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Objectives: Pancreatic metastases (PMs) account for 1% to 2% of pancreatic tumors, and their prognostic significance is poorly defined. We evaluated the incidence and clinical characteristics of primary tumors and defined prognostic factors., Methods: This retrospective study of 39 Japanese tertiary referral hospitals (January 2005 to August 2015) analyzed patient and tumor characteristics and survival time. Kaplan-Meier analysis and Cox proportional hazards models were applied to evaluate overall survival and prognostic factors, respectively., Results: We enrolled 159 patients with a pathologic diagnosis of PM. The most common primary tumor was renal cell carcinoma (38.4%), followed by lung cancer (24.5%), colorectal cancer (11.3%), and sarcoma (6.3%). Eight patients were lost during follow-up, and 151 patients were included for statistical analysis. Median overall survival was 43.0 months, and the 5-year survival rate was 42.6%. Multivariate analysis identified 3 independent prognostic factors: extrapancreatic metastasis (hazard ratio, 2.13; 95% confidence interval, 1.11-4.07; P = 0.02), tumor-related symptoms at diagnosis (hazard ratio, 5.39; 95% confidence interval, 2.92-9.91; P < 0.001), and pathologic diagnosis of primary tumors (P < 0.001)., Conclusions: Treatment strategies and prognoses for PMs completely differ according to the primary tumor type. A definitive pathologic diagnosis of PMs is essential for selecting the appropriate treatment.

Background: The benefits of narrow band imaging (NBI) in colorectal polyp detection remain questionable. Previous NBI has poorer brightness and resolution than white light (WL). However, recently these factors were improved by the new-generation video processor system (EVIS LUCERA ELITE) in comparison with the previous system (EVIS LUCERA SPECTRUM). The aim of this study was to investigate whether NBI with EVIS LUCERA ELITE could improve the visibility of colorectal polyps compared to WL., Methods: We analyzed prospectively 240 colorectal polyps (group 1: ELITE with CF-HQ290 scope, 80 polyps; group 2: ELITE with PCF-Q260AZI scope, 80 polyps; group 3: SPECTRUM with PCF-Q260AZI scope, 80 polyps) whose videos were recorded using NBI and WL at Kyoto Prefectural University of Medicine. The videos were evaluated in a randomized order by three experts and three non-experts. Each polyp was assigned a polyp visibility score from 4 (excellent visibility) to 1 (poor visibility). The polyp visibility scores in each mode and their relationship to the clinical characteristics were analyzed., Results: The mean polyp visibility scores of NBI with ELITE system were significantly higher than those of WL (ELITE with CF-HQ290: 3.14 ± 0.87 vs. 2.75 ± 0.98, p < 0.0001, ELITE with PCF-Q260AZI: 3.03 ± 0.92 vs. 2.83 ± 0.93, p = 0.0006). Conversely, the mean polyp visibility score of NBI using SPECTRUM system with PCF-Q260AZI was significantly lower than WL (2.75 ± 1.06 vs. 3.05 ± 0.92, p < 0.0001)., Conclusions: Our study showed that NBI using EVIS LUCERA ELITE improved polyp visibility.

5-aminolevulinic acid (5-ALA)-based fluorescence diagnosis is now clinically applied for accurate and ultrarapid diagnosis of malignant lesions such as lymph node metastasis during surgery. 5-ALA-based diagnosis evaluates fluorescence intensity of a fluorescent metabolite of 5-ALA, protoporphyrin IX (PPIX); however, the fluorescence of PPIX is often affected by autofluorescence of tissue chromophores, such as collagen and flavins. In this study, we demonstrated PPIX fluorescence estimation with autofluorescence elimination for 5-ALA-based fluorescence diagnosis of malignant lesions by simplified and optimized multispectral imaging. We computationally optimized observation wavelength regions for the estimation of PPIX fluorescence in terms of minimizing prediction error of PPIX fluorescence intensity in the presence of typical chromophores, collagen and flavins. By using the fluorescence intensities of the optimized wavelength regions, we verified quantitative detection of PPIX fluorescence by using chemical mixtures of PPIX, flavins, and collagen. Furthermore, we demonstrated detection capability by using metastatic and non-metastatic lymph nodes of colorectal cancer patients. These results suggest the potential and usefulness of the background-free estimation method of PPIX fluorescence for 5-ALA-based fluorescence diagnosis of malignant lesions, and we expect this method to be beneficial for intraoperative and rapid cancer diagnosis.

