX/STOX., Conclusions: S-1 and irinotecan with or without bevacizumab was well tolerated and showed similar response rates and survival compared to the FOLFOX regimen. This combination should be considered as an experimental first-line treatment for mCRC.

We evaluated the relationship between colorectal neoplasms and visceral obesity using computed tomographic colonography and adipocytokine levels. We included 123 patients and classified them into four groups as per computed tomographic colonography: no lesion (NL; n=40), adenomatous polyp (polyp; n=41), early colorectal cancer (eCRC; n=21), and advanced CRC (aCRC; n=21). We also measured the patients' serum metabolic markers and adipocytokine levels. The visceral adiposity index in the polyp and eCRC groups was significantly higher than that in the NL group. Visceral obesity is an important risk factor for the development of colonic polyps. Computed tomographic colonography could be a useful examination technique not only for diagnosis of colorectal neoplasms but also for simultaneous evaluation of visceral obesity.

Previous reports of the influence of UGT1A1 gene polymorphisms on the pharmacokinetics of irinotecan metabolism have not assessed Asian patients treated with FOLFIRI plus bevacizumab for advanced and recurrent colorectal cancer. Twenty-one Japanese colorectal cancer patients received intravenous FOLFIRI (bolus irinotecan, folinic acid, and fluorouracil followed by 46-hour fluorouracil infusion) followed by bevacizumab (5 mg/kg) in Cycle 1. In Cycle 2, patients received bevacizumab followed by FOLFIRI. The regimen was in 2-week cycles. The area under-the-curves ratio (AUC0-last) (Cycle 2/Cycle 1) was determined from plasma concentrations of irinotecan and metabolites (SN-38, SN-38G). Safety, efficacy, and drug-drug interactions were analyzed. Median observation period was 7.8 months; median number of cycles 15. Drug-drug interactions were evaluated in eight patients without irinotecan dose reduction. Mean AUC0-last ratios (with/without bevacizumab) of irinotecan, SN-38, and SN-38G were 0.959, 0.927, and 0.931 respectively. Response rate was 65%; median progression-free survival 16.4 months. Response occurred in four patients with, and nine without, UGT1A1 polymorphism. No significant differences occurred between efficacy, safety, or polymorphism status. This cohort showed no differences in safety or efficacy compared to previous reports. Bevacizumab did not affect the pharmacokinetics of irinotecan and its metabolites, irrespective of UGT1A1 polymorphism status., (© 2014, The American College of Clinical Pharmacology.)

Background: Colorectal cancer infrequently causes brain metastasis, and the prognosis is poor., Objective: The aim of this study was to identify the prognostic factors associated with survival and outcome of treatment for patients with brain metastasis from colorectal cancer., Design: This is a retrospective study from a prospectively collected database., Settings: The investigation took place in a high-volume multidisciplinary tertiary cancer center in Japan., Patients: From 1979 to 2010, 113 consecutive patients who were treated for brain metastasis from colorectal cancer were identified., Main Outcome Measures: The primary outcome measure was overall survival., Results: Sixty-three patients had neurosurgical resection (including curative resection for 46 patients) followed by whole brain radiotherapy, 9 had stereotactic radiosurgery, 30 had whole brain radiotherapy, and 11 had steroid and palliative care. As a whole, the overall median survival time from diagnosis of brain metastasis was 5.4 months (95% CI, 4.3-7.6 months), and the 1-year survival rate was 29% (95% CI, 22%-38%). In the group of patients who underwent curative neurosurgical resection, the overall median survival time was 15.2 months (95% CI, 9.2-17.8 months), and the 1-year survival rate was 57% (95% CI, 43%-71%). On multivariate analysis, 1 or 2 brain metastatic lesions, no extracranial metastatic lesions, and neurosurgical resection were independent favorable prognostic factors overall (p = 0.0057, 0.0197, and <0.0001), and 1 or 2 brain metastatic lesions, no extracranial metastatic lesion, and no emergence of secondary brain metastatic lesions were independent favorable prognostic factors in the group of patients who underwent curative neurosurgical resection (p = 0.0137, 0.0081, and 0.0010)., Limitations: This study was limited by its single-institute, retrospective, nonrandomized design and selection bias., Conclusions: Neurosurgical resection in select patients is a reasonable option for brain metastasis from colorectal cancer, although it is not associated with long-term (5-year) survival. (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A121 ).

