Gene expression analysis in colorectal cancer using practical DNA array filter.

PURPOSE: We examined the usability of a newly developed, compact-sized DNA array filter for studying the gene expression pattern of individual colorectal cancer. METHODS: Complementary DNA probes were prepared from mRNA extracted from colonic cancer specimens and adjacent normal mucosa and then were labeled with chemiluminescence. These labeled probes were allowed to bind to the gene fragments on the filter. A specialized scanning charge-coupled device camera measured the intensity of each chemiluminescent spot, which is an indicator of the degree to which a specific gene is expressed. Gene expression image was quantified into intensity of signals by using computer software. RESULTS: Characteristic gene expression patterns were obtained from the colonic cancer cell line, RPMI4788, and the leukemia cell line, HL60, by using this compact-sized DNA array filter in the preliminary experiment. Up-regulation of nm23, TIMP1, VEGF, and cyclin E and down-regulation of some tumor suppressor genes (p53, TOSO, and SIVA), beta-catenin, and metallothionein were observed in colonic cancer specimen when compared with those of normal mucosa. CONCLUSIONS: We have obtained unique gene expression patterns from colorectal cancer and normal tissue by using a newly developed compact-sized DNA array filter system. Collecting, storing, and analyzing of gene expression data from many samples of colorectal cancer will enable us to identify distinct subsets of patients based on molecular characteristics in the near future.

Horizontal inclination of the longitudinal axis of the colonic J-pouch: defining causes of evacuation difficulty.

PURPOSE: Functional outcome after low anterior resection for rectal cancer is improved by the construction of a colonic J-pouch. One disadvantage of this type of reconstruction is evacuation difficulty, which has been associated with large pouches. The purpose of this study was to elucidate the causes of evacuation difficulty in large pouches using pouchography. METHODS: The angle between the longitudinal axis of the pouch and the horizontal line (pouch-horizontal angle) on lateral pouchography was determined in 26 patients with 10-cm J-pouch reconstructions (10-J group) and 27 patients with 5-cm J-pouch reconstructions (5-J group). Measurement were made at three months, one year, and two years after surgery. Clinical function was evaluated using a questionnaire one year postoperatively. RESULTS: The pouch-horizontal angle in the 10-J group was significantly smaller than that in the 5-J group at all three time points. In both groups the pouch-horizontal angle at one year was significantly smaller than that at three months. There were no significant differences between the pouch-horizontal angles at one and two years. An evacuation difficulty was significantly more common in the 10-J group than the 5-J group. CONCLUSIONS: The evacuation difficulty observed in patients with large colonic J-pouch reconstructions may be attributed to the development of a horizontal inclination within one year of surgery.

Enlargement of colonic pouch after proctectomy and coloanal anastomosis: potential cause for evacuation difficulty.

PURPOSE: Although the functional outcome after low anterior resection for rectal cancer using colonic J-pouch reconstruction is superior to that using conventional straight reconstruction, the one drawback of colonic J-pouch reconstruction is difficulty with evacuation. Recently it has been suggested that construction of a larger colonic J-pouch causes the evacuation difficulty. The purpose of this study was to elucidate the cause of evacuation difficulty with colonic J-pouch reconstruction. METHODS: We compared pouchography of 26 patients with 10-cm colonic J-pouch reconstructions (10-J group) and 27 patients with 5-cm colonic J-pouch reconstructions (5-J group) at three months, one year, and two years after surgery. Functional assessments were performed one year postoperatively. Clinical function was evaluated using a questionnaire. Evacuation function was evaluated by the balloon expulsion and saline evacuation tests. RESULTS: The greatest width of the pouch in the 10-J group in the anteroposterior view was significantly greater than that in the 5-J group at all three measurement times (3 months, 4.9 vs. 4 cm; P = 0.0011; 1 year, 9 vs. 5.6 cm; P < 0.0001; 2 years, 9.2 vs. 5.8 cm; P < 0.0001). The value in the 10-J group at one year after surgery was 1.9 times that at three postoperative months; in the 5-J group this ratio was 1.4. There was a significant difference between these ratios (P < 0.0001). No significant difference existed between the values at two years and one year after surgery in either the 10-J or the 5-J group. An evacuation difficulty was significantly more common in the 10-J group than the 5-J group. Evacuation function in the 10-J group was significantly inferior to that in the 5-J group. CONCLUSIONS: The evacuation difficulty observed in patients with larger colonic J-pouch reconstructions is associated with excessive distention of the pouch occurring within one year of surgery.

