Annals of Coloproctology

Volume 21(3); June 2005

Original Articles

Adjuvant Effect of NSAIDs on the Cytotoxicity of Colon Cancer Cells to 5-FU.: Lee, Tae Bum , Kim, Kyung Jong , Min, Young Don , Kang, Sung In , Jung, Kwon Ryul , Lee, Jae Up , Choi, Cheol Hee; J Korean Soc Coloproctol. 2005;21(3):121-128.

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Abstract PDF: PURPOSE
Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the conversion of arachidonic acid to prostaglandins, is believed to be an important enzyme related to colorectal cancer. A large number of studies have supported the concept that non-steroidal anti-inflammatory drugs (NSAIDs) targeting COX alter the biologic processes of colon carcinogenesis. Although COX-2 inhibitors generally reduce the growth rate of established tumors, tumor regression is rarely observed. Hence, it is reasonable that COX-2 inhibitors be given in conjunction with standard anti-cancer therapy in treating cancer. We investigated whether aspirin and meloxicam not only are cytotoxic but also potentiate the antitumor effect of 5-Fluorouracil (5-FU) against colon cancer cells.
METHODS
Expressions of COX-1 and COX-2 were determined by using the reverse transcriptase-polymerase chain reaction (RT-PCR) & Western blotting assay in 9 colon cancer cell lines. The cytotoxicities of NSAIDs and/or 5-FU were determined by using a microculture tetrazolium dye (MTT) assay.
RESULTS
COX-1 mRNA and protein, as well as COX-2 mRNA, were variably expressed in all the cell lines tested whereas COX-2 protein was expressed in HT-29 and to a lesser extent in HCT-8, but not in the other cell lines. We selected two representative cell lines, HT-29 expressing COX-2 protein and SNU-C1 not expressing it. The dose-dependent cytotoxicity was observed in both cell lines treated with aspirin and with meloxicam. A combination treatment of aspirin or meloxicam with 5-FU revealed some additive effect, rather than a synergistic effect, for both cells lines. This additive effect was remarkable even for low concentrations of the drugs. Furthermore, the additive effect was highest when the combination was adminstered sequentially, 5-FU followed by aspirin or meloxicam, in both cell lines.
CONCLUSIONS
These results suggest that a combination therapy using NSAIDs and 5-FU might be useful in the treatment of colon cancer cells not expressing COX-2, as well as in colon cancer cells expressing COX-2.

Expression and Function of ABC Transporters as Multidrug Resistance Mechansims in Colon Cancer Cells.: Jeong, Gui Ae , Kim, Kyung Jong , Min, Young Don , Lee, Tae Bum , Kang, Sung In , Jung, Kwon Ryul , Choi, Cheol Hee; J Korean Soc Coloproctol. 2005;21(3):129-137.

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Abstract PDF: PURPOSE
Multidrug resistance (MDR) is a phenomenon whereby tumor cells acquire resistance to a broad range of structurally and functionally diverse chemotherapeutic drugs. The most widely implicated mechanism of MDR is that concerned with altered membrane transporters in tumor cells. P-glycoprotein (Pgp), multidrug resistance protein (MRP), and breast-cancer-resistance protein (BCRP) are well-known membrane transporters that pump out antitumor agents by using an ATP-dependent process, the so-called ATP-binding cassette (ABC) superfamily or transporter. This study was undertaken to test the prevalence of each ABC transporter and to determine which transporter has functional acitivity in various colon cancer cells.
METHODS
Expressions of Pgp, MRP, and BCRP mRNA were determined in 9 colon-cancer cell lines by using an RT-PCR assay. The sensitivity to anticancer agents substrate for each ABC transporter in the colon cancer cells determined using an MTT assay. The accumulation of fluorescent compounds for functional detection of each ABC transporter was determined by using flow cytometry.
RESULTS
Pgp mRNA was variably expressed in 6 of 9 colon cancer cells lines. MRP and BCRP mRNA were expressed in all the 9 cell lines. A smaller cytotoxic effect to paclitaxel and a smaller amount of rhodamine123 accumulation were observed in Colo 320HSR expressing the highest levels of Pgp than in SNU-C5 not expressing Pgp. These effects in Colo320HSR were reversed with the addition of various Pgp inhibitors, but such a reversal did not occur in SNU-C5. The cytotoxic effect to VP-16 was not related to the expression levels of MRP in Colo320HSR and SNU-C, but the amount of calcein-AM accumulation was reversed with addition of probenecid, MRP inhibitor. The cytotoxic effect and the drug accumulation of mitoxantrone were not related to the expression levels of BCRP.
CONCLUSIONS
This study suggests that of the ABC transporters, primarily Pgp and MRP have functional activity in colon cancer cell lines.

