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Purpose: Ulcerative colitis (UC) is associated with a high risk of colorectal cancer. To identify genes that could predict the development of cancer in UC, we conducted a DNA microarray analysis using nonneoplastic rectal mucosa of UC patients.Experimental Design: Gene expression in nonneoplastic mucosa of 53 UC patients were examined. Gene expression profiles were examined using human Genome U133 Plus 2.0 gene chip array (Affymetrix). Among 53 UC patients, 10 had UC-associated cancer (UC-Ca group) whereas 43 did not (UC-NonCa group).Results: By comparing gene expression profiles of nonneoplastic rectal mucosae between the UC-Ca and UC-NonCa groups, we could identify 40 genes that were differentially expressed between two groups. The list of discriminating genes included low-density lipoprotein receptor–related protein (LRP5 and LRP6). Previous studies suggested that LRP5 and LRP6 expression promotes cancer cell proliferation and tumorigenesis and are considered as candidate oncogenes. In the present study, both LRP5 and LRP6 showed significantly higher expression in the UC-Ca group, which suggests the importance of these genes in the development of UC-associated colorectal cancers. With the 40 selected discriminating genes, we did class prediction of the development of colorectal neoplasms in UC patients. Using the k-nearest neighbor method and the support vector machine, we could predict the development of UC-associated neoplasms with an accuracy of 86.8% and 98.1%, respectively.Conclusions: These findings have important implications for the early detection of malignant lesions in UC and may provide directions for future research into the molecular mechanisms of UC-associated cancer.

Supplementary Figure 1 from Gene Expression Signature and the Prediction of Ulcerative Colitis–Associated Colorectal Cancer by DNA Microarray

Supplementary Table 1 from Prediction of Sensitivity of Rectal Cancer Cells in Response to Preoperative Radiotherapy by DNA Microarray Analysis of Gene Expression Profiles

Preoperative radiotherapy has been widely used to improve local control of disease and to improve survival in the treatment of rectal cancer. However, the response to radiotherapy differs among individual tumors. Our objective here was to identify a set of discriminating genes that can be used for characterization and prediction of response to radiotherapy in rectal cancer. Fifty-two rectal cancer patients who underwent preoperative radiotherapy were studied. Biopsy specimens were obtained from rectal cancer before preoperative radiotherapy. Response to radiotherapy was determined by histopathologic examination of surgically resected specimens and classified as responders or nonresponders. By determining gene expression profiles using human U95Av2 Gene Chip, we identified 33 novel discriminating genes of which the expression differed significantly between responders and nonresponders. Using this gene set, we were able to establish a new model to predict response to radiotherapy in rectal cancer with an accuracy of 82.4%. The list of discriminating genes included growth factor, apoptosis, cell proliferation, signal transduction, or cell adhesion–related genes. Among 33 discriminating genes, apoptosis inducers (lumican, thrombospondin 2, and galectin-1) showed higher expression in responders whereas apoptosis inhibitors (cyclophilin 40 and glutathione peroxidase) showed higher expression in nonresponders. The present study suggested the possibility that gene expression profiling may be useful in predicting response to radiotherapy to establish an individualized tailored therapy for rectal cancer. Global expression profiles of responders and nonresponders may provide insights into the development of novel therapeutic targets. (Cancer Res 2006; 66(7): 3370-4)

Supplementary Table S1 from Distal Colorectal Cancers with Microsatellite Instability (MSI) Display Distinct Gene Expression Profiles that Are Different from Proximal MSI Cancers

Supplementary Figure S1 from Distal Colorectal Cancers with Microsatellite Instability (MSI) Display Distinct Gene Expression Profiles that Are Different from Proximal MSI Cancers

Supplementary Figure 1 from Prediction of Sensitivity of Rectal Cancer Cells in Response to Preoperative Radiotherapy by DNA Microarray Analysis of Gene Expression Profiles

Background and study aims We developed a laparoscopy endoscopy cooperative surgery (LECS) to overcome the limitations of endoscopic resection for colorectal tumors. The aim of this study was to evaluate the feasibility of LECS, which combines endoscopic submucosal dissection (ESD) and laparoscopic partial colectomy. Patients and methods We performed LECS for 17 colorectal tumors in 17 patients (male:female 10:7; mean age, 66.5 years). The clinicopathological outcomes of these 17 cases and the feasibility of LECS were evaluated retrospectively. Indications for LECS were as follows: 1) intramucosal cancer and adenoma accompanied by wide and severe fibrosis; 2) intramucosal cancer and adenoma involving the diverticulum or appendix; and 3) submucosal tumors. Results We successfully performed LECS procedures in 17 cases (intramucosal cancer [n = 6], adenoma [n = 9], schwannoma [n = 1], and gastro-intestinal stromal tumour [GIST] [n = 1]. Mean tumor diameter was 22.4 mm (range, 8 – 41 mm). LECS was successfully performed in all 17 cases without conversion to open surgery; the R0 rate was 100 %. LECS was applied to the following situations: involving the appendix (n = 6), tumor accompanied by severe fibrosis (n = 5), involving the diverticulum (n = 3), submucosal tumor (n = 2), and poor endoscopic operability (n = 1). We experienced no adverse events (e. g., leakage or anastomotic stricture) and the median hospital stay was 6.4 dayus (range, 4 to 12). All 17 patients who were followed for ≥ 3 months (median, 30.8 months; range, 3 – 72 months) showed no residual/local recurrence. Conclusion LECS was a safe, feasible, minimally invasive procedure that achieved full-thickness resection of colorectal tumors and showed excellent clinical outcomes.

Localized small rectal neuroendocrine tumors (NETs) without any vascular involvement rarely metastasize, and their resection alone is considered curative. We herein report a case of localized rectal NET (10×8 mm) without vascular involvement. Although resected initially, it recurred as liver metastasis 30 years later. For rectal NETs smaller than 10 to 20 mm, surveillance for 12 months is considered sufficient. However, this case suggests that such tumors can recur even 30 years after curative resection. The interval of recurrence is the longest among reported cases.

