Purpose: There are clinical unmet needs in predicting therapeutic response and precise strategy for the patient with advanced biliary tract cancer (BTC). We aimed to identify genomic alterations predicting therapeutic response and resistance to gemcitabine and cisplatin (Gem/Cis)-based chemotherapy in advanced BTC. Materials and Methods: Genomic analysis of advanced BTC multi-institutional cohorts was performed using targeted panel sequencing. Genomic alterations were analyzed integrating patients’ clinicopathologic data, including clinical outcomes of Gem/Cis-based therapy. Significance of genetic alterations was validated using clinical next-generation sequencing (NGS) cohorts from public repositories and drug sensitivity data from cancer cell lines. Results: 193 BTC patients from three cancer centers were analyzed. Most frequent genomic alterations were TP53 (55.5%), KRAS (22.8%), ARID1A (10.4%) alterations, and ERBB2 amplification (9.8%). Among 177 patients with BTC receiving Gem/Cis-based chemotherapy, ARID1A alteration was the only independent predictive molecular marker of primary resistance showing disease progression for 1st-line chemotherapy in the multivariate regression model (odds ratio, 3.12; p=0.046). In addition, ARID1A alteration was significantly correlated with inferior progression-free survival on Gem/Cis-based chemotherapy in the overall patient population (p=0.033) and in patients with extrahepatic cholangiocarcinoma (CCA) (p=0.041). External validation using public repository NGS revealed that ARID1A mutation was a significant predictor for poor survival in BTC patients. Investigation of multi-OMICs drug sensitivity data from cancer cell lines revealed that cisplatin-resistance was exclusively observed in ARID1A mutant bile duct cancer cells. Conclusion Integrative analysis with genomic alterations and clinical outcomes of the first-line Gem/Cis-based chemotherapy in advanced BTC revealed that patients with ARID1Aalterations showed a significant worse clinical outcome, especially in extrahepatic CCA. Well-designed prospective studies are mandatory to validate the predictive role of ARID1Amutation.

Myelin degeneration is one of the characteristics of aging and degenerative diseases. This study investigated age-related alterations in expression of myelin basic protein (MBP) in the hippocampal subregions (dentate gyrus, CA2/3 and CA1 areas) of gerbils of various ages; young (1 month), adult (6 months) and aged (24 months), using western blot and immunohistochemistry. Western blot results showed tendencies of age-related reductions of MBP levels. MBP immunoreactivity was significantly decreased with age in synaptic sites of trisynaptic loops, perforant paths, mossy fibers, and Schaffer collaterals. In particular, MBP immunoreactive fibers in the dentate molecular cell layer (perforant path) was significantly reduced in adult and aged subjects. In addition, MBP immunoreactive mossy fibers in the dentate polymorphic layer and in the CA3 striatum radiatum was significantly decreased in the aged group. Furthermore, we observed similar age-related alterations in the CA1 stratum radiatum (Schaffer collaterals). However, the density of MBP immunoreactive fibers in the dentate granular cell layer and CA stratum pyramidale was decreased with aging. These findings indicate that expression of MBP is age-dependent and tissue specific according to hippocampal layers.
Adult* ; Aging ; Blotting, Western ; CA1 Region, Hippocampal ; Gerbillinae* ; Hippocampus* ; Humans ; Immunohistochemistry ; Myelin Basic Protein* ; Myelin Sheath* ; Perforant Pathway

Remission is a primary end point of in clinical practice and trials of treatments for rheumatoid arthritis (RA). The 2011 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria were developed to provide a consensus definition of remission. This study aimed to assess the concordance between the new remission criteria and the physician’s clinical judgment of remission and also to identify factors that affect the discordance between these two approaches. A total of 3,209 patients with RA were included from the KORean Observational Study Network for Arthritis (KORONA) database. The frequency of remission was evaluated based on each approach. The agreement between the results was estimated by Cohen's kappa (κ). Patients with remission according to the 2011 ACR/EULAR criteria (i.e. the Boolean criteria) and/or physician judgment (n = 855) were divided into three groups: concordant remission, the Boolean criteria only, and physician judgment only. Multinomial logistic regression analysis was used to identify factors responsible for the assignment of patients with remission to one of the discordant groups rather than the concordant group. The remission rates using the Boolean criteria and physician judgment were 10.5% and 19.9%, respectively. The agreement between two approaches for remission was low (κ = 0.226) and the concordant remission rate was only 5.5% (n = 177). Pain affected classification in both discordant groups, whereas fatigue was associated with remission only by physician clinical judgment. The Boolean criteria were more stringent than clinical judgment. Patient subjective symptoms such as pain and fatigue were associated with discordance between the two approaches.
Arthritis ; Arthritis, Rheumatoid* ; Classification ; Consensus ; Fatigue ; Humans ; Judgment* ; Logistic Models ; Observational Study ; Rheumatic Diseases