Effect of Biofeedback Treatment in Patients with Fecal Incontinence.: Park, In Ja , Yu, Chang Sik , Kim, Hee Cheol , Jung, Young Hak , Han, Kyong Rok , Park, Sang Kyu , Kim, Jung Rang , Song, Jin Sook , Lee, Hyang Ran , Kim, Jin Cheon; J Korean Soc Coloproctol. 2005;21(3):138-144.

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Abstract PDF: PURPOSE
We aimed to assess the efficacy of biofeedback therapy for patients with fecal incontinence (FI) according to the etiology.
METHODS
Twenty-nine patients with fecal incontinence were treated with biofeedback therapy using a EMG-based system. The efficacy was assessed by using changes in the FI score (Cleveland Clinic, Florida: 0~20) and satisfaction based on a subjective evaluation score from 0 to 100. The median follow up duration was 12 (3~25) months.
RESULTS
Ten patients had idiopathic fecal incontinence. Fourteen patients had fecal incontinence due to a sphincter saving operation for rectal cancer. Four cases had spinal cord injury and one patient had a major external sphincter tearing due to trauma. The mean age was 52 (16~78) years. The median number of biofeedback sessions was 10 (3~15) overall. The mean efficacy was 42.8%, and the mean satisfaction score was 56.6. Improvements in the FI score and in the patients' satisfaction varied according to the etiology, 69.5% and 71.5 in the idiopathic group, 28.5% and 49.3 in the postoperative group, and 35% and 24 in the spinal cord injury group. In the idiopathic group, 50% of the patients showed an improvement in the FI score of more than 75%, and 90% of the patients showed an improvement of more than 50%. The number of liquid incontinence episodes was improved 78.3% later in the biofeedback group, and this result was much better than in the postoperative incontinence group (31.8%, p=0.03).
CONCLUSIONS
The success rate of the biofeedback therapy for fecal incontinence is acceptable. Subjective satisfaction is relatively higher than the improvement in the ecal incontinence score. Idiopathic fecal incontinence may be the best indication for biofeedback therapy.

Lift-up Submucosal Hemorrhoidectomy.: Yang, Hyung Kyu , Lim, Cheong Ho , Shin, Hyeon Keun , Kang, Choon Hoon , Jeong, Seung Kyu , Choi, Jai Pyo; J Korean Soc Coloproctol. 2005;21(3):145-151.

