Relationship between dominant frequency, organization index, and left atrial size in patients with atrial fibrillation.

INTRODUCTION: Frequency domain analysis is a methodology for quantifying the organization of atrial fibrillation (AF) pattern to understand the pathophysiology of the electrical mechanism. We aimed to investigate whether the dominant frequency (DF) and organization index (OI) can indicate left atrial (LA) dilatation in patients with AF. METHODS AND RESULTS: This observational, retrospective, single-center cohort study assessed 100 patients with persistent AF. The study population was divided into two groups based on an anterior-posterior LA dimension (LAD of 50 mm) measured by transthoracic echocardiography. The groups were one-to-one propensity score-matched. Frequency domain analysis was performed using signals at leads II and V1 on surface electrocardiogram to calculate the DF and OI. In all patients, the DF was shown to have an inverse relationship with LAD (R = -.369, p < .001 in lead II; R = -.330, p = .001 in lead V1), while the OI was directly associated with LAD (R = .234, p = .190 in lead II; R = .283, p = .004 in lead V1). However, no significant relationship between the signal amplitude and LAD was observed. Compared to patients with LAD ≤ 50 mm, those with LAD > 50 mm had a lower DF (5.057 ± 0.740 vs. 4.542 ± 0.898, p = .002) and higher OI (0.261 ± 0.104 vs. 0.322 ± 0.116, p = .007) in lead V1. These findings were consistent with those found in lead II. CONCLUSION: Patients with persistent AF and a larger LA size had a significantly higher OI and lower DF than those with a smaller LA size. Atrial electrical properties of structural remodeling are associated with increased organization of atrial signals.

A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.

We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

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. METHOD: We recruited 103 subjects who were diagnosed with ovarian metastasis and subjected to surgery between June 1989 and December 2005. Clinical and pathological variables were evaluated. Survival and its associated factors were analysed with a median follow-up of 31 months after ovarian surgery (range 1-129 months). RESULTS: The mean age at diagnosis was 46 years (range 14-72 years), synchronous ovarian metastasis occurred in 74 patients and metachronous in 29 patients. The primary tumour was more commonly associated with the colon rather than the rectum (84/1608, 5.2%vs 19/1534, 1.2%, P < 0.001). Combined metastases occurred in 69 patients (67%). Complete resection was achieved in 34 (33%) patients without other metastases. The estimated 5-year disease free survival and overall survival rate were 40.1% and 26.6%, respectively. From univariate analysis, lymphovascular invasion (35.6%vs 12.8%, P = 0.034), combined metastasis (50.9%vs 15.6%, P = 0.0035) and bilaterale ovarian metastasis (36.4%vs 10.6%, P = 0.015) were identified as significant poor prognosis factors, and from multivariate analysis combined metastasis and bilaterale ovarian metastasis were significant (P = 0.034 and P = 0.015, respectively). CONCLUSION: This study suggests a role for regular follow-up computed tomography scans within 6 months postoperatively and tumour marker assays for the early detection of ovarian metastasis in premenopausal women after primary surgery, especially in colonic patients with poor prognostic factors.

Risk factors for lymph node metastasis in submucosal invasive colorectal cancer.

BACKGROUND: Recent studies have shown a 7-15% lymph node (LN) metastasis rate in submucosal invasive colorectal cancer (SICC). Identifying risk factors for LN metastasis is crucial in selecting therapeutic modalities for SICC. We assessed the possibility of and the risk factors for LN metastasis in SICC. METHODS: We performed a retrospective study on 168 SICC patients who underwent curative resection between June 1989 and December 2004 at Asan Medical Center. The level of submucosal invasion was classified into upper third (sm1), middle third (sm2), and lower third (sm3). The following carcinoma-related variables were assessed: tumor size, tumor location, depth of submucosal invasion, cell differentiation, lymphovascular invasion, neural invasion, and tumor cell dissociation (TCD). RESULTS: The overall LN metastasis rate was 14.3%. Significant predictors of LN metastasis both univariately and multivariately were sm3 (p = 0.039), poorly differentiated cancer (p = 0.028), and TCD (p = 0.045). Lymphovascular invasion was a risk factor for LN metastasis in univariate analysis (p = 0.019); however, in multivariate analysis, lymphovascular invasion could not predict LN metastasis. No statistical difference was observed in the risk of LN metastasis with regard to tumor location, size, and neural invasion. CONCLUSION: The depth of submucosal invasion, cell differentiation, and tumor cell dissociation were significant pathologic predictors of LN metastasis in SICC. Because SICC is associated with a considerable risk of LN metastasis, local excision may be performed carefully in SICC without adverse features.

