Ki Ouk Min

Mutational analysis of MED12 exon 2 in uterine leiomyoma and other common tumors

Recurrent somatic mutations in MED12 exon 2 have recently been reported in uterine leiomyomas. The recurrent nature of the mutations strongly suggests that the mutations may play important roles in the pathogenesis of uterine leiomyomas. The aim of our study was to see whether MED12 exon 2 mutations occur in other human tumors besides uterine leiomyomas. We also attempted to confirm occurrence of the MED12 mutations in uterine leiomyomas of Korean patients. For this, we analyzed 1,862 tumor tissues, including a variety of carcinomas, leukemias and stromal tumors by single‐strand conformation polymorphism analysis. We found MED12 mutations in 35 uterine leiomyomas (35/67; 52.2%) and one colon carcinoma (0.3%), but none in other tumors. The MED12 mutations consisted of missense (77%) and inframe insertion‐deletion (23%) mutations, the pattern of which was similar to the earlier report. Our data indicate that MED12 exon 2 mutations may be tissue‐specific to uterine leiomyoma and rare in other tumors. Our study suggests that the MED12 mutations play unique roles in the pathogenesis of uterine leiomyomas and mutated MED12 could be therapeutically targeted in uterine leiomyomas.

Malignant gastrointestinal stromal tumor of the gallbladder.

Gastrointestinal stromal tumors (GISTs) of the gallbladder are representative of an extremely rare group of tumors. We have encountered a patient with a malignant GIST of the gallbladder and presented it with a review of some articles. A 72-yr-old woman initially presented with right upper quadrant abdominal pain, fever and chills. Emergency cholecystectomy was performed under the impression of gallbladder empyema. Liver metastasis was found at 7 months postoperatively and the patient expired 9 months after the surgery. At the time of cholecystectomy, the gallbladder showed a necrotic serosal surface with an irregular thickened wall. A mass, 6 cm in length and 3 cm in width, encircled the whole wall of the neck and upper body of the gallbladder. Microscopic findings revealed frequent mitotic figures (more than 20/50 HPF) and tumor necrosis. Hyperchromatic, pleomorphic and spindle shaped neoplastic cells that were arranged in a pattern of short fascicles infiltrated the entire layer of the gallbladder. The tumor cells were immunoreactive for CD117 antigen (c-kit protein) and vimentin. They were negative for desmin, smooth muscle actin and S-100 protein. Mutations of the c-kit proto-oncogene were not found in this case. These findings were sufficient to provide enough clinical, histopathological and immunohistochemicalevidence in diagnosing our case as a malignant GIST.

Methylation of p16INK4A and p57KIP2 are involved in the development and progression of gastric MALT lymphomas

p16INK4A and p57KIP2 are inhibitors of cyclin-dependent kinases and their inactivation by methylation has been reported as a major tumorigenic mechanism in tumors. To examine whether methylation of p16INK4A and p57KIP2 is involved in the development and progression of gastric MALT lymphomas, 24 gastric low-grade lymphomas of MALT, 11 diffuse large B-cell lymphomas, and 10 each case of gastric lymphoid follicles with and without Helicobacter pylori infection were studied. H. pylori infection was positive in 85.7% of the gastric lymphomas. In the gastric lymphoid follicles positive for H. pylori, methylation of p16INK4A was detected in 10% of cases, while methylation of p57KIP2 was not detected. In low-grade MALT lymphomas, p16INK4A and p57KIP2 were methylated in 41.7 and 29.2% of the cases, respectively. In diffuse large B-cell lymphomas, methylation of p16INK4A and p57KIP2 was found in 72.7 and 36.4% of the cases, respectively. All but one case with p16INK4A and p57KIP2 methylation was H. pylori positive and most of them were stage I. Our results indicate that methylation of p16INK4A followed by p57KIP2 methylation involves during the tumorigenesis of gastric MALT lymphomas associated with H. pylori infection. As methylation of these two genes was more frequent in the higher grade (P<0.05), it may contribute to the malignant progression of gastric MALT lymphomas.

Lower Urinary Tract Symptoms in Benign Prostatic Hyperplasia Patients: Orchestrated by Chronic Prostatic Inflammation and Prostatic Calculi?

Objective: This study aims to examine the relationship between chronic prostatic inflammation and prostatic calculi, and clinical parameters of benign prostatic hyperplasia (BPH). Materials and Methods: This study was based on 225 patients who underwent transurethral resection of the prostate for BPH. Chronic inflammation was graded as 0 (n = 44), I (n = 54), II (n = 88) or III (n = 39) according to severity. Prostatic calculi were classified into types A (n = 66), B (n = 44), M (n = 77) and N (n = 38). The relationship between inflammation and calculus type was analyzed, and clinical parameters of BPH were compared for each group. Results: There was no correlation between severity of inflammation and calculus type. Prostatic volume increased with the severity of inflammation and showed significant differences between G2, G3 and G0. The International Prostate Symptom Score also increased with increasing inflammation. There was no significant difference between each clinical parameter according to calculus type. Conclusions: Prostatic calculi had no significant association with chronic inflamma- tion and clinical parameters of BPH. Chronic inflammation was associated with the volume of the prostate and storage symptoms; thus, it is not only presumed to be related to the progression of BPH, but may also be one of the causes of lower urinary tract symptoms.

