Annals of Coloproctology

Volume 19(3); June 2003

Original Articles

Enhanced Induction of CEA Specific Tumor Immunity by TatCEA Fusion Protein.: An, Chang Hyeok , Kang, Wong Kyung , Oh, Seong Taek , Cho, Hyun Il , Kim, Tae Gui; J Korean Soc Coloproctol. 2003;19(3):121-128.

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Abstract PDF: PURPOSE
The human carcinoembryonic antigen (CEA) is expressed in several tumor types, including colorectal cancer, and is a tumor-associated antigen used as a target for antigen-specific immunotheraphy. CEA is a self-antigen associated with development, expressed in fetal cells and rarely expressed in normal colorectal epithelial cells. The induction of immune response to CEA is very difficult. In this study, we attempted to increase the tumor immunity specific to CEA by using dendritic cells pulsed with fusion proteins of CEA and Tat (transactivator of transcription), which transduces extracellular proteins into cytoplasm and causes antigens to be presented with MHC class I pathway.
METHODS
The Tat gene was amplified in the PNL4-3 HIV plasmid and then inserted into PCEP4 plasmid vector. The CEA gene was cloned from cDNA from LoVo human colorectal cell line and then amplified through polymerase chain reaction method. After cloning of PCEP4 plasmid vector, the dendritic cell was sensitized and internalized with CEA and Tat-CEA protein. Then the Western blot analysis of the expression of CEA in the gene-modified dendritic cell and the immunofluorescent staining of the expression of CEA in CEA or Tat-CEA-pulsed dendritic cell were performed. A detection of IFN-gamma-releasing CD8 cell and a cytotoxicity of T-cell were was assesed using ELISPOT assay. The Immunoglobulin (Ig) G isotypes were analyzed with enzyme-linked immunosorbent assay. The statistical significance was assessed using Students t-test.
RESULTS
CEA pulsed in dendritic cells was distributed over the cell surface and TatCEA was observed in the cytoplasm. The cellular immune responses by immunization with dendritic cells pulsed with TatCEA (322/10(4) lymphocytes) were significantly increased compared with those with CEA (244/10(4) lymphocytes) by IFN-gamma ELISPOT assay (P<0.05). The cytotoxic T lymphocyte (CTL) activity using mouse T-cell, EL-4 pulsed peptide (EAQNTTYL) as target cells was 23.3+/-2.75% (E:T=1:100) in the CEA group and 22.9+/-2.23% (E:T=1:100) in the TatCEA group. In ELISA analysis of the IgG isotype, the titer of IgG2a and IgG3, representing Th1 immune response, was lower than that of IgG1, representing Th2 immune response, in both the CEA group and the TatCEA group.
CONCLUSIONS
These results suggest that TatCEA could be used for the development of a tumor vaccine and cellular immunotherapy using CTLs induced in vitro.

Antitumor Effect of Dendritic Cell Pulsed with Tumor Cell Lysate Against Hepatic Metastases in Murine Model.: Suh, Kwang Wook , Kang, Seung Hyun , Kim, Ae Young , Kim, Hyung Il; J Korean Soc Coloproctol. 2003;19(3):129-136.

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Abstract PDF: PURPOSE
Activated bone marrow-derived dendritic cells (DCs) express high level of MHC class I and II molecules as well as intercellular adhesion molecule and B7, required for T cell activation. This study was designed to examine whether DCs pulsed with tumor lysates were capable of inducing tumor specific CTLs.
METHODS
To generate mature DCs, bone marrow cells of female BALB/c mice were cultured in the presence of GM-CSF and IL-4. Mature DCs were idenfied by surface expression of MHC class II molecules and costimulatory molecules. By FACS analysis, it was found that most DCs highly expressed B7-1, B-7-2 and CD40 as well as MHC class II molecules. BAlB/c were immunized subcutaneously. Cytolytic activity was determined by chromium release assay using splenocytes harvested from immunized mice 7 days after the immunization, Cytolytic activity was measured against CT-26 and RAG tumor cells. In vivo protection experiment was performed. Mice were immunized subcutaneously wity DCs pulsed with CT-26 lysates (1x10(6) per mouse) and were challenged intrahepatically with wild type CT-26 (5x10(4) per mouse) two weeks following immunization. Three weeks after the challenge, animals were euthanized for identification of hepatic tumors.
RESULTS
Lysis of CT-26 cells were significantly greater with the splenocytes from the immunized mice. Incidence and mean volume of hepatic cancer in the immunized group were 50% (5/10) and 78+/-22 mm3. These results were significantly different from those from control groups:100% (10/10) and 1014.5+/-667.8 mm3 in media treated group, 90% (9/10) and 855.5+/-270.6 mm3 in mice treated with irradiated CT-26, 100% (10/10) and 994 255 mm3 in the animals treated with DC alone.
CONCLUSIONS
DCs pulsed with CT-26 lysates could successfully induce antitumor immunity in the BLAB/c against syngeneic CT-26 carcinoma cells. Pulsing method was so simple that neither genetic engineerings nor cellular fusion were not necessary. Even though the present study did not conduct survival experiments, it was thought that clinical application of DC-based immunotherapy could be expedited by pulsing of tumor lysate into the DCs.