Background and Aim: A treatment strategy for tumors with only venous invasion and characteristics of small rectal carcinoids with metastasis have not been clearly documented. The present study aims to determine the risk factors for lymph node metastasis and to elucidate characteristics of small tumors with metastasis. Methods: We investigated a total of 229 patients with rectal carcinoids. The relationship between each clinicopathological variable and the presence of lymph node metastasis was evaluated. Results: Tumor size (larger than 10 mm), presence of central depression, depth of tumor invasion, lymphatic invasion, and venous invasion were significantly associated with the incidence of lymph node metastasis (P

No appropriate management of chronic intestinal pseudo-obstruction (CIP) has been established. The clinicopathological parameters of 103 cases collected by a nationwide questionnaire study were reviewed. The CIP cases were primary in 86 (83%) cases and secondary in 15 (15%) cases. The age of onset of the primary type was significantly younger than that of the secondary type (p = 0.011). The diseased segments of the bowel were the large bowel in 60 (58%), the small bowel in 17 (17%), and both in 23 (22%) cases, respectively. Abdominal distension and pain were common symptoms regardless of the types of the diseased bowel; however, constipation was frequently seen in the large bowel type (p = 0.0258). Vomiting and diarrhea were seen with marginally higher frequency in the small bowel type (p = 0.0569, 0.0642). Surgical treatment was most effective in the large bowel type, less effective in the small bowel type, and least effective in the large and small bowel type. The prognosis of the primary CIP was significantly better than that of the secondary CIP (p = 0.033). The segments of the diseased bowels should be considered in determining the indications for surgical treatments in CIP patients.

Lynch syndrome (HNPCC) is an autosomal dominant hereditary cancer syndrome, and members of affected families are at-risk for developing colorectal and other associated tumors. Such individuals should disseminate familial genetic information, so they can seek specific medical assessment or genetic testing to reduce mortality and morbidity rates by early detection. Since published results have been encouraging, we explored which factors influence the likelihood of good communication within families regarding medical assessment. We studied 40 individuals from 33 families who satisfied the Japanese clinical criteria for Lynch syndrome and their relatives at our hospital. We determined the status of relatives of the 40 individuals after genetic counseling and testing using questionnaires and semi-structured interviews based on pedigree charts. We also examined their knowledge or perception of colorectal cancer syndrome, levels of intimacy and whether or not they encouraged their relatives to have specific medical assessments. We found that 75% of the individuals advised their relatives to seek medical assessment, and any significant background factors that promoted such encouragement were observed. They tended to encourage first degree relatives and discuss the issue with other family members such as spouses before undertaking such attempts at encouragement. The reasons and methods of imparting encouragement were essentially identical. We also found that genetic testing for at-risk or more distant relatives was not encouraged so often. Therefore, providing individuals who have been tested for Lynch syndrome with opportunities for disseminating familial genetic information through appropriate genetic counseling is important.

FOLFOX (a combination of leucovorin, fluorouracil and oxaliplatin) has achieved substantial success in the treatment of colorectal cancer (CRC) patients. However, about half of all patients show resistance to this regimen and some develop adverse symptoms such as neurotoxicity. In order to select patients who would benefit most from this therapy, we aimed to build a predictor for the response to FOLFOX using microarray gene expression profiles of primary CRC samples. Forty patients who underwent surgery for primary lesions were examined. All patients had metastatic or recurrent CRC and received modified FOLFOX6. Responders and nonresponders were determined according to the best observed response at the end of the first-line treatment. Gene-expression profiles of primary CRC were determined using Human Genome GeneChip arrays U133. We identified discriminating genes whose expression differed significantly between responders and nonresponders and then carried out supervised class prediction using the k-nearest-neighbour method. We identified 27 probes that were differentially expressed between responders and nonresponders at significant levels. Based on the expression of these genes, we constructed a FOLFOX response predictor with an overall accuracy of 92.5%. The sensitivity, specificity, positive and negative predictive values were 78.6%, 100%, 100% and 89.7%, respectively. The present model suggests the possibility of selecting patients who would benefit from FOLFOX therapy both in the metastatic and the adjuvant setting. To our knowledge, this is the first study to establish a prediction model for the response to FOLFOX chemotherapy based on gene expression by microarray analysis.

Many authors have reported on so-called inflammatory abdominal aortic aneurysm (IAAA) clinically or histologically. However, there have been few reports associating both presentations. The purpose of this paper was to report the relationship between clinical data and histological findings of IAAA. We examined 10 cases of nonruptured IAAA. IAAA varied from the “scarring stage” to the “active stage” according to the clinical rank of inflammation based on C-reactive protein and/or erythrocyte sedimentation rate. Abdominal or back pain, and weight loss were common clinical symptoms in both stages, although they were observed more frequently in the active stage. Mantle sign was characteristic of the active stage. Patients with higher clinical ranks of inflammation were likely to have thicker adventitia although this difference was not significant. A significant correlation was observed between the clinical ranks of inflammation and histological scores of inflammatory cell infiltration in the aneurysmal adventitia. In most cases, white blood cell counts were within the normal range. Inflammatory cell infiltration was characteristic of the active stage and fibrous thickening of the adventitia was the most common character in both stages. Our data suggest that histologically diagnosed IAAA should correspond to the active stage of grossly diagnosed IAAA, and IAAA in the scarring stage will be histologically diagnosed as a noninflammatory atherosclerotic aneurysm.

We carried out a retrospective questionnaire survey of 792 submucosal colorectal carcinoma (CRC) cases from 15 institutions affiliated with the Colorectal Endoscopic Resection Standardization Implementation Working Group in Japanese Society for Cancer of the Colon and Rectum. In these cases, endoscopic resection (ER) and surveillance was carried out without additional surgical resection. Local recurrence or metastasis was observed in 18 cases. Local submucosal recurrence was observed in 11 cases, and metastatic recurrence was observed in 13 cases. Among the 15 cases in which the depth of submucosal invasion was measured, two cases showed depth less than 1000 µm, which has other risk factors for metastasis. Metastatic recurrence was observed in the lung, liver, lymph node, bone, adrenal glands, and the brain; in some cases, metastatic recurrence was observed in multiple organs. Death due to primary disease was observed in six cases. The average interval between ER and recurrence was 19.7 ± 9.2 months. In 16 cases, recurrence was observed within 3 years after ER. Thus, validity of ER without additional surgical resection for cases with the conditions that the depth of submucosal invasion is less than 1000 µm and the histological grade is well or moderately differentiated adenocarcinoma with no lymphatic and venous involvement was proven.

