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Background/aims: Optimal risk stratification based on simplified geriatric assessment to predict treatment-related toxicity and survival needs to be clarified in older patients with diffuse large B-cell lymphoma (DLBCL)., Methods: This multicenter prospective cohort study enrolled newly diagnosed patients with DLBCL (≥ 65 yr) between September 2015 and April 2018. A simplified geriatric assessment was performed at baseline using Activities of Daily Living (ADL), Instrumental ADL (IADL), and Charlson's Comorbidity Index (CCI). The primary endpoint was event-free survival (EFS)., Results: The study included 249 patients, the median age was 74 years (range, 65-88), and 125 (50.2%) were female. In multivariable Cox analysis, ADL, IADL, CCI, and age were independent factors for EFS; an integrated geriatric score was derived and the patients stratified into three geriatric categories: fit (n = 162, 65.1%), intermediate-fit (n = 25, 10.0%), and frail (n = 62, 24.9%). The established geriatric model was significantly associated with EFS (fit vs. intermediate-fit, HR 2.61, p < 0.001; fit vs. frail, HR 4.61, p < 0.001) and outperformed each covariate alone or in combination. In 87 intermediate-fit or frail patients, the relative doxorubicin dose intensity (RDDI) ≥ 62.4% was significantly associated with worse EFS (HR, 2.15, 95% CI 1.30-3.53, p = 0.002). It was related with a higher incidence of grade ≥ 3 symptomatic non-hematologic toxicities (63.2% vs. 27.8%, p < 0.001) and earlier treatment discontinuation (34.5% vs. 8.0%, p < 0.001) in patients with RDDI ≥ 62.4% than in those with RDDI < 62.4%., Conclusion: This model integrating simplified geriatric assessment can risk-stratify older patients with DLBCL and identify those who are highly vulnerable to standard dose-intensity chemoimmunotherapy.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH., Methods: This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009-2020 were enrolled., Results: At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed., Conclusion: These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens., Competing Interests: Jin Seok Kim has received honoraria and consulting fees from Handok Inc. Jun Ho Jang has received research support from Alexion, AstraZeneca Rare Disease. Sung-Soo Yoon has received research funding from Chong Kun Dang Pharm, JW Pharmaceutical, Kyowa Kirin, Roche-Genentech, and Yuhan Pharmaceutical; has served on the advisory board for Amgen, Antengene, Astellas, Celgene, Janssen, Merck, Novartis, and Takeda; and has received consulting fees from Ticaros Therapeutics. BokJin Hyun, HyunSun Nam, and Eunhye Kim are employees of Handok Inc. Min Joo Kwak and Yong Kyun Won were an employee of Handok Inc. at the time of study. Jong Wook Lee has served on advisory boards and has received honoraria and research grants from Alexion, AstraZeneca Rare Disease. Deog-Yeon Jo, Seo-Yeon Ahn, Je-Hwan Lee, Sung-Hyun Kim, Chul Won Choi, Ho-Jin Shin, Min-Kyoung Kim, Jae Hoon Lee, Yeung-Chul Mun, and Jee Hyun Kong have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Background: The present study investigated an interpersonal model of development of depressive symptoms in employees, where occupational stress affects burnout, which in turn affects risk for depression, and whether this mediation is moderated by grit., Methods: A total of 11,421 participants, aged 19 to 65 years, who were employees of 18 private companies and local government organizations in Korea were included. They completed questionnaires, including the Korean version of occupational stress scale, Oldenburg Burnout Inventory, Center for Epidemiologic Studies Depression scale and Grit scale. Mediation and moderation analyses were carried out in the Statistical Package for the Social Sciences PROCESS macro., Results: The association between occupational stress and depressive symptoms was mediated by exhaustion (b = -0.256, 95 % CI [0.244, 0.268]) and disengagement (b = -0.052, 95 % CI [0.039, 0.065]). Moreover, the effect of exhaustion on depressive symptoms was moderated by each grit, with the effect being stronger for employees with low grit (b = 0.939, p < 0.001 for passion and b = 0.629, p < 0.001 for perseverance) than for those with high grit (b = 0.944, p < 0.001 for passion and b = 0.686, p < 0.001 for perseverance)., Limitations: The cross-sectional design of the study does not allow causal inferences., Conclusions: These findings contribute to the understanding of how occupational stress predicts depressive symptoms in the workplace and provide practical implications for preventing burnout and nurturing grit to protect employees' mental health in the workplace., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: We conducted a nationwide, multicenter, prospective registry study for newly diagnosed patients with peripheral T-cell lymphoma (PTCL) to better define the clinical characteristics, treatment patterns, survival outcomes, and the role of upfront autologous stem cell transplantation (ASCT) in these patients., Materials and Methods: Patients with PTCL receiving chemotherapy with curative intent were registered and prospectively monitored. All patients were pathologically diagnosed with PTCL., Results: A total of 191 patients with PTCL were enrolled in this prospective registry study. PTCL, not otherwise specified (PTCL-NOS) was the most common pathologic subtype (n=80, 41.9%), followed by angioimmunoblastic T-cell lymphoma (AITL) (n=60, 31.4%). With a median follow-up duration of 3.9 years, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 39.5% and 60.4%, respectively. The role of upfront ASCT was evaluated in patients who were considered transplant-eligible (n=59). ASCT was performed as an upfront consolidative treatment in 32 (54.2%) of these patients. There were no significant differences in PFS and OS between the ASCT and non-ASCT groups for all patients (n=59) and for patients with PTCL-NOS (n=26). However, in patients with AITL, the ASCT group was associated with significantly better PFS than the non-ASCT group, although there was no significant difference in OS., Conclusion: The current study demonstrated that the survival outcomes with the current treatment options remain poor for patients with PTCL-NOS. Upfront ASCT may provide a survival benefit for patients with AITL, but not PTCL-NOS.