Background: Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer., Methods: We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20-80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m(2) oxaliplatin, 200 mg/m(2)l-leucovorin, 400 mg/m(2) bolus fluorouracil, and 2400 mg/m(2) infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m(2) intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699., Findings: Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7-13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7-12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86-1·27; less than non-inferiority margin of 1·33, pnon-inferiority=0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 [34%] vs 22 [9%]; p<0·0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0·019) and diarrhoea (23 [9%] vs seven [3%]; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab)., Interpretation: SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations., Funding: Taiho., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Surgery is the most optimal and curative intent strategy for liver recurrence from colorectal cancer. There are scoring systems and grade classification for liver resection. If we carry out preoperative imaging of liver metastases strictly following to liver resection, we can expect to get a cure state satisfactory. Early detection and repeated liver resection improve the outcome of residual liver recurrence after liver resection. The maximum number of liver metastases for cure intent liver resection is unclear. Further examination is necessary.

Fluorouracil (5-FU) plus irinotecan combined with bevacizumab has significant activity in metastatic colorectal cancer (mCRC), but S-1 has become a substitute for continuous infusion of 5-FU and has a very low incidence of hand-foot syndrome. With the S-1 plus irinotecan regimen (SIR), the response rate was 62.5%, and the progression-free survival was 8.0 months. We report here on an update of efficacy and safety of the SIR plus bevacizumab (SIRB) regimen as first line treatment for mCRC patients. Fifty-one eligible patients with histologically confirmed advanced or recurrent colorectal cancer received this treatment. S-1 was administered orally on days 1-14 of a 21-day cycle. Patients were assigned on the basis of body surface area (BSA) to receive one of the following oral doses twice daily: 40 mg, 50 mg, or 60 mg. Irinotecan (150 mg/m(2)) plus bevacizumab (7.5 mg/kg) were administered by intravenous infusion on day 1. Safety analysis identified a grade 3/4 neutropenia rate of 26%. Other grade 3/4 toxicities were diarrhea (8%), nausea (6%), vomiting (2%), and hypertension (8%). The response rate was 67% and the median progression-free survival time was 373 days. The SIRB regimen appears to be highly active and well tolerated as first-line treatment for mCRC.

Purpose: To evaluate the efficacy and tolerability of systemic chemotherapy with irinotecan (CPT-11), UFT and leucovorin (LV) combined with hepatic arterial infusion (HAI) consisting of 5-fluorouracil (5-FU) in colorectal cancer patients with unresectable liver metastases., Methods: Patients were treated concurrently with escalating doses of intravenous CPT-11 (100, 120, and 140 mg/m²) on day 1 of each 14-day treatment cycle, with oral UFT (300 mg/m² per day) and LV (75 mg/body per day) on days 1-7 of each cycle, and with HAI 5-FU (2,000 mg/week) on days 8-14 of each cycle., Results: Twelve patients were enrolled in the phase I study. The maximum-tolerated dose was not reached. Consequently, the recommended dose of CPT-11 for the phase II study was determined to be 140 mg/m². Twenty-two patients were evaluated in the phase II study. Five patients experienced grade 3 neutropenia, two experienced grade 3 anorexia, two experienced nausea, and two experienced vomiting. An overall response was observed in 19 out of 22 patients (86.4%). The median progression-free survival period was 11.2 months, and the 3-year survival rate was 50.6%. Fourteen patients (63.6%) were ultimately able to undergo a complete liver resection., Conclusions: Chemotherapy with CPT-11 and UFT/LV combined with HAI yielded a high response rate and enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. Further trials are warranted.