The Effectiveness of Biofeedback Therapy for Children Patients with Chronic Constipation.: Jung, Sang Ho , Kim, Jong Tae , Cho, Hyun Un , Go, Hong Jun , Jung, Gwang Gun , Park, Soon Tae , Ha, Woo Song , Hong, Soon Chan , Lee, Young Joon , Lee, Byung Ju , Choi, Sang Kyung; J Korean Soc Coloproctol. 2003;19(3):137-143.

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Abstract PDF: PURPOSE
Chronic constipation is not uncommon even in children. Recently biofeedback treatment (BT) is considered as a useful modality in the treatment of various types of constipation. The aim of this study was to evaulate the effectiveness of BT in children with chronic constipation.
METHODS
We reviewed 24 cases of childhood constipation (17 boys, 7 girls) who visited the Jinju Hakmoon colorectal surgery clinic and GNUH1 between April, 2001 and September, 2002. Balloon-mediated anorectal manometry system was used for BT. The effects of therapy was assessed by bowel movement, defecation time, fecal soiling and balloon evacuation test in the early course of therapy. The long term follow up survey was done by telephone interview at January 2003 and the effects of therapy was assessed by bowel movement, defecation time, fecal soiling and parents' satisfaction.
RESULTS
Patients received the BT for the three times on average, and as the result of the therapy, 20 patients experienced disappearance of symptoms (87%) or at least improvement of symptoms. In terms of manometric values, the mean resting pressure was 113.4 mmHg before the BT, but decreased to 86.3 mmHg after the BT (P=0.0012). Mean pushing pressure dropped to 85.98 mmHg from 130.45 mmHg (P=<0.0001). Mean sensitivity decreased from 55 ml to 35 ml (P=0.0053). Mean compliance decreased from 20.28 H2O/cm to 4.21 H2O/cm (P=0.0015). 13 patients (76%) showed disappearance or improvement of symptoms in the long term follow up.
CONCLUSIONS
The Balloon mediated biofeedback therapy is effective in children with chronic constipation. It is safe, easy to administer and also improve symptoms and objective parameters of anorectal function. Balloon mediated biofeedback therapy could be the first-line therapy in child patient with chronic constipation who failed conservative management.

Expression of Cyclooxygenase-2 and Inducible Nitric Oxide Synthase in Colorectal Cancer.: Yang, Keun Ho , Bae, Byung Noe , Kim, Jung Yeon , Kim, Ki Hwan , Han, Se hwan , Kim, Hong Joo , Kim, Young Duck , Kim, Hong Yong , Kim, Sung Jun; J Korean Soc Coloproctol. 2003;19(3):144-150.

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Abstract PDF: PURPOSE
Recently, it has been recognized that both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) produce important endogeneous factors of human tumor progression. The aims of this study is to investigate the correlation between the expression of COX-2 and iNOS and to assess the clinicopathological significance of COX-2 and iNOS expression in patients with colorectal cancer.
METHODS
One hundred and five patients, who underwent curative resection of colorectal cancer from 1994 to 1997 were analyzed retrospectively. The monoclonal antibody to the COX-2 and iNOS were used for the immunohistochemical analysis.
RESULTS
In 105 patients the COX-2 and iNOS positive rate were 86.7% and 69.5% respectively. There was significant correlation between COX-2 and iNOS expression (r= 0.378, P<0.01), that is, the lesions which expressed high level of COX-2 also expressed iNOS highly. The proliferation index (Ki-67 labeling index) was correlated with iNOS (P=0.013), and the microscopic differentiation with COX-2 (P=0.004). However, the expression of COX-2 and iNOS proteins did not correlate with any other clinicopathological parameters including patient survival.
CONCLUSIONS
Although the pattern of positive expression was similar in both enzymes, the expression of both enzymes was not related to prognosis in patients with colorectal cancer. But COX-2 and iNOS seems to have a role not only in carcinogenesis but also tumor cells proliferation. To evaluate the exact role of these enzymes, further studies of the apoptosis and cancer metastasis and of links between the cancer related factors of COX-2 and iNOS are warranted.