Several guidelines classify autologous stem cell transplantation (ASCT) as a low to intermediate risk group for infection. In a nationwide population-based study, using the Korean Health Insurance Review and Assessment Service database, patients with lymphoma and multiple myeloma (MM) who underwent ASCT from 2002 to 2016 were retrospectively analyzed. Cumulative incidence rates (CIRs) and risk factors of opportunistic infections were investigated. CIRs of fungal, Varicella zoster virus (VZV), cytomegalovirus (CMV), and Pneumocystis jirovecii infections in lymphoma were 7.9%, 16.0%, 7.4%, and 5.1%, respectively, and CIRs in MM were 6.3%, 19.1%, 4.2%, and 5.6%, respectively. Fungal infection was significantly higher in patients with previous infection (Hazard ratio (HR) 2.003, p = 0.005) in lymphoma. Incidence of CMV infection was significantly higher in patients with prior CMV infection: HR 4.920, p < 0.001 (lymphoma); HR 3.022, p = 0.030 (MM). VZV infection was significantly lower in patients receiving prophylaxis: HR 0.082, p < 0.001 (lymphoma); HR 0.096, p < 0.001 (MM). For P. jirovecii infection, busulfex and melphalan conditioning (HR 1.875, p = 0.032) and previous P. jirovecii infection (HR 4.810, p < 0.001) had a higher incidence in MM. Patients who underwent ASCT should receive VZV prophylaxis and prophylaxis for fungal and P. jirovecii may be considered in patients with previous same infection., (© 2023. The Author(s).)

Purpose: Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy worldwide. Although substantial improvement has been achieved by the frontline rituximab-based chemoimmunotherapy, up to 40%-50% of patients will eventually have relapsed or refractory disease, whose prognosis is extremely dismal., Materials and Methods: We have carried out two prospective cohort studies that include over 1,500 DLBCL patients treated with rituximab plus CHOP (#NCT01202448 and #NCT02474550). In the current report, we describe the outcomes of refractory DLBCL patients. Patients were defined to have refractory DLBCL if they met one of the followings, not achieving at least partial response after 4 or more cycles of R-CHOP; not achieving at least partial response after 2 or more cycles of salvage therapy; progressive disease within 12 months after autologous stem cell transplantation., Results: Among 1,581 patients, a total of 260 patients met the criteria for the refractory disease after a median time to progression of 9.1 months. The objective response rate of salvage treatment was 26.4%, and the complete response rate was 9.6%. The median overall survival (OS) was 7.5 months (95% confidence interval, 6.4 to 8.6), and the 2-year survival rate was 22.1%±2.8%. The median OS for each refractory category was not significantly different (p=0.529)., Conclusion: In line with the previous studies, the outcomes of refractory DLBCL patients were extremely poor, which necessitates novel approaches for this population.

Purpose: This observational study aimed to evaluate the safety and efficacy of pegteograstim prophylaxis in patients with lymphoma and solid malignancies., Methods: This study was conducted at 18 sites in Korea between November 2015 and August 2018., Results: In total, 611 patients (female, 61.2%) with a median age of 58 (range, 18-88) years were included. Most patients had lymphomas (n = 371, 60.7%) and breast cancer (n = 230, 37.6%) and were administered R-CHOP21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone per 21 days) (n = 284, 46.5%) and AC (doxorubicin and cyclophosphamide) (n = 177, 29.0%). The total pegteograstim dose in the 611 patients was 14,970 mg (2495 doses), with each patient receiving an average daily dose of 6.0 mg. Neutropenia grade 4 occurred in 97 patients (15.9%), and febrile neutropenia (FN) occurred in 31 patients (5.1%). Among the 611 patients, 267 patients (43.7%) developed 882 adverse events (AEs), and 11 patients (1.8%) experienced 18 adverse drug reactions (ADRs). There were 62 patients (10.2%) who experienced 81 cases of serious adverse events (SAEs), with FN and pneumonia being the most frequent at 14 and 13 episodes, respectively, in 13 patients (2.1%). Meanwhile, 1 patient (0.2%) developed 2 episodes of serious ADRs (grade 1 and grade 2 hypotension). No safety concerns in the elderly and patients with liver and/or renal disease were identified., Conclusion: The prophylactic use of pegteograstim might have good overall safety and efficacy in patients with lymphomas and solid malignancies in routine clinical practice, even in those who are elderly and have liver and renal diseases., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)-a new category of anaplastic large cell lymphoma associated with textured breast implants-has a distinct variation in incidence and is especially rare in Asia. We report the first case of BIA-ALCL in Korea and present its histological and genetic characteristics. A 44-year-old female patient presented with a typical clinical course and symptoms, including breast augmentation with textured breast implants, late-onset peri-implant effusion, and CD30+ALK- histology, followed by bilateral implant removal and total capsulectomy. For histological analysis, we performed immunohistochemistry of the bilateral breast capsules. For transcriptome analysis, we identified highly upregulated gene sets employing RNA-sequencing and characterized the lymphoma immune cell components. In the lymphoma-associated capsule, CD30+ cells infiltrated not only the lymphoma lesion but also the peritumoral lesion. The morphologies of the myofibroblasts and vessels in the peritumoral lesion were similar to those in the tumoral lesion. We observed strong activation of the JAK/STAT3 pathway and expression of programmed death ligand-1 in the lymphoma. Unlike the molecular profiles of BIA-ALCL samples from Caucasian patients-all of which contained activated CD4+ T cells-the Asian patient's profile was characterized by more abundant CD8+ T cells. This study contributes to a better understanding of the pathogenesis and molecular mechanisms of BIA-ALCL in Asian patients that will ultimately facilitate the development of clinical therapies., (© 2020 The Aesthetic Society.)