Involvement of galectin-3 expression in colorectal cancer progression and metastasis.

Galectin-3 is a beta-galactoside-specific lectin that binds to laminin sugar-sites and is involved in tumor malignancy. Galectin-3 expression in relation to primary tumor and liver metastasis of colorectal cancer was examined to determined its involvement in cancer progression and metastasis. Immunohistochemical staining of galectin-3 was performed on 117 primary lesions and 15 liver metastases of colorectal cancer using TIB166 monoclonal antibody. The expression of galectin-3 was evaluated by grading the intensity of the staining as either negative, weakly positive, or strongly positive. Normal mucosa of all patients were strongly positive for galectin-3, but the staining in these tissues was still significantly less than in the primary lesions of the cancer (31.6%). Galectin-3 expression in the primary lesions was significantly increased, correlating with the progression of clinical stage (p=0. 0224), liver metastasis (p<0.0001), venous invasion (p=0.0048), and lymph node metastasis (p=0.0289). Liver metastatic lesions also showed up-regulated levels of galectin-3 compared to the primary lesions (p=0.0030). The group showing strongly positive galectin-3 had a significantly poorer prognosis than the negative/weakly positive group in terms of disease-free survival (p=0.0224). The strong expression of galectin-3 in colorectal cancer correlates with cancer progression, liver metastasis, and poor prognosis for patients.

High ligation of the inferior mesenteric artery with hypogastric nerve preservation in rectal cancer surgery.

We describe herein a technique of performing upward node dissection following high ligation of the inferior mesenteric artery for patients with T3 and T4 rectal carcinomas. The course of the hypogastric nerve is confirmed macroscopically during the procedure to ensure its preservation. This technique offers both increased radicality and the prevention of ejaculatory dysfunction.

Examination of nodal metastases by a clearing method supports pelvic plexus preservation in rectal cancer surgery.

PURPOSE: In rectal cancer surgery preservation of urinary and sexual function is attempted by means of operations preserving the autonomic nerves of the pelvic plexus. Emergence of residual cancer because of a more shallow plane of dissection is a problem of concern with these methods, so we examined indications for pelvic plexus preservation. METHODS: We studied 198 patients with rectal carcinoma who underwent abdominopelvic lymphadenectomy. Lymph nodes along the superior hemorrhoidal artery and middle hemorrhoidal artery medial to the pelvic plexus were defined as perirectal nodes, and nodes along the middle hemorrhoidal artery lateral to the pelvic plexus and along the internal iliac artery represented lateral intermediate nodes. Node metastases were examined by the clearing method. RESULTS: Metastasis to perirectal nodes occurred in 12.5 percent in patients with pT1 tumors, 28.9 percent of those with pT2 tumors, and 50.0 percent of those with rectosigmoid junctional cancer. Metastasis to lateral intermediate nodes was absent in patients with pT1 or pT2 tumors and was as low as 2.5 percent in patients with rectosigmoid junctional cancer. CONCLUSIONS: In patients with T1, T2, and rectosigmoid junctional cancer, perirectal node dissection is necessary, but chances of residual cancer should remain minimal when the pelvic plexus is preserved.

Coloanal anastomosis using a circular stapling device following perineal rectosigmoidectomy for rectal prolapse.

Perineal rectosigmoidectomy with a hand-sewn anastomosis is thought to be the most appropriate procedure for elderly patients deemed unfit to tolerate a major abdominal operation. However, the use of a circular stapling device to perform the coloanal anastomosis following rectosigmoidectomy shortens the operative time and provides a more secure anastomosis than the traditional hand-sewn technique.