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Abstract PDF: PURPOSE
Hemorrhoidal tissues are normal anatomic structures present in every individual, and they act as cushions and are anchored to the internal anal sphincter by a connective tissue system. When the anchoring connective tissues undergo bears degenerative changes, the hemorrhoids not only bulge but also descend into the lumen of the anal canal. The veins also become distended. The previous hemorrhoidectomy methods (excision and ligation methods) tend to remove excessive amounts of hemorrhoidal tissues, possibly causing incontinence or stenosis. This study introduces a modified hemorrhoidectomy method.
METHODS
A retrospective study was done with 650 patients (358 males, 292 females) who underwent hemorroidectomies from Jan. 1997 to Jan. 2000. Under saddle-block anesthesia, the patient was placed in a prone jack-knife position. After narrow incisions on the mucosa of the selected pile, a bilateral submucosal dissection was performed. The pedicle was ligated by transfixing sutures 2 or 3 times with 2-0 chromic catgut to lift up the mucosa.
RESULTS
The mean operation time per hemorrhoidal pile was 12.7 minutes, and the mean hospital-stay was 4.3 days. Acute and delayed postoperative anal bleeding occurred in 7 (1.1%) and 3 (0.5%) patients, respectively. The symptoms of both subsided spontaneously. Ninety-three (93) patients (14.3%) reguired nelaton catheterization for voiding difficulty, and one patient (0.2%) showed mild anal stenosis. The most frequent complaint was skin-tag formation (148 cases, 22.8%). In 140 cases, the skin tag was removed under local anesthesia.
CONCLUSIONS
It is desirable to keep the normal structure of the anal canal by removing as little of the cushions as possible. Our 'lift-up submucosal hemorrhoidectomy' shows good results and is an easy operative method when compared with Parks' original method.

Hemorrhoidectomy Specimens: Necessity for Routine Pathologic Evaluation.: Lee, Min Ro , Hong, Chang Won , Yoon, Sang Nam , Park, Kyu Joo; J Korean Soc Coloproctol. 2005;21(3):152-156.

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Abstract PDF: PURPOSE
The aim of this study was to determine the necessity for routine pathologic evaluation of hemorrhoidectomy specimens.
METHODS
Between March 1998 and February 2001, 280 patients (185 males, 95 females) underwent a hemorrhoidectomy at Seoul National University Hospital. All patients had grade III~IV hemorrhoids, and the mean age of the patients was 51 years (range: 21~74 years). All hemorrhoidectomy specimens were examined with a hematoxylin and eosin stain of one representative section by a pathologist. We performed a retrospective analysis regarding the pathologic results for the hemorrhoidectomy specimens.
RESULTS
Two hundred sixty-seven specimens (267, 95.4%) had typical hemorrhoids reported as external and internal hemorrhoids, external hemorrhoids, hemorrhoidal varices, and thrombi. Ten patients (10, 3.2%) had additional benign pathologes such as fibroepithelial polyps (6 cases), a flat condyloma (1 case), hypertrophied papillae with a condyloma, like papillomatosis and keratosis (1 case), dyskeratotic squamous cells with koilocytotic atypia (1 case), and an inflammatory polyp (1 case). Interestingly, three patients (3, 1.1%) had carcinomas in the hemorrhoidectomy specimens. Two patients had squamous- cell carcinomas; one suffered from delayed wound healing after a previous hemorrhoidectomy, and the other had indurated lesions on the hemorrhoids. One patients who had under gone a low anterior resection due to stage-C rectal cancer 7 months before had a adenocarcinoma.
CONCLUSIONS
Because of the possibility of unsuspected anal cancer, we recommend pathologic examination of hemorr hoidectomy specimens, especially in cases of suspected indurated lesions within the hemorrhoids, delayed wound healing after a previous hemorrhoidectomy, or previous history of colon cancer.

Relationship between Microsatellite Instability and Dihydropyrimidine Dehydrogenase Expression as a Predictor of Response to 5-Fluorouracil Chemotherapy for Colorectal Cancer.: Rhyou, Jai Hyun , Lee, Suk Hwan , Lee, Woo In , Lee, Ryung Ah , Kim, Kwang Ho , Chung, Soon Sup , Park, Eung Bum; J Korean Soc Coloproctol. 2005;21(3):157-166.