Bleeding, perforation, and residual/local recurrence are the main complications associated with colonoscopic treatment of colorectal tumor. However, current status regarding the average incidence of these complications in Japan is not available. We conducted a questionnaire survey, prepared by the Colorectal Endoscopic Resection Standardization Implementation Working Group, Japanese Society for Cancer of the Colon and Rectum (JSCCR), to clarify the incidence of postoperative bleeding, perforation, and residual/local recurrence associated with colonoscopic treatment. The total incidence of postoperative bleeding was 1.2% and the incidence was 0.26% with hot biopsy, 1.3% with polypectomy, 1.4% with endoscopic mucosal resection (EMR), and 1.7% with endoscopic submucosal dissection (ESD). The total incidence of perforation was 0.74% (0.01% with the hot biopsy, 0.17% with polypectomy, 0.91% with EMR, and 3.3% with ESD). The total incidence of residual/local recurrence was 0.73% (0.007% with hot biopsy, 0.34% with polypectomy, 1.4% with EMR, and 2.3% with ESD). Colonoscopic examination was used as a surveillance method for detecting residual/local recurrence in all hospitals. The surveillance period differed among the hospitals; however, most of the hospitals reported a surveillance period of 3-6 months with mainly transabdominal ultrasonography and computed tomography in combination with the colonoscopic examination.

Purpose Liver metastasis is one of the major types of recurrence after surgery for colorectal cancer. Traditional methods of predicting liver metastasis are limited in their accuracy, suggesting the need to develop new predictors. We developed a 10-gene signature that is closely associated with the development of liver metastasis after colorectal cancer. Patients and methods We examined a total of 189 frozen specimens of primary colorectal cancers using both microarray and quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Initially, we studied gene expression in colorectal cancer tissue from 160 randomly selected patients who had undergone surgical resection of colorectal cancer and evaluated the association between the level of gene expression and the occurrence of liver metastasis. We developed a gene-expression model for the prediction of liver metastasis based on the RT-PCR findings. We then used specimens from 29 other patients for validation. Results The expression of 14 genes was correlated with liver metastasis according to both microarray and RT-PCR analysis. We constructed an accurate predictive model based on the results for 10 of these genes, which included epiregulin (EREG), amphiregulin (AREG), cyclooxygenase 2 (COX-2) and lymphocyte-specific protein tyrosine kinase (LCK). The 10-gene signature was an independent predictor of liver metastasis. The model was validated in the independent set of 29 patients. The predictive accuracy of the model in a test set of patients was 86.2%. Conclusion The 10-gene signature identified in this study is closely associated with the occurrence of liver metastasis in colorectal cancer patients.

A 70-year-old woman with a pelvic tumor had undergone exploratory laparoscopy at another institution, which revealed many peritoneal nodules. Immunohistochemical staining of a biopsy specimen of the peritoneal nodules was positive for KIT. Thus, a gastrointestinal stromal tumor (GIST) was diagnosed and imatinib treatment was begun. After 16 months of this treatment, the tumor size had decreased from 51 x 55 mm to 22 x 17 mm, and surgery was performed. Laparotomy revealed complete regression of the peritoneal lesions. The primary tumor was seen to arise from the small intestine and to loosely adhere to the rectum. We performed partial resection of the small intestine. Imatinib therapy was restarted 1 month postoperatively, and the patient is doing well after 12 months of follow-up. We report this case to show that there is the possibility of curative salvage surgery after long-term imatinib treatment in some patients with peritoneal metastases of a GIST.

Laparoscopic surgery for rectal cancer has been considered more demanding than laparoscopic colectomy due to its technical difficulties. The aim of this study was to show safety and feasibility of laparoscopic low anterior resection for lower rectal cancer reconstructed by double-stapling technique (DST). The present study reviewed 159 patients with rectal cancer undergoing laparoscopic anterior resection reconstructed by DST. They were subdivided into two groups: 98 patients with upper rectal cancer located between 75 and 150 mm from the anal verge (group A) and 61 with lower rectal cancer located within 75 mm from the anal verge (group B). Short-term results and pathological findings were compared between the two groups. There was no conversion in both groups. Operating time and intraoperative blood loss were similar in the two groups. No mortality occurred in either group. Overall morbidity rate was 10.2% in group A and 11.5% in group B (p = 0.798). Anastomotic leak rate was similar in the two groups (2.0% in group A versus 3.3% in group B; p = 0.638). Pathological examination of resected specimen showed no involvement of distal resection margin or circumferential resection margin in both groups. The present study shows that laparoscopic surgery is safe and feasible for lower rectal cancer in a very select group of patients.

Total mesorectal excision (TME) with preoperative chemoradiation therapy is an accepted standard treatment for low rectal cancer. Although the laparoscopic approach is accepted for the treatment of colon cancer, its value for low rectal cancer is unknown. The purpose of this study was to evaluate whether preoperative chemoradiation therapy exerted an adverse influence on laparoscopic TME for low rectal cancer.We studied 125 consecutive patients who underwent laparoscopic TME for low rectal cancer. Twenty patients with preoperative chemoradiation therapy (CRT-Lap group) were compared with 105 patients without chemoradiation therapy (non-CRT-Lap group).Operating time in the CRT-Lap group (276 min, range 160-390 min) was no different from that in the non-CRT-Lap group (263 min, range 143-456 min). The CRT-Lap group had more blood loss during the operation (70 vs. 37 ml), but mean blood loss was100 ml. The distal tumor margin was longer in the CRT-Lap group (25.8 vs. 18.6 mm). The number of lymph node harvested did not differ between the groups (14.5 vs. 15.4). Conversion to open surgery was necessary only in one case in the non-CRT-Lap group. There was no anastomotic leakage in the CRT-Lap group, whereas three patients (3.1%) had anastomotic leakage in the non-CRT-Lap group.Laparoscopic TME with preoperative chemoradiation therapy is a safe procedure with reasonable operating time and does not appear to pose any threat to the surgical and oncologic outcomes.