Detection of a rectocele-like prolapse in the colonic J-pouch using pouchography: cause or effect of evacuation difficulties?

The functional outcome after a low anterior resection for rectal cancer is improved by a colonic J-pouch reconstruction. One functional problem with J-pouches is difficulty in evacuation, which is more common with large reconstructions. Since rectoceles are common findings on defecography in patients with evacuation difficulties, we proposed that a rectocele-like prolapse may be thus found in patients with large J-pouches. Pouchography was used to identify a rectocele-like prolapse (RP) in 26 patients with a 10-cm J-pouch (10-J group) and 27 patients with a 5-cm J-pouch (5-J group). Pouchography was performed at 3 months, 1 year, and 2 years after surgery. Functional assessments were performed 1 year postoperatively. Clinical function was evaluated using a questionnaire. The evacuation function was evaluated by the balloon expulsion and saline evacuation test. No patients had an RP at 3 months or 1 year after surgery. An RP was significantly more common in the 10-J group than in the 5-J group at 2 years after surgery (P = 0.0374). An evacuation difficulty was significantly more common in the 10-J group than in the 5-J group. The evacuation function in the 10-J group was also significantly inferior to that in the 5-J group. An RP appearing 2 years after surgery is more common in patients with evacuation difficulties and large colonic J-pouch reconstructions.

Longterm effects of hepatic arterial interleukin-2-based immunochemotherapy after potentially curative resection of colorectal liver metastases.

BACKGROUND: Our previous study of hepatic arterial infusion of interleukin-2 (IL-2)-based immunochemotherapy demonstrated a high response rate of patients with unresectable liver metastases. In this study, we applied this therapy to the prevention of liver recurrence in patients who underwent potentially curative resection of liver metastases. STUDY DESIGN: A pilot study was conducted of 18 patients with liver metastases from primary colorectal cancer who underwent potentially curative liver resection followed by adjuvant immunochemotherapy. The regimen consisted of a weekly hepatic arterial infusion of IL-2 (1.4-2.1 X 10(6) U) and 5-fluorouracil (250 mg) and a bolus of mitomycin C (2-4 mg) for 6 months. RESULTS: Among 18 patients, 14 are still alive with a median postoperative survival of 52 months (as of April 1998). The 5-year overall survival rate was 75%. Although recurrent cancer developed in 6 of the 18 patients, no patients had recurrence in the residual liver. This complete prevention of liver recurrence is believed to have contributed to the high 5-year survival rate (75%) as compared with the survival rate of patients treated with surgery alone (average, 30%-40%) or with several other forms of adjuvant therapy. CONCLUSIONS: Interleukin-2-based immunochemotherapy is useful in combination with liver resection for the prevention of liver recurrence in colorectal cancer patients with liver metastases. A multicenter randomized trial is recommended.

Anterior resection following posterior transsacral stapling and transection of the anal canal for low-lying rectal cancer in males.

In anterior resection with anastomosis using the double-staple technique for low-lying rectal cancer in male patients, the approach to the anal canal with a stapling instrument via the abdominal area is limited by the narrow pelvis. The stapling and transection of the anal canal via the posterior transsacral approach prior to performing an anterior resection thus enables the lower rectum and anal canal to be visualized, so that the anal canal can be accurately stapled and transected even in male patients with a narrow pelvis.

Indication for using high ligation of the inferior mesenteric artery in rectal cancer surgery. Examination of nodal metastases by the clearing method.

PURPOSE: In surgery for rectal cancer, it is unclear whether the inferior mesenteric artery should be ligated at a high or low position. The study contained herein was undertaken to clarify the indications for high ligation of the inferior mesenteric artery. METHODS: Subjects included 198 patients with rectal cancer who underwent resection with high ligation of the inferior mesenteric artery. Nodal metastases were examined by the clearing methods. RESULTS: The incidence of metastases to the lymph nodes surrounding the origin of the inferior mesenteric artery (root nodes) was 8.6 percent. Inferior mesenteric artery root nodal metastases occurred more frequently with pT3 and pT4 cancer. The five-year survival rate in patients with inferior mesenteric artery root nodal metastases was 38.5 percent; this rate was significantly lower than in those without inferior mesenteric artery root nodal metastases (73.4 percent). CONCLUSIONS: Although the five-year survival rate in patients with inferior mesenteric artery root nodal metastases was lower than in those without metastases, inferior mesenteric artery root nodal dissection should be performed after high ligation of the inferior mesenteric artery for patients with pT3 and pT4 cancers.