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Abstract PDF: PURPOSE
Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in 5-FU catabolism, so the enzymatic activity of DPD reflects the 5-FU response. Moreover, recent studies have revealed that microsatellite instability (MSI) status correlates well with the prognosis and the 5-FU chemosensitivity in colorectal cancer (CRC). This study aimed to determine whether DPD mRNA expression is related with the MSI status of primary CRC as a prognostic predictor.
METHODS
Tumor samples and adjacent normal colonic mucosal tissues were collected from 59 patients. DPD mRNA expression was calculated by using the real-time RT-PCR method. The MSI status was examined by using multiplex fluorescent PCR with five reference markers. The results of DPD mRNA expression and MSI status were compared with the clinicopathologic variables and with each other.
RESULTS
The mean age of the 59 patients was 59 (range: 36~81) years. In 55 patients (93.2%), the colorectal cancers were histologically well or moderately differentiated. Forty-nine of the tumors (49, 83.1%) were located distal to the splenic flexure, and 46 patients (78%) had TNM stage II (n=17) or stage III (n=29) cancer. The DPD mRNA expression level was informative in all 59 cases. The median expression level was 2.5 (range: 0~67.33). There was no correlation between the DPD mRNA expression level and age, gender, location, or TNM stage. MSI status was informative in 43 cases (72.9%). Thirty-six cases (36, 83.7%) were microsatellite-stable (MSS), 4 cases (9.3%) showed low-level microsatellite instability (MSI-L), and 3 cases (7.0%) showed high-level microsatellite instability (MSI-H). Proximal CRC showed a higher proportion of MSI-H than distal CRC (25% vs. 2.9%, P=0.03). We could not find any correlation between the DPD mRNA expression level and the MSI status in tumor tissues (r=0.29, P=0.09).
CONCLUSIONS
The expression level of DPD mRNA raried among the tumors studied. The relatively low frequency of MSI in distal CRC prohibits the use of MSI status as a predictor of 5-FU chemosensitivity. We suggest that a well-designed large-scale study would be helpful to confirm the relation between DPD mRNA expression and MSI status as a predictor of 5-FU chemosensitivity in CRC patients.

Impact of the Number of Lymph Nodes Retrieved on Reliability of Nodal Staging of Stage II Colorectal Carcinomas.: Lee, Tae Mu , Choi, Hong Jo , Park, Ki Jae , Kim, Jung Min , Roh, Young Hoon , Roh, Mee Sook; J Korean Soc Coloproctol. 2005;21(3):167-173.

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Abstract PDF: PURPOSE
The variety of outcomes in patients with stage II colorectal carcinomas might be due to understaging caused by an inadequate number of lymph nodes (LNs) being examined. The aim of this study was to determine if any number of examined LNs reflects a reliable node-negative staging for colorectal carcinomas (CRCs).
METHODS
Data on 241 patients (132 males) who underwent potentially curative resections for pT3 and pT4 CRC were reviewed. The patients ranged in age from 21 to 87 (mean: 58.2) years with a median follow-up of 43 (range: 7~96) months. The relationship between the number of LNs harvested and both the 5-year disease-free survival (DFS) and the overall survival (OS) rates were assessed for stage II CRCs.
RESULTS
A median of 15 LNs (range: 3~104) was harvested per tumor specimen, and lymph-node metastases were present in 107 cases (44.4%). The proportion of lymph-node metastases increased as a function of the number of LNs harvested (P=0.0002; 95% confidence interval, 0.3333~0.8138). The number of LNs revealed to be the best number for dividing stage II patients into subgroups with different DFS and OS rates was ten. The 5-year DFS and OS rates of the 48 patients (35.8%) with nine or fewer LNs harvested were 68.6% and 76.8%, respectively, whereas those of the 86 patients (64.2%) with ten or more LNs harvested were 87.2% and 91.9%, respectively (DFS, P=0.0082; OS, P=0.0303). Moreover, there were no statistical differences between the node-negative patients with nine or fewer LNs harvested and the 67 stage III patients with N1 in respect to the DFS (68.6% vs. 56.7%; P= 0.2031) and the OS (76.8% vs. 68.3%; P=0.2772) rates.
CONCLUSIONS
This study suggests that examining a greater number of lymph nodes increases the likelihood of accurate nodal staging and that a minimum of ten LNs per surgical specimen should be harvested and examined to label a pT3 or pT4 CRC as node-negative.

