Background: Nilotinib is a tyrosine kinase inhibitor approved by the Ministry of Food and Drug Safety for frontline and 2nd line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). This study aimed to confirm the safety and efficacy of nilotinib in routine clinical practice within South Korea. Methods: An open-label, multicenter, single-arm, 12-week observational post-marketing surveillance (PMS) study was conducted on 669 Korean adult patients with Ph + CML from December 24, 2010, to December 23, 2016. The patients received nilotinib treatment in routine clinical practice settings. Safety was evaluated by all types of adverse events (AEs) during the study period, and efficacy was evaluated by the complete hematological response (CHR) and cytogenetic response. Results: During the study period, AEs occurred in 61.3% (410 patients, 973 events), adverse drug reactions (ADRs) in 40.5% (271/669 patients, 559 events), serious AEs in 4.5% (30 patients, 37 events), and serious ADRs in 0.7% (5 patients, 8 events). Furthermore, unexpected AEs occurred at a rate of 6.9% (46 patients, 55 events) and unexpected ADRs at 1.2% (8 patients, 8 events). As for the efficacy results, CHR was achieved in 89.5% (442/494 patients), and minor cytogenetic response or major cytogenetic response was achieved in 85.8% (139/162 patients). Conclusion This PMS study shows consistent results in terms of safety and efficacy compared with previous studies. Nilotinib was well tolerated and efficacious in adult Korean patients with Ph + CML in routine clinical practice settings.

BACKGROUND AND PURPOSE: Patients treated with interferon-beta (IFN-β) can develop neutralizing antibodies (NAbs) against IFN-β that can negatively affect the therapeutic response. This study assessed the prevalence of NAbs and the impact of NAb positivity on the therapeutic response to IFN-β in Korean patients with multiple sclerosis (MS). METHODS: This was a multicenter study involving 150 MS patients from 9 Korean medical centers who were treated with IFN-β for at least 6 months. Sera that had not been influenced by acute treatment were assessed for NAbs using a luciferase reporter gene assay. To evaluate the association between persistent positivity for NAbs and disease activity, NAbs were tested at 2 different time points in 75 of the 150 patients. Disease activity was defined as the presence of clinical exacerbations and/or active MRI lesions during a 1-year follow-up after NAb positivity was confirmed. RESULTS: NAbs were found in 39 of the 150 (26%) MS patients: 30 of the 85 (35%) who were treated with subcutaneous IFN-β-1b, 9 of the 60 (15%) who were treated with subcutaneous IFN-β-1a, and 0 of the 5 (0%) who were treated with intramuscular IFN-β-1a. Thirty of the 39 patients exhibiting NAb positivity were tested at different time points, and 20 of them exhibited persistent NAb positivity. Disease activity was observed more frequently in patients with persistent NAb positivity than in those with transient positivity or persistent negativity [16/20 (80%) vs. 4/55 (7%), respectively; p < 0.001]. When disease activity was compared between patients with persistent and transient NAb positivity, the difference was unchanged and remained statistically significant [16/20 (80%) vs. 2/10 (20%), p=0.004]. CONCLUSIONS: These results further support that persistent NAb positivity is associated with disease activity in MS patients treated with IFN-β.
Antibodies, Neutralizing* ; Follow-Up Studies ; Genes, Reporter ; Humans ; Interferon-beta* ; Luciferases ; Magnetic Resonance Imaging ; Multiple Sclerosis* ; Prevalence