Importance: There is limited information describing the full spectrum of coronavirus disease 2019 (COVID-19) and the duration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA detection in children., Objective: To analyze the full clinical course and the duration of SARS-CoV-2 RNA detectability in children confirmed with COVID-19 in the Republic of Korea, where rigorous public health interventions have been implemented., Design, Setting, and Participants: This case series of children with COVID-19 was conducted in 20 hospitals and 2 nonhospital isolation facilities across the country from February 18, 2020, to March 31, 2020. Children younger than 19 years who had COVID-19 were included., Exposures: Confirmed COVID-19, detected via SARS-CoV-2 RNA in a combined nasopharyngeal and oropharyngeal swab or sputum by real-time reverse transcription-polymerase chain reaction., Main Outcomes and Measures: Clinical manifestations during the observation period, including the time and duration of symptom occurrence. The duration of SARS-CoV-2 RNA detection was also analyzed., Results: A total of 91 children with COVID-19 were included (median [range] age, 11 [0-18] years; 53 boys [58%]). Twenty children (22%) were asymptomatic during the entire observation period. Among 71 symptomatic cases, 47 children (66%) had unrecognized symptoms before diagnosis, 18 (25%) developed symptoms after diagnosis, and only 6 (9%) were diagnosed at the time of symptom onset. Twenty-two children (24%) had lower respiratory tract infections. The mean (SD) duration of the presence of SARS-CoV-2 RNA in upper respiratory samples was 17.6 (6.7) days. Virus RNA was detected for a mean (SD) of 14.1 (7.7) days in asymptomatic individuals. There was no difference in the duration of virus RNA detection between children with upper respiratory tract infections and lower respiratory tract infections (mean [SD], 18.7 [5.8] days vs 19.9 [5.6] days; P = .54). Fourteen children (15%) were treated with lopinavir-ritonavir and/or hydroxychloroquine. All recovered, without any fatal cases., Conclusions and Relevance: In this case series study, inapparent infections in children may have been associated with silent COVID-19 transmission in the community. Heightened surveillance using laboratory screening will allow detection in children with unrecognized SARS-CoV-2 infection.

In 2016, the World Health Organization revised the diagnostic criteria for myeloproliferative neoplasms (MPNs) based on the discovery of disease-driving genetic aberrations and extensive analysis of the clinical characteristics of patients with MPNs. Recent studies have suggested that additional somatic mutations have a clinical impact on the prognosis of patients harboring these genetic abnormalities. Treatment strategies have also advanced with the introduction of JAK inhibitors, one of which has been approved for the treatment of patients with myelofibrosis and those with hydroxyurea-resistant or intolerant polycythemia vera. Recently developed drugs aim to elicit hematologic responses, as well as symptomatic and molecular responses, and the response criteria were refined accordingly. Based on these changes, we have revised the guidelines and present the diagnosis, treatment, and risk stratification of MPNs encountered in Korea.

ABSTRACT As another wave of COVID-19 outbreak has approached in July 2020, a larger scale COVID-19 pediatric Asian cohort summarizing the clinical observations is warranted. Children confirmed with COVID-19 infection from the Republic of Korea, the Hong Kong Special Administrative Region (HKSAR) and Wuhan, China, during their first waves of local outbreaks were included. Their clinical characteristics and the temporal sequences of the first waves of local paediatric outbreaks were compared. Four hundred and twenty three children with COVID-19 were analyzed. Wuhan had the earliest peak, followed by Korea and HKSAR. Compared with Korea and Wuhan, patients in HKSAR were significantly older (mean age: 12.9 vs. 10.8 vs. 6.6 years, p  < 0.001, respectively) and had more imported cases (87.5% vs. 16.5% vs. 0%, p  < 0.001, respectively). The imported cases were also older (13.4 vs. 7.6 years, p  < 0.001). More cases in HKSAR were asymptomatic compared to Korea and Wuhan (45.5% vs. 22.0% vs. 20.9%, p  < 0.001, respectively), and significantly more patients from Wuhan developed fever (40.6% vs. 29.7% vs. 21.6%, p =0.003, respectively). There were significantly less imported cases than domestic cases developing fever after adjusting for age and region of origin ( p  = 0.046). 5.4% to 10.8% of patients reported anosmia and ageusia. None developed pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PMIS-TS). In general, adolescents were more likely to be asymptomatic and less likely to develop fever, but required longer hospital stays. In conclusion, majority patients in this pediatric Asian cohort had a mild disease. None developed PIMS-TS. Their clinical characteristics were influenced by travel history and age.