If hepatic or pulmonary metastases from colorectal cancer are resectable, we perform the operation, and the 5-year survival rate is 40-50%. Median survival time is over 20 months recently for systemic chemotherapy. However, surgical treatment is the only way to obtain a cure. RFA has the advantage of being minimally invasive. But the local recurrence rate is slightly high. It is important to detect a local recurrence early and perform repeated RFA. Repeated RFA improve the prognosis and get the same overall survival rate of liver resection. If both the hepatic and pulmonary metastases are resectable, we perform both resections, with a good surgical outcome. If we cannot perform a second metastasectomy after first metastasectomy, the prognosis is very poor compared to the prognosis for liver metastasis only or lung metastasis only. It is necessary to add many cases to decide the surgical indication for such cases of both liver and lung metastases.

The number of surgeries for colorectal cancer in elderly patients is increasing in correspondence to Japan's aging society. It is important to evaluate the patient's condition in order to carry out operations safely. The Onodera index (Onodera index in order (PNI: prognostic nutritional index)=serum alb value × 10+the lymphocyte counts of peripheral blood) is a simple and useful tool for choosing the method of operation. In our experience, 75% of elderly patients had pre-operative complications. Respiratory and circulatory complications occurred more frequently after operations. Pre- and post-operative adequate management can help facilitate a safer operation. Even if a curative operation was carried out for an elderly patient, both the cancer-specific survival rate and the 5-year relative survival rate were good. If the operation is tolerable for the elderly patient, curative resection should be performed. Chemotherapy in elderly should be also evaluated by the patient's activities of daily living and the regimen of chemotherapy should be selected.

Purpose: The liver is the most common site of metastasis in patients with colorectal cancer (CRC), and this is a determinant of the prognosis. However, no reliable molecular predictors of liver metastasis have yet been identified., Methods: Sixty-two surgical specimens of colorectal cancer were studied. The first group included 25 patients who achieved a disease-free survival period of at least 6 years (CRC-M0), and the second group included 37 patients with synchronous (n = 22) or metachronous (n = 15) liver metastasis (CRC-M1). SMAD4, p53, and Ki-67 expression levels were assessed immunohistochemically., Results: The loss of SMAD4 expression and elevated Ki-67 expression were found significantly more frequently in CRC-M1 patients than in CRC-M0 patients (P = 0.0047 and P = 0.013, respectively). Statistically significant differences were also observed between the CRC-M0 group and the metachronous metastasis group. No difference was seen in the overexpression of p53 between the groups. A combination analysis of SMAD4 and Ki-67 revealed no cases with maintained levels of SMAD4 and a low Ki-67 expression had or developed liver metastasis., Conclusion: The loss of SMAD4 expression and elevated Ki-67 expression was therefore found to significantly correlate with liver metastasis, regardless of the time of occurrence, thus indicating these factors to be predictive markers for liver metastasis in patients with CRC.

Postoperative follow-up provides no evidence of prolongation of the prognosis after colorectal cancer surgery. But there is definite evidence of the improvement of surgical outcome if the metastatic lesion is respectable. It is important to detect a recurrence early and in the respectable state. Establishing a good follow-up system is meaningful. The Japanese guideline follow-up planning was compared with the ASCO 2005 and ESMO 2009 surveillance recommendations. Japanese planning is considered to be clearly more rigorous than those of Europe and America and able to discover recurrences early.

