Jin C. Kim

Comparative outcome between chemoradiotherapy and lateral pelvic lymph node dissection following total mesorectal excision in rectal cancer.

Objective:To evaluate comparative outcome between adjuvant postoperative chemoradiotherapy (postoperative CRT) and lateral pelvic lymph node dissection (LPLD) following total mesorectal excision (TME) in rectal cancer patients. Background:Although TME results in lower rate of locoregional recurrence compared with conventional surgery, these 2 treatment modalities following TME have not adequately been appraised until the present trend of preoperative chemoradiotherapy. Patients and Methods:Between 1995 and 2000, patients with stage II and III rectal cancer underwent TME plus postoperative CRT (n = 309) or LPLD (n = 176). Patients in the postoperative CRT group received 8 cycles of 5-fluorouracil plus leucovorin and 45 Gy pelvic radiotherapy. Patients in the LPLD group underwent lateral lymph node dissection outside the pelvic plexus. Results:The 5-year overall and disease-free survival rates were 78.3% and 67.3% in the postoperative CRT group, respectively, and 73.9% and 68.6% in the LPLD group, respectively, without significant differences between these groups. Patients in the LPLD group with stage III lower rectal cancer had a locoregional recurrence rate 2.2-fold greater than those in the postoperative CRT group (16.7% vs. 7.5%, P = 0.044). Multivariate analysis showed that APR and advanced T-category (T4) were significantly associated with locoregional recurrence, whereas lymph node metastases, high preoperative serum carcinoembryonic antigen, and APR were significantly associated with shortening of disease-free survival. Conclusions:Postoperative-CRT and LPLD following TME resulted in comparable survival rates, but the locoregional recurrence rate was higher in the LPLD group. These findings suggest that initial surgery is appropriate for rectal cancer patients who are candidates for low anterior resection without extensive local disease (T1–T3), regardless of lymph node status.

Source of errors in the evaluation of early rectal cancer by endoluminal ultrasonography

PURPOSE: Although preoperative evaluation of early rectal cancers can be done by endoluminal sonography and by means of colonoscopic findings, it is still controversial whether endoluminal sonography can effectively discriminate mucosal from submucosal lesions. This study was performed to verify objective causes of errors in the evaluation of early rectal cancer (T0/1) using a review of videotaped endoluminal sonography images. METHODS: Eighty-nine patients with suspected early rectal cancer on endoluminal sonography were included. Two different scanners with appropriate probes were used according to tumor location,i.e., transrectal ultrasonography was used to scan up to 8 cm of the rectum above the anal verge, whereas endoscopic ultrasonography was used to assess higher lesions. Endoluminal sonography images were correlated with histologic infiltration and were reevaluated carefully to identify sources of errors. RESULTS: Sensitivity and specificity were 83.1 and 96.5 percent, respectively, for tumor staging, whereas sensitivity was very low compared with specificity (16.7vs. 90.2 percent) for metastatic lymph nodes. Endoluminal sonography images showed irregularity of the underlying tumor border (P<0.01) and hypoechoic blurring or cutoff of the inner and outer hypoechoic layers (P<0.001), all of which closely correlated with histologic infiltration of tumor cells. Overstaging occurred more than twice as often as understanding in tumor reevaluation (14vs. 5 occurrences). In contrast to tumors, lymph nodes showed a similar amount of both overstaging (four cases) and understanding (five cases). The sources of errors were summarized as five types: false instrumentation, interpretive errors, anatomic defects, imaging failure, and inevitable errors. CONCLUSIONS: Because false instrumentation, interpretive errors, and anatomic defects were considered preventable, 23 (82.1 percent) of the 28 errors might have been avoided. Therefore, a clear image by endoluminal sonography can effectively distinguish mucosal from submucosal lesions in early rectal cancer.

Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients.