The modified irinotecan plus bolus 5-fluorouracil/L-leucovorin (IFL) regimen (irinotecan plus bolus 5-fluorouracil/L-leucovorin) used to be one of the standard treatments for metastatic colorectal cancer until approval of oxaliplatin in Japan. We evaluated the efficacy of modified IFL therapy for Japanese patients.Forty-seven patients with metastatic colorectal cancer received irinotecan (100 mg/m(2)) and bolus 5-fluorouracil (500 mg/m(2)) plus L-leucovorin (10 mg/m(2)) on days 1 and 8 every 3 weeks until progression or unmanageable toxicity occurred. The data on toxicity and tumor response were analyzed retrospectively.All patients discontinued modified IFL therapy due to cancer progression, except for one patient who developed severe liver dysfunction. The overall response rate was 25%. The median progression-free survival time (PFS) was 8.6 [corrected] months. The median overall survival time (OS) was 27.8 [corrected] months for all patients, 30.9 [corrected] months for patients receiving subsequent oxaliplatin therapy, and 14.5 [corrected] months for patients without oxaliplatin (P = 0.0031). According to multivariate analysis results, good performance status, a normal white cell count, and absence of local recurrence were associated with a better PFS. Tumor response was a good prognostic factor for both PFS and OS. Gastrointestinal symptoms were the most common toxicities, including grade 3 diarrhea (8%) and grade 3 anorexia (10%). Grade 4 neutropenia occurred in 6% of patients. No other drug-related severe adverse events or deaths were observed.Modified IFL therapy is an effective and well-tolerated regimen for Japanese patients with metastatic colorectal cancer. Modified IFL therapy combined with biological agents might remain an option for some patients who refuse a central venous catheter.

Rectal transection and anastomosis at the lower rectum is the most challenging part of laparoscopic low anterior resection. Therefore, some have demonstrated that rectal transection should be performed using instruments for open surgery with small laparotomy. In our institute, however, rectal transection using a currently available endostapler followed by anastomosis with a double stapling technique is usually performed. The important points of our technique are as follows: trocar placement, optimal device choice, harmonious movement between the operator and assistant for rectal transection, optimal point of piercing with the center rod of the circular stapler, and ideal positioning of the proximal colon. Seventy-eight patients underwent low anterior resection using this technique. There were no conversions to open surgery. All rectal transections were completed laparoscopically with an available endostapler. A diverting ileostomy was created in six cases. Anastomotic leakage occurred in only two patients (2.6%) and rectovaginal fistula in only one patient (1.3%). Our standardized technique is considered to be safe and feasible for rectal transection and anastomosis using the double stapling technique (DST).

The prognosis of solitary liver metastasis involving the caudate lobe is unclear. This study analyzed the outcomes after resection of the caudate lobe for solitary colorectal liver metastasis. We reviewed the records of 114 cases in which potentially curative hepatectomy were performed for solitary colorectal liver metastasis. Solitary liver metastasis involving the caudate lobe was seen in 14 cases (Caudate group). The outcomes were compared with those of the remaining 100 cases with metastasis in a site other than the caudate lobe (Other group). No hospital deaths occurred. The 5-year survival rate for all cases was 61%. Recurrence-free and cumulative survivals were similar in the two groups, as were the intraoperative blood loss, duration of operation, and postoperative hospital stay. The distance of the surgical margin was significantly shorter in the Caudate group than in the Other group (0.6 mm vs. 6.6 mm; p = 0.001). A concomitant resection of the inferior vena cava was performed in four patients in the Caudate group but in no patients in the Other group (p < 0.001). Despite a minimal surgical margin, the resection of solitary colorectal liver metastasis offers favorable short- and long-term outcomes comparable to those for colorectal liver metastasis at other sites.

Background This study evaluated the difference of postoperative complications according to the radiation technique after preoperative radiotherapy for rectal cancer. Methods Among 224 patients with rectal cancer who underwent preoperative radiotherapy, 159 patients were treated with the 2-portal technique and 65 patients with the 4-portal technique. Comparison was performed between these 2 groups. Results The 5-year disease-free survival and local recurrence rate showed no difference between the 2 groups. There was also no difference in postoperative mortality. However, the 4-portal group had a significantly lower morbidity rate of 36.9% than the 2-portal group of 54.1% ( P = .02). The rate of major complications that needed reoperation was also significantly lower in the 4-portal group (0%) than the 2-portal group (11.9%) ( P = .01). The anastomotic leakage rate was significantly lower in the former (2.8% vs 20.0%, P = .033). Conclusion The 4-portal technique is a better technique than the 2-portal technique for decreasing postoperative complications in preoperative radiotherapy for rectal cancer.

This study was designed to clarify indication and benefit of pelvic sidewall dissection for rectal cancer. The retrospective, multicenter study collected the data of rectal cancer patients who underwent surgery between 1991 and 1998 and were prospectively followed. Of 1,977 patients with rectal cancers, 930 underwent pelvic sidewall dissection without adjuvant radiotherapy. Positive lateral lymph nodes were found in 129. Multivariate analysis disclosed a significantly increased incidence of positive lateral lymph nodes in female gender, lower rectal cancers, non-well-differentiated adenocarcinoma, tumor size of ≥4 cm and T3-T4. The five-year survival rate for 1,977 patients was 79.7 percent. The survival of patients with positive lateral lymph nodes was significantly worse than that of Stage III patients with negative lateral lymph nodes (45.8 vs. 71.2 percent, P

