Mee Yon Cho

Current Trends of the Incidence and Pathological Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) in Korea 2000-2009: Multicenter Study.

Purpose As a result of various independently proposed nomenclatures and classifications, there is confusion in the diagnosis and prediction of biological behavior of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A comprehensive nationwide study is needed in order to understand the biological characteristics of GEP-NETs in Korea. Materials and Methods We collected 4,951 pathology reports from 29 hospitals in Korea between 2000 and 2009. Kaplan-Meier survival analysis was used to determine the prognostic significance of clinicopathological parameters. Results Although the GEP-NET is a relatively rare tumor in Korea, its incidence has increased during the last decade, with the most significant increase found in the rectum. The 10-year survival rate for well-differentiated endocrine tumor was 92.89%, in contrast to 85.74% in well differentiated neuroendocrine carcinoma and 34.59% in poorly differentiated neuroendocrine carcinoma. Disease related death was most common in the biliary tract (62.2%) and very rare in the rectum (5.2%). In Kaplan-Meier survival analysis, tumor location, histological classification, extent, size, mitosis, Ki-67 labeling index, synaptophysin expression, lymphovascular invasion, perineural invasion, and lymph node metastasis showed prognostic significance (p<0.05), however, chromogranin expression did not (p=0.148). The 2000 and 2010 World Health Organization (WHO) classification proposals were useful for prediction of the prognosis of GEP-NET. Conclusion The incidence of GEP-NET in Korea has shown a remarkable increase during the last decade, however, the distribution of tumors in the digestive system differs from that of western reports. Assessment of pathological parameters, including immunostaining, is crucial in understanding biological behavior of the tumor as well as predicting prognosis of patients with GEP-NET.

Sensitive and Specific Detection of Early Gastric Cancer with DNA Methylation Analysis of Gastric Washes

BACKGROUND & AIMSnAberrant DNA methylation is an early and frequent process in gastric carcinogenesis and could be useful for detection of gastric neoplasia. We hypothesized that methylation analysis of DNA recovered from gastric washes could be used to detect gastric cancer.nnnMETHODSnWe studied 51 candidate genes in 7 gastric cancer cell lines and 24 samples (training set) and identified 6 for further studies. We examined the methylation status of these genes in a test set consisting of 131 gastric neoplasias at various stages. Finally, we validated the 6 candidate genes in a different population of 40 primary gastric cancer samples and 113 nonneoplastic gastric mucosa samples.nnnRESULTSnSix genes (MINT25, RORA, GDNF, ADAM23, PRDM5, MLF1) showed frequent differential methylation between gastric cancer and normal mucosa in the training, test, and validation sets. GDNF and MINT25 were most sensitive molecular markers of early stage gastric cancer, whereas PRDM5 and MLF1 were markers of a field defect. There was a close correlation (r = 0.5-0.9, P = .03-.001) between methylation levels in tumor biopsy and gastric washes. MINT25 methylation had the best sensitivity (90%), specificity (96%), and area under the receiver operating characteristic curve (0.961) in terms of tumor detection in gastric washes.nnnCONCLUSIONSnThese findings suggest MINT25 is a sensitive and specific marker for screening in gastric cancer. Additionally, we have developed a new method for gastric cancer detection by DNA methylation in gastric washes.

Histological subclassification of cirrhosis using the Laennec fibrosis scoring system correlates with clinical stage and grade of portal hypertension

BACKGROUND & AIMSnFurther histological subclassification of cirrhosis may be useful because of heterogeneity of severity within cirrhosis. We aimed to determine the relationship between histological subclassification and clinical stage of cirrhosis as well as grade of portal hypertension.nnnMETHODSnOne hundred-twenty-three biopsy-proven cirrhosis patients, whose clinical stage of cirrhosis and hepatic venous pressure gradient (HVPG) could be estimated, were included in this prospective study. Histology of cirrhosis was blindly subclassified using the Laennec fibrosis scoring system semi-quantitatively without knowledge of the clinical stage or the HVPG results. The Laennec system subclassifies cirrhosis as mild - thin septa, moderate - at least two broad septa, and severe - at least one very broad septum or many minute nodules. Clinical stages were determined by the presence or absence of varices, ascites, and variceal hemorrhage. Biological and laboratory data were also collected.nnnRESULTSnAlcohol intake was the most common cause of cirrhosis in this cohort (87, 70.7%). Histology of cirrhosis subclassified using the Laennec scoring system significantly correlated with both the clinical stage of cirrhosis (p < 0.001) and HVPG (mild: 8.1 ± 2.6 mm Hg, moderate: 12.4 ± 3.3mm Hg, severe: 16.3 ± 4.0 mm Hg, p < 0.001). With higher grades of histological subclassification of cirrhosis, increased frequency in both severe portal hypertension (HVPG ≥ 12 mm Hg) and episodes of variceal hemorrhage were observed (p < 0.001).nnnCONCLUSIONSnHistological subclassification of cirrhosis by the Laennec fibrosis scoring system is tightly correlated with both the clinical stage of cirrhosis and grade of portal hypertension. This suggests that cirrhosis should be subclassified into different stages according to its histological severity.

Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study

In experimental models, bone marrow‐derived mesenchymal stem cells (BM‐MSCs) have the capacity to differentiate into hepatocytes and exhibit antifibrotic effects. However, there have been no studies in humans with alcoholic cirrhosis.

Hepatic vein arrival time as assessed by contrast-enhanced ultrasonography is useful for the assessment of portal hypertension in compensated cirrhosis.

The measurement of the hepatic venous pressure gradient (HVPG) for the estimation of portal hypertension (PH) in cirrhosis has some limitations, including its invasiveness. Hepatic vein arrival time (HVAT), as assessed by microbubble contrast‐enhanced ultrasonography (CEUS), is negatively correlated with the histological grade of liver fibrosis because of the associated hemodynamic abnormalities. Anatomical and pathophysiological changes in liver microcirculation are the initial events leading to PH. However, the direct relationship between HVAT and PH has not been evaluated. The present study measured both HVPG and HVAT in 71 consecutive patients with compensated cirrhosis and analyzed the relationship between the two parameters (i.e., the derivation set). Results were validated in 35 compensated patients with cirrhosis at another medical center (i.e., the validation set). The derivation set had HVPG and HVAT values of 11.4 ± 5.0 mmHg (mean ± standard deviation; range, 2‐23) and 14.1 ± 3.4 seconds (range, 8.4‐24.2), respectively; there was a statistically significant negative correlation between HVPG and HVAT (r2 = 0.545; P < 0.001). The area under the receiver operating characteristic curve (AUROC) was 0.973 for clinically significant PH (CSPH; HVPG, ≥10 mmHg), and the sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios for CSPH for an HVAT cut‐off value of 14 seconds were 92.7%, 86.7%, 90.5%, 89.7%, 6.95, and 0.08, respectively. In addition, a shorter HVAT was associated with worse Child‐Pugh score (P < 0.001) and esophageal varices (P = 0.018). In the validation set, there was also a significant negative correlation between HVAT and HVPG (r2 = 0.538; P < 0.001), and AUROC = 0.953 for CSPH. HVAT was significantly correlated with PH. These results indicate that measuring HVAT is useful for the noninvasive prediction of CSPH in patients with compensated cirrhosis. (HEPATOLOGY 2012;56:1053–1062)

Frequent Alteration of MLL3 Frameshift Mutations in Microsatellite Deficient Colorectal Cancer

Background MLL3 is a histone 3- lysine 4 methyltransferase with tumor-suppressor properties that belongs to a family of chromatin regulator genes potentially altered in neoplasia. Mutations in MLL3 were found in a whole genome analysis of colorectal cancer but have not been confirmed by a separate study. Methods and Results We analyzed mutations of coding region and promoter methylation in MLL3 using 126 cases of colorectal cancer. We found two isoforms of MLL3 and DNA sequencing revealed frameshift and other mutations affecting both isoforms of MLL3 in colorectal cancer cells and 19 of 134 (14%) primary colorectal samples analyzed. Moreover, frameshift mutations were more common in cases with microsatellite instability (31%) both in CRC cell lines and primary tumors. The largest isoform of MLL3 is transcribed from a CpG island-associated promoter that has highly homology with a pseudo-gene on chromosome 22 (psiTPTE22). Using an assay which measured both loci simultaneously we found prominent age related methylation in normal colon (from 21% in individuals less than 25 years old to 56% in individuals older than 70, Ru200a=u200a0.88, p<0.001) and frequent hypermethylation (83%) in both CRC cell lines and primary tumors. We next studied the two loci separately and found that age and cancer related methylation was solely a property of the pseudogene CpG island and that the MLL3 loci was unmethylated. Conclusions We found that frameshift mutations of MLL3 in both CRC cells and primary tumor that were more common in cases with microsatellite instability. Moreover, we have shown CpG island-associated promoter of MLL3 gene has no DNA methylation in CRC cells but also primary tumor and normal colon, and this region has a highly homologous of pseudo gene (psiTPTE22) that was age relate DNA methylation.

The prevalence of and risk factors for Barrett's esophagus in a Korean population: A nationwide multicenter prospective study.