The genotypic consequences of numerous single-nucleotide variants in human mismatch repair genes are mostly undetermined. We examined 27 reported single-nucleotide variants, rarely or ambiguously verified in a population-based study, to identify single-nucleotide polymorphisms (SNPs), haplotypes, and the genotype–phenotype association in Korean populations of 330 healthy individuals, 107 sporadic colorectal cancer patients, and 107 of their first-degree relatives. Real-time PCR 5′-nuclease assays (TaqMan® MGB assay) were used to determine 24 single-nucleotide variants, and restriction fragment length polymorphism (RFLP) assays were used to determine 3 variants. Of these 27 variants, 4 (hMSH2 gIVS12-6, hMLH1 655, hMLH1 1151, and hMSH2 1168, in descending order) were identified as SNPs occurring in 4.5 to 53.1% of healthy individuals, with polymorphism levels of 0.023–0.3 (mean, 0.092). East Asian populations had an ethnic predilection for the hMLH1 1151 SNP. The genotype distribution for all four SNPs showed no association with sporadic colorectal cancer. Twenty-three variants were not identified in the Korean population, suggesting that fifteen of these variants are colorectal cancer-related mutations and eight are SNPs. Two haplotype patterns existed exclusively, but with rare frequency, in sporadic colorectal cancer patients. The hMLH1 655 allele was closely correlated with hMLH1 protein expression (P= 0.02), but none of the four SNPs was associated with clinicopathologic variables. Among the 27 single nucleotide variants of mismatch repair genes, 12 were suggestive of nonfunctional SNPs and 15 may be colorectal cancer-related mutations. Further verification in other ethnic groups may provide the genotypic and phenotypic significance of single nucleotide variants found in mismatch repair genes.

Methylation of the hMLH1 and hMSH2 promoter in early-onset sporadic colorectal carcinomas with microsatellite instability

Abstract Background and aims. Microsatellite instability (MSI) occurring from defects in mismatch repair has been found to be associated with about 15% of sporadic colorectal carcinomas. This study examined the incidence of MSI in early-onset sporadic colorectal carcinomas and the role of methylation of the hMLH1 and hMSH2 promoter in sporadic colorectal carcinoma presenting with MSI. Patients and methods. MSI in 38 early-onset and 40 late-onset sporadic colorectal carcinomas were determined as MSI-H, MSI-L, and MSS using five markers. Methylation of the promoter region in hMLH1 and hMSH2 was assessed using methylation-specific PCR (MSP). Their protein expressions were also identified on immunohistochemical staining. Results. MSI-H, MSI-L, and MSS were found in six (15.8%), three (7.9%), and 29 (76.3%) cases, respectively, in the early-onset group, and in one (2.5%), five (12.5%), and 34 (85%) cases in the late-onset group. Five cases (71.4%) of MSI-H and two cases (25%) of MSI-L showed methylation of the promoter region in hMLH1. No cases with methylation of the promoter region expressed the hMLH1 protein. Only one case of MSI-H showed methylation of the promoter region in hMSH2 with lack of expression of hMSH2. Conclusion. The mutator pathway in colorectal carcinogenesis appeared more frequently in early-onset than in late-onset colorectal carcinoma. Many cases with MSI in sporadic colorectal carcinoma may be associated with methylation of the promoter in hMLH1.

Distribution of carcinoembryonic antigen and biologic behavior in colorectal carcinoma

PURPOSE: Carcinoembryonic antigen is assumed from the results of several experiments to be associated with invasion of colorectal carcinoma by adhesion or contact inhibition. The patterns and the intensity of carcinoembryonic antigen distribution in colorectal carcinoma were assessed to verify whether they were correlated with malignant potential from those biologic characteristics. METHODS: Carcinoembryonic antigen distribution was tested in the archival samples of 149 colorectal carcinomas by immunohistochemistry, using three characterized anti-carcinoembryonic antigen monoclonal antibodies: T84.66, PR1A3, and PR3B10. The distribution patterns in neoplastic tissue were categorized into unstained, apicoluminal, and diffuse-cytoplasmic patterns. Tumor, invasive tumor margin, and tissue surrounding the tumor were examined. RESULTS: Although all three antibodies revealed a positive correlation, T84.66 showed better discrimination than the others. Although none of the negative staining of the tumor or invasive tumor margin showed recurrence, the apicoluminal pattern showed recurrence, and the diffuse pattern showed the most frequent recurrence (P<0.01). Recurrence was also associated with staining intensity in the apicoluminal pattern in both the tumor and invasive tumor margin (P<0.05). Infiltrative tumor growth and lymph node metastasis were more frequent in cases of positive staining in tissue surrounding the tumor. Patients with the apicoluminal pattern achieved longer survival than patients with the diffuse-cytoplasmic pattern in the invasive tumor margin (P=0.024) by a multivariate analysis including tumor stage and histologic differentiation. CONCLUSION: The distribution of carcinoembryonic antigen in tumors and surrounding tissue seems to be closely correlated with invasiveness and metastatic behavior in colorectal carcinoma. Carcinoembryonic antigen immune staining can be considered as an efficient tool to determine groups with risk of recurrence.