The goal of the present study was to evaluate the efficacy of the novel LigaSure Vessel Sealing System (Valleylab, Boulder, CO) when used for liver resection.Sixty patients (n = 30 in each group) with liver pathology from a single center were randomized to undergo liver resection with either the LigaSure system or with conventional clamping methods. Patients were stratified according to tumor size (5 or5 cm), type of hepatectomy (minor or major), and liver damage (normal or injured). Estimated blood loss during liver transection was used as the primary end point, whereas liver transection speed and morbidity rate were used as secondary end points.There were no hospital deaths. The median blood loss during liver transection was less in the LigaSure than in the conventional group (200 vs 322 mL; P = .185). The amount of blood loss during minor hepatectomy was significantly less in the LigaSure than in the conventional group (186 vs 412 mL, P = .012). The liver transection speed was significantly faster in the LigaSure than in the conventional group (2.3 vs 1.6 cm(2)/min, P.001. The number of ties required during liver transection was significantly less in the LigaSure than in the conventional group (6 vs 69 ties, P.001). The morbidity rate was similar when comparing the 2 groups, indicating that the LigaSure sealing device and conventional methods had comparable efficacy in sealing the bile duct in the portal triad. Postoperative bile leak was observed in 1 patient (3%) in the LigaSure group and in 3 patients (9%) in the conventional group (P = .301).The LigaSure system is an effective and safe tool for decreasing liver resection time.

There have been few placebo-controlled randomized double-blind studies of the clinical effects of selective cyclooxygenase-2 (COX-2) inhibitors on the regression of colorectal tumors. This study was designed to examine the regressive effect of a selective COX-2 inhibitor, tiracoxib (JTE-522), on colorectal polyps in patients with familial adenomatous polyposis (FAP), and its safety. Sixty-one patients with FAP diagnosed by Japanese criteria were assigned randomly to receive placebo or JTE-522, at either 150 mg or 200 mg, once daily orally for 26 weeks. Prior to and at the end of the medication period, endoscopy was performed. Adenomas located near an india-ink tattoo injected at the first colonoscopy were identified and measured. The response variables were the percent changes from the baseline in polyp numbers and in specified polyp diameters. Any adverse events that appeared in at least four persons were taken into consideration and compared between the JTE-522 treatment groups and the placebo group. No change in polyp number (median, 0) was observed in any of the three groups. There were no differences between the placebo group and the two treatment groups in the change in polyp size. JTE-522 was well tolerated. Our findings, in keeping with other reports on COX-2 inhibitors, indicated that the inhibition of a COX-2 with a moderate dose of a selective COX-2 inhibitor did not induce clinically sufficient regression of adenomas in patients with FAP in a limited (6-month) medication period.

Preoperative radiotherapy has been widely used to improve local control of disease and to improve survival in the treatment of rectal cancer. However, the response to radiotherapy differs among individual tumors. Our objective here was to identify a set of discriminating genes that can be used for characterization and prediction of response to radiotherapy in rectal cancer. Fifty-two rectal cancer patients who underwent preoperative radiotherapy were studied. Biopsy specimens were obtained from rectal cancer before preoperative radiotherapy. Response to radiotherapy was determined by histopathologic examination of surgically resected specimens and classified as responders or nonresponders. By determining gene expression profiles using human U95Av2 Gene Chip, we identified 33 novel discriminating genes of which the expression differed significantly between responders and nonresponders. Using this gene set, we were able to establish a new model to predict response to radiotherapy in rectal cancer with an accuracy of 82.4%. The list of discriminating genes included growth factor, apoptosis, cell proliferation, signal transduction, or cell adhesion–related genes. Among 33 discriminating genes, apoptosis inducers (lumican, thrombospondin 2, and galectin-1) showed higher expression in responders whereas apoptosis inhibitors (cyclophilin 40 and glutathione peroxidase) showed higher expression in nonresponders. The present study suggested the possibility that gene expression profiling may be useful in predicting response to radiotherapy to establish an individualized tailored therapy for rectal cancer. Global expression profiles of responders and nonresponders may provide insights into the development of novel therapeutic targets. (Cancer Res 2006; 66(7): 3370-4)

The clinical situation of familial adenomatous polyposis (FAP) in Japan has changed in the period since the last analysis of data of the Japanese Polyposis Center. To reevaluate our data and elucidate the changes we analyzed the records of the 1390 FAP patients in 900 families registered with the Polyposis Committee of the Japanese Society for Cancer of the Colon and Rectum. In the 13-year period 1990-2003, clinical differences between men and women with FAP diminished. The postoperative prognosis was substantially better in patients without advanced colorectal cancer (stageor = T2) than in those with early cancer or no cancer. Mean age at death improved from 42.5 years in the period before 1990 to 46.0 years, and it was a result of a decreased proportion of deaths from colorectal cancer. The distribution of colorectal cancer in FAP patients was similar to that in the general population. Desmoid tumors accounted for about 10% of deaths in the recent 13 years (1990-2003). The cumulative risk of rectal cancer in the preserved rectum was 12% at 10 years and 23% at 15 years. The registry system in Japan revealed a new clinical situation in FAP patients, and the findings of this study will be useful to improve the prognosis of patients with FAP.

Motivation: Single nucleotide polymorphisms have been investigated as biological markers and the representative high-throughput genotyping method is a combination of the Invader assay and a statistical clustering method. A typical statistical clustering method is the k-means method, but it often fails because of the lack of flexibility. An alternative fast and reliable method is therefore desirable. Results: This paper proposes a model-based clustering method using a normal mixture model and a well-conceived penalized likelihood. The proposed method can judge unclear genotypings to be re-examined and also work well even when the number of clusters is unknown. Some results are illustrated and then satisfactory genotypings are shown. Even when the conventional maximum likelihood method and the typical k-means clustering method failed, the proposed method succeeded.