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.

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.

Efficacy of 3-dimensional endorectal ultrasonography compared with conventional ultrasonography and computed tomography in preoperative rectal cancer staging.

BACKGROUND: This study was performed to verify reports of the decreased accuracy of endorectal ultrasonography (EUS) in preoperative staging of rectal cancer, and to compare the efficacy of 3-dimensional (3D) EUS with that of 2-dimensional (2D) EUS and computed tomography (CT). METHODS: Eighty-six consecutive rectal cancer patients undergoing curative surgery were evaluated by 2D EUS, 3D EUS, and CT scan. RESULTS: The accuracy in T-staging was 78% for 3D EUS, 69% for 2D EUS, and 57% for CT (P < .001-.002), whereas the accuracy in evaluating lymph node metastases was 65%, 56%, and 53%, respectively (P < .001-.006). Examiner errors were the most frequent cause of misinterpretation, occurring in 47% of 2D EUS examinations and in 65% of 3D EUS examinations. By eliminating examiner errors, the accuracy rates in T-staging and lymph node evaluation could be improved to 88% and 76%, respectively, for 2D EUS, and to 91% and 90%, respectively, for 3D EUS. Conical protrusions along the deep tumor border on 3D images were correlated closely with infiltration grade, advanced T-stage, and lymph node metastasis. CONCLUSIONS: We found that 3D EUS showed greater accuracy than 2D EUS or CT in rectal cancer staging and lymph node metastases. Concrete 3D images based on tumor biology appear to provide more accurate information on tumor progression.

Hepatic arterial infusion alternating with systemic chemotherapy in patients with non-resectable hepatic metastases from colorectal cancer.

BACKGROUND AND AIM: Hepatic arterial infusion (HAI) chemotherapy has a number of limitations, including a low rate of complete response and frequent extrahepatic recurrence, in colorectal cancer patients with non-resectable hepatic metastases. METHODS: Twenty-nine colorectal cancer patients with non-resectable hepatic metastases were consecutively enrolled for HAI alternating with systemic chemotherapy (HA + SC group). The protocol comprised six cycles of alternating HAI (5-FU + leucovorin for 14 days, and mitomycin C on the first day) and systemic chemotherapy (5-FU + leucovorin). Colorectal cancer patients with two or more hepatic metastases treated using hepatic resection and systemic chemotherapy (HR + SC group) were selected as a comparative group. RESULTS: Within the HA + SC group, complete response was achieved in eight patients (28%), whereas 13 patients (45%) showed progressive disease. Six of the eight patients with complete response lived for more than 38 months. Extrahepatic recurrences were more frequent in the HR + SC group than the HA + SC group (47 vs 21%, P = 0.024). The two groups did not differ with respect to overall and hepatic progression-free survival (P = 0.947 and 0.444, respectively), displaying median +/- SE values of 38 +/- 7 and 20 +/- 3 months in the HA + SC group, and 39 +/- 9 and 33 +/- 14 months in the HR + SC group, respectively. One patient in each group experienced toxic hepatitis, and sclerosing cholangitis occurred in one patient of the HA + SC group. Other complications were mostly grade 1 or 2. CONCLUSIONS: HAI alternating with systemic chemotherapy led to a promising response and hepatic progression-free survival, possibly reducing extrahepatic recurrence in colorectal cancer patients with non-resectable liver metastases.

Experimental radioimmunoguided surgery for peritoneal metastases of gastric cancer using anticarcinoembryonic antigen-specific T84.66 F(ab')2.