Novel Chemosensitive Single-Nucleotide Polymorphism Markers to Targeted Regimens in Metastatic Colorectal Cancer

Purpose: Methods for predicting individual responsiveness to targeted chemotherapy are urgently needed, considering the frequent resistance and extremely high cost. Experimental Design: A chemosensitive single-nucleotide polymorphism (SNP) discovery schema is presented that utilizes (i) genome-wide SNP screening with a human SNP array and an in vitro chemosensitivity assay in 118 colorectal cancers, (ii) clinical association analysis in the other 98 patients who had received chemotherapy for metastatic cancer, and (iii) biological utility assessment using cell viability assays of transfected colorectal cancer (CRC) cells. Results: Nine SNPs related to bevacizumab and cetuximab regimen sensitivity were chosen during screening. Overall responses for bevacizumab regimens revealed that patients carrying the TT genotype at ANXA11 rs1049550 or at least one G allele at LINS1 rs11247226 seemed greater chemosensitive than those carrying at least one C allele or the AA genotype, respectively (P < 0.05). For cetuximab regimens, patients carrying the GG genotype at DFNB31 rs2274159 or LIFR rs3729740 seemed greater chemosensitive than those carrying at least one A allele (P = 0.025 and P = 0.07). Cytotoxicity analyses showed that all RKO and HCT116 CRC clones transfected with the G allele at LIFR rs3729740 and the C allele at ISX rs361863 were more sensitive to cetuximab regimens than those with the A and T allele, respectively (P ≤ 0.001–0.024). Conclusions: Chemosensitive SNP markers were identified using a novel three-step process. The candidate marker LIFR rs3729740 and possibly ISX rs361863 will hopefully predict responsive patients to cetuximab regimens, although further validation is needed in large cohorts. Clin Cancer Res; 17(5); 1200–9. ©2011 AACR.

Evaluation of novel histone deacetylase inhibitors as therapeutic agents for colorectal adenocarcinomas compared to established regimens with the histoculture drug response assay

Background and aimsThis study was to evaluate the efficacy of histone deacetylase (HDAC) inhibitors in colorectal cancer together with other established regimens.Materials and methodsChemosensitivities of 114 colorectal cancer patients to established regimens (fluorouracil (5-FU with leucovorin (FL), capecitabine, FL with irinotecan (FLIRI), and FL with oxaliplatin (FLOX)) as well as five hydroxamic acid derivatives (suberoylanilide hydroxamic acid, PXD101, and three novel candidates of CG-1, CG-2, and CG-3) were comparatively evaluated using the histoculture drug response assay.ResultsThe chemosensitivity with established regimens was between 34.2% and 52.6%, when the cutoff value of the inhibition ratio was set at 30%, and between 54.5% and 84.1% with HDAC inhibitors. All HDAC inhibitors displayed synergistic effects in combination with established regimens of FLOX and FLIRI (P ≤ 0.0001–0.002). Advanced T- and N-category tumors and patients with synchronous adenoma displayed higher chemosensitivity to CG-3, CG-2, and CG-1, respectively, on a multivariate analysis (P = 0.023, 0.044, and 0.045, respectively). Tumors with mismatch repair defects were closely correlated with chemosensitivities to combined regimens of PDX101 with FLOX and FLIRI (P = 0.044 and 0.048, respectively).ConclusionsOur findings firstly demonstrated the chemo-responsiveness of colorectal cancers to HDAC inhibitors with therapeutic efficacy comparable to the established regimens. Additionally, tumor growth and heredity were significantly associated with specific regimens, supporting their possible role as chemosensitive predictors.