Irinotecan has been used in the first-line treatment of metastatic colorectal cancer. However, no clear predictive marker of irinotecan efficacy has been identified. It is controversial whether the response to irinotecan could be predicted by the expression level of topoisomerase-I, a direct target of irinotecan. The present study aimed to identify a feasible predictive marker of irinotecan efficacy. We hypothesized that the efficacy of SN38 (an active metabolite of irinotecan) is related to the cell proliferation and the phosphorylation status of RB in colorectal cancer cells. Indeed, the IC50 of SN38 was positively correlated with the doubling time of each cell line (R2=0.9315). Moreover, the phosphorylation level of RB was related to SN38 sensitivity. Consistent with the in vitro data, colorectal cancer tissues of irinotecan responders showed a significantly higher rate of phosphorylated RB (serine 780) expression using immunohistochemistry (P=0.0006), although a generally used proliferative marker, Ki-67, showed no significance. Finally, we investigated whether the phosphorylation of RB plays a crucial role in the efficacy of irinotecan. To suppress the expression of phosphorylated RB, we performed the knockdown of CDKs, which are known to phosphorylate RB. Intriguingly, the knockdown of both CDK4 and CDK6, but not CDK2, allowed RB to become the most hypophosphorylated form and converted the SN38-sensitive cells to a resistant state. Taking together the above findings from in vitro and clinical research, the immunohistochemistry of phosphorylated RB protein might be feasible to predict the irinotecan efficacy of colorectal cancer in clinical practice.

Purpose: Many studies have proposed alternative designations for lymph node (LN) status in colorectal cancer (CRC); however, knowledge of histopathological features in metastatic lymph nodes (MLNs) is limited. This study investigated the clinicopathological significance of poorly differentiated clusters (PDCs) in MLNs., Methods: Slides from 159 patients with pathological Stage III CRC were reviewed. Those with <12 dissected LNs (DLNs) were ineligible. PDCs composed of ≥5 cancer cells lacking full glandular formation and ≥10 PDCs under ×20 objective lens were defined as positive, and the number of MLNs with positive PDCs (MLNs-PDCs) was counted. Results were correlated with patient survival and comparisons made with other indications of LN status., Results: The mean numbers of MLNs and MLNs-PDCs were 2.8 and 1.0, respectively, and were moderately and positively correlated with each other. Univariate analysis identified cutoffs of ≥5 MLNs (86 vs. 55%, p = 0.024), ≥2 MLNs-PDCs (85 vs. 63%, p = 0.008), and ≥30% LN ratio (85 vs. 44%, p = 0.036) to indicate a positive LN status. However, no cutoff for DLNs was obtained. MLNs-PDCs (≥2) were associated with pT4 tumor (p = 0.0035), open surgery (p = 0.016), greater number of MLNs (p < 0.0001), and positive-PDC primary tumor (p < 0.0001). In multivariate analysis, a prognostic model incorporating ≥2 MLNs-PDCs provided the lowest Akaike information criterion value; consequently, both pT4 tumors (p < 0.001) and ≥2 MLNs-PDCs (p = 0.038) were revealed to be significant prognosticators., Conclusion: Results showed that applying the number of MLNs-PDCs could improve stratification in pStage III CRC and may be a valuable candidate for LN status.