The Prognosis of Anal Cancer According to the Modality of Therapy.: Lee, Soon , Joo, Jai Kyun , Ryu, Seong Yeob , Kim, Hyeong Rok , Kim, Dong Yi , Kim, Young Jin; J Korean Soc Coloproctol. 2003;19(3):152-156.

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Abstract PDF: PURPOSE
Anal cancer is a relatively uncommon malignancy, representig only 1.8 to 3.4% of all colorectal cancers. In the past, an abdominoperineal resection (APR) was the treatment of choice for an anal cancer. Since the introduction of chemoradiation (radiation combined with 5-Fu and mitomycin) therapy which proved to enhance the responsiveness of the lesion, the limited resection with preservation of anal sphincter function became the gold standard treatment of the anal lesion. Few studies have examined the effectiveness of each modality due to the rarity of this disease. We compared the results of treatment in two groups, one treated with APR and the other with chemoradiation, and evaluated the prognosis of the anal cancer and the advantages and disadvantages of each method.
METHODS
This study was performed from January 1992 to December 2001 in the Department of Surgery, Chonnam University Hospital. It considered many factors, including sex, age, chief complaint, location of the lesion, size of the lesion, histopathologic pattern, method of treatment, and metastasis, based on a retrospective review of clinical files and biopsy results.
RESULTS
For the patients, the male to female ratio was 1.8:1.0; the mean age was 64.6 (47~90); the chief complaint was anal mass; with symptoms of anal bleeding and pain; and the mean prevalence rate of disease was 8.5 months. According to the staging, 4 patients were T1 (14%), 19 (67.8%) were T2 and 4 (14.3%) were T3. By histologic biopsy, there were 23 squamous cell and 5 cloacogenic carcinoma. Four patients were initially treated by an APR at a local clinic, while 22 underwent combined chemoradiation therapy. Of the four patients who underwent a chemoradiation after an APR, two died as a result of liver and bone metastasis. According to the TNM classification, the 5-year survival rates were 75, 67, 60, 83, and 55% for T1, T2, T3, M0, M1, respectively; the 5-year survival was 71% the for combined chemotherapy and radiation and 53% for the APR.
CONCLUSIONS
In the anal cancer treatment, remission occured in over 50% of patients treated with combined chemoradiation therapy. Also, when the surgery had added, the prognosis was not worse than primary choice of APR. Therefore, combined chemoradiation therapy should be considered the treatment of choice, reducing the amount of resection and conserving the sphincter function.

Impact of the Number of Nodes Examined on the Prognosis of Dukes B Colorectal Cancer.: Oh, Soo Youn , Lee, Suk Hwan , Ku, Hae Soo , Kim, Kwang Ho , Park, Eung Bum; J Korean Soc Coloproctol. 2003;19(3):157-164.

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Abstract PDF: PURPOSE
Metastasis to the regional lymph nodes is the most important prognostic indicator in patients with colorectal cancer (CRC). The number of lymph nodes examined for adequate staging is still controversial. The aim of this study was to determine if the number of lymph nodes after curative surgery is associated with long-term outcome in patents with Dukes B CRC.
METHODS
A retrospective analysis was performed in 174 consecutive patients with Dukes B CRC who underwent curative resection from 1990 to 1999. Patients were stratified according to the number of nodes examined as group A (less than 12 nodes) and group B (12 or more nodes). End-points were local and systemic recurrence and relapse-free survival. Comparisons between the groups were performed by Kaplan-Meier methods and chi-square test as appropriate.
RESULTS
There were 115 men (66%). The mean number of nodes examined was 13.4 with the median of 11. No significant difference was found in the number of nodes examined between colon and rectum (16+/-10.6 vs. 13+/-10.0, P=0.675). However, the number of lymph nodes examined tends to be more in recent period of study and if the specimens were examined in the fresh status. With the median follow-up of 44 months, there were 5 local recurrences (2.9%), 22 systemic recurrences (12.6%), and 2 combined local and systemic recurrences (1.1%). Most of the recurrences were observed in group A (79%). The difference of 5-year relapse-free survival rates between the groups was also statistically significant (group A: 73.5%, group B: 91.7%, log-rank test, P=0.0114). The pT stage and number of lymph nodes examined were the independent variables associated with relapse-free survival in multivariate analysis.
CONCLUSIONS
The number of lymph nodes examined has prognostic value in patients undergoing curative resection for CRC. Based on our analysis, we recommended at least 12 lymph nodes should be analyzed for accurate staging of CRC.

Brain Metastasis of Colorectal Cancer.: Kim, In Kyoung , Lee, Ryung Ah , Moon, Sun Mi , Hwang, Dae Yong , Gwak, Ho Shin , Chang, Ung Kyu , Rhee, Chang Hun; J Korean Soc Coloproctol. 2003;19(3):165-169.