Case Reports

Perianal Extramammary Paget's Disease Associated with an Anal Duct Adenocarcinoma: A Case Report.: Lee, Kang Youn , Yun, Min Young , Choi, Sun Keun , Hur, Yun Suk , Lee, Kun Young , Kim, Sei Joong , Cho, Young Up , Ahn, Seung Ick , Hong, Kee Chun , Shin, Suk Hwan , Kim, Kyung Rae , Woo, Ze Hong; J Korean Soc Coloproctol. 2005;21(3):174-177.

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Abstract PDF: Extramammary Paget's disease occurs commonly on the external female genitalia and rarely occurs in the perianal region. Recently, we experienced a case of perianal extramammary Paget's disease associated with an anal duct adenocarcinoma. The patient was a 60-year-old man. The perianal skin lesion was eczematous and encircled the anus. A wide-excision, split-thickness skin graft and temporal T-loop colostomy were performed. Histopathologically, the tumor was a well-differentiated anal duct adenocarcinoma. There was a prominent pagetoid spread of about 6x4 cm. The tumor cell was positive for carcinoembryonic antigen, but the paget cell was negative. The patient was treated with radiation therapy and with single 5-FU chemotherapy six times. Five months later, the perianal region was nearly normal.

Complete Rectal Prolapse Combined with Rectal Cancer: A Case Report.: Lee, Tae Soon , Bae, Ok Suk , Park, Sung Dae; J Korean Soc Coloproctol. 2005;21(3):178-180.

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Abstract PDF: Colorectal cancer and rectal prolapse occur more frequently in elderly patients. Although the relationship between complete rectal prolapse and colorectal cancer has not yet been clarified, when both diseases develop simultaneously in a patient, it may be due to just coincidence or to a promotion of prolapse due to accelerated constipation caused by cancer. Thus, patients with a sudden onset of rectal prolapse should be screened for colorectal cancer. We report a case of complete rectal prolapse combined with early rectal cancer in a 75 year-old woman who was successfully treated with a perineal rectosigmoidectomy.

Review

Epigenetic Alterations and Loss of Imprinting in Colorectal Cancer.: Kim, Jong Woo; J Korean Soc Coloproctol. 2005;21(3):181-190.

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Abstract PDF: Two forms of genomic instability have been described in colorectal cancer: chromosomal (CIN) and microsatellite instability (MIN). Colorectal cancer has been considered to progress through one of these two major pathways. However, recently a CpG island methylator pathway (CIMP) has been established among sporadic MIN cancers. Aberrant methylation of a promoter CpG island is associated with inactivation of tumor suppressor genes and is one of the epigenetic alterations identified to be involved in tumorigenesis. Now, several types of epigenetic alterations appear to play roles complementary to genetic mutations in colorectal carcinogenesis and seem to contribute to the progression of cancer. Epigenetic alterations also increase the probability that genetic changes will lead to cancer initiation. So far, major epigenetic alterations have been categorized into four groups of dysregulations: 1) hypomethylation with oncogene activation and chromosomal instability, 2) hypermethylation with tumor suppressor gene silencing, 3) chromatin modifications, and 4) loss of imprinting (LOI). Especially, LOI is a common epigenetic variant and should have a field effect on the colon, making it more vulnerable to genetic insults. Genomic imprinting is parental-origin-specific allele silencing, a form of gene silencing that is epigenetic in origin and does not involving alterations in the DNA sequence but does involve methylation and other modifications that are heritable during cell division. LOI is the loss of parental-origin-specific marks, leading either to aberrant activation of a normally silent allele of a growth promoter gene or to silencing of the growth inhibitor allele. Most of the attention has been focused on LOI of the IGF2 (insulin-like growth factor II) gene in a Wilms' tumor and colorectal cancer. LOI of IGF2 involves abnormal activation of a normally silent maternally inherited allele and has been associated with personal and family history of colorectal cancer, supporting a role for LOI in carcinogenesis. LOI may be a valuable predictive marker of an individual's risk for colorectal cancer. Now, epigenetics and imprinting are emerging areas in the study of human-cancer genetics.

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