The Effects of Alcohol Abstinence on BDNF, Ghrelin, and Leptin Secretions in Alcohol‐Dependent Patients with Glucose Intolerance

BACKGROUND Alcohol use affecting the risk of type 2 diabetes mellitus (T2DM) is poorly identified as well as the role of brain-derived neurotrophic factor (BDNF), ghrelin, and leptin in alcohol dependence with T2DM. We tested the hypothesis that alcohol abstinence affects diabetes-related factors and BDNF, ghrelin, and leptin secretions in alcohol-dependent patients with glucose intolerance. METHODS A total of 64 male alcohol-dependent patients were classified into normal glucose tolerance (NGT), pre-diabetes mellitus (pre-DM), and diabetes mellitus (DM) groups according to a 75-g oral glucose tolerance test (OGTT). All participants got alcohol dependence rehabilitation treatment for 30 days, and then we compared changes in BDNF, ghrelin, and leptin between pre- and post-alcohol abstinence. RESULTS After alcohol abstinence, both pre-DM and DM groups had significantly decreased levels of fasting glucose. All 3 groups exhibited elevated ghrelin levels and reduced leptin levels, but BDNF levels were significantly increased only in the pre-DM group. The pre-DM group had large increases in BDNF and ghrelin levels compared with those of the NGT group. Moreover, decreases in homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose, and leptin levels in the DM group were larger than those in the NGT group. CONCLUSIONS Alcohol abstinence might influence diabetes-related factors of alcohol-dependent patients with glucose intolerance. Further, BDNF, ghrelin, and leptin differently affect this improvement, depending on the stage of DM. In the pre-DM group, elevated BDNF and ghrelin levels are likely to influence insulin sensitivity, insulin resistance, and fasting glucose levels. Further, reduced leptin levels after abstinence might be related to improved glucose kinetics in patients with diabetes.

MicroRNA expression profiling and Notch1 and Notch2 expression in minimal deviation adenocarcinoma of uterine cervix.

BackgroundMicroRNA (miRNA) expression is known to be deregulated in cervical carcinomas. However, no data is available about the miRNA expression pattern for the minimal deviation adenocarcinoma (MDA) of uterine cervix. We sought to detect deregulated miRNAs in MDA in an attempt to find the most dependable miRNA or their combinations to understand their tumorigenesis pathway and to identify diagnostic or prognostic biomarkers. We also investigated the association between those miRNAs and their target genes, especially Notch1 and Notch2.MethodsWe evaluated miRNA expression profiles via miRNA microarray and validated them using.real-time PCR assays with 24 formalin-fixed, paraffin-embedded tissue blocks of MDA and 11 normal proliferative endocervical tissues as control. Expression for Notch1 and 2 was assessed by immunohistochemistry.ResultsMiRNA-135a-3p, 192-5p, 194-5p, and 494 were up-regulated, whereas miR-34b-5p, 204-5p, 299-5p, 424-5p, and 136-3p were down-regulated in MDA compared with normal proliferative endocervical tissues (all P <0.05). Considering the second-order Akaike Information Criterion consisting of likelihood ratio and number of parameters, miR-34b-5p showed the best discrimination power among the nine candidate miRNAs. A combined panel of miR-34b-5p and 194-5p was the best fit model to discriminate between MDA and control, revealing 100% sensitivity and specificity. Notch1 and Notch2, respective target genes of miR-34b-5p and miR-204-5p, were more frequently expressed in MDA than in control (63% vs. 18%; 52% vs. 18%, respectively, P <0.05). MiR-34b-5p expression level was higher in Notch1-negative samples compared with Notch1-positive ones (P <0.05). Down-regulated miR-494 was associated with poor patient survival (P = 0.036).ConclusionsMDA showed distinctive expression profiles of miRNAs, Notch1, and Notch2 from normal proliferative endocervical tissues. In particular, miR-34b-5p and 194-5p might be used as diagnostic biomarkers and miR-494 as a prognostic predictor for MDA. The miR-34b-5p/Notch1 pathway as well as Notch2 might be important oncogenic contributors to MDA.

Pseudomyxoma peritonei: extraperitoneal spread to the pleural cavity and lung.

Abdominal and pelvic recurrence of pseudomyxoma peritonei after the surgery is occasionally seen but extraperitoneal spread and hematogeneous metastases are rare. This case of pseudomyxoma peritonei provides interesting radiologic findings of extraperitoneal spread, which occurred after an extremely long interval from initial diagnosis.