Objectives: Cdc4 (Fbxw7) is a potential tumor suppressor that regulates ubiquitination and proteolysis of multiple targets such as cyclin E, c-Myc, c-Jun and Notch. CDC4 mutations were investigated in 194 colorectal carcinomas and adenomas for comparison between sporadic and hereditary cancers., Methods: Mutations of the CDC4 gene were analyzed by PCR-SSCP and sequencing, and loss of heterozygosity (LOH) was analyzed by microsatellite marker analysis., Results: Somatic CDC4 mutations were detected in 9% (3 of 33) of hereditary nonpolyposis colorectal cancer (HNPCC), 9% (3 of 33) of familial adenomatous polyposis (FAP) carcinomas, and 10% (7 of 73) of sporadic carcinomas. CDC4 mutations were also detected in adenomas at frequencies of 6% (2 of 31) and 4% (1 of 24) in FAP and sporadic cases, respectively. Frameshift mutations were observed in HNPCC tumors, while single-base substitutions predominantly occurred in FAP and sporadic tumors. LOH at the chromosome 4q region was rarely detected in tumors with CDC4 mutations., Conclusions: The results indicate that the frequency of CDC4 mutations in colorectal tumors is similar in patients with HNPCC and FAP compared to patients with sporadic carcinomas. Moreover, infrequent LOH suggests that the CDC4 gene does not follow the general 2-hit model., (Copyright 2009 S. Karger AG, Basel.)

Background/aims: Although numerous authors have reported various prognostic factors for liver metastases from colorectal cancer, there is not yet a general classification., Methodology: A total of 478 colorectal cancer patients from 18 institutes were studied. Prognostic factors were investigated using univariate and multivariate analyses., Results: Independent prognostic factors for colorectal liver metastases were number of liver metastases, size of the largest liver metastases, mesenteric lymph node metastases (pN0/1: < or =3 lesions, pN2: > or =4 lesions), and extrahepatic metastases (EM0: absence of extrahepatic metastasis, EM1: presence of extrahepatic metastases). We defined the following classification system; Stage A: HT1 (< or =4 lesions and < or =5cm) and pN0/1, Stage B: HT2 (> or =5 lesions or >5cm) and pN0/1, or HT1 and pN2, Stage C: HT2 and pN2, HT3 (> or =5 lesions and >5cm) with any pN, or any HT and any pN with EM1. Five-year survival rates were 53.5% for Stage A patients, 25.4% for Stage B patients, and 5.8% for Stage C patients. Median survival time was 70.4 months, 31.4 months, and 17.2 months, respectively., Conclusions: Our classification was advocated to evaluate prognoses for liver metastases from colorectal cancer. It can help guide decision making in terms of liver resection and assessing patient prognosis.

We examined the expression of sVEGFR1 in colorectal cancer tissue and corresponding normal colorectal mucosa to assess the clinical significance of sVEGFR1 in colorectal cancer. We also assessed the relationship between sVEGFR1 levels and various clinicopathologic factors and prognoses. sVEGFR1 and VEGF levels were measured in fresh-frozen tumor extracts from 84 primary colorectal cancer tissues and 27 corresponding normal mucosa using ELISA. Mean of sVEGFR1 levels were 3.17 ng/mg protein. sVEGFR1 levels increased significantly in cancer tissue compared with normal mucosa. Although VEGF levels increased in cancer tissues, the ratio of sVEGFR1/VEGF in cancer tissue was significantly lower than that in normal tissue. No significant correlation between sVEGFR1 or VEGF levels and any clinicopathologic parameter was found. Overexpression of sVEGFR1 was significantly associated with a favorable prognosis. Based on sVEGFR1 levels in colorectal cancer without distant metastases, patients with higher sVEGFR1 levels (>=1.5 ng/mg protein) demonstrated significant longer recurrence-free survival than patients with lower sVEGFR1 levels (<1.5 ng/mg protein) (P = 0.0017). Multivariate analysis showed that the sVEGFR1 levels in cancer tissue were an independent prognostic indicator of disease progression. sVEGFR1 expression was significantly elevated in colorectal cancer tissue compared with normal mucosa and the intratumoral balance between sVEGFR1 and VEGF was significantly different between tumor tissue and normal controls. Furthermore, sVEGFR1 levels showed a significant prognostic value. Further studies concerning the biologic and therapeutic significance of sVEGFR1 in colorectal cancer are warranted.