目的: 胃癌術後の食事制限がBMI変化に及ぼす影響を検討する. 対象: 2001年8月から2002年6月までに根治度AあるいはBの手術を受け, 術後栄養指導の後, アンケート調査に回答された胃癌症例63例. 方法: 術後3か月目にアンケート調査を行った. 胃癌術後早期には好ましくないと思われる食品20品目について, 1. 術前より食べる習慣がない, 2. 食べていない, 3. 控えめに食べる, 4. 気にせず食べる, のいずれかを回答してもらった. 1. を除いた品目数中, 2. の割合が50%以上の患者さんをA群, 4. の割合が50%以上をC群, いずれにも該当しないものをB群と分類し, 術後3か月の時点で, 術前のBMI との変化を検討した. 結果: A群30例, B群20例, C群13例であった. BMIの変化では, A群が-2.46kg/m2, B 群が-2.77kg/m2, C群が-1.65kg/m2で, C群はA群, B群に比べて有意に術後BMIの減少が少なく抑えられていた. 胃局所切除術, 胃分節切除術, D2郭清を伴う幽門側胃切除術について術式ごとに解析しても, この傾向は保たれていた. 考察: 胃癌術後のBMI 変化からみると, 食事制限については愁訴なく術前同様に摂取できる患者さんについては, 医療者の方から制限を設けず, 自由に摂取してもらった方がBMIの減少は少なく抑えられると考えられた. しかし, 食事に起因する愁訴のある症例や, 術前から術後の栄養障害が危惧されるような症例については, 積極的な栄養指導が必要であると考えられた.

A 73-year-old man presented with an abnormal gastric shadow during a check-up of atomic bomb survivors. Radiological examination and endoscopy of the upper gastrointestinal tract revealed a protruding tumor, type 0-I+IIa, on the lesser curvature of the midstomach. An initial diagnosis of early gastric cancer was made and a segmental gastrectomy was planned. However, distal gastrectomy with D3 lymph node dissection was necessary, because intraoperative frozen section showed that the paraaortic lymph nodes (N3) were positive for cancer. The tumor in the resected specimen was, microscopically, a well-differentiated tubular adenocarcinoma (tub1) with pT2 (MP), pN3, ly2, and v1, in final (f) stage IV. The tumor cells of the type 0-I segment appeared as gastric phenotype and those of the type 0-IIa segment as intestinal phenotype. The border between the two was distinct. The tumor had focally invaded the muscularis propria where only the gastric phenotype was shown and the histological type became less differentiated. Thus, special attention should be paid to possible unexpected deep-wall invasion and lymph node metastasis in well-differentiated adenocarcinomas of the gastric phenotype. Further, in this patient, diffusely proliferating low-grade lymphoma was also observed incidentally in the gastric mucosa within and around the carcinoma. This was diagnosed as mucosa-associated lymphoid tissue (MALT)-type lymphoma with aberrant expression of BCL10. Finally, this case was considered to be a colliding gastric and intestinal phenotype well-differentiated adenocarcinoma of the stomach developed in an area involved by MALT-type lymphoma. Because no Helicobacter pylori was detected throughout the mucosae and the patient had no history of its infection, the three tumors may have developed under the same conditions as those seen in Helicobacter pylori infection, but without this infection.

Patients with long-standing ulcerative colitis (UC) are known to have an increased risk for the development of colorectal cancer (CRC). The aim of this study was to clarify the cumulative risk for the development of dysplasia or invasive cancer and the effectiveness of surveillance colonoscopy in the Japanese population. A total of 217 patients received a total of 1027 surveillance colonoscopies between January 1979 and December 2001 at the University of Tokyo hospital. Patients with invasive cancer found in the surveillance group were compared to those referred to our hospital from the other hospitals without surveillance colonoscopy. Surveillance colonoscopy confirmed 15 patients with definite dysplasia. Of these, five were proved to have invasive cancer in the resected specimens. The cumulative risk for the development of invasive cancer at 10, 20, and 30 years was 0.5, 4.1, and 6.1%, respectively, while that for the development of definite dysplasia at 10, 20, and 30 years was 3.1, 10.0, and 15.6%, respectively. All the patients with invasive cancer in the surveillance group remained alive, while three out of four patients in the nonsurveillance group died. Our surveillance programme is useful for detecting UC-associated CRC, and survival may be improved by surveillance colonoscopy.

Background. The justification for surgical resection of liver metastases from gastric cancer remains controversial. Methods. Twenty-two patients who underwent 26 hepatectomies for liver metastases of gastric cancer between 1985 and 2001 were analyzed. Fifteen clinicopathologic factors were evaluated with univariate and multivariate analyses for survival after hepatic resection. Results. The overall 1-year, 3-year, and 5-year survival rates after hepatectomy for gastric metastases were 73%, 38%, and 38%, respectively. Five patients survived for more than 3 years without recurrence, 3 of whom had synchronous metastases resected at the time of gastrectomy. The best results after surgical resection for liver metastases of gastric cancer were obtained with solitary metastases less than 5 cm in size. The number of liver metastases (solitary or multiple) was the only significant prognostic factor according to both univariate and multivariate analyses. Conclusion. Surgical resection for liver metastases of gastric cancer may be beneficial for patients with a solitary metastasis, whether it is synchronous or metachronous. (Surgery 2003;133:507-11.)

The administration of steroids is not always effective for the treatment of ulcerative colitis (UC). Their long-term use often causes adverse effects which sometimes result in their stoppage and acute exacerbation. Therefore, an alternative treatment is necessary in order to decrease steroid dosage and avoid the clinical problems associated with steroids. Methods The effectiveness and adverse effects of a leukocytapheresis (LCAP) were investigated in a controlled multicenter trial with randomized assignment of 76 active-stage UC patients in two groups. In the LCAP group (39 patients), LCAP weekly for 5 weeks as an intensive therapy was added to the on-going drug therapy, while steroids were maintained but not increased, and then LCAP was gradually reduced to once every 4 weeks as a maintenance therapy. In the high dose prednisolone (h-PSL) group (37 patients), PSL was added or increased 30 approximately 40 mg/day for moderately severe and 60 approximately 80 mg/day for severe patients and then gradually tapered. Findings The LCAP group showed a significantly higher effectiveness (74% vs. 38%; p=0.005) and lower incidence of adverse effects (24% vs. 68%; p

