Publications by authors named "Jin Seok Kim"

369 Publications

Updated recommendations for the treatment of venous thromboembolism.

Blood Res 2021 Feb 23. Epub 2021 Feb 23.

Division of Hematology-Oncology, Department of Internal Medicine, CHA University School of Medicine, Seongnam, Korea.

Venous thromboembolism (VTE), which includes pulmonary embolism and deep vein thrombosis, is a condition characterized by abnormal blood clot formation in the pulmonary arteries and the deep venous vasculature. It is often serious and sometimes even fatal if not promptly and appropriately treated. Moreover, the later consequences of VTE may result in reduced quality of life. The treatment of VTE depends on various factors, including the type, cause, and patient comorbidities. Furthermore, bleeding may occur as a side effect of VTE treatment. Thus, it is necessary to carefully weigh the benefits versus the risks of VTE treatment and to actively monitor patients undergoing treatment. Asian populations are known to have lower VTE incidences than Western populations, but recent studies have shown an increase in the incidence of VTE in Asia. A variety of treatment options are currently available owing to the introduction of direct oral anticoagulants. The current VTE treatment recommendation is based on evidence from previous studies, but it should be applied with careful consideration of the racial, genetic, and social characteristics in the Korean population.
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http://dx.doi.org/10.5045/br.2021.2020083DOI Listing
February 2021

Adaptive natural killer cells facilitate effector functions of daratumumab in multiple myeloma.

Clin Cancer Res 2021 Feb 18. Epub 2021 Feb 18.

Department of Internal Medicine, Yonsei University College of Medicine

Purpose: To investigate the different roles of heterogeneous natural killer (NK) cell subpopulations in multiple myeloma (MM) and to identify NK cell subsets that support the robust anti-myeloma activity of daratumumab via antibody-dependent cellular cytotoxicity (ADCC).

Experimental Design: We performed single-cell RNA sequencing of NK cells from newly diagnosed MM (NDMM) patients and delineated adaptive NK cells in their bone marrow (BM). We further characterized the distinct immunophenotypic features and functions of adaptive NK cells by multicolor flow cytometry in 157 NDMM patients.

Results: Adaptive NK cells exhibit a significantly lower level of CD38 expression compared with conventional NK cells, suggesting that they may evade daratumumab-induced fratricide. Moreover, adaptive NK cells exert robust daratumumab-mediated effector functions , including cytokine production and degranulation, compared with conventional NK cells. The composition of adaptive NK cells in BM determines the daratumumab-mediated functional activity of BM NK cells in NDMM patients. Unlike conventional NK cells, sorted adaptive NK cells from the BM of NDMM patients exert substantial cytotoxic activity against myeloma cells in the presence of daratumumab.

Conclusions: Our findings indicate that adaptive NK cells are an important mediator of ADCC in MM and support direct future efforts to better predict and improve the treatment outcome of daratumumab by selectively employing adaptive NK cells.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3418DOI Listing
February 2021

Daratumumab monotherapy for patients with relapsed or refractory natural killer/T-cell lymphoma, nasal type: an open-label, single-arm, multicenter, phase 2 study.

J Hematol Oncol 2021 Feb 15;14(1):25. Epub 2021 Feb 15.

Division of Hematology/Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, 81 Irwon-ro, Irwon-dong, Gangnam-gu, Seoul, 06351, South Korea.

Background: Natural killer/T-cell lymphoma (NKTCL) is a disease with limited treatment options and poor outcomes. Daratumumab monotherapy demonstrated clinical activity in a single-patient case report. We present data from the primary analysis of a phase 2 study of daratumumab monotherapy in relapsed or refractory (R/R) NKTCL.

Methods: This phase 2 study with Simon's two-stage design evaluated daratumumab in patients with histologically confirmed extranodal NKTCL, nasal type, per WHO classification that was refractory to or relapsed after ≥ 1 line of chemotherapy, who were not candidates for other treatment modalities. All patients received daratumumab 16 mg/kg intravenously once weekly for Cycles 1 and 2, every other week for Cycles 3 through 6, and every 4 weeks thereafter until progression or unacceptable toxicity; all cycles were 28 days. The primary end point was objective response rate (ORR) based on blinded independent central review per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification).