Indications for colonic J-pouch reconstruction after anterior resection for rectal cancer: determining the optimum level of anastomosis.

PURPOSE: Functional outcome after anterior resection for rectal cancer is improved by colonic J-pouch reconstruction compared with straight anastomosis. The indications for colonic J-pouch reconstruction have yet to be determined. Therefore, we attempted to determine the level at which J-pouch reconstruction provides an advantage over straight anastomosis. METHODS: A total of 48 patients who underwent 5-cm colonic J-pouch reconstruction (J-pouch group) and 80 patients who underwent straight anastomosis (straight group) underwent functional assessment one year postoperatively. RESULTS: The functional outcome in the J-pouch group was significantly better than that in the straight group when the distance of the anastomosis from the anal verge was less than 8 cm. The difference was particularly obvious when the level of the anastomosis was below 4 cm. However, functional outcome in the straight group when the anastomosis was between 9 and 12 cm from the anal verge was also satisfactory and did not differ from that in the J-pouch group when the anastomosis was between 5 and 8 cm from the anal verge. CONCLUSIONS: Colonic J-pouch reconstruction is indicated when the distance of anastomosis from the anal verge is less than 8 cm, and it is essential when the distance is less than 4 cm.

Results from pelvic exenteration for locally advanced colorectal cancer with lymph node metastases.

PURPOSE: We examined the survival benefit of pelvic exenteration for locally advanced colorectal cancer with lymph node metastases, because this issue remains controversial. METHODS: Medical records of 50 patients who underwent curative pelvic exenteration for colorectal cancer were reviewed retrospectively. Nodal metastases were examined by the clearing method in 29 patients and by the conventional manual method in 21 patients. RESULTS: Invasion to contiguous pelvic organs was present in 40 patients (80 percent) and absent in 10 patients (20 percent). Node metastases were present in 33 patients (66 percent). Operative morbidity and mortality rates were 22 percent (11 patients) and 6 percent (3 patients), respectively. Respective five-year survival rates were 60 and 80 percent in the groups with and without organ invasion (no significant difference). Five-year survival rates in patients with nodal metastases was 54.6 percent but was significantly higher, 82.4 percent, in patients without nodal metastases. Five-year survival in 28 patients with both organ invasion and nodal metastases was 53.6 percent. CONCLUSIONS: Long-term survival was afforded by pelvic exenteration for locally advanced colorectal cancer with nodal metastases.

The extent of lymph node dissection for colon carcinoma: the potential impact on laparoscopic surgery.

BACKGROUND: The surgeon is no longer able to palpate the mesocolon for lymph node metastases during laparoscopic colectomy. The extent of lymph node dissection should be determined beforehand for cancer control. METHODS: The distribution of lymph node metastases was obtained by the clearing method on colon carcinomas for 164 patients. RESULTS: For pericolic spread: for pT1 tumors, the distance from the primary tumor to a metastatic lymph node was 2.5 cm; for pT2, the distance was within 5 cm; for 97.0 % of pT3 tumors with lymph node metastases, the distance was within 7 cm; for 93.3 % of pT4 tumors with lymph node metastases, the distance was within 7 cm. For central spread: for pT1 tumors, the rate of metastasis to central lymph nodes was 0 %; for pT2, the rate of metastasis was 20.0 % to intermediate lymph nodes; for pT3, the rate of metastasis was 30.6 % to intermediate lymph nodes and 15.3 % to main lymph nodes; for pT4, the rate of metastasis was 44.4 % to intermediate lymph nodes and 22.2 % to main lymph nodes. CONCLUSIONS: Central lymph node dissection is not required for patients with T1 carcinomas, but proximal and distal 3-cm margins of resection are required. For T2, central lymph node dissection that includes the intermediate lymph node should be performed, as well as 5-cm proximal and distal margins of resection. For T3 and T4, central lymph node dissection including the main lymph node should be performed, as well as 7-cm proximal and distal margins of resection. [See editorial on pages 177-8, this issue.]