Background: Hodgkin's lymphoma (HL) constitutes 10%-20% of all malignant lymphomas and has a high cure rate (5-year survival, around 90%). Recently, interest has increased concerning preventing secondary complications (secondary cancer, endocrine disorders) in long-term survivors. We aimed to study the epidemiologic features and therapeutic outcomes of HL in children, adolescents, and young adults in Korea., Methods: We performed a multicenter, retrospective study of 224 patients aged < 25 years diagnosed with HL at 22 participating institutes in Korea from January 2007 to August 2016., Results: A higher percentage of males was diagnosed at a younger age. Nodular sclerosis histopathological HL subtype was most common, followed by mixed cellularity subtype. Eighty-one (36.2%), 101 (45.1%), and 42 (18.8%) patients were classified into low, intermediate, and high-risk groups, respectively. Doxorubicin, bleomycin, vinblastine, dacarbazine was the most common protocol (n = 102, 45.5%). Event-free survival rate was 86.0% ± 2.4%, while five-year overall survival (OS) rate was 96.1% ± 1.4%: 98.7% ± 1.3%, 97.7% ± 1.6%, and 86.5% ± 5.6% in the low, intermediate, and high-risk groups, respectively ( P = 0.021). Five-year OS was worse in patients with B-symptoms, stage IV disease, high-risk, splenic involvement, extra-nodal lymphoma, and elevated lactate dehydrogenase level. In multivariate analysis, B-symptoms and extra-nodal involvement were prognostic factors for poor OS. Late complications of endocrine disorders and secondary malignancy were observed in 17 and 6 patients, respectively., Conclusion: This is the first study on the epidemiology and treatment outcomes of HL in children, adolescents, and young adults in Korea. Future prospective studies are indicated to develop therapies that minimize treatment toxicity while maximizing cure rates in children, adolescents, and young adults with HL., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

Patients with transplant-ineligible relapsed and refractory multiple myeloma (RRMM) have a short life expectancy, especially when they have failed both the proteasome inhibitor and immunomodulator therapies. This study aimed to assess the efficacy and safety of pomalidomide, cyclophosphamide, and dexamethasone (PCd) in elderly patients with RRMM. This phase 2 clinical trial recruited 55 elderly patients with RRMM. The patients underwent a 28-day treatment cycle: pomalidomide (4 mg/day on days 1-21, administered orally) and cyclophosphamide (400 mg/day on days 1, 8, and 15; administered orally) plus dexamethasone. The median (range) age of the patients was 73.3 (64-86) years, and 8 (14.5%) patients who were ≥ 80 years old. Eight (14.5%) and 31 (56.4%) patients exhibited stage III (revised international staging system) and frail status (simplified frailty scale), respectively. The overall response rate (ORR) and clinical benefit rate (CBR) of PCd therapy were 58.2% and 72.7%, respectively. The median PFS and median overall survival (OS) were 6.90 months (95% CI, 4.7-9.0) and 18.48 months (95% CI, 9.4-27.6), respectively. The incidence rate of grade ≥ 3 non-hematological toxicities was 70.8%. In particular, the incidence rate of primary infection was 45.4%, including 21.8% for pneumonia, 9.0% for sepsis, and 14.6% for febrile neutropenia. In conclusion, PCd is an effective regimen for elderly patients with RRMM who had failed both bortezomib and lenalidomide treatments, but in whom the treatment-associated infection is the main cause of morbidity and mortality., (© 2020 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Although lenalidomide plus dexamethasone (RD) is a therapeutic option for relapsed/refractory multiple myeloma (RRMM), limited real-world clinical data exist. The purpose of this study was to estimate efficacy and safety of RD in RRMM patients of the clinical practice. Data from patients at 25 university hospitals in South Korea between October 2009 and December 2016 were collected retrospectively. We report the effectiveness and safety of RD in 546 RRMM patients in routine clinical practice in South Korea. Patients (median age, 65 years) typically received median 7 cycles of RD, and 184 (33.7%) patients were treated with 10 or more cycles of RD. Patients with renal impairment (CLCr < 40 mL/min; 10.4%), comorbid conditions (≥ 2; 12.0%), and poor performance status (≥ 2; 25.1%) were included. The overall response rate was 64.2%: complete response (13.1%), very good partial response (VGPR 19.9%). With median follow-up duration of 18.6 months, median PFS and OS were 11.2 months and 25.2 months, respectively. In multivariate analysis, less than 2 comorbid conditions, normal LDH, failed one chemotherapy prior to RD, and ≥ 10 cycles of RD therapy had significantly prolonged PFS (P = 0.007, P = 0.011, P = 0.007, and P < 0.001, respectively). Adverse events were acceptable. RD is effective and safe in real-life clinical practice, including patients with comorbidities. RD is an effective and safe treatment in a real clinical setting which includes patients with comorbidities. Early and continual use of RD treatment may improve RRMM survival outcomes.

Objective: We aimed to evaluate the effect of stem cell source and dose on the survival of various donor subgroups, such as matched sibling donor (MSDs) and alternative donors (ADs), upon bone marrow (BM) or peripheral blood stem cell (PBSC) infusion in aplastic anemia (AA)., Methods: We retrospectively investigated the effects of stem cell source and dose on allogeneic hematopoietic stem cell transplantation (alloHSCT) in AA., Results: A total of 267 patients were included in this analysis. The BM-treated group showed an association with low incidence of any-grade acute graft versus host disease (GvHD) (p < 0.001). A higher stem cell dose was related with a low incidence of extensive chronic GvHD in MSDs (p = 0.025). Multivariate analysis for overall survival (OS) revealed that only age at alloHSCT <31 years (p = 0.010) and prior platelet transfusion <86 U (p = 0.046) in MSDs and higher stem cell dose (hazard ratio = 2.596, p = 0.045) in ADs were favorable prognostic factors., Conclusion: PBSCs could be preferred in AD because high stem cell dose may be easily achieved to improve the OS at the expense of acute GvHD. However, BM stem cells are preferred in MSDs., (© 2019 S. Karger AG, Basel.)