Purpose: N(1),N(12)-diacetylspermine (DiAcSpm) in the urine of colorectal and breast cancer patients was examined to establish its usefulness as a novel diagnostic tool for detecting these cancers at clinically early stages., Experimental Design: Urine samples from 248 colon cancer patients and 83 breast cancer patients as well as 51 patients with benign gastrointestinal diseases treated in Tokyo Metropolitan Komagome Hospital during the period of August 1999 to January 2004 were collected. DiAcSpm was analyzed by ELISA and its sensitivity for malignant conditions was compared with that of serum carcinoembryonic antigen (CEA), CA19-9, and CA15-3., Results: The sensitivity of urinary DiAcSpm for colon cancer patients (n = 248) was 75.8% (mean +/- 2 SD for 52 healthy controls as a cutoff value), which was markedly higher than the sensitivities of serum CEA (39.5%, P < 0.0001) and CA19-9 (14.1%, P < 0.0001). DiAcSpm was elevated in 60% of tumor-node-metastasis cancer stage 0 + I patients, whereas only 10% (P < 0.0001) and 5% (P < 0.0001) of these patients were CEA- and CA19-9-positive, respectively. The sensitivity of urinary DiAcSpm for 83 cases of breast cancer (60.2%) was higher than the sensitivities of CEA (37.3%, P = 0.0032) and CA15-3 (37.3%, P = 0.0032). DiAcSpm was elevated in 28% of tumor-node-metastasis stage I + II patients, whereas only 3% (P = 0.0064) and 0% (P = 0.001) of these patients were CEA- and CA15-3-positive, respectively., Conclusion: The observations indicate that urinary DiAcSpm is a more sensitive marker than CEA, CA19-9, and CA15-3 and that it can efficiently detect colorectal and breast cancers at early stages.

Thymidine phosphorylase (TP) is a unique enzyme involved not only in angiogenesis, but in 5-fluorouracil (5-FU) metabolism as well. TP is produced by both tumor and stromal cells. The aim of this study was to reveal the clinical implication of TP localization in tumor tissues. Advanced colorectal cancer specimens (n=97) were prepared for immunohistochemical staining using monoclonal antibodies against TP, p53, vascular endothelial growth factor (VEGF), factor VIII, CD68 and thymidylate synthase (TS). Clinicopathological factors and the clinical prognosis were examined for each indicator. High tumor TP expression and high stromal TP expression were observed in 38% (36/95 cases) and 49% (47/95 cases) of the cases, respectively. High tumor TP expression tended to correlate with microvessel density (MVD) (p=0.0511). Among patients who underwent curative resection, those with high stromal TP expression had a favorable prognosis (p=0.0127). High stromal TP status was also a strong prognostic factor in the group receiving adjuvant 5-FU derivatives (p=0.0222). TP produced by tumor cells has a stimulatory effect on tumor angiogenesis, while that produced by stromal cells plays an entirely different role. The latter may enhance the anticancer effect of 5-FU via its catalyzed function.

Purpose: If the chemotherapy at home is as effective as the chemotherapy at an outpatient clinic, QOL of the patients will be improved. In this paper the future of chemotherapy at home was clarified from the outcome of the chemotherapy for advanced and recurrent colorectal cancer., Method: Hepatic arterial infusion chemotherapy (HAI) (5-FU 2,000 mg/w, continuous infusion for 7 days, n=123) for unresectable liver metastases and FL chemotherapy (5 FU 1,500 mg + l-LV 375 mg/w, continuous systemic chemotherapy for 7 days, n=32) for extra hepatic recurrence were carried out at home by a portable pump system every other week., Results: The response rates were 61.2% in HAI and 18.8% in FL. MST were 14.7 months in HAI and 10.8 months in FL. It was important to establish a surveillance network system to continue the chemotherapy at home., Conclusions: It was suggested that the chemotherapy at home was effective and to maintain the patient's QOL as one of the options.