Background: Fujifilm developed blue laser imaging (BLI) via a laser light source with a narrow-band light observation function. It has a brighter BLI bright mode for tumor detection., Objective: To investigate whether the BLI bright mode can improve the visibility of colorectal polyps compared with white light (WL)., Design: We studied 100 colorectal polyps (protruding, 42; flat, 58; size, 2-20 mm) and recorded videos of the polyps by using the BLI bright mode and WL at Kyoto Prefectural University of Medicine and Fukuoka Chikushi University Hospital. The videos were evaluated by 4 expert endoscopists and 4 nonexperts. Each endoscopist evaluated the videos in a randomized order. Each polyp was assigned a visibility score from 4 (excellent visibility) to 1 (poor visibility)., Setting: Japanese academic units., Main Outcome Measurements: The visibility scores in each mode and their relationship to the clinical characteristics were analyzed., Results: The mean visibility scores of the BLI bright mode were significantly higher than those of WL for both experts and nonexperts (experts, 3.10 ± 0.95 vs 2.90 ± 1.09; P = .00013; nonexperts, 3.04 ± 0.94 vs 2.78 ± 1.03; P < .0001). For all nonexperts, the visibility scores of the BLI bright mode were significantly higher than those of WL; however, these scores were significantly higher in only 2 experts. For experts, the mean visibility scores of the BLI bright mode was significantly higher than those of WL for flat polyps, neoplastic polyps, and polyps located on the left side of the colon and the rectum., Limitations: Small sample size and review of videos., Conclusions: Our study showed that polyps were more easily visible with the BLI bright mode compared with WL. (, Clinical Trial Registration Number: UMIN000013770.)., (Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Poorly differentiated clusters (PDCs) at the invasive front of tumors in colorectal cancer (CRC) have recently been highlighted as histological prognosticators. We aimed to assess the clinical importance of extent of PDCs in CRC., Methods: A total of 239 patients with non-mucinous pT2 and pT3 CRC were pathologically reviewed. PDCs were defined as cancer clusters composed of ≥5 cancer cells lacking full glandular formation. Patients were classified according to the number of PDCs observed under a × 20 objective lens. Patients with <5 clusters were classified as G1, those with 5 to 9 clusters were classified as G2, and those with ≥10 clusters were classified as G3. In addition, in order to semi-quantitatively evaluate the PDCs, the extent of the highest grade of PDCs at the tumor's invasive front was measured and summated, if separately distributed. We identified cutoffs for the extents of PDCs and compared the results with the patients' survival rates., Results: The number of patients with G1, G2, and G3 clusters was 140, 46, and 53, respectively. The presence of G3 PDCs was significantly correlated with lymphatic permeation (P < 0.0001) and node involvement (P < 0.0001). The 5-year overall survival rates of G1, G2, and G3 were 91%, 88%, and 76%, respectively. Based on the Kaplan-Meier method, 5- and 10-mm cutoffs were identified as the statistically reliable stratification for the extents of G3 clusters, and 15, 20, and 18 G3 patients exhibited extents of <5 mm, 5 to 9 mm, and ≥10 mm, respectively; however, cutoffs for the extents of G1 and G2 clusters were not obtained. In the subgroup analysis, when the extents of G3 clusters were subclassified into <5 mm as G3a, 5 to 9 mm as G3b, and ≥10 mm as G3c, the 5-year overall survival rates were 83%, 62%, and 44%, respectively., Conclusions: G3 PDCs were highly indicative of tumor aggressiveness. Quantitative evaluation that takes into account the extent of PDCs would provide more concise prognostic information. Our results suggest that G3 PDCs with a larger extent are closely associated with unfavorable patient outcome.