Objective The aim of this study was to evaluate the prevalence of Barretts esophagus (BE) in the general Korean population by evaluating screening esophagogastroduodenoscopy. In addition, the risk factors for BE were identified. Method An esophagogastroduodenoscopy examination was performed in 25,536 subjects who had upper endoscopy screening from January 2006 to July 2006. Results Two hundred and fifteen subjects were confirmed to have BE by pathology, thus the prevalence of BE was calculated to be 0.84%. The endoscopic findings were subdivided into 2 groups: BE without reflux esophagitis (RE), which included 167 (77.7%), and BE with RE, which included 48 (22.3%). The analysis of symptoms showed that only 60.1% of the subjects with BE had reflux symptoms. Chest pain [odds ratio (OR): 1.48, 95% confidence interval (CI): 1.04-2.11] and epigastric soreness (OR: 1.42, 95% CI: 1.05-1.93) were found more frequently in the subjects with BE compared with the normal subjects. The multivariate analysis showed that the risk factors for all subjects with BE were a male sex (OR: 1.82, 95% CI: 1.32-2.50), nonsteroidal anti-inflammatory drug use (OR: 2.02, 95% CI: 1.28-3.20), hiatal hernia (OR: 5.66, 95% CI: 3.70-8.66), and an age ≥60 compared with an age <40 (OR: 1.81, 95% CI: 1.07-3.09). There was no significant difference associated with RE. Conclusions The prevalence of BE in Korean patients presenting for a routine health check-up was 0.84%, lower than reported in Western countries. Among the subjects with BE 77.7% did not have endoscopic erosions and there were no reflux symptoms in 39.9%. These results suggest that regular endoscopic screening with a high index of suspicion is necessary for the diagnosis of BE.

Current trends in the epidemiological and pathological characteristics of gastrointestinal stromal tumors in Korea, 2003-2004.

Despite remarkable progress in understanding and treating gastrointestinal stromal tumors (GISTs) during the past two decades, the pathological characteristics of GISTs have not been made clear yet. Furthermore, concrete diagnostic criteria of malignant GISTs are still uncertain. We collected pathology reports of 1,227 GISTs from 38 hospitals in Korea between 2003 and 2004 and evaluated the efficacy of the NIH and AFIP classification schemes as well as the prognostic factors among pathologic findings. The incidence of GISTs in Korea is about 1.6 to 2.2 patients per 100,000. Extra-gastrointestinal GISTs (10.1%) are more common in Korea than in Western countries. In univariate analysis, gender, age, tumor location, size, mitosis, tumor necrosis, vascular and mucosal invasions, histologic type, CD34 and s-100 protein expression, and classifications by the NIH and AFIP criteria were found to be significantly correlated with patients survival. However, the primary tumor location, stage and classification of the AFIP criteria were prognostically significant in predicting patients survival in multivariate analysis. The GIST classification based on original tumor location, size, and mitosis is more efficient than the NIH criteria in predicting patients survival, but the mechanism still needs to be clarified through future studies.

Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial.

Bone marrow‐derived mesenchymal stem cell (BM‐MSC) transplantation has been suggested as an effective therapy for liver cirrhosis. The efficacy and safety of autologous BM‐MSC transplantation in the treatment of alcoholic cirrhosis were investigated. Seventy‐two patients with baseline biopsy‐proven alcoholic cirrhosis who had been alcohol‐abstinent for more than 6 months underwent a multicenter, randomized, open‐label, phase 2 trial. Patients were randomly assigned to three groups: one control group and two autologous BM‐MSC groups that underwent either one‐time or two‐time hepatic arterial injections of 5 × 107 BM‐MSCs 30 days after BM aspiration. A follow‐up biopsy was performed 6 months after enrollment, and adverse events were monitored for 12 months. The primary endpoint was improvement in fibrosis quantification based on picrosirius red staining. The secondary endpoints included liver function tests, Child‐Pugh score, and Model for End‐stage Liver Disease score. Outcomes were analyzed by per‐protocol analysis. In terms of fibrosis quantification (before versus after), the one‐time and two‐time BM‐MSC groups were associated with 25% (19.5 ± 9.5% versus 14.5 ± 7.1%) and 37% (21.1 ± 8.9% versus 13.2 ± 6.7%) reductions in the proportion of collagen, respectively (P < 0.001). In the intergroup comparison, two‐time BM‐MSC transplantation in comparison with one‐time BM‐MSC transplantation was not associated with improved results in fibrosis quantification (P > 0.05). The Child‐Pugh scores of both BM‐MSC groups (one‐time 7.6 ± 1.0 versus 6.3 ± 1.3 and two‐time 7.8 ± 1.2 versus 6.8 ± 1.6) were also significantly improved following BM‐MSC transplantation (P < 0.05). The proportion of patients with adverse events did not differ among the three groups. Conclusion: Autologous BM‐MSC transplantation safely improved histologic fibrosis and liver function in patients with alcoholic cirrhosis. (Hepatology 2016;64:2185‐2197)

Beneficial effects of candesartan, an angiotensin‐blocking agent, on compensated alcoholic liver fibrosis ‐ A randomized open‐label controlled study

Recent studies have shown that the renin‐angiotensin system is implicated in hepatic fibrogenesis in vitro and in vivo. However, no study was done in humans with alcoholic liver disease.