Purpose: RECK, a membrane-anchored regulator of matrix metalloproteinases (MMPs), is widely expressed in healthy tissue, whereas it is expressed at lower levels in many tumor-derived cell lines. Studies in mice and cultured cells have shown that restoration of RECK expression inhibits tumor invasion, metastasis, and angiogenesis. However, the clinical relevance of these findings remains to be fully documented. Here we examined the expression of RECK and one of its targets, MMP-9, in colorectal cancer tissue., Experimental Design: The RECK and MMP-9 expression levels in colorectal cancer samples from 53 patients were determined by immunohistochemical techniques. The expression level of each protein was scored, and the patients were divided into two groups based on these scores. In 33 cases, we performed gelatin zymography to estimate the degree of MMP-2 and MMP-9 activation. Microvessel density and vascular endothelial growth factor (VEGF) expression were also evaluated histologically., Results: RECK protein was detected in 30 of 53 (56.6%) specimens. Importantly, patients with tumors expressing relatively high levels of RECK (high-RECK group) had a significantly lower risk of recurrence than did patients with tumors expressing relatively low levels of RECK (low-RECK group; P = 0.011). Moreover, RECK-dominant (RECK score > or = MMP-9 score) patients showed a significantly lower incidence of recurrence than did MMP-9-dominant patients (P = 0.0003). Multivariate analysis revealed that the RECK/MMP-9 balance was an independent prognostic factor (P = 0.0122). The expression of VEGF and microvessel density were inversely correlated with the level of RECK expression., Conclusions: RECK/MMP-9-balance is an informative prognostic indicator for colorectal cancer. Our data also suggest that RECK suppresses tumor angiogenesis, probably by limiting the availability of VEGF in tumor tissues.

We analyzed the significance of the measurement of urine di-acetyl spermine (DiAcSpm) as a cancer marker for colorectal cancer treatment. We measured both the urine DiAcSpm(ELISA, normal range: 0-0.25 mumol/creatinine) and serum CEA (normal range: 0-5.0 ng/ml) of preoperative and postoperative colorectal cancer patients every month. We compared the positive rate from the cancer stage and the power of prognostic prediction. We divided the colorectal cancer patients into 4 groups: Group A: both levels were high; Group B: only the CEA level was high; Group C: only the DiAcSpm level was high; Group D: both levels were within a normal range. The positive rates of DiAcSpm and CEA from cancer staging were as follows: Stage 0: 62% and 9.5%, Stage I: 60% and 10%, Stage II: 70% and 42%, Stage III: 82% and 47%, and Stage IV: 88% and 63%, respectively. There was a significant difference (p < 0.0001) between both levels, especially for early-stage cases. The two-year survival rate was 0% in Group A, 100% in Group B, 72.7% in Group C and 100% in Group D. The difference among the 4 groups was significant (p < 0.0001). This showed that urine DiAcSpm predicted the prognosis after colorectal cancer surgery more exactly than serum CEA.

We measured TS and DPD activities in 40 patients with colorectal cancer who had undergone surgical reduction in our department between May 1997 and April 1998, including 26 patients with preoperative UFT (450 mg/body/day) chemotherapy for 2 weeks, and evaluated the clinical significance of TS and DPD activities as predictive factors of UFT sensitivity. TS activity was collated with histological type from a clinical pathological examination (p = 0.0103). Also, the tendency for TS activity to become high with the stage was observed. According to the evaluation of pathological response, histological effectiveness greater than grade 2 was noted in 7.7%. The apoptosis index (AI) in tumors with preoperative UFT chemotherapy was higher than those without such treatment, which showed a higher correlation with DPD activity of tumor tissue than TS activity (p = 0.0465). Recurrence was seen in 7 cases (lung metastasis: 2, liver metastasis: 4, and local recurrence: 1) in the preoperative chemotherapy group. TS activity was high in all patients with recurrence. TS showed significantly high activity in patients with recurrence compared with the non-recurrence (p = 0.0034) patients. Therefore, these results suggested that activity of both TS and DPD was a key factor for anti-tumor effectiveness of UFT. In particular, TS activity was an important predictive factor for effectiveness of UFT in recurrences.