Background/aims: This study aimed to analyze the endoscopic mucosal resection (EMR) with a novel uniquely shaped, double-loop snare (Dualoop, Medico's Hirata Inc., Tokyo, Japan) for colorectal polyps., Methods: This was a clinical trial conducted in two referral centers, Kyoto Prefectural University of Medicine and National Cancer Center Hospital in Japan. First, the firmness of various snares including 'Dualoop' was experimentally analyzed with a pressure gauge. Five hundred and eighty nine consecutive polyps that underwent EMR with 'Dualoop' were compared to 339 polyps with the standard round snare. Lesion characteristics, en bloc resection, and complications were analyzed., Results: 'Dualoop' had the most firmness among the various snares. The average tumor size was 9.3 mm (5-30), and en bloc resection was achieved in 95.4%. The rate of en bloc resection for middle polyps 15-19 mm in diameter was significantly higher with the 'Dualoop' than that with the round snare (97.9 vs. 80.0%, p < 0.05). The rate of en bloc resection was 64.7% for large polyps ≥20 mm in diameter using 'Dualoop'. Higher age, larger tumor size, and superficial polyps were associated with the failure of en bloc resection., Conclusion: EMR with 'Dualoop' was effective for resecting both middle and large polyps en-bloc., (© 2014 S. Karger AG, Basel.)

Background: Fujifilm has developed a novel endoscope system with two kinds of lasers that enables us to allow narrow-band light observation with blue laser imaging (BLI). The aim of this study was to evaluate BLI magnification in comparison with narrow-band imaging (NBI) magnification for the diagnosis of colorectal neoplasms., Methods: This was a multicenter open study. A total of 104 colorectal neoplasms were examined with BLI and NBI magnifications in Kyoto Prefectural University of Medicine and Fukuoka University Chikushi Hospital. Vascular and surface patterns of tumors under BLI magnification were compared with those under NBI magnification, using a published NBI classification. The main outcome was the correlation between the NBI classification diagnosed by BLI or NBI magnification and the histopathological analyses., Results: Sixty-two cases of adenoma, 34 cases of intramucosal cancer and shallowly invaded submucosal cancer, and eight cases of deeply invaded submucosal cancer were diagnosed. The diagnostic accuracy of BLI magnification in the NBI classification was 74.0 % (77/104), similar to that of NBI magnification (77.8 %). The consistency rate between BLI and NBI magnification in the NBI classification was 74.0 %. Concerning image evaluation, the interobserver variability of two expert endoscopists (N.Y. and T.H.) in BLI magnification was κ = 0.863. On the other hand, the intraobserver variability of the two endoscopists was κ = 0.893 (N.Y.) and 0.851 (T.H.)., Conclusions: BLI magnification by laser source could predict histopathological diagnosis and invasion depth of colorectal neoplasms. The diagnostic effectiveness of this method was similar to that of NBI magnification.

Accurate evaluation of metastatic lymph nodes (LNs) is indispensable for adequate treatment of colorectal cancer (CRC) patients. Here, we demonstrate detection of metastases of human CRC in removed fresh LNs using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence. A spectral unmixing method was employed to reduce the overlap of collagen autofluorescence on PpIX fluorescence. A total of 17 surgery patients with advanced CRC were included in this study. After 5-ALA at a dose of 15 mg/kg of body weight was applied orally 2 h prior to surgery, 87 LNs were subjected to spectral fluorescence imaging and histopathological diagnosis, and statistical analysis was performed. No apparent side effect was observed to be associated with 5-ALA administration. The spectral unmixing fluorescence intensity of PpIX in metastatic LNs was 10.2-fold greater than that in nonmetastaic LNs. The receiver-operating-characteristic (ROC) analysis showed that the area under the curve (AUC) was calculated as 0.95. Our results show the potential of 5-ALA-induced PpIX fluorescence processed by spectral unmixing for detecting metastases in excised fresh LNs from patients with CRC, suggesting that this rapid and feasible method is applicable to gross evaluation of resected LN samples in pathology laboratories.