PURPOSE: In gastric cancer, peritoneal dissemination is the most frequent cause of the noncurative resection and recurrence after curative resection. We therefore evaluated the feasibility of radioimmunoguided surgery (RIGS) in the treatment of peritoneal metastases of gastric cancer and the use of anti-CEA-specific T84.66 F(ab')2 as an efficient immune agent. METHODS: Two human gastric cancer cell lines, MKN45 and RF48, were intraperitoneally xenografted into nude mice, which were later injected with 125I-labeled T84.66 F(ab')2. Peritoneal tumors were localized by RIGS 5 days after antibody injection. The minimum number of cells detected by a gamma probe was assayed by in vitro tumor cell localization. RESULTS: We observed 37 peritoneal metastases: 8 invisible (long diameter, <1 mm), 6 small (1- < 5 mm), and 23 large (> or =5 mm) tumors. The accuracy, sensitivity and specificity of RIGS in detecting peritoneal metastasis were 82% (69/84), 76% (28/37), and 87% (41/47), respectively. RIGS accuracy did not differ with respect to tumor diameter. Mean labeling indices over minimal and maximal normal counts were 6.1+/-1.2 (mean +/- SEM) and 4.7+/-1, respectively. Mean scores of CEA immunostaining and silver grains in tumors were significantly higher than those in the nontumor-bearing peritoneum (P < 0.001). There was a close correlation among radioactivity, immunostaining and microautoradiography (P < 0.001-0.005). We observed six false-positive and nine false-negatives which may have been due to high blood background and negative radioimmune reactivity, respectively. CONCLUSIONS: 125I-labeled T84.66 F(ab')2 efficiently targeted peritoneally disseminated gastric cancer cells, suggesting that RIGS using this immune agent may accurately detect occult peritoneal metastases in patients with gastric cancer.

Correlation between hMLH1/hMSH2 and p53 protein expression in sporadic colorectal cancer.

BACKGROUND/AIMS: The aim of this study was to analyze expression of hMLH1 and hMSH2 mismatch repair proteins in terms of p53 protein expression and clinicopathological parameters in sporadic colorectal cancer. METHODOLOGY: Four hundred and two cases of curative colorectal surgery for primary colorectal cancer were included in this study (patients with a familial history of colorectal cancer and familial adenomatous polyposis were not included). Clinicopathological parameters were reviewed retrospectively. HMLH1, hMSH2 and p53 protein expression in tumor tissue sections was determined using immunohistochemical staining with specific monoclonal antibodies. RESULTS: Of the 402 cases, immunohistochemical analysis showed 35 (8.7%) had loss of expression of hMLH1, 19 (4.7%) had loss of expression of hMSH2, and three cases (0.7%) had loss of expression of both proteins. Multivariate analysis showed that early age of onset (p=0.023), right side dominance (p<0.001) and poorly differentiated or mucinous cell type (p<0.001) were associated with loss of expression of hMLH1 or hMSH2. Loss of expression of hMLH1 or hMSH2 correlated with low p53 expression (p<0.001). In terms of clinicopathological parameters, p53 expression was associated only with hMLH1 or hMSH2 expression. CONCLUSIONS: Colorectal cancers not expressing hMLH1 or hMSH2 may have distinct features from those expressing these mismatch repair proteins. p53 expression appears to be implicated in a compensatory pathway with mismatch repair proteins.

Characterization of mutator phenotype in familial colorectal cancer patients not fulfilling amsterdam criteria.

PURPOSE: Although the mutator phenotype, including genetic and epigenetic alterations of the mismatch repair (MMR) system, seems to be pronounced in familial colorectal cancer, there have been few integrative studies comprising the entire mutator pathway. This study was done to identify the entire mutator pathway determining risk factors in patients with familial colorectal cancer not fulfilling the Amsterdam criteria. EXPERIMENTAL DESIGN: We consecutively recruited 134 colorectal cancer patients with a family history of accompanying cancers. Patients with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria, familial adenomatous polyposis, or those receiving preoperative radiotherapy were excluded. Mutator phenotype was assessed by assaying microsatellite instability (MSI) at 24 markers, hMLH1-promoter methylation, mutations at MMR genes (hMLH1, hMSH2, hMSH6, and hPMS2), and immune staining of MMR proteins (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2). RESULTS: Of the 208 cancers in first-degree and/or second-degree relatives of patients, colorectal and gastric cancers (81%) were most common. Of the 134 proband colorectal cancers, 23 (17%) were MSI in high level, and 32 (24%) were MSI in low level. MMR alterations, including known polymorphism and splicing substitution, were identified in eight patients (6%). Twenty-eight tumors with mutator phenotype were further identified by hMLH1-promoter methylation and/or loss of MMR protein expression. In 51 tumors (38%), mutator phenotype was associated with right-sided colon cancer (P < 0.001) and younger age at onset (P=0.032), but the number of patients with a mutator phenotype did not differ with respect to inheritance patterns of accompanying cancers, either successive or horizontal transmission (P=0.815). Familial impact value, which differentially associated the degree of relatives with all accompanying cancers, effectively discriminated MSI in high level from microsatellite stable/MSI in low level tumors. CONCLUSION: Familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers inherited by dominant or recessive transmission. MMR gene mutations, however, are less associated with mutator phenotype in familial colorectal 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.