Objectives: The aim of this study was to compare the pharmacokinetic characteristics and safety of two extended-release formulations of cilostazol after multiple oral doses in healthy Korean subjects., Materials and Methods: A randomized, open-label, multiple-dose, two-period, crossover study was conducted in 30 healthy male subjects. In each treatment period, subjects received oral doses of 200 mg cilostazol SR (Pletaal SR Cap.) or cilostazol CR (Cilostan CR Tab.) once daily for 5 consecutive days, with a washout period of 9 days. Plasma concentrations of cilostazol and its metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method., Results: 24 subjects completed the study. The maximum plasma concentrations (C max,ss , geometric mean (geometric coefficient of variation, CV%)) of cilostazol after cilostazol SR and cilostazol CR regimens were 1,532.7 (43.2%) ng/mL and 548.3 (58.9%) ng/mL, respectively, and the areas under the plasma concentration-time curves within dosing intervals (AUC τ , geometric mean (CV%)) were 17,060.7 (39.2%) h×ng/mL and 7,485.7 (55.0%) h×ng/mL, respectively. The geometric mean ratios (cilostazol SR/cilostazol CR) of the C max,ss and AUC τ values were 2.7954 (90% confidence interval: 2.3561 - 3.3166) and 2.2791 (90% confidence interval: 1.9770 - 2.6273), respectively. Both cilostazol SR and cilostazol CR were well tolerated in all subjects, and no serious adverse events occurred. The total incidence of headache, which is the most common adverse drug reaction, was significantly higher with cilostazol SR (63.0%) than cilostazol CR (25.9%)., Conclusion: Cilostazol SR showed significantly higher C max and AUC τ of cilostazol than cilostazol CR after 5 days of multiple dosing of extended-release formulations of cilostazol.

Background: This retrospective study compared postoperative pain between patients undergoing open thyroidectomy (OT) and bilateral axillo-breast approach (BABA) robotic thyroidectomy (RT)., Materials and Methods: We analyzed the electronic medical records of 1269 patients who underwent OT or RT at Chung-Ang University Hospital between January 1, 2010 and April 30, 2016. On the basis of the surgical procedure performed, patients were categorized into an OT (n=1128) and a BABA RT (BRT) group (n=141). On the basis of covariates, patients in these groups were matched using propensity score matching (n=86 in each group)., Results: After propensity score matching, no intergroup differences were observed in the covariates. The visual analogue scale scores for pain on postoperative day 0 were lower in the BRT than in the OT group (2.57±0.95 vs. 2.28±0.95, P=0.040). However, no statistically significant differences were observed in the use of rescue analgesics, the numerical rating scale score for nausea, and the use of rescue antiemetics., Conclusions: Pain on postoperative day 0 was lesser in the BRT than in the OT group. Similarly, the severity of nausea was lesser in the BRT group, despite longer operation time and broad dissection performed for docking the robotic arms.

Purpose: Head and neck squamous cell carcinoma (HNSCC) is a deadly disease in which precision medicine needs to be incorporated. We aimed to implement next-generation sequencing (NGS) in determining actionable targets to guide appropriate molecular targeted therapy in HNSCC patients., Materials and Methods: Ninety-three tumors and matched blood samples underwent targeted sequencing of 244 genes using the Illumina HiSeq 2500 platform with an average depth of coverage of greater than 1,000×. Clinicopathological data from patients were obtained from 17 centers in Korea, and were analyzed in correlation with NGS data., Results: Ninety-two of the 93 tumors were amenable to data analysis. TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n=23, 25%), CCND1 (n=22, 24%), and PIK3CA (n=19, 21%). The total mutational burden was similar between human papillomavirus (HPV)-negative vs. positive tumors, although TP53, CDKN2A and CCND1 gene alterations occurred more frequently in HPV-negative tumors. HPV-positive tumors were significantly associated with immune signature-related genes compared to HPV-negative tumors. Mutations of NOTCH1 (p=0.027), CDKN2A (p < 0.001), and TP53 (p=0.038) were significantly associated with poorer overall survival. FAT1 mutations were highly enriched in cisplatin responders, and potentially targetable alterations such as PIK3CA E545K and CDKN2A R58X were noted in 14 patients (15%)., Conclusion: We found several targetable genetic alterations, and our findings suggest that implementation of precision medicine in HNSCC is feasible. The predictive value of each targetable alteration should be assessed in a future umbrella trial using matched molecular targeted agents.

Background: There has been a campaign by the National Education on Sleeping Habits and Living Environment, to reduce the incidence of sudden infant death syndrome (SIDS). However, more than 100 infants die suddenly and unexplainably before the age of 1 year in Korea. Long QT syndrome (LQTS), an inheritable cardiac disease, has been reported to likely be associated with up to 14% of SIDS cases. However, genetic studies of the association between SIDS and LQTS have not yet been conducted in Korea., Methods: We conducted genetic analysis using genomic DNA extracted from paraffin-embedded tissue blocks from 200 SIDS cases autopsied between 2005 and 2013. We analyzed the following genetic mutations associated with LQTS, KCNQ1 , SCN5A , KCNE1 , KCNE2 , KCNJ2 , and CAV3 ., Results: Of the 200 SIDS cases, 58% involved male infants (116 male and 84 female infants, respectively), the mean age was 140 days (median, 107 days; range, 24-270 days), and they were all of Asian-Korean ethnicity. SIDS IA category criteria comprised 45 cases (22.5%) while the rest were SIDS IB. Fifteen infants (7.5%) had R1193Q in SCN5A , of doubtful pathogenicity, and no pathogenic LQTS variants were observed., Conclusion: This genetic investigation of LQTS in SIDS showed a low diagnostic yield. These findings suggest that LQTS molecular autopsy could be cautiously conducted in selected cases with family involvement to improve the available genetic counseling information. Meanwhile, a national SIDS registry should be established to document and evaluate the genetic risk of SIDS in Korea., Competing Interests: Disclosure: The authors have no potential conflicts of interest to disclose.