Purpose: Flexible spectral imaging color enhancement (FICE), or image-enhanced endoscopy, can enhance visualization of surface and vascular patterns of colorectal polyps. Resolution of FICE has recently been improved. We evaluated diagnostic accuracy for neoplastic and non-neoplastic colorectal polyp differentiation with detection of surface patterns by FICE without magnification., Methods: Retrospective analysis of 151 colorectal polyps evaluated by FICE without magnification was performed. Neoplastic surface patterns were defined as tubular and oval pit. We aimed to determine sensitivity, specificity, positive and negative predictive values (PPV and NPV), and accuracy in correlating diagnosis by FICE without magnification with histology. Moreover, findings were compared to those of white-light endoscopy (WL) and chromoendoscopy (CHR)., Results: Of the 151 colorectal polyps, 95 were identified as neoplastic and 56 were identified as non-neoplastic. FICE without magnification had a sensitivity of 89.4%, specificity of 89.2%, PPV of 93.4%, NPV of 83.3%, and accuracy of 89.4%. The accuracy of FICE value was higher than that of WL (sensitivity of 74.7%, specificity of 73.2%, PPV of 82.5%, NPV of 63.0%, and accuracy of 74.1%) and was worse than that of CHR (sensitivity of 96.8%, specificity of 89.2%, PPV of 93.9%, NPV of 96.1%, and accuracy of 94.7%). Imaging evaluation was validated by inter-/intra-observer measurements, demonstrating consistent results., Conclusions: The detection of surface patterns by FICE without magnification is useful for differential diagnosis of colorectal polyps. We believe that FICE without magnification is more convenient and easier method than CHR.

Background: Lymph node (LN) metastasis in colorectal cancer (CRC) is a critical factor in making accurate prognoses and therapeutic decisions. This study evaluated the clinical performance of the one-step nucleic acid amplification (OSNA) assay in accurately diagnosing LN metastases in CRC patients through the specific detection of cytokeratin 19 mRNA levels in LNs., Methods: The OSNA assay was performed on 121 LNs dissected from early-stage CRC patients (pStage 0 or I) or from patients with benign colorectal disease (study 1). Separately, 385 LNs were dissected from 85 CRC patients (any stage); the OSNA assay was performed on half of each LN, and the results were compared with histopathological examination in 2-mm intervals of the other LN half (study 2)., Results: In study 1, all 121 histopathologically negative LNs were also negative by the OSNA assay (concordance rate for metastasis negative: 1.0, 95% confidence interval [95% CI]: 0.976-1.0). In study 2, the concordance rate between the OSNA assay and the 2-mm-interval histopathological examination was 0.971 (95% CI: 0.950-0.984), with a sensitivity of 0.952 (95% CI: 0.881-0.987) and a specificity of 0.977 (95% CI: 0.953-0.991)., Conclusions: The OSNA assay provided a judgment performance equivalent to a 2-mm-interval histopathological examination, a more detailed assay than the common pathological examination. Therefore, the OSNA assay is considered a new molecular examination method for the diagnosis of LN metastases in CRC patients in clinical settings.