Efficient targeting of gastric cancer cells using radiolabeled anti-carcinoembryonic antigen-specific T84.66 fragments in experimental radioimmunoguided surgery.

BACKGROUND: Radioimmunoguided surgery (RIGS) appears as an efficient tool for accurate tumor detection up to the level of micrometastases by detecting radiolabeled antibody-bound tumor cells during operation. Anti-CEA-specific T84.66 fragments were examined as to whether they efficiently detected gastric cancer cells in experimental RIGS. T84.66, anti-CEA-specific antibody, has widely been used as an immune carrier in the preclinical and clinical trials of radioimmunotherapy and radioimmunoscintiscan. MATERIALS AND METHODS: Fifty-one tumors from two human gastric carcinoma cell lines with profuse (MKN45) and low (RF48) CEA expression were successfully implanted subcutaneously in the backs of 32 nude mice. Tumors were localized after 125I-labeled T84.66 F(ab')2 and Fab' injection. RESULTS: The radioactivity of F(ab')2-pretreated mice was greater than that of Fab'-pretreated in all organs and tumors (p<0.001-0.035). Localization indices of the tumor in various organs revealed 7.4 to 32.5 in F(ab')2-pretreated and 1 to 7.1 in Fab'-pretreated mice. Silver grains and immune staining were predominantly distributed in tumor cells regardless of fragment types and cell lines. There was no false-negative evaluation of tumor in F(ab')2-pretreated mice. Sensitivity and specificity of tumor localization by RIGS were the highest in the F(ab')2-pretreated mice (95% for MKN45- and 82% for RF46-xenografted mice) and the least in the Fab'-pretreated mice (66% for MKN45- and 67% for RF46-xenografted mice). In all organs, three quarters of the false-positive evaluations occurred from silver grains as radioimmune complex or dissociated nuclides in the circulation that can be eliminated with time. CONCLUSION: Anti-CEA-specific T84.66 fragments achieved a great affinity and avidity with accurate localization of gastric carcinoma in experimental RIGS.

Geno- and pheno-typic characterization in ten patients with double-primary gastric and colorectal adenocarcinomas.

BACKGROUND AND AIMS: Although a number of double-primary gastric and colorectal cancers have been known to correlate with the mutator pathway, a possible association with known hereditary cancers regarding geno-pathogenesis has rarely been investigated. This study was intended to identify a possible association of hereditary cancers and the implications of the mutator or tumor-suppressor pathway in double-primary gastric and colorectal cancers. MATERIALS AND METHODS: Fresh colorectal tissues and lymphocytes from ten patients with double-primary gastric and colorectal cancers were obtained consecutively. The mutator pathway was evaluated by detecting hMSH2 and hMLH1 mutations, microsatellite instability (MSI) using 12 microsatellite markers, and hMLH1 promoter region methylation. Protein expressions of hMSH2, hMLH1, APC, E-cadherin, and beta-catenin were identified by immune staining. RESULTS: There was no pathogenic mutation in any introns or exons of hMSH2, hMLH1 or CDH1, and in exons 3, 5, 6, and 15 of CTNNB1. Either MSI or methylator phenotype was found in five gastric cancers and in four colorectal cancers. No patients met the Amsterdam criteria of hereditary nonpolyposis colorectal cancer (HNPCC) or its equivalent of hereditary gastric cancer. Two patients with gastric cancers among their first-degree relatives showed no E-cadherin expression. The two of the three patients with rectal cancers among their first-degree relatives showed mutator phenotype either in the gastric or in the colorectal cancer. A subset of double-primary gastric and colorectal cancers may thereby be categorized as variant forms of hereditary gastric or colorectal cancer. Both cytoplasmic and nuclear beta-catenins were expressed in all gastric and colorectal cancers. Among the gastric and colorectal cancers with either MSI or methylator phenotype, four of five gastric cancers showed both APC and E-cadherin expression, whereas one of four colorectal cancers showed them. CONCLUSION: This may suggest that the mutator pathway and the aberrant tumor suppressor pathway of the APC-E-cadherin may be cooperative or separately activated in the geno-pathogenesis of double-primary gastric and colorectal cancers.