We compared the effectiveness of 5-FU + l-LV with CDDP + 5-FU as a systemic chemotherapy for unresectable recurrence of colorectal cancer. The protocol we carried out in one group was as follows: (Group 1) 5-FU 2,000 mg mixed with l-LV 100-200 mg in the disposable balloon pump was administered continuously for 1 week. In the other group, (Group 2) we administered CDDP 5 mg/day every 5 days for a week and continuous 5-FU 500 mg/day for 3 weeks in the hospital, and in the outpatient clinic CDDP 5 mg/day every 2 days for a week with UFT-E 300-600 mg/day, orally, everyday. The response rate of Group 1 was 18.8% and that of Group 2 was 19.3%; the median survival time (MST) was 10.8 months for Group 1 and 8.4 months for Group 2. There were no significant differences between the 2 groups regarding these parameters. Hand foot syndrome (HFS) was observed in 43.8% of the patients, and stomatitis in 37.5% of all cases as adverse effect of systemic chemotherapy using 5-FU + l-LV. But the grade of the adverse effect was low and patients could continue with this systemic chemotherapy.

We compared the effectiveness of 5-FU + l-LV with CDDP + 5-FU as a systemic chemotherapy for unresectable recurrence of colorectal cancer. The protocol we carried out in one group was as follows: (Group 1) 5-FU 2,000 mg mixed with l-LV 100-200 mg in the disposable balloon pump was administered continuously for 1 week. In the other group, (Group 2) we administered CDDP 5 mg/day every 5 days for a week and continuous 5-FU 500 mg/day for 3 weeks in the hospital, and in the outpatient clinic CDDP 5 mg/day every 2 days for a week with UFT-E 300-600 mg/day, orally, everyday. The response rate of Group 1 was 18.8% and that of Group 2 was 19.3%; the median survival time (MST) was 10.8 months for Group 1 and 8.4 months for Group 2. There were no significant differences between the 2 groups regarding these parameters. Hand foot syndrome (HFS) was observed in 43.8% of the patients, and stomatitis in 37.5% of all cases as adverse effect of systemic chemotherapy using 5-FU + l-LV. But the grade of the adverse effect was low and patients could continue with this systemic chemotherapy.

Lateral lymph node dissection is technique for reducing local recurrence rate after resection of rectal cancer. In this study, we will report a decade experience for lateral lymph node dissection of rectal cancer in 491 cases. Lateral lymph node metastases occurred in 15.4% of rectal cancer which was below peritoneal reflection and through muscularis propria into non-peritoneal. It is a problem that it has never been well designed study of lateral lymph node dissection for rectal cancer. On the other hand, TME has also contributed reducing local recurrence rate. But, distant margin for resection of rectal cancer is controversial.

We report a case in which low-dose CPT-11 chemotherapy was effective for metastatic liver tumor of sigmoid colon cancer. A 49-year-old male with metastatic liver tumor, who had undergone sigmoidectomy with D2 lymphadenectomy, was treated by low-dose CPT-11 chemotherapy (CPT-11 30 mg/m2 x 3 days, every 2 weeks). After 7 courses of this chemotherapy, CT and ultrasound examinations showed a reduction of tumor size in the liver. This chemotherapy also showed no high grade toxicities. Therefore, low-dose CPT-11 chemotherapy seems to be effective for metastatic colorectal cancer, and safe in view of toxicities.

5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutic agents, and is known to be a radiosensitizer. Previously, we reported that adenoviral transduction of the Escherichia coli (E. coli) uracil phosphoribosyltransferase (UPRT) gene induced marked sensitivity in human colon cancer cells to 5-FU. The aim of the current study was to investigate the efficacy of virally-directed UPRT and 5-FU to enhance the radiosensitivity of HT29 human colon cancer cells. Cytotoxicity as a result of radiation treatment following AdCA-UPRT infection and 5-FU exposure was confirmed by radiation dose-response analysis with colony formation assay. In vivo chemoradio-gene therapy using the UPRT/5-FU/radiation system showed tumor regressive effects even against large HT29-established subcutaneous tumors in nude mice. Our results suggested that adenovirus-mediated UPRT gene transduction combined with 5-FU administration and radiation may be an effective new chemo-radio-gene therapy for colorectal cancer.