Background and Aim: Endoscopic mucosal resection (EMR) is the standard procedure for colorectal tumors. High mucosal elevation by submucosal injection is important for definite en bloc resection and the prevention of perforation. Hyaluronic acid (HA) is a reportedly useful injection solution for high and long-lasting mucosal elevation, but the ideal HA concentration for optimization of mucosal elevation maintenance, injection pressure, and cost is unknown. In the present study, we assessed the appropriate concentration of HA for EMR., Methods: A resected porcine colon and esophagus were used. The injection solutions examined were 0.9% normal saline (NS) and four concentrations of an 800-KDa HA preparation (0.4%, 0.2%, 0.13%, and 0.1%). Each solution (2 mL) was injected into the submucosa; injection pressure was calculated, and elevation was measured. The durations of mucosal elevation and EMR were additionally assessed in the living minipig colon., Results: In the resected porcine colon, the mucosal elevation was measured 0, 2, 4, and 6 min after the submucosal injection. All concentrations of HA solution maintained greater mucosal elevation at all times than NS (P < 0.05). An almost similar result was obtained in the resected porcine esophagus. The injection pressure correlated with the HA concentration. In the living minipig colon, mucosal elevation diminished 2 min after the submucosal injection with NS, but was maintained 2 min after injection with 0.4%, 0.2%, and 0.13% HA. The average duration of EMR was 139 s., Conclusions: Mucosal elevation by HA was greater than that by NS in resected and living animal models. We recommend 0.13% HA for maintaining mucosal elevation, injection pressure, and cost., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background: Magnifying endoscopy with flexible spectral imaging color enhancement (FICE) is an image-enhanced endoscopy that captures the surface and vascular patterns of colorectal tumors. We evaluated and compared FICE magnification to narrow-band imaging (NBI) magnification., Methods: Flexible spectral imaging color enhancement or NBI magnification was performed to the visualize surface and vascular patterns of colorectal tumors, classified into 4 types: Type A, Type B, Type C1/C2, and Type C3, as previously reported. A total of 235 colorectal tumors were examined. The correlations between classifications found by FICE or NBI magnification and histopathological diagnoses were examined. Image evaluation was validated by assessing inter-observer and intra-observer agreements on examinations., Results: Twenty-eight hyperplastic polyps (HPs), 115 tubular adenomas (TAs), 72 mucosal and slightly invaded submucosal cancers (M-sSM), and 20 massively invaded submucosal cancers (mSM) were diagnosed. By FICE magnification, HP and TA were observed in 93.3 and 6.7% of Type A (15 lesions), respectively. TA, M-sSM, and HP were observed in 82.6, 15.4, and 2.0% of Type B (52 lesions),respectively. M-sSM, TA, and mSM were observed in 50.0,46.0, and 4.0% of Type C1/2 (50 lesions), respectively.mSMs were observed in all 7 Type C3 lesions. In diagnosing mSM in Type C3, the sensitivity and specificity of FICE magnification were 77.7 and 100%, respectively, compared to those of NBI, at 63.6 and 99.0%, respectively. Imaging evaluation was validated accurately by intra- and intraobserver measurements showing consistent results., Conclusions: The classification of colorectal tumors by FICE magnification correlated well with the histopathological diagnoses, similar to findings for NBI magnification. FICE magnification can be evaluated accurately with the same diagnostic classifications as those used for NBI magnification.

Aim: To evaluate a new hemostatic method using hemostatic forceps to prevent perforation and perioperative hemorrhage during colonic endoscopic submucosal dissection (ESD)., Methods: We studied 250 cases, in which ESD for colorectal tumors was performed at the Kyoto Prefectural University of Medicine or Nara City Hospital between 2005 and 2010. We developed a new hemostatic method using hemostatic forceps in December 2008 for the efficient treatment of submucosal thick vessels. ESD was performed on 126 cases after adoption of the new method (the adopted group) and the new method was performed on 102 of these cases. ESD was performed on 124 cases before the adoption of the new method (the unadopted group). The details of the new method are as follows: firstly, a vessel was coagulated using the hemostatic forceps in the soft coagulation mode according to the standard procedure, and the coagulated vessel was removed using the forceps in the "endocut" mode without perioperative hemorrhage. Secondly, the partial surrounding submucosa was dissected using the forceps in the endocut mode. In the current study, we evaluated the efficacy of this method., Results: Coagulated vessels were successfully removed using the hemostatic forceps in all 102 cases without severe perioperative hemorrhage. Moderate perioperative hemorrhage occurred in five cases (4.9%); however, it was stopped by immediately reuse of the hemostatic forceps. The partial surrounding submucosa was dissected using the forceps in all 102 cases. In the adopted group, the median operation time was 105 min. The proportion of endoscopic en bloc resection was 92.8% (P < 0.01) compared to 80.6% in the unadopted group. The postoperative hemorrhage and perforation rates were 2.3% and 2.3%. The rate of perforation was significantly lower than that in the unadopted group (9.6%, P < 0.01). We evaluated the ease of use of this method by allowing our three trainees to performed ESD on 46 cases, which were accomplished without any severe hemorrhage., Conclusion: The new method effectively treated submucosal thick vessels and shows promise for the prevention of perforation and perioperative hemorrhage in colonic ESD.

