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.

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.

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.

Metastases from carcinoma of the colon and rectum detected in small lymph nodes by the clearing method.

A study of regional lymph node metastases was performed using the clearing method in 322 patients with carcinoma of the colon and rectum (140 with carcinoma of the colon and 182 with carcinoma of the rectum) who had undergone surgical resection. The mean number of nodes examined per patient was 76.4 and the metastatic rate (patients with metastases divided by the total of patients) was 61.4 percent, with a metastatic incidence (nodes with metastases divided by the total of examined nodes) of 6.4 percent for carcinoma of the colon using the clearing method. For carcinoma of the rectum, the mean number of nodes examined was 73.7 with a metastatic rate of 57.1 percent and a metastatic incidence of 7.1 percent. In contrast, node analysis by the conventional manual method resulted in a mean of 18.1 nodes being examined, with a metastatic rate and incidence of 42.1 and 12.8 percent, respectively, for carcinoma of the colon. Manual examination of lymph nodes in carcinoma of the rectum resulted in a mean of 21.2 nodes being examined, with a metastatic rate and incidence of 50.0 and 16.8 percent, respectively. Compared with the manual method, the clearing method provided a greater number of nodes, a higher metastatic rate and a lower metastatic incidence. These differences may be explained by the detection of metastatic regional nodes smaller than 4 millimeters in maximum diameter by the clearing method. By TNM classification there were more pN3 than pN2 lesions. The five year survival rate after curative resection was 78.5 percent for pN1 lesions, 45.7 percent for pN2 lesions and 45.4 percent for pN3 lesions for carcinoma of the colon and 72.7 percent for pN1 lesions, 75.0 percent for pN2 and 53.9 percent for pN3 lesions for carcinoma of the rectum. There was no significant survival difference between the patients with pN1, pN2 and pN3 carcinomas. The presence of regional nodes metastases should be examined in detail. Therapies and prognosis of carcinoma of the colon and rectum should be discussed based on accurate staging.

[Rectal cancer therapy compatible with preservation of function].

Rectal cancer surgery causes often postoperative morbidities such as defecation disturbance, dysuria and male sexual impotence. Compatibility of cancer eradication and function preservation are the problem should be resolved in the rectal cancer surgery. Defecation function were preserved in the patients with middle and upper rectal cancer by anterior resection transsacral resection, invagination or pull-through operation. Since 1984, usage of suture instruments made it practicable to increase sphincter preserving operation up to more than 65% of rectal cancer. Postoperative 5-years survivals were 81% of anterior resection, 71% of invagination operation and 57% of pull-through. Autonomic nerves preserving operation (ANP), aimed to prevent the urinary and sexual disfunction were studied both sides of the cancer spreads and extend of nerve plexuses. And ANP were adopted to the 185 cancers, limited to the submucosa or the proper muscle coat, by Study Group of Welfare Ministry. Their postoperative disfunction decreased to 15% of urination and 21% of male potency, while 33% and 81% respectively following conventional operation. Local excision for early cancer, which are defined as mucosal or submucosal cancer are discussed.

[Clinical evaluation of second-look operations in colorectal cancer].

The second look operation (SLO) for early detection of recurrent tumor is indicated rarely because of the advance in diagnostic techniques such as imaging radiology, tumor marker serology and colonofiberscopy. The SLO was performed in 21 out of 362 curative cases of colorectal cancer resected in our department; 13 for re-elevation of plasma CEA level (Group 1), 6 for unclear symptoms or signs (Group 2) and 2 for postchemotherapy or postirradiation (Group 3). Liver metastases were found in four cases in group 1 and two in group 2. Nothing was found in three cases in group 1 and two in group 2. In group 3 the radical operation was carried out in all cases following SLO with good survival results. In group 1 and 2 the excisional rate of liver metastases in 57%, its salvage rate 75%, and the excisional rate of the lymph nodes is 50%, with a salvage rate of 100%. The SLO today is indicated for cases of asymptomatic re-elevation of CEA titer, for cases of undeterminable signs or for cases of postchemotherapeutic or postirradiation improvement.

[Study of long-survival cases with liver metastasis of colorectal cancer by hepatic arterial infusion chemotherapy].

We performed arterial infusion chemotherapy through hepatic artery in 33 patients with liver metastasis of colorectal cancer. Regarding the survival rate, the 1-year survival rate was 55.6% and the 5-year rate was 27.8% in cases of H2, and 1-year as 28.9% in H3. According to criteria of Saito-Koyama, the response rate was 24.2%, including 2 CR and 6 PR cases. There were more patients with H2 factor and without peritoneal dissemination who survived for one year and more. The dose of 5-FU was 9.6 +/- 3.6 g in case of longer survivals and 5.1 +/- 3.0 g in non-responders. There were significant differences between them. The pretreatment value of CEA was lower than 100 ng/ml in 8 of 11 longer survivals, and the CEA values were decreased after this treatment in 9 of 11 responders. On the other hand, it was noted that the non-responders had a higher level of CEA such as more than 100 ng/ml, and in these cases CEA was not decreased after treatment. There are two favourable responders who are still living 9 and 5 years after successful treatment. Their pretreatment value of CEA was lower at 13.6 and 23.8 ng/ml, respectively, and these levels were decreased to 1.0 ng/ml with administration of 5-FU with ADM and 5-FU with MMC. It was concluded that arterial infusion chemotherapy was good for treatment of metastatic liver tumors from colorectal cancers.

[Prognostic predictors in colorectal cancer].

The prognostic significance of clinicopathologic factors in colorectal cancer was evaluated in a multivariate analysis. The most important independent factor affecting survival was stage (depth of penetration through the bowel wall and the presence of positive lymph nodes). All other clinicopathologic factors were of less importance than stage in determining prognosis. Although the prognostic relevance of biologic and molecular variables has been investigated extensively, the importance of these factors as prognostic predictors remains uncertain and further studies are needed.

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.

The role of basement membrane in colorectal cancer invasion and liver metastasis.

BACKGROUND: Basement membrane (BM) is a specialized extracellular matrix component that plays a key role in tumor invasion and metastasis. METHODS: Immunohistochemical staining for two major components of BM, type IV collagen (C IV), and laminin (LN), utilizing avidin-biotin-peroxidase complex detection to examine 182 primary colorectal cancers (pT2 or greater) and 20 liver metastases. RESULTS: The distribution of C IV was the same as of LN in colorectal cancer tissue, and in normal tissue. Both C IV and LN staining were more frequently positive in the superficial zone but infrequently in the deep zone of the primary tumor. BM preservation, C IV and LN staining in both the superficial and deep zones, was seen in 18.7% of the subjects. The rate of BM preservation significantly decreased with increasing histologic grade (P < 0.01). No correlation was observed between pT number and BM preservation. The rate of BM preservation in cases of liver metastasis was 84.4%, significantly higher than the rate in cases without liver metastasis (P < 0.001). BM was observed even at the advancing front of tumor invasion and was preserved in 95.0% of the liver metastases. CONCLUSIONS: BM is a functional substance that appears to accompany cancer rather than function as a structural barrier against cancer invasion and liver metastasis.

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.]

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.

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.

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.