目的: 大動脈周囲, 特に大動脈裂孔周囲リンパ節の解剖所見を解剖体と手術所見で比較し, その相違について検討した. 対象と方法: 38体の医学教育研究用に献体された成人解剖体と大動脈裂孔周囲のリンパ解剖が観察できた16例の胃癌手術例を対象とし, 大動脈裂孔周囲の腰リンパ本幹の経路, 乳糜槽との関連を検討した. 結果: 解剖体では, 左の腰リンパ本幹は平均2.07 (1～3) 本, 右は1.16 (1～2) 本で, 腰リンパ本幹はしばしば大動脈裂孔を通して縦隔へ達し, そこで胸管を形成していた. 大動脈裂孔以外を通るリンパ管は細いリンパ管で4例 (13%) あった. 乳糜槽の形成は, 2例 (5%) に認められた. 手術所見では全例に太い腰リンパ本幹を認めた. 大動脈裂孔を通らない症例も存在した (4例25%). 大動脈裂孔を通してのリンパ経路が主であった. 考察: 腹部大動脈周囲リンパ節から胸管へ流れる経路は, 大動脈裂孔を通る経路が主流と考えられた. したがって, 大動脈周囲リンパ節郭清に際しては, 左右腎動脈背側にある大動脈裂孔を意識することが重要と考えられた. しかし, 横隔膜の内側脚と中間脚の間へ流れる経路が併存しうることも留意する必要がある.

To test the clinical usefulness of hepatic asialogycoprotein receptor analysis in liver surgery, we have conducted univariate and multivariate analysis for the detection of cirrhotic patients and prediction of morbidity after hepatic resection. Liver scintigraphy using technetium 99m-labeled asialoglycoprotein analog (TcGSA), ICG test, and CT hepatic volumetry were undertaken in 158 surgical patients including 111 who underwent hepatic resection. Hepatic functional parameters including Child-Pugh score, indocyanine green retention at 15 minutes (ICG-R15), clearance index (HH15), receptor index (LHL15), receptor concentration ([R]0), total hepatic receptor amount (R0) and hepatic parenchymal volume (HPV) were compared among patients with normal, cirrhotic, and non-cirrhotic damaged liver. Preoperative hepatic functional parameters, resected parenchymal fraction (RPf), operative blood loss, and total receptor amount of the remnant liver (R0-remnant) were compared between patients with and without signs of postoperative liver failure. All parameters but HPV were significantly different among patients with normal, cirrhotic, and noncirrhotic damaged liver. The multivariate analysis selected two significant (p0.05) parameters, [R]0 and Child-Pugh score for the detection of liver cirrhosis. Of the 111 patients who underwent resection, 14 developed transient signs of postoperative liver failure. Of the parameters tested, presence of liver cirrhosis, LHL15, R0, intraoperative blood loss, and R0-remnant were significantly different between patients with and without signs of postoperative liver failure (p0.05). The multivariate logistic regression analysis selected only R0-remnant as a significant (p = 0.022) parameter for the prediction of liver failure. The morbidity rate in patients with R0-remnant under 0.05 mmoles was 100%, and the rate decreased in inverse proportion to R0-remnant. In conclusion, combining the ASGP-R concentration ([R]0) and the Child-Pugh score best detected liver cirrhosis in surgical candidates. Cirrhotic patients and patients with a low R0-remnant are at higher risk for postoperative liver failure. The present study confirms the usefulness of hepatic asialogycoprotein receptor analysis in liver surgery.

Extended lymphadenectomy including lateral node dissection (EXT-L) contributes to a low incidence of local recurrence of lower rectal cancer. However, EXT-L is frequently associated with impairment of sexual and urinary function. We therefore compared the effectiveness of preoperative radiotherapy with that of EXT-L.One hundred fifteen patients were studied. Seventy-eight patients underwent preoperative radiotherapy with a total dose of 50 Gy (Rad[+] group), and 37 did not (Rad[-] group). Seventy-five patients received EXT-L (EXT-L[+] group), and 40 did not (EXT-L[-] group). Patients were further divided into 4 subgroups (Rad[+]EXT-L[-], Rad(+)EXT-L[+], Rad[-]EXT-L(+), and Rad[-]EXT-L[-]), and clinicopathologic features were examined. In the Rad(+) group, the relation between the p53 gene and survival was also examined.There was a significant difference in disease-free survival between the Rad(+) and Rad(-) groups (5-year disease-free survival rate, 74.6% vs 45.9%; P =.006). However, there was no significant difference between the Rad(+)EXT-L[-] and Rad[-]EXT-L(+) groups. The p53 gene status did not affect survival in the Rad(+) group.This study suggests that in terms of curative effect, preoperative radiotherapy can be one alternative therapy in place of EXT-L for patients with lower rectal cancer.

Although hemihepatic portal vein embolization (PVE) has been used preoperatively to extend indications for hepatectomy in patients with colorectal metastases, the effects of this procedure on tumor growth and outcome remain controversial. To address this issue, we assessed the proliferative activity of intrahepatic metastases after PVE and the long-term outcome of this procedure. Eighteen patients with colorectal metastases underwent preoperative PVE between 1996 and 2000 (PVE group). Twenty-nine patients who underwent major hepatic resection without PVE served as control (non-PVE group). The hepatic parenchymal fraction of the left lobe had significantly increased from 38.1 +/- 3.2% to 45.9 +/- 2.9% 3 weeks after PVE (+20.5%, P

Purpose: Factors influencing the development or rupture of abdominal aortic aneurysms (AAAs) have not yet been confirmed. This study delineated the risk factors for rupture of AAAs as evaluated by means of a combination of three-dimensional (3D) reconstruction and clinical data analysis. Methods: The study population comprised Japanese patients in whom an atherosclerotic AAA had been diagnosed between January 1980 and December 1997. We obtained 3D-based data by means of computer-aided 3D reconstruction from computed tomography studies of AAAs. The data included the tortuosity of the aneurysm, maximum transverse diameter, length of the aneurysm, aneurysmal volume, aneurysmal surface area, largest aneurysmal cross-sectional area, ratio of transverse aneurysmal diameter to the length of the aneurysm (T/L), and amount of mural thrombus. Clinical data were collected from patient files. All data were assessed by means of multivariate analysis for their predictive value for expansion or rupture of AAA. Results: The most efficient predictor of annual expansion rate of maximum transverse diameter (EX-D) was a combination of largest aneurysmal cross-sectional area, tobacco use, and tortuosity. The most efficient predictor of annual expansion rate of aneurysmal volume (EX-V) was a combination of aneurysmal volume and blood urea nitrogen level. The most efficient predictors of aneurysmal rupture was a combination of EX-D, diastolic blood pressure, and T/L. Conclusion: Three-dimensional–based data on aneurysmal morphology, including T/L, largest aneurysmal crosssectional area, and aneurysmal volume, had strong predictive value for expansion and rupture of AAAs. (J Vasc Surg 2001;33:453-61.)