[Prognostic factors of stage II rectal cancer].

BACKGROUND/AIMS: We aimed to verify the prognostic factors of stage II rectal cancer and the effect of radiation therapy on the survival and local recurrence rate. METHODS: This study was undertaken in 202 patients who underwent curative resection of rectal cancer and confirmed to be stage II between July 1989 and December 1996. Univariate and multivariate (Cox's model) analyses of survival were employed to identify prognostic factors. Statistical significance was assigned by p value of <0.05. RESULTS: Overall recurrence occurred in 32 patients. Four patterns of recurrence were observed: hematogenous recurrence in 17 patients, local recurrence in 11, peritoneal seeding in two and simultaneous hematogenous and local recurrence in two cases. Overall 5-year survival rate was 85.6% and 5 year disease free survival rate was 82.8%. There was no significant difference in local recurrence rate and survival according to radiation therapy or location of cancer. In multivariate analysis, the number of harvested lymph node was only a prognostic factor. CONCLUSIONS: The number of harvested lymph nodes has prognostic value in stage II rectal cancer. Postoperative radiation therapy should be considered for stage II rectal cancer with poor prognostic factors although radiation did not decrease local recurrence rate in present study.

[Clinical features and prognostic factors in primary adenocarcinoma of the appendix].

BACKGROUND/AIMS: Primary appendiceal adenocarcinoma is a rare neoplasm that constitutes less than 0.5% of all gastrointestinal neoplasm. The aim of this study was to figure out its clinicopathologic characteristics that are not well understood. METHODS: We reviewed the medical records of nineteen patients (9 males and 10 females) with histologically proven appendiceal adenocarcinoma. They had been treated at Asan Medical Center between June 1989 and December 2002. Their median follow-up duration was 72.5 months. RESULTS: Their median age was 56.5 (range, 33-80) years. Thirteen patients had mucinous variants and the other five had adenocarcinoma. Seven patients (36.8%) were diagnosed as acute appendicitis. In fact, none of the patients was diagnosed correctly before surgery. The operative procedure, included right hemicolectomy in 9 patients, appendectomy alone in 2 patients, and debulking of their tumors or a biopsy in 8 patients. The 5-year survival rate was 20.5%. The patients with mucinous type had better prognosis than those with the non-mucinous type (p<0.01). In the patients with mucinous type, the survival rate after debulking operation was similar to that after right hemicolectomy. CONCLUSIONS: The most important prognostic factor of primary appendiceal adenocarcinoma was histology. The outcome of debulking operation is being watched compared with that of right hemicolectomy in mucinous variant.

Coexpression of carcinoembryonic antigen and E-cadherin in colorectal adenocarcinoma with liver metastasis.

Carcinoembryonic antigen (CEA) has been suggested as a metastatic activator in colorectal carcinoma, whereas the E-cadherin expression is downregulated in a variety of carcinomas. CEA and E-cadherin expressions were simultaneously assessed with regard to tumor progression in the various sites of colorectal carcinomas with liver metastasis. Twenty-six consecutive patients who had colorectal carcinoma with liver metastasis underwent curative surgery for primary tumor and liver metastasis. CEA and E-cadherin expression were identified on immunohistochemical staining using the labeled streptavidin-biotin method. Their mRNA expression was also detected by RT in situ PCR using one-step reverse transcription-polymerase chain reaction (RT-PCR). CEA and E-cadherin expression scores in the tumor center were greater than those in the tumor margin in both primary tumor and liver metastasis (P<0.001 to 0.006). CEA expression scores were closely associated with E-cadherin expression scores on the corresponding tumor site (P<0.001 to 0.017). CEA and E-cadherin mRNA expression was greatest in the hepatocytes adjacent to liver metastasis, next greatest in the primary tumor, and least in the liver metastasis (P<0.001 to 0.002). CEA mRNA expression was also closely correlated with E-cadherin mRNA expression in the primary tumor (P<0.001) and in the adjacent hepatocytes of the liver metastasis (P=0.018). Patients with a lesser CEA expression score in the liver metastasis margin appeared to have a longer disease-free survival period than did those with a greater CEA expression score. Expression of CEA and E-cadherin was closely correlated with the mRNA levels. Furthermore, these correlations may be implicated in the tumor progression of colorectal carcinoma considering their biological properties.

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

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.