Although nilotinib has improved efficacy compared to imatinib, suboptimal response and intolerable adverse events (AEs) limit its effectiveness in many patients with chronic myeloid leukemia in chronic phase (CML-CP). We investigated the 2-year efficacy and safety of nilotinib and their relationships with plasma nilotinib concentrations (PNCs). In this open-label, multi-institutional phase 4 study, 110 Philadelphia chromosome-positive CML-CP patients were treated with nilotinib at a starting dose of 300 mg twice daily. Molecular responses (MRs) and AEs were monitored for up to 24 months. The 24-month cumulative MR 4.5 rate was evaluated as the primary endpoint. Plasma samples were collected from 94 patients to determine PNCs, and the per-patient mean was used to categorize them into four mean PNC (MPNC) groups. Cumulative MR rates and safety were compared between groups. With a median follow-up of 22.2 months, the 24-month cumulative MR 4.5 rate was 56.2% (95% confidence interval, 44.0%-8.3%), and the median time to MR 4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR 4 , and MR 4.5 between MPNC groups. One patient died due to acute viral hepatitis, and two developed hematological or cytogenetic relapse, while no progression to accelerated or blast phase was observed. Safety results were consistent with previous studies with no new safety signal identified. Across the MPNC groups, there was no significant linear trend in the frequency of AEs. Nilotinib is highly effective for the treatment of CML-CP with manageable AEs. The measurement of PNC has no predictive value for patient outcomes and is thus not found to be clinically useful. This study is registered with clinicaltrials.gov, Number NCT03332511., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Bortezomib-melphalan-prednisone (VMP) showed superior efficacy versus MP as first-line treatment for transplantation-ineligible multiple myeloma (MM). This study investigated the efficacy of VMP for Korean patients with MM.Overall, 177 MM patients received 9 cycles of VMP in this prospective, multicenter, observational study. The primary endpoint was 2-year progression-free survival (PFS).Thirty-nine (22%) patients were aged ≥ 75 years and 83 (47.4%) patients had International Staging System stage III. A median of 5 cycles were delivered. Overall response rate (ORR) was 72.9%, and complete response (CR) rate was 20.3%. With a median follow-up of 11.9 months, median PFS was 17 months. The 2-year PFS and overall survival (OS) rates were 29.2% and 80.0%, respectively. Median OS was not reached. PFS was significantly different depending on performance status (Eastern Cooperative Oncology Group < 2 vs. ≥ 2; p = 0.0002), β2-microglobulin level (< 5.5 vs. ≥ 5.5 mg/L; p = 0.0481), and cumulative dose of bortezomib (< 35.1 vs. ≥ 35.1 mg/m2; p < 0001). The common adverse events (AEs) were in line with the well-known toxicity profiles associated with VMP.In conclusion, VMP is a feasible and effective front-line treatment for transplant-ineligible older patients with MM in Korea. Continuing therapy with prompt adjustment of treatment according to AEs may be important to improve outcomes of elderly patients.

Background: The objective of this study was to evaluate the efficacy and safety of dovitinib in patients with adenoid cystic carcinoma (ACC)., Methods: ACC patients with documented disease progression within the past 12 months were eligible. Patients received oral dovitinib (500 mg once daily for 5 consecutive days followed by a 2-day rest every week) until disease progression or unacceptable toxicities. The primary endpoint was the probability of 4-month progression-free survival (PFS). Metabolic response was evaluated with positron emission tomography (PET)/computed tomography (CT) scans performed at the baseline and after 8 weeks of treatment., Results: Between September 2011 and April 2013, 32 patients with metastatic and/or unresectable ACC were enrolled in this prospective, multicenter trial. The 4-month PFS probability was 80.4%, and the median PFS was 6.0 months (95% confidence interval, 4.4-7.6 months). Tumor shrinkage was observed in 22 patients (68.8%), and 1 patient had a confirmed partial response. The disease control rate was 96.9%. Among 26 patients with PET/CT scans both before and after treatment (at 8 weeks), the metabolic activity of ACC was reduced in 13 patients (50.0%), and 5 patients (19.2%) achieved a metabolic partial response, which was defined as a ≥25% reduction in maximum standardized uptake values. Common grade 3 and 4 adverse events were asthenia (50.0%) and neutropenia (25.0%)., Conclusions: Dovitinib shows modest antitumor activity in the treatment of ACC., (© 2015 American Cancer Society.)

The Korean National Residue Programme comprises three different approaches for evaluating domestic and imported foods of animal origin: monitoring, surveillance/enforcement and an exploratory test programme. Monitoring and surveillance/enforcement testing programmes are routinely implemented by 17 Provincial Veterinary Services for domestic products and regional offices of the Animal and Plant Quarantine Agency (QIA) for imported products. The exploratory project conducted at QIA headquarters is designed to test substances that are not included in monitoring and enforcement testing programmes. Here, we carried out exploratory testing for determining the presence of 42 veterinary drugs that have no established Korean maximum residue limits and analysed their levels simultaneously, in a total of 3108 samples of domestic and imported animal-origin foods. Of the tested drugs, acetylsalicylic, paracetamol, clopidol, diclazuril, amprolium, toltrazuril and its metabolites (toltrazuril sulphone and toltrazuril sulphoxide) and phenylbutazone and its metabolites (oxyphenylbutazone) were detected.