Results: In total, 32 Asian patients received daratumumab. The ORR was 25.0% (95% confidence interval [CI] 11.5-43.4); all 8 responders had a partial response; and the median duration of response was 55.0 days (95% CI 29-339). At 10.2 months of median follow-up, median progression-free survival (PFS) was 53.0 days (95% CI 43-106); the 4-month PFS rate was 13.0%. Median overall survival (OS) was 141.0 days (95% CI 94-438); the 6-month OS rate was 42.9%. Nineteen (59.4%) patients had grade 3/4 treatment-emergent adverse events (TEAEs); the most common was thrombocytopenia (25.0%; n = 8). TEAEs leading to death occurred in 4 patients (death, respiratory failure, septic shock, and pneumonia); all were unrelated to daratumumab.

Conclusions: In patients with R/R NKTCL, daratumumab monotherapy was well tolerated with no new safety concerns and achieved an ORR of 25.0%. However, no patients achieved complete response, and duration of response was short. Trial registration ClinicalTrials.gov, NCT02927925. Registered 7 October 2016.
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http://dx.doi.org/10.1186/s13045-020-01020-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885403PMC
February 2021

Impact of depression on adherence to lenalidomide plus low-dose dexamethasone in patients with relapsed or refractory myeloma.

Support Care Cancer 2021 Feb 11. Epub 2021 Feb 11.

Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, South Korea.

Purpose: While continued lenalidomide and low-dose dexamethasone (Rd) treatment could improve survival outcomes for multiple myeloma (MM), the association of depression on the adherence to Rd regimen in myeloma patients has never been studied even though depression is a common symptom among MM patients. This study aims to evaluate the impact of depression prior to Rd treatment on adherence to the treatment among patients with MM.

Methods: This multicenter cohort study was conducted from January 2015 to October 2018 at five tertiary hospitals in Korea. Patients who completed fewer than 4 cycles, 4-11 cycles, and more than 12 cycles were categorized as the poor adherence group (PAG), moderate adherence group (MAG), and good adherence group (GAG), respectively.

Results: Among141 patients, 41.8% of them had depression before beginning Rd treatment and 46% of participants were in the GAG. Compared with patients in the GAG (30.3%), patients in the PAG were more likely to have depression at baseline (90.0%) and had the higher distress scores (6.35 vs. 4.28, P < 0.01). Presence of depression prior to Rd treatment was significantly associated with poor adherence (IRR = 6.67, 95% CI = 1.45, 30.61) after adjusting for age, sex, education, ECOG, ISS stage, number of previous treatments, and disease status prior to Rd treatment.

Conclusions: Patients with depression had a substantially high risk of poor adherence compared to patients without depression. Given that Rd treatment is mainly offered by outpatient clinics, active interventions to reduce depression should be considered for MM patients prior to Rd treatment.
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http://dx.doi.org/10.1007/s00520-021-06017-yDOI Listing
February 2021

A novel predictive model for late recurrence after catheter ablation for atrial fibrillation using left appendage volume measured by cardiac computed tomography.

Int J Cardiovasc Imaging 2021 Feb 10. Epub 2021 Feb 10.

Division of Cardiology, Department of Internal Medicine, Korea University College of Medicine, Korea University Medical Center, Seoul, Republic of Korea.

Larger left atrial appendage (LAA) volume is associated with a higher risk of late recurrence (LR) in patients undergoing radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF). However, it is unclear whether LAA volume predicts LR, independent of established risk factors. We sought to evaluate the value of LAA volume in predicting LR after RFCA for AF and to develop a score prediction model including LAA volume for these patients. We retrospectively studied 992 patients who underwent RFCA for AF and cardiac computed tomography before RFCA at a single center. At 3 years after RFCA, 362 patients (36.5 %) experienced recurrence. The multivariate Cox regression model showed that age ≥ 75 years (10 points), non-paroxysmal AF (9 points), diabetes mellitus (4 points), left atrial volume index (1 point per 10 ml/m rounded to the nearest integer), and the second (4.7 to < 7 ml/m; 4 points) and third (≥ 7 ml/m; 5 points) tertiles of the LAA volume index were independent risk factors LR. The above-mentioned risk factors were included in the integrated score model, and the C-index of the proposed score model was 0.715 (95 % confidence interval [CI] 0.679-0.752). LAA volume is an independent predictor of LR and the predictive model including LAA volume showed good discrimination power. These findings provide evidence for the inclusion of LAA volume in the risk stratification for AF recurrence in patients undergoing RFCA for AF.
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http://dx.doi.org/10.1007/s10554-021-02169-4DOI Listing
February 2021