PURPOSE: Everolimus only inhibits mammalian target of rapamycin complex 1 (mTORC1), whereas Ku0063794 inhibits both mTORC1 and mTORC2. Although they have similar anticancer effects, their combination has a synergistic effect against hepatocellular carcinoma (HCC) cells. We aimed to determine the mechanism underlying the synergistic effects of everolimus and Ku0063794 associated with autophagy in HCC cells. MATERIALS AND METHODS: We compared the effects of everolimus and Ku0063794, individually or in combination, on both the in vitro and in vivo models of HCCs. RESULTS: HepG2 cells treated with both agents had significantly lower rates of cell proliferation and higher apoptosis than the individual monotherapies (p < 0.05). Autophagic studies consistently indicated that, unlike the monotherapies, the combination therapy significantly reduced autophagy (p < 0.05). Autophagic blockage directly promoted the pro-apoptotic effects of combination therapy, suggesting autophagy as the survival mechanism of HCC cells. Unlike the monotherapies, combination therapy showed the potential to inhibit sirtuin 1 (SIRT1), the positive regulator of autophagy. SIRT1 overexpression abrogated the autophagy-inhibiting and pro-apoptotic effects of combination therapy. In a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with combination therapy than in mice treated with the respective monotherapies (p < 0.05). The immunohistochemical and immunofluorescence stains of the tumor obtained from the xenograft model showed that combination therapy had the potential of reducing autophagy and promoting apoptosis. CONCLUSION: The combination of everolimus and Ku0063794 potentiates anticancer effects on HCCs through a decrease in autophagy, which is prompted by SIRT1 downregulation.
Animals ; Apoptosis ; Autophagy* ; Carcinoma, Hepatocellular* ; Cell Proliferation ; Coloring Agents ; Down-Regulation ; Everolimus* ; Fluorescent Antibody Technique ; Hep G2 Cells ; Heterografts ; In Vitro Techniques ; Mice ; Mice, Nude ; Sirolimus ; Sirtuin 1 ; TOR Serine-Threonine Kinases

PURPOSE: As several years have passed since the implementation of the Korean diagnosis-related group (DRG) payment system for appendicitis, its early outcomes should be assessed to determine if further improvements are warranted. METHODS: We retrospectively analyzed clinical data from Korean patients who underwent appendectomy, dividing the sample into 2 groups of those who received services before and after implementation of the DRG system. Based on the DRG code classification, patient data were collected including the amount of DRG reimbursement and the total in-patient costs. We subsequently performed univariate and multivariate analyses to identify independent factors contributing to higher total in-patient cost. RESULTS: Although implementation of the DRG system for appendicitis significantly reduced postoperative length of stay (2.8 ± 1.0 days vs. 3.4 ± 1.9 days, P < 0.001), it did not reduce total in-hospital cost. The independent factors related to total inhospital cost included patient age of 70 years or more (odds ratio [OR], 3.214; 95% confidence interval [CI], 1.769-5.840; P < 0.001) and operation time longer than 100 minutes (OR, 3.690; 95% CI, 2.007-6.599, P < 0.001). In addition, older patients (≥70 years) showed a nearly 10 times greater relative risk for having a comorbid condition (95% CI, 5.141-20.214; P < 0.001) and a 3.255 times greater relative risk for having higher total in-hospital cost (95% CI, 1.731-6.119, P < 0.001). CONCLUSION: It appears that older patients (>70 years) have greater comorbidities, which contribute to higher inpatient costs. Thus, our study suggests that patient age be considered as a DRG classification variable.
Appendectomy* ; Appendicitis ; Classification ; Comorbidity ; Diagnosis-Related Groups ; Hospital Costs ; Humans ; Inpatients ; Length of Stay ; Multivariate Analysis ; Retrospective Studies

PURPOSE: To investigate the feasibility and safety of solo surgery with single-port laparoscopic appendectomy, which is termed herein solo-SPLA (solo-single-port laparoscopic appendectomy). METHODS: This study prospectively collected and retrospectively analyzed data from patients who had undergone either non-solo-SPLA (n = 150) or solo-SPLA (n = 150). Several devices were utilized for complete, skin-to-skin solo-SPSA, including a Lone Star Retractor System and an adjustable mechanical camera holder. RESULTS: Operating times were not significantly different between solo- and non-solo-SPLA (45.0 +/- 21.0 minutes vs. 46.7 +/- 26.1 minutes, P = 0.646). Most postoperative variables were also comparable between groups, including the necessity for intravenous analgesics (0.7 +/- 1.2 ampules [solo-SPLA] vs. 0.9 +/- 1.5 ampules [non-solo-SPLA], P = 0.092), time interval to gas passing (1.3 +/- 1.0 days vs. 1.4 +/- 1.0 days, P = 0.182), and the incidence of postoperative complications (4.0% vs. 8.7%, P = 0.153). Moreover, solo-SPLA effectively lowered the operating cost by reducing surgical personnel expenses. CONCLUSION: Solo-SPLA economized staff numbers and thus lowered hospital costs without lengthening of operating time. Therefore, solo-SPLA could be considered a safe and feasible alternative to non-solo-SPLA.
Analgesics ; Appendectomy* ; Hospital Costs ; Humans ; Incidence ; Postoperative Complications ; Prospective Studies ; Retrospective Studies