With carcinoma of the thoracic esophagus, clinical evidence of invasion of adjacent organs (T4) indicates a highly advanced stage, and most surgeons avoid esophagectomy. Although the therapeutic strategy for such disease is generally selected based on preoperative evaluation and intraoperative inspection, their accuracy and the relation to survival outcomes after esophagectomy have seldom been analyzed on the basis of exact histopathologic evidence. We performed esophagectomy, with perioperative adjuvant therapy when possible, on patients with clinical-T4 tumors unless absolutely unresectable conditions were detected. Among the 500 patients who underwent esophagectomy, the 78 patients whose tumors were confirmed to be T4 pathologically were compared with patients whose tumors were assessed as T4 preoperatively or intraoperatively to evaluate the role of esophagectomy for clinical-T4 carcinoma. Esophagectomy was possible for 99% of the pathologic-T4 tumors preoperatively assessed as resectable, but the resection was grossly incomplete in 35%. The true-positive rates in tumors preoperatively and intraoperatively assessed as T4 were 51% and 84%, respectively. The hospital mortality rate in patients with pathologic-T4 tumors was 4%. The overall 5-year survival rate for patients with pathologic-T4 tumors was 14%, compared with 60% for those with tumors assessed as T4 intraoperatively but not pathologically. Esophagectomy with perioperative adjuvant therapy yielded occasional cure with an acceptable mortality rate for patients with pathologic-T4 tumors assessed as technically resectable. Preoperative assessment and intraoperative macroscopic inspection had limitations for predicting pathologic-T4 disease and incomplete resection. Only patients with definitive evidence of unresectability should be excluded from esophagectomy.

Many types of infections associated with colorectal cancer have been reported. Here, we describe a rare case of thoracic empyema that was observed during immunotherapy for recurrent colon cancer. Culture of the pleural fluid yielded Streptococcus bovis, which is known to be associated with gastrointestinal lesions, especially colorectal malignancies. The possible correlation between these two clinical entities-empyema and colon cancer-is discussed.

Background: Several researchers reported that local excision with or without postoperative chemo-radiation therapy is an alternative approach for sphincter preservation in patients with locally invasive rectal carcinoma. However, indications and long-term results have not yet been determined. Methods: Seventy-two patients with T2 colorectal carcinomas underwent bowel resection with regional lymph node dissection. The associations between lymph node metastasis (LNM) and clinicopathologic factors were examined with special reference to the presence or absence of moderate to severe degree of focal dedifferentiation or mucinous component at the invasive margin (unfavorable histology). Results: Multivariate logistic regression analysis revealed that both sex and unfavorable histology were significantly associated with LNM ( P = 0.0102, 0.0226, respectively). However, the associations between LNM and lymphatic invasion or tumor location were not statistically significant ( P = 0.0947, 0.1738). Conclusions: When locally resected T2 rectal carcinoma specimens have unfavorable histology at the invasive margin, additional bowel resection with lymph node dissection should be recommended.

Ulcerative colitis (UC) and Crohn's disease (CD), the major forms of inflammatory bowel diseases (IBDs). are multifactorial disorders of unknown etiology. We reported a possible association of rare variable number of tandem repeat (VNTR) alleles of the "MUC3" gene with a susceptibility to UC. However, an entire structure of "MUC3" is still unknown because the long stretches of tandem repeats in this "gene" make its cloning extraordinarily difficult. In this study, we report evidence that "MUC3" consists of two genes, MUC3A and MUC3B, both of which encode membrane-bound mucins with two epidermal growth factor-like motifs, and we describe the complete 3'-terminal structures of these two genes. We have also analyzed the single nucleotide polymorphisms (SNPs) in the exonic sequences of the 3' portions of these two genes to investigate whether sequence variations in these regions can cause person-to-person differences in the susceptibility to IBDs, and report here that non-synonymous SNPs of MUC3A, involving a tyrosine residue with a proposed role in cell signaling, may confer genetic predisposition to CD (P = 0.0132). Our findings suggest that variants of MUC3A may be involved in the occurrence of UC and CD in distinct manners.

The multistep genetic model of colorectal carcinogenesis is based on the concept of the adenoma-carcinoma sequence. The adenoma-carcinoma sequence theory has been generally accepted for polypoid early colorectal cancers (ECCs). On the other hand, an increasing number of nonpolypoid (superficial) ECC have been reported. Nonpolypoid (superficial) ECCs show distinct characteristics histologically and genetically, and some claim these lesions may develop by de novo type carcinogenesis. In fact, clinicopathologic studies have shown that most nonpolypoid (superficial) cancers have no adenomatous lesions in the surrounding area. Genetic analyses have also revealed that nonpolypoid (superficial) ECCs show a pattern of genetic alterations different from that of polypoid ECCs. The K-ras mutation rate is lower in nonpolypoid (superficial) ECCs than in polypoid ECCs, but there is no significant difference in the p53 mutation rate between two types of tumor. During the development of ECCs, the K-ras gene seems to determine the macroscopic configuration: whether polypoid or nonpolypoid (superficial). These results suggest that nonpolypoid (superficial) ECCs originate from a pathway different from the conventional genetic pathway that follows the adenoma-carcinoma sequence. However, this does not mean that this new pathway is following de novo type carcinogenesis, because there is a possibility that nonpolypoid (superficial) adenomas, or so-called flat adenomas, develop into nonpolypoid (superficial) ECCs following the adenoma-carcinoma sequence. At the present time, there is still not enough evidence to conclude whether nonpolypoid (superficial) ECC is derived from de novo carcinogenesis or the conventional adenoma-carcinoma sequence. Further analysis, especially concerning APC gene mutation in ECCs, is essential to elucidate the carcinogenesis of nonpolypoid (superficial) ECCs.