Safety, Pharmacokinetics and Pharmacodynamics of a Next-Generation Subcutaneously Administered Coagulation Factor IX Variant, Dalcinonacog Alfa, in Previously Treated Hemophilia B Patients.

J Thromb Haemost 2021 Feb 4. Epub 2021 Feb 4.

Catalyst Biosciences, South San Francisco, CA, USA.

Background: Dalcinonacog alfa (DalcA), a next-generation, recombinant human factor IX (FIX) variant was developed using a rational design approach for increased procoagulant activity and longer duration of action to be administered subcutaneously (SQ) for prophylaxis of hemophilia B bleeding episodes.

Objectives: To investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of DalcA.

Methods: This multicenter, Phase1/2a study (NCT03186677) was conducted in 11 males aged 12-65 years with severe hemophilia B. In cohort 1, subjects received intravenous (IV) 75 IU/kg BeneFIX® and DalcA. Cohorts 2 and 3 had DalcA IV 75 IU/kg and SQ 75 IU/kg or 150 IU/kg. Cohort 4 was omitted. Cohort 5 received daily SQ 150 IU/kg DalcA for 6 days and Cohort 6 received IV 75 IU/kg and daily SQ 150 IU/kg DalcA for 9 days. Blood sampling was performed for chemistry, hematology, PK, PD and anti-drug antibody (ADA) measurement. Subjects were monitored for safety endpoints for 30 days post-dosing.

Results: DalcA demonstrated a 24-fold greater potency over BeneFIX® and longer mean residence time (33.8 hours). SQ bioavailability 8.2-20.3%, beta half-life 53.9-106.9 hours and T 24-48 hours. A median 15.7% FIX activity level [IQR 14.9-16.6%] was reached after 6 daily doses. Neutralizing antibodies to ISU304, but not wt-FIX, occurred in 2 cousins.

Conclusions: The data demonstrated that DalcA achieved protective FIX activity levels between 11-18%, corresponding to a reduced chance of spontaneous bleeds. Based on the results, a Phase 2b trial to assess the safety and efficacy of 28 daily SQ doses of DalcA was performed.
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http://dx.doi.org/10.1111/jth.15259DOI Listing
February 2021

Early Recurrence Is Reliable Predictor of Late Recurrence After Radiofrequency Catheter Ablation of Atrial Fibrillation.

JACC Clin Electrophysiol 2021 Jan 20. Epub 2021 Jan 20.

Division of Cardiology, Korea University College of Medicine and Korea University Medicine Anam Hospital, Seoul, Republic of Korea.

Objectives: This study aimed to compare the risk of late recurrence in patients with and without early recurrence.

Background: Early recurrence of atrial fibrillation (AF) or atrial tachycardia (AT) after radiofrequency catheter ablation (RFCA) in AF patients is known to be a transient phenomenon. The theoretical basis of the blanking period is based on such observations. However, the clinical implications of early recurrence need further validation.

Methods: Consecutive RFCA cases in a tertiary hospital were analyzed. Early recurrence was defined as any AT or AF event occurring within 90-days post-RFCA. Early recurrence as AT and AF were also analyzed separately.

Results: A total of 3,120 patients underwent RFCA. Early recurrence occurred in 751 patients (24.1%). Patients who experienced early recurrence had a larger left atrium, worse hemodynamics in the left atrial appendage, and a higher prevalence of nonparoxysmal AF and heart failure. Among patients who experienced early recurrence, 69.6% of patients eventually had late recurrence. Early recurrence was associated with a 4.3- and 3.6-fold increase in the risk of late recurrence after single and multiple procedures, respectively. After multivariate adjustment, early recurrence was an independent risk factor for late recurrence with 3.6- and 2.8-fold increase in the risk of late recurrence after single and multiple procedures, respectively. Early recurrence AT had a lower risk of late recurrence compared with early recurrence AF.