Background: Coronary artery calcium score (CACS) is a well-recognized marker for subclinical coronary atherosclerosis, particularly in asymptomatic populations. To date, however, the added prognostic benefit of CACS compared with traditional risk factors in an Asian population remains unknown. This study therefore investigated the benefit of CACS over traditional risk factors for all-cause mortality in a large multicenter registry of asymptomatic Korean adults., Methods and results: A total of 34,386 individuals were retrospectively enrolled to participate in a general health examination. The Framingham 10-year risk score (FRS) was calculated according to the traditional risk stratification algorithm and CACS was calculated in log(CACS+1) for continuous data and categorized as 0, 1-100, 101-400 and >400. During a median follow-up of 4.9 years (IQR, 3.0-7.1), there were 303 all-cause deaths (0.9%). Following adjustment, CACS was independently associated with all-cause death (hazard ratio, 1.10; 95% confidence interval (CI): 1.05-1.17; P<0.001). Notably, CACS added further prognostic value above and beyond FRS (likelihood ratio, χ(2)=75.42, P<0.001; continuous net reclassification improvement=0.40, 95% CI: 0.29-0.51, P≤0.001; improving C-statistic from 0.64, 95% CI: 0.61-0.67 to 0.68, 95% CI: 0.64-0.71; ∆C=0.04, 95% CI: 0.01-0.06, P=0.002)., Conclusions: In an asymptomatic Korean population, CACS improved prediction of all-cause mortality over and above that of a conventional risk tool.

Fibronectin (FN), a large heterodimeric glycoprotein, can be found in soluble form in plasma or in insoluble form as an extracellular matrix protein. Cellular FN is produced by various types of benign and malignant epithelial and mesenchymal cells and is widely distributed in malignant tumors. We evaluated FN expression in cancer cells (epithelial FN; E-FN) and intratumor stroma (stromal FN, S-FN) of 1596 invasive breast cancer samples using immunohistochemistry on tissue microarrays. Correlations of FN expression with clinicopathologic factors and patient survival were investigated. Among 1512 informative cases, E-FN expression was observed in 355 (23.5%) cases, and S-FN expression showed no/weak staining in 362 (23.9%), moderate staining in 744 (49.2%), and strong staining in 406 (26.9%) cases. E-FN expression was correlated with advanced pT (P < .001) and pN (P < .001), histologic type (P = .006), high histologic grade (P < .001), lymphovascular invasion (P < .001), hormone receptor negativity (P < .001), and human epidermal growth factor receptor-2 (HER2) positivity (P < .001). Strong S-FN expression showed an association with advanced pN (P = .002), histologic type (P < .001), high histologic grade (P < .001), lymphovascular invasion (P < .001), and HER2 positivity (P < .001). Patients with E-FN expression showed worse overall survival (P < .001) and disease-free survival (P < .001) than did those with negative expression of FN. E-FN expression was an independent prognostic factor, especially in the hormone receptor-positive group. Expression of S-FN did not have a significant effect on patient survival. In conclusion, E-FN expression could be a promising prognostic marker in patients with invasive breast cancer., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background/aims: Hepatitis B virus (HBV) is the major cause of chronic liver disease in Korea, but viral prevalence has decreased because of hepatitis B vaccination programs. In this study, we investigated longitudinal changes in HBV in fection in the general Korean population., Methods: HBV surface antigen (hepatitis B surface antigen, HBsAg) seropositivity was assessed from the Korea National Health and Nutrition Examination Survey (I to V). In total, 50,140 subjects were tested for serum HBsAg positivity over a period of 12 years (1998 to 2010)., Results: The prevalence of HBsAg seropositivity decreased over the study period. The rates of HBsAg carriers were 4.61% in 1998, 4.60% in 2001, 3.69% in 2005, 3.01% in 2008, and 2.98% in 2010 (p < 0.0001). The reduction in HBV infection rates was more prominent in younger age groups. Among teenagers (10 to 19 years), the percentage of HBsAg carriers decreased from 2.2% in 1998 to 0.12% in 2010 (p < 0.0001). Among those aged 10 to 39 years, the percentage of HBV infection decreased from 4.72% in 1998 to 2.29% in 2010 (p < 0.0001). However, no decreasing trend in HBsAg positivity was observed among those aged 50 or older (p > 0.05). Neither gender nor socioeconomic status were associated with the decreased prevalence of HBsAg carriers., Conclusions: HBV infection has decreased in the Korean population since the advent of vaccination programs. However, the decrease is limited to the younger population, and viral persistence remains in the middle-aged and older population.

This study was conducted to evaluate the promoting effect of Ishige sinicola, an alga native to Jeju Island, Korea, on hair growth. When vibrissa follicles were cultured in the presence of I. sinicola extract for 21 days, I. sinicola extract increased hair-fiber length. After topical application of I. sinicola extract onto the back of C57BL/6 mice, anagen progression of the hair shaft was induced. The I. sinicola extract significantly inhibited the activity of 5α-reductase. Treatment of immortalized vibrissa dermal papilla cells (DPCs) with I. sinicola extract resulted in increase of cell proliferation, which was accompanied by the increase of phospho-GSK3β level, β-catenin, Cyclin E and CDK2, whereas p27kip1 was down-regulated. In particular, octaphlorethol A, an isolated component from the I. sinicola extract, inhibited the activity of 5α-reductase and increased the proliferation of DPCs. These results suggest that I. sinicola extract and octaphlorethol A, a principal of I. sinicola, have the potential to treat alopecia via the proliferation of DPCs followed by the activation of β-catenin pathway, and the 5α-reductase inhibition.