Whole-exome sequencing identifies recurrent AKT1 mutations in sclerosing hemangioma of lung

Significance This report is an in-depth genetic profiling of pulmonary sclerosing hemangioma (PSH). We have discovered that PSH harbor recurrent AKT1 mutations (45.6%), most of which were AKT1 p.E17K mutations. This mutation may be the single-most common driver alteration to develop PSHs. In contrast to lung adenocarcinoma, PSH genomes harbor only a single driver mutation (AKT1 or β-catenin), which may provide clues to understanding the benign biology of PSH and for differential genomic diagnosis of lung tumors. Pulmonary sclerosing hemangioma (PSH) is a benign tumor with two cell populations (epithelial and stromal cells), for which genomic profiles remain unknown. We conducted exome sequencing of 44 PSHs and identified recurrent somatic mutations of AKT1 (43.2%) and β-catenin (4.5%). We used a second subset of 24 PSHs to confirm the high frequency of AKT1 mutations (overall 31/68, 45.6%; p.E17K, 33.8%) and recurrent β-catenin mutations (overall 3 of 68, 4.4%). Of the PSHs without AKT1 mutations, two exhibited AKT1 copy gain. AKT1 mutations existed in both epithelial and stromal cells. In two separate PSHs from one patient, we observed two different AKT1 mutations, indicating they were not disseminated but independent arising tumors. Because the AKT1 mutations were not found to co-occur with β-catenin mutations (or any other known driver alterations) in any of the PSHs studied, we speculate that this may be the single-most common driver alteration to develop PSHs. Our study revealed genomic differences between PSHs and lung adenocarcinomas, including a high rate of AKT1 mutation in PSHs. These genomic features of PSH identified in the present study provide clues to understanding the biology of PSH and for differential genomic diagnosis of lung tumors.

Comparison of quantitative results among two automated Rapid Plasma Reagin (RPR) assays and a manual RPR test

BACKGROUND We compared two automated Rapid Plasma Reagin (RPR) assay kits with a manual RPR assay kit to evaluate the possibility of using the two automated RPR assays as an alternative to the manual RPR assay for a quantitative monitoring. METHODS One hundred eighty-five samples were analyzed, including 16 sera from patients with primary, secondary, and latent syphilis. Measured RPR unit (R.U.) values of two automated RPR assay kits, Mediace RPR (Sekisui Chemical Co., Ltd, Japan) and HBi Auto RPR (HBI Co., Ltd, Korea), were compared with the RPR titers of Macro-Vue RPR card test (Becton Dickinson BD Microbiology systems, USA). As a confirmatory test, Anti-Treponema pallidum EUROLINE WB (IgG) and Anti-Treponema pallidum EUROLINE WB (IgM) (Euroimmun, Germany) were used. RESULTS There was a prozone effect with Mediace RPR at RPR titer (card test) of 1:16, but not with HBi Auto RPR. The R.U. values of the two automated RPR assays did not show proportional increase to the RPR titer. Agreement between manual RPR and two automated RPR assay kits, Mediace RPR assay and HBi Auto RPR assay, were 83.8% and 83.2%, respectively. CONCLUSIONS The two automated RPR assay kits could not be used as an alternative to manual RPR test for quantitative analysis of RPR titer. As Mediace RPR shows a prozone effect at relatively low RPR titer, caution is needed in the interpretation of the measured values.

Nasal Angiocentric Lymphoma With Hemophagocytic Syndrome

Objectives Hemophagocytic syndrome(HS) is a fatal complication of nasal angiocentric lymphoma (AL) and difficult to distinguish from malignant histiocyosis. Epstein-Barr virus(EBV)-associated HS is frequently observed in lymphoma of T-cell lineage and EBV is highly associated with nasal AL. Clinicopathologic features of 10 nasal ALs with HS were reviewed to determine the clinical significance and the pathogenetic association with EBV. Methods Ten patients of HS were identified from a retrospective analysis of 42 nasal ALs diagnosed from 1987 to 1996. Immunohistochemical study and in situ hybridization were performed on the paraffin-embedded tumor specimens obtained from 10 patients. Serologic study of EBV-Ab was performed in 3 available patients. Results Five patients had HS as initial manifestation, 3 at the time of relapse and 2 during the clinical remission of AL. Four patients were treated by combination chemotherapy (CHOP) and others had only supportive care. The median survival of all patients with HS was 4.1 months (range 2 days–36.5 months) and all had fatal outcome regardless of the treatment-modality. AH cases were positive for UCHL1 (CD45RO) and EBV by EBER in situ hybridization. The data of serologic tests indicated the active EBV infection. Conclusions HS is a fatal complication of nasal AL and has a high association with EBV. Reactivation of EBV may contribute to HS and further investigation of predictive factors and effective treatment of HS should be pursued in the future.