BACKGROUND AND OBJECTIVES: We compared the efficacy and safety of valsartan and rosuvastatin combination therapy with each treatment alone in hypercholesterolemic hypertensive patients. SUBJECTS AND METHODS: Patients who met inclusion criteria were randomized to receive 1 of the following 2-month drug regimens: valsartan 160 mg plus rosuvastatin 20 mg, valsartan 160 mg plus placebo, or rosuvastatin 20 mg plus placebo. The primary efficacy variables were change in sitting diastolic blood pressure (sitDBP) and sitting systolic blood pressure (sitSBP), and percentage change in low-density lipoprotein-cholesterol (LDL-C) in the combination, valsartan, and rosuvastatin groups. Adverse events (AEs) during the study were analyzed. RESULTS: A total of 354 patients were screened and 123 of them were finally randomized. Changes of sitDBP by least squares mean (LSM) were -11.1, -7.2, and -3.6 mm Hg, respectively, and was greater in the combination, as compared to both valsartan (p=0.02) and rosuvastatin (p<0.001). Changes of sitSBP by LSM were -13.2, -10.8, and -4.9 mm Hg, and was greater in the combination, as compared to rosuvastatin (p=0.006) and not valsartan (p=0.42). Percentage changes of LDL-C by LSM were -52, -4, and -47% in each group, and was greater in the combination, as compared to valsartan (p<0.001), similar to rosuvastatin (p=0.16). Most AEs were mild and resolved by the end of the study. CONCLUSION: Combination treatment with valsartan and rosuvastatin exhibited an additive blood pressure-lowering effect with acceptable tolerability, as compared to valsartan monotherapy. Its lipid lowering effect was similar to rosuvatatin monotherapy.
Blood Pressure ; Drug Therapy, Combination ; Humans ; Least-Squares Analysis ; Rosuvastatin Calcium ; Valsartan

In this article, on page 230, Fig. 2A needs to be corrected.

The purpose of this study was to investigate the age-related NADPH oxidase (arNOX) activity in patients with age-related knee osteoarthritis (OA). Serum and cartilage arNOX activities were determined using an oxidized ferricytochrome C reduction assay. Full-thickness knee joint cartilages obtained through total knee replacement surgery were graded according to the Outerbridge (OB) classification. Radiographic severity of OA was determined on Knee X-rays according to the Kellgren-Lawrence (K/L) grading system. Cartilage beta-galactosidase, HIF-1alpha, and GLUT-1 expression levels were evaluated as markers for tissue senescence, hypoxia, and glycolysis. Higher arNOX activities occurred with higher levels of cartilage beta-galactosidase, HIF-1alpha, and GLUT-1 (P = 0.002). arNOX activity in cartilages with surface defects (OB grade II, III) was higher than in those without the defects (OB grade 0, I) (P = 0.012). Cartilage arNOX activity showed a positive correlation with serum arNOX activity (r = -0.577, P = 0.023). Serum arNOX activity was significantly higher in the OA subgroup with bilateral ROA than in the OA with no or unilateral ROA (2.449 +/- 0.81, 2.022 +/- 0.251 nM/mL, respectively, P = 0.019). The results of this study demonstrate that OA itself is not a cause to increase arNOX activities, however, arNOX hyperactivity is related to a high degree of cartilage degradation, and a high grade and extent of ROA in age-related OA.
Biomarkers/metabolism ; Cartilage Diseases/*enzymology ; Cartilage, Articular/*enzymology ; Enzyme Activation ; Female ; Humans ; Male ; Middle Aged ; NADH, NADPH Oxidoreductases ; Osteoarthritis, Knee/*diagnosis/*enzymology ; Osteoporosis/*diagnosis/*enzymology ; Reproducibility of Results ; Sensitivity and Specificity ; Statistics as Topic