Objective: To evaluate the effectiveness of OROS® hydromorphone in reducing breakthrough pain (BTP) medication frequency in Korean patients with chronic cancer pain., Settings and Design: Multicenter, prospective, open-label, phase IV study., Participants: Patients with chronic malignant pain using immediate-release oxycodone more than two times per day for BTP., Interventions: Patients were stabilized on their ongoing drug for 3 days immediately before baseline measurements (day 0). Medication was changed to OROS® hydromorphone at a dose equianalgesic to oxycodone using a 2.5:1 controlled-release oxycodone to hydromorphone hydrochloride conversion ratio; the patients were observed for 7 days. Dose was titrated, if required, and the patients were observed for another 7 days. Effectiveness and safety parameters were measured at baseline, day 7, and day 14., Main Outcomes: BTP medication frequency on days 7 and 14, compared to baseline., Results: Of the 141 patients screened, 114 received study drug and 98 completed the study. Compared to day 0, daily BTP medication frequency on day 14 decreased from 2.93 to 2.00 (p > 0.0001), daily BTP frequency decreased from 3.67 to 2.44 (p > 0.0001), and end-of-dose pain frequency decreased by 44 percent. Pain was controlled adequately during daytime and night-time. Pain intensity decreased by 11 percent as assessed using the Korean Brief Pain Inventory and by 17 percent as assessed using the numerical rating scale. About 61.2 percent patients and 60.2 percent physicians were satisfied with the treatment. Common adverse events, which occurred in 91.2 percent patients, were constipation, somnolence, and dizziness., Conclusion: Once-daily OROS® hydromorphone is efficient in the reduction of cancer pain-related BTP episodes, including end-of-dose pain.

Ethnic and regional differences in the epidemiology and pathological aspects of Hodgkin's lymphoma (HL) between Western and Asian patients may be associated with differences in clinical features and prognosis. We retrospectively analyzed the clinical and histopathological characteristics, therapeutic outcomes, and prognostic factors of 539 HL patients treated at 16 centers in Korea. We found that the incidence of histological subtypes of HL in Korea was similar to that in Western and other Asian countries. However, the incidence peaked between 16 and 30 years of age, unlike the bimodal age distribution seen in Western countries. In patients with stage I-IIA non-bulky disease, the complete response (CR) rate was similar between combined modality therapy and chemotherapy alone (93% vs. 84%, P = 0.44), and there was no difference in relapse-free survival (RFS) and overall survival (OS). Patients with stage I-II disease plus unfavorable factors and those with advanced-stage disease treated with combination chemotherapy regimens had an overall CR rate of 77%, with no difference between doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and non-ABVD regimens (77.2% vs. 76.8%, P = 0.95). Among those patients who achieved final CR, there was no significant difference in RFS or OS between those who achieved interim CR and PR. Only the presence of B symptoms was independently predictive of a shorter RFS. Age > 45 years, Eastern Cooperative Oncology Group 2-4, and B symptoms were independent risk factors for death. Although the incidence of HL was lower in Korea than in Western countries, the distribution of morphological subtypes, treatment outcomes, and patient prognosis were similar.

Over its long survival duration, marginal zone B-cell lymphoma (MZL) routinely involves frequent relapses. In this study, we conducted a retrospective analysis to identify the clinical features and outcomes of relapsed or refractory MZL. From 1995 to 2008, a total of 92 patients with relapsed MZL were retrospectively analyzed. The median age of our subjects was 53.5 years (range: 23-82 years). The most common primary sites of involvement were the orbit and ocular adnexa (28.3%) followed by the lymph node and lymphatic organs (23.9%), and multiple mucosa-associated lymphoid tissue (MALT) sites (13.0%). The median time to relapse from initial diagnosis was 25.5 months. Of the 53 patients with Stage I or II at diagnosis, 42 patients (79.2%) evidenced locoregional recurrence. Among these locoregional relapsed patients, 27 patients achieved CR (54.1%) or PR (18.9%). In addition to the 39 patients initially in advanced Stage III or IV, a total of 50 patients were in advanced stage at relapse. Among those patients with advanced stage at relapse, 44 patients were treated. The overall response rate was 54.5% (24 patients), with 18 CRs and 6 PRs. The median time to progression (TTP) was 34.1 months (95% CI: 11.3-56.9 months) and the estimated 5-year overall survival (OS) was 84.3%. The majority of them was controlled well with salvage treatment, and could achieve prolonged survival. However, patients' refractory to initial therapy and advanced relapse evidenced shorter TTP and OS. Thus, we need to consider more aggressive treatment in cases of refractory MZL or advanced relapsed MZL., ((c) 2009 Wiley-Liss, Inc.)

Aim: The Korean Multiple Myeloma Working Party performed a nationwide registration of multiple myeloma patients via a web-based data bank system., Methods: We retrospectively analyzed registered data from 3,209 patients since 1999., Results: The median overall survival (OS) was 50.13 months (95% confidence interval: 46.20-54.06 months). Patients < or =40 years demonstrated a longer OS than patients >65 years of age (median OS 71.13 vs. 36.73 months, p < 0.001). Patients who received novel agents at any time during their treatments showed a longer OS than patients who did not (median OS 42.23 vs. 55.50 months, p < 0.001). Response to treatment was associated with OS, with tandem autologous stem cell transplantation (SCT) producing longer OS than single autologous SCT., Conclusions: We demonstrated associations between survival outcomes and treatment modalities as well as baseline disease characteristics in a registry of multiple myeloma patients using a web-based data analysis., (Copyright 2009 S. Karger AG, Basel.)