BACKGROUND/AIMS: The first edition of the Korean treatment guidelines for chronic myelogenous leukemia (CML) was published in 2006. We intend to update those guidelines to include the use of next-generation tyrosine kinase inhibitors (TKIs). METHODS: New guidelines were developed in 2012 based on the results of a survey and a consensus meeting of various Korean experts, the reports of recent clinical studies, and updated guidelines from external study groups. RESULTS: An assessment of risk factors is strongly recommended before treating newly diagnosed chronic phase CML. Imatinib, dasatinib, and nilotinib are reimbursable in Korea as first-line treatments, and the patient's age, comorbidities, and possible adverse events should be considered in the choice of treatment. Molecular studies are recommended for assessing treatment efficacy instead of invasive cytogenetic response evaluations, and an early response is believed to correlate with a good prognosis. Second-line TKIs can be considered for patients who fail or are intolerant of first-line therapy, pending analysis of ABL tyrosine kinase mutation status. For treating advanced stages, a combination of TKIs with cytotoxic agents and hematopoietic cell transplantation is recommended. The adverse effects of TKI therapy can be managed via dose reduction and supportive care, or switching to an alternate TKI. CONCLUSIONS: The use of TKIs has improved the outcome of CML treatment. Treatment-free remission after discontinuing TKIs might be possible in select patients who achieve sufficient response, indicating that curative treatment for CML can be expected in the future.
Cell Transplantation ; Comorbidity ; Consensus ; Cytogenetics ; Cytotoxins ; Hematology* ; Humans ; Korea ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive* ; Prognosis ; Protein-Tyrosine Kinases ; Risk Factors ; Transplants ; Treatment Outcome ; Dasatinib ; Imatinib Mesylate

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

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

Valacyclovir is an oral antiviral agent used in the treatment of herpesvirus infection. Although neuropsychiatric symptoms may accompany the use of this drug, valacyclovir is increasingly used to treat herpes zoster, as it is more effective when orally administered. This paper reports one case of neurotoxicity of valacyclovir in patients with end stage renal disease who were undergoing maintenance hemodialysis. Valacyclovir can induce life-threatening neurotoxicity, especially in end stage renal disease patients despite the appropriate dose reduction. Furthermore, Valacyclovir-induced neurotoxicity can be effectively managed by intensive hemodialysis.
Herpes Zoster ; Herpesviridae Infections ; Humans ; Kidney Failure, Chronic ; Renal Dialysis*

We assessed the success rate of empirical antifungal therapy with itraconazole and evaluated risk factors for predicting the failure of empirical antifungal therapy. A multicenter, prospective, observational study was performed in patients with hematological malignancies who had neutropenic fever and received empirical antifungal therapy with itraconazole at 22 centers. A total of 391 patients who had abnormal findings on chest imaging tests (31.0%) or a positive result of enzyme immunoassay for serum galactomannan (17.6%) showed a 56.5% overall success rate. Positive galactomannan tests before the initiation of the empirical antifungal therapy (P=0.026, hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.10-4.69) and abnormal findings on the chest imaging tests before initiation of the empirical antifungal therapy (P=0.022, HR, 2.03; 95% CI, 1.11-3.71) were significantly associated with poor outcomes for the empirical antifungal therapy. Eight patients (2.0%) had premature discontinuation of itraconazole therapy due to toxicity. It is suggested that positive galactomannan tests and abnormal findings on the chest imaging tests at the time of initiation of the empirical antifungal therapy are risk factors for predicting the failure of the empirical antifungal therapy with itraconazole. (Clinical Trial Registration on National Cancer Institute website, NCT01060462)
14-alpha Demethylase Inhibitors/adverse effects/therapeutic use ; Adolescent ; Adult ; Aged ; Antifungal Agents/adverse effects/*therapeutic use ; Aspergillosis/complications/*drug therapy ; Candidiasis/complications/*drug therapy ; Coccidioidomycosis/complications/drug therapy ; Febrile Neutropenia/complications/drug therapy ; Female ; Hematologic Neoplasms/complications/drug therapy/*microbiology ; Humans ; Itraconazole/adverse effects/*therapeutic use ; Male ; Mannans/blood ; Middle Aged ; Prospective Studies ; Treatment Outcome ; Young Adult