Lymph node metastases detected in the mesorectum distal to carcinoma of the rectum by the clearing method: justification of total mesorectal excision.

BACKGROUND: Total mesorectal excision effectively reduces the local recurrence rate of carcinoma of the rectum. This study was undertaken to clarify the rationale for total mesorectal excision. STUDY DESIGN: We retrospectively reviewed the records of 198 patients who underwent resection of a carcinoma of the rectum. The presence of nodal metastases in the mesorectum distal to the primary tumor was examined by the clearing method. RESULTS: The metastatic rate in the distal mesorectum was 20.2 percent. The metastatic rates according to the extent and site of the tumor were as follows: pT1, 0 percent; pT2, 0 percent; pT3, 21.9 percent; pT4, 50 percent; rectosigmoid, 10 percent; upper rectum, 26.3 percent; and lower rectum, 19.2 percent. The longest distal spread from the primary tumor to the metastatic node was 2 cm in carcinoma of the rectosigmoid, 4 cm in carcinoma of the upper rectum, and 3 cm in carcinoma of the lower rectum. CONCLUSIONS: Total mesorectal excision is required for patients with T3 and T4 tumors in the lower rectum, and excision of all mesorectal tissue down to at least 5 cm below the tumor is required for patients with T3 and T4 tumors in the upper rectum.

Does lateral lymph node dissection improve survival in rectal carcinoma? Examination of node metastases by the clearing method.

BACKGROUND: The treatment of rectal carcinoma by lateral lymph node dissection has risks and benefits. Therefore, we investigated the therapeutic efficacy of lateral lymph node dissection. STUDY DESIGN: We studied 198 patients with rectal carcinoma who underwent lateral lymph node dissection. Metastases to the lymph nodes were examined by the clearing method. The incidence of urinary and male sexual dysfunction was determined by measuring the residual urine volume and individual interview 1 year after operation. RESULTS: The rate of metastasis to lateral lymph nodes was 11.1 percent, and metastasis to the lateral lymph nodes occurred more frequently with lower rectal carcinoma classified as pT3 or pT4 in the TNM system. The rate of local recurrence was 12.5 percent and the 5-year survival rate after curative resection was 70.1 percent. The 5-year survival rate in patients with metastasis to the lateral lymph nodes was 25.1 percent, and this rate was significantly lower than the 5-year survival rate of 74.3 percent in patients without metastasis to the lateral lymph nodes. Urinary dysfunction was observed in 67.5 percent of patients, and male sexual dysfunction was found in 97.4 percent of men younger than 60 years of age with prior sexual ability. CONCLUSIONS: The prognosis for patients with metastasis to the lateral lymph nodes is poor, and the improvement in survival rate from lateral lymph node dissection is minimal.

Comparison between the Japanese general rules and the TNM system in the regional lymph node classification of carcinoma of the colon.

BACKGROUND: Metastasis to regional lymph nodes from carcinoma of the colon is an important prognostic factor. In the tumor, node, metastasis classification, node metastases are classified into four grades based on the number and distribution of metastatic nodes. In the Japanese General Rules for Clinical and Pathological Studies on Cancers of the Colon, Rectum and Anus, node metastases are classified into four grades based solely on the distribution of metastatic nodes. STUDY DESIGN: Based on the findings of node metastases in 152 patients with carcinoma of the colon obtained by the clearing method, the node classifications by the Japanese General Rules and tumor, node, metastasis classifications were compared. RESULTS: The case distribution by the Japanese General Rules grading was 38.2 percent in n(-), 30.3 percent in n1(+), 19.7 percent in n2(+), and 11.8 percent in n3(+) disease. In the tumor, node, metastasis classification, the distribution was 22.4 percent in pN1 and pN3 and 17.1 percent in pN2 disease. The five-year survival rate by the Japanese General Rules was 97.9 percent in n(-), 72.6 percent in n1(+), 51.2 percent in n2(+), and 30.0 percent in n3(+) disease, whereas in tumor, node, metastasis classification, this rate was 79.4 percent in pN1, 45.2 percent in pN2, and 44.8 percent in pN3 disease. CONCLUSIONS: In the classification of regional node metastases from carcinoma of the colon, the Japanese General Rules showed a wider range in distribution and 5-year survival rate compared with the tumor, node, metastasis system.