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Abstract PDF: PURPOSE
Brain metastasis is infrequent in colorectal cancer patients. The purpose of this study was to analyze the clinical characteristics including the survival, type of treatment, and metastatic patterns of brain metastasis in colorectal cancer.
METHODS
Between January 1993 and September 2002, we analyzed 2,019 surgical patients with colorectal carcinoma operated at Korea Cancer Center Hospital. Among these patients, 13 patients were identified with metastatic colorectal cancer to the brain. The medical records of these patients were reviewed retrospectively and survival analysis was performed.
RESULTS
During the study period, the incidence of brain metastasis of colorectal cancer was 0.6%. Male-to-female ratio was 1:1.6. Mean age was 55.2+/-9.7 years and median age was 56 years (34~67years). The most frequent primary tumor site was the rectum (11 cases, 84.6%). and the most frequent symptom of brain metastasis was headache. According to the TNM staging system, there were 1 case in stage II, 8 cases in stage III, and 4 cases in stage IV at the time of initial diagnosis of colorectal cancer. Brain metastases were often occurred concurrently with lung metastases (9 cases, 69.2%), otherwise solitary brain metastasis was found in 4 cases. Between the diagnosis of primary cancer and the diagnosis of brain metastasis, the mean interval was 25.9+/-6.9 months and the median interval was 16 months (5~97) in stage II and III patients. The mean survival time after the diagnosis of brain metastasis was 18.5 months for patients who underwent surgery and 3.3 months for patients who received non-surgical therapy.
CONCLUSIONS
Brain metastasis of colorectal cancer is relatively uncommon and the incidence is significantly low, commonly more or less than 1%. It is often accompanied by pulmonary metastasis. The results of this study show that surgical resection may increase the survival of these patients. Though inability to the awareness of the possibility and early diagnosis of brain metastasis in colorectal cancer could affect the poor prognosis, aggressive treatment in suitable cases might enhance the survival for this group of patients.

Case Report

A Case of Familial Adenomatous Polyposis Combined with Hepatocellular Carcinoma.: Kim, Kwang Il , Lee, Jae Woon , Jo, Hae Chang , Park, Jong Hoon , Bae, Byung Jo; J Korean Soc Coloproctol. 2003;19(3):170-176.

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Abstract PDF: Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by formation of multiple colorectal adenomas with nearly 100 percent potential for malignant transformation. FAP is a rare condition with an incidence of 1 in 10,000 live births. Germline mutations in the adenomatous polyposis coli gene (APC) located on chromosome 5q21 have been founded in many patients with FAP. Patients with FAP can have extracolonic manifestations of their disease. These include tumors of the upper gastrointestinal tract (hamartomatous polyps, adenomas, carcinomas), small intestine adenomas or cacinoma, bile duct adenomas, papillary thyroid carcinoma, osteomas of the mandible, skull, and long bones, a variety of soft tissue lesions, including fibromas, lipomas, and desmoid tumors, congenital hypertrophy of the retinal pigment epithelium (CHRPE) and hepatoblastoma. Hepatocellular carcinoma combined with FAP is a very rare condition. Just 8 cases of Hepatocellular carcinoma with a history of FAP have been reported in the literature. We now present a report of a case of Hepatocellular carcinoma with FAP (Gardner's syndrome) in a 19 year-old girl.

Review

Role of Protein Kinase C Signaling in Intestinal Ischemic Preconditioning.: Um, Jun Won; J Korean Soc Coloproctol. 2003;19(3):177-190.

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Abstract PDF: Ischemic preconditioning (IPC) is a phenomenon that a brief episode of ischemia to a tissue renders the tissue resistance from a subsequent prolonged ischemia. It is generally accepted that this protection is a receptor-mediated process, and is realized via signal transduction pathways. Protein kinase C (PKC), known to play key regulatory roles in cellular processes, has been proposed as a primary cellular mediator of preconditioning. However, the role of PKC in eliciting cardioprotection remains controversial. The evidences for the 'PKC hypothesis' of preconditioning in various tissue and organs are summarized. Especially in intestine, a brief ischemia induced a reversible epithelial injury to the jejunum that is associated with activation of several PKC isoforms. Injury induced by an additional period of ischemia is reduced by the prior IPC, and this effect is abolished by non-selective PKC inhibition but not by a selective inhibitor of cPKC/or PKCdelta. This result suggest that activation of nPKC isoform (especially PKCepsilon) during and following ischemic insults may play an important role in protection against I/R injury in the intestine, and this mechanism is identical with previous study in heart tissue.

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