BACKGROUND/AIMS: To evaluate the technical feasibility and clinical efficacy of double endoscopic nasobiliary drainage (ENBD) as a new method of draining multiple bile duct obstructions. METHODS: A total of 38 patients who underwent double ENBD between January 2004 and February 2010 at the Asan Medical Center were retrospectively analyzed. We evaluated indications, laboratory results, and the clinical course. RESULTS: Of the 38 patients who underwent double ENBD, 20 (52.6%) had Klatskin tumors, 12 (31.6%) had hepatocellular carcinoma, 3 (7.9%) had strictures at the anastomotic site following liver transplantation, and 3 (7.9%) had acute cholecystitis combined with cholangitis. Double ENBD was performed to relieve multiple biliary obstruction in 21 patients (55.1%), drain contrast agent filled during endoscopic retrograde cholangiopancreatography in 4 (10.5%), obtain cholangiography in 4 (10.5%), drain hemobilia in 3 (7.9%), relieve Mirizzi syndrome with cholangitis in 3 (7.9%), and relieve jaundice in 3 (7.9%). CONCLUSIONS: Double ENBD may be useful in patients with multiple biliary obstructions.
Carcinoma, Hepatocellular ; Cholangiography ; Cholangiopancreatography, Endoscopic Retrograde ; Cholangitis ; Cholecystitis, Acute ; Cholestasis ; Chungcheongnam-do ; Constriction, Pathologic ; Drainage* ; Hemobilia ; Humans ; Jaundice ; Klatskin's Tumor ; Liver Transplantation ; Mirizzi Syndrome ; Retrospective Studies

IgG4-related sclerosing disease is a disease entity that has recently attracted attention, manifesting as a multiorgan disease characterized by high serum IgG4 levels, extensive IgG4-positive plasma cells and lymphocyte infiltration of the affected organs, with the pancreas (autoimmune pancreatitis) and kidney as representative targets. In cases of renal involvement, parenchymal lesions are predominant, such as renal cortical lesions or diffuse renal enlargement. However, mass-like lesions involving the renal pelvis are very rare, and mass forming or pelvic involvement types should be distinguished from lymphomas, metastatic cancers and other genitourinary malignancies to avoid unnecessary surgery. Herein, we report a case of IgG4-related sclerosing disease involving the kidney as an unusual involvement pattern presenting as a mass-like lesion with pelvic and perirenal involvement.
Immunoglobulin G ; Kidney ; Kidney Diseases* ; Kidney Pelvis ; Lymphocytes ; Lymphoma ; Pancreas* ; Plasma Cells ; Unnecessary Procedures

Endoscopic retrograde cholangiopancreatography has become a standard procedure for the diagnosis and treatment of pancreatobiliary disease. Like any invasive procedure, it carries a small, but significant rate of serious complications such as duodenal perforation. Primary surgical closure is the treatment of choice for the cases of duodenal perforation. However, there have been some case reports in which endoscopic metal clip closure of an iatrogenic duodenal perforation was successful. We experienced three cases of successful treatment of the iatrogenic duodenal perforation using endoscopic clipping and fibrin glue injections during a duodenoscope insertion.
Cholangiopancreatography, Endoscopic Retrograde ; Duodenoscopes ; Fibrin Tissue Adhesive

BACKGROUND/AIMS: Histologically confirmed metastatic pancreatic cancers are infrequent. The aim of this study was to analyze clinical, therapeutic and prognostic features of pancreatic metastases. METHODS: We retrospectively evaluated stage of primary malignancies, interval between diagnosis of primary tumors and detection of pancreatic metastases, treatment for metastases to the pancreas, survival rate, and prognostic factors in 31 patients with pancreatic metastases. RESULTS: The mean age at the time of primary cancer diagnosis was 52.4+/-13.2 years. Primary cancers were renal cell carcinoma (n=16), non-small cell lung cancer (n=6), small cell lung cancer (n=3), colorectal carcinoma (n=2), osteosarcoma (n=1), gastric carcinoma (n=1), malignant melanoma (n=1), and thymic carcinoma (n=1). Pancreatic metastases were synchronous in six cases and metachronous in twenty five cases, with median interval time of 40.8 months (range 3-186) between the diagnosis of primary tumor and detection of pancreatic metastases. The median survival after the detection of the metastases was 16 months. In multivariate analysis, non-renal cell carcinoma as primary malignancy and positive symptom related to pancreatic metastases were associated with poor prognosis (hazard ratio [HR], 8.33; 95% CI, 2.1-33; p=0.003, and HR, 4.02; 95% CI, 1.27-12.7; p=0.018). CONCLUSIONS: Metastatic tumors to the pancreas have to be kept in mind when a patient with pancreatic mass has a history of other malignancy, even if treated several years before. In the absence of widely metastatic disease, aggressive diagnostic and therapeutic approach may offer the chance of long-term survival in selected patients.