Analysis of regional lymph node metastases from rectal carcinoma by the clearing method. Justification of the use of sigmoid in J-pouch construction after low anterior resection.

PURPOSE: It has been reported that functional outcome following low anterior resection of resection of rectal cancer is improved by construction of a colonic J-pouch compared with straight anastomosis. Hence, we tried to justify use of the sigmoid colon in the construction of a J-pouch by the analysis of regional lymph node metastases. METHODS: A total of 182 patients underwent resection for rectal cancer. Node metastases were examined by the clearing method. According to Japanese General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus (JGR), nodes were classified into the perirectal nodes (PR-N), pericolic nodes (PC-N), central intermediate nodes (C-IM-N), central main nodes (C-M-N), lateral intermediate nodes (L-IM-N), and lateral main nodes (L-M-N). RESULTS: Metastatic rate (number of patients with node metastases/total number of patients) of PR-N was 57.1 percent. Metastatic rate of C-IM-N was 18.7 percent and that of C-M-N was 7.1 percent. Metastatic rates of L-IM-N and L-M-N were 8.8 and 3.3 percent, respectively, and both were highest in the case of lower rectal cancer. Metastatic rate of PC-N was only 1.1 percent. The number of cases without node metastases (n(-) cases) was 78, that with only PR-N metastases (PR-N cases) was 63, that with intermediate but not main node metastases (IM-N cases) was 29, and that with main node metastases (M-N cases) was 12. Five-year survival rate after curative resection was 88.5 percent for n(-) cases, 70.9 percent for PR-N cases, 65.9 percent for IM-N cases, and 41.7 percent for M-N cases. CONCLUSIONS: In low anterior resection, high ligation of the inferior mesenteric artery and dissection of C-M-N, C-IM-N and PR-N are necessary, with the addition of the L-IM-N and L-M-N in the case of lower rectal cancer. Resection of sigmoid colon is not required, and therefore, a J-pouch can be constructed using the sigmoid colon. Nodal classification according to the JGR was predictive of case distribution and five-year survival rate.

Functional outcome after low anterior resection with low anastomosis for rectal cancer using the colonic J-pouch. Prospective randomized study for determination of optimum pouch size.

PURPOSE: Functional outcome after low anterior resection with ultralow coloanal anastomosis for rectal cancer is improved by construction of a colonic J-pouch vs. straight anastomosis. Optimum size of this pouch has yet to be determined. Therefore, we initiated a prospective, randomized trial using 5-cm and 10-cm pouches to determine this size. METHODS: Patients with tumors 5 to 10 cm from the anal verge were included in the study. Before a low anterior resection anastomosis was performed, patients were randomized to either a 5-cm J-pouch group (5-J group) or a 10-cm J-pouch group (10-J group). Functional assessments were performed one year postoperatively. Clinical functions were evaluated using a functional scoring system. Physiologic functions, such as sphincter and reservoir function, were evaluated by anorectal manometry and evacuation function by the balloon expulsion and saline evacuation tests. RESULTS: Forty patients among 43 randomized patients were assessed for functional outcome one year postoperatively (5-J group, n = 20; 10-J group, n = 20). The functional score was similar for the two groups, although reservoir function in the 5-J group was significantly less than in the 10-J group. Sphincter function was similar between the two groups. Evacuation function in the 5-J group was significantly superior to that in the 10-J group. CONCLUSIONS: The 5-cm J-pouch conferred adequate reservoir function without compromising evacuation.