Background: Endoscopic submucosal dissection (ESD) has been reported to be effective for the en bloc resection of large colorectal tumors. Our study investigated whether ESD was suitable for elderly people with large colorectal tumors in terms of its invasiveness., Patients and Methods: We studied 119 colorectal tumors that were treated with ESD at Kyoto Prefectural University of Medicine or Nara City Hospital between 2006 and 2009. We classified each patient as either elderly, i.e., more than 75 years old, or non-elderly, i.e., less than 75 years old. Thirty-two of the cases were classified as elderly. Performance status, tumor size, operation time, rate of en bloc resection, histopathological diagnosis, complications, and hospital stay after ESD were analyzed retrospectively in both groups., Results: In the elderly group, the average tumor size was 32.6 mm; the average operation time, 96 min; the rate of en bloc resection, 81.2%; the rate of perforation, 3.1%; and hospital stay after ESD, 5.1 days. Histopathological diagnosis for 16 tumors was adenoma; for 13, carcinoma with invasion into the mucosa; and for three, carcinoma with invasion into the submucosa. There were no statistical differences between the two groups in any of these data. The case with perforation was treated conservatively without urgent surgery in the elderly group., Conclusions: ESD for colorectal tumors resulted in favorable rates of en bloc resection in elderly people. Perforation occurred in elderly people, but these patients were cured with conservative treatment. ESD is a safe and minimally invasive treatment for elderly people with colorectal tumors.

The incidence of colorectal carcinomas has been increasing over the last 50 years in Japan. In order to determine whether adenoma-carcinoma sequence (ACS) or de novo cancer development, generally considered to be two separate genetic pathways, might be responsible, K-ras codon 12 mutations, good markers for ACS, were examined in 59 and 84 cases of advanced colorectal cancer surgically resected in Cancer Institute Hospital of the Japanese Foundation for Cancer Research in 1960-1969 and in 1990-1999, respectively. There was no significant difference of K-ras codon 12 mutation between the 25.4% (15/59) in the 1960s and 36.9% (31/84) in the 1990s (P = 0.148), and the reference of distal colon cancer also showed no significant difference between 24.4% (11/45) and 36.4% (20/55). Yet elderly males showed a significant difference: 27.3% (6/22) in the 1960s and 59.3% (16/27) in the 1990s. The references of males, elderly patients (over 75 years old) and distal colon cancer in the 1990s were significantly more likely to demonstrate mutations than their counterparts in the 1960s. There was no variation with the tumor location. The results suggest that the ACS pathway might have primarily contributed to the increased incidence of colorectal cancer in elderly males in Japan.

Hypothesis: There have been few reports on the minimum surgical margins (SMs) required for successful liver resection in patients with colorectal metastases. This minimum requirement may be narrower than the previously recommended margin of 10 mm., Objectives: To identify the minimum margins by assessing the presence of micrometastases around the tumor using genetic and histological techniques, and to investigate whether SMs are associated with patterns of tumor recurrence or patient survival., Design: Prospective and retrospective studies., Setting: Tertiary referral cancer center., Patients and Methods: Fifty-eight patients who underwent 62 liver resections for hepatic metastasis from colorectal cancer between December 1, 1996, and November 30, 2000, were included in the study. Tissue samples taken from the tumor, surrounding liver parenchyma, and Glisson pedicle near the tumor were tested for K-ras and p53 mutations using the mutant allele-specific amplification method. For the retrospective study on patient outcomes, 194 patients who had undergone liver resections between 1980 and 2000 were analyzed according to their SMs., Results: Of the 62 sets of samples from liver metastases, 39 were positive for K-ras and p53 gene mutations or both. Micrometastases in the liver parenchyma surrounding colorectal metastases were present in 2.0% (4/199) of tested samples and were located within 4 mm of the tumor border. Micrometastases via Glisson pedicle were more common (14.3% [3/21]), but these were also confined to a short distance from the tumor edge (