MYH, OGG1, MTH1, and APC alterations involved in the colorectal tumorigenesis of Korean patients with multiple adenomas

This study was done to characterize base excision repair (BER) genes and adenomatous polyposis coli (APC) alterations in the tumorigenesis of multiple colorectal adenomas in Korean patients. In total, 217 adenomas (mean number = 10) and 117 cancers were available from 143 patients. The heterozygous genotype of OGG1 c.1-18G>T was closely associated with multiple adenoma families (P < 0.001), while MYH A359V mutation exhibited a tendency (P = 0.053). MYH R170G mutation was exclusively identified in one patient. The G:C>T:A transversion or attenuated familial adenomatous polyposis (AFAP) mutations of APC was identified in the specific genotypes of BER variants. Tubular adenomas or adenomas with none-to-mild dysplasia were significantly associated with polymorphic genotypes of OGG1 IVS4-15 and S326C. In addition, large and pedunculated adenomas were more frequent in patients with G:C>T:A transversion and AFAP mutations of APC, respectively. However, BER variants were not associated with mismatch repair or altered p53 protein expression. Conclusively, two novel mutations of MYH and a novel OGG1 polymorphism seemed to be associated with multiple colorectal adenomas in Korean families, differing from those in other ethnic groups. Some BER variants involved in specific APC mutations are associated with characteristics of histogenesis other than altered mismatch repair or p53 pathway.

Ovarian metastases from colorectal cancer: a clinicopathological analysis of 103 patients

Objective  To improve management of ovarian metastasis through assessment of clinicopathological features and treatment outcomes associated with ovarian metastasis from colorectal cancer.

Enhancement of colorectal tumor targeting using a novel biparatopic monoclonal antibody against carcinoembryonic antigen in experimental radioimmunoguided surgery

Biparatopic CEA, carcinoembryonic antigen (MAb) was newly designed and tested as to whether it enhanced the accuracy of tumor detection by reducing non‐specific binding in experimental radioimmunoguided surgery. Biparatopic MAb was prepared by using cross‐linking of reduced Fab′ fragments from PR1A3 and T84.66. Fifty‐nine tumors from 2 human colorectal carcinoma cell lines with high (KM‐12c) and low (Clone A) carcinoembryonic antigen (CEA) expression were successfully implanted subcutaneously on the backs of 42 nude mice. Tumors were localized using 125I‐labeled MAbs: IgG, F(ab′)2 and Fab′ of PR1A3, and biparatopic MAb of PR1A3 and T84.66. Radioactivity counted on a portable radioisotope detector correlated well with that counted on a gamma counter (p < 0.001). Accumulations of radioactivity in control mice without tumorigenesis were the greatest in PR1A3 IgG‐pretreated mice and the least in biparatopic MAb‐pretreated mice. Tumors of 2 cell lines did not differ in the distribution of radiolabeled MAbs. Localization indices of the tumor in various organs revealed 1.3 to 4.1 in PR1A3 IgG‐pretreated mice, 2.4 to 6.6 in fragment MAbs of PR1A3‐pretreated mice and 2 to 4.6 in biparatopic MAb‐pretreated mice. Silver grains and immune staining were predominantly distributed in tumor cells of all types of MAb‐pretreated mice. Sensitivity and specificity of tumor localization by radioimmunoguided surgery (RIGS) were the highest in the biparatopic MAb‐pretreated mice (90.9% and 94.5%, respectively) and the least in the PR1A3 IgG‐pretreated mice (50% and 72%). The biparatopic MAb using 2 anti‐CEA MAbs against different epitopes achieved a great affinity and avidity with accurate localization of colorectal carcinoma in experimental radioimmunoguided surgery.