Conclusions: Early recurrence was a reliable predictor for late recurrence. The clinical significance of the blanking period in the current guidelines may need to be revisited.
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http://dx.doi.org/10.1016/j.jacep.2020.09.029DOI Listing
January 2021

Association of pericardial adipose tissue with left ventricular structure and function: a region-specific effect?

Cardiovasc Diabetol 2021 Jan 25;20(1):26. Epub 2021 Jan 25.

Division of Cardiology, Korea University Ansan Hospital, 123, Jeokgeum-ro, Danwon-gu, Gyeonggi-do, 15355, Ansan, South Korea.

Background: The independent role of pericardial adipose tissue (PAT) as an ectopic fat associated with cardiovascular disease (CVD) remains controversial. This study aimed to determine whether PAT is associated with left ventricular (LV) structure and function independent of other markers of general obesity.

Methods: We studied 2471 participants (50.9 % women) without known CVD from the Korean Genome Epidemiology Study, who underwent 2D-echocardiography with tissue Doppler imaging (TDI) and computed tomography measurement for PAT.

Results: Study participants with more PAT were more likely to be men and had higher cardiometabolic indices, including blood pressure, glucose, and cholesterol levels (all P < 0.001). Greater pericardial fat levels across quartiles of PAT were associated with increased LV mass index and left atrial volume index (all P < 0.001) and decreased systolic (P = 0.015) and early diastolic (P < 0.001) TDI velocities, except for LV ejection fraction. These associations remained after a multivariable-adjusted model for traditional CV risk factors and persisted even after additional adjustment for general adiposity measures, such as waist circumference and body mass index. PAT was also the only obesity index independently associated with systolic TDI velocity (P < 0.001).

Conclusions: PAT was associated with subclinical LV structural and functional deterioration, and these associations were independent of and stronger than with general and abdominal obesity measures.
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http://dx.doi.org/10.1186/s12933-021-01219-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836147PMC
January 2021

Carfilzomib in addition to lenalidomide and dexamethasone in Asian patients with RRMM outside of a clinical trial.

Ann Hematol 2021 Jan 15. Epub 2021 Jan 15.

Department of Hematology, Seoul St. Mary's Hematology Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.

Carfilzomib, lenalidomide, and dexamethasone (KRd) effectively improve survival in patients with relapsed and refractory multiple myeloma (RRMM). However, the outcome of KRd treatment in Asian patients reflecting a general RRMM population outside of a clinical trial has not been reported. Fifty-five RRMM patients who were treated with carfilzomib in combination with Rd from the time of the first approval of KRd in the Republic of Korea were analyzed. The median age was 61 years. The percentage of patients with an ECOG performance status ≥ 3, creatinine clearance < 50 mL/min, high-risk cytogenetics, and ≥ 4 lines of prior treatment were 9%, 22%, 31%, and 27%, respectively. Forty-one patients started treatment with KRd, whereas the remaining 14 patients (25%) were added carfilzomib during the Rd treatment. In the whole cohort, the overall response rate was 73% and progression-free survival was 8.8 months. The addition of carfilzomib in patients who were refractory or had disease progression during Rd treatment reattained a response in half of the patients. The advantage of carfilzomib with Rd was significant in patients in the first relapse. Toxicity profile was acceptable, excluding severe infections. Carfilzomib in combination with Rd is effective and has a reasonable adverse event rate in Asian patients with RRMM.
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http://dx.doi.org/10.1007/s00277-021-04407-0DOI Listing
January 2021

Evaluation of the Physicochemical Properties, Pharmacokinetics, and In Vitro Anticancer Effects of Docetaxel and Osthol Encapsulated in Methoxy Poly(ethylene glycol)--Poly(caprolactone) Polymeric Micelles.

Int J Mol Sci 2020 Dec 28;22(1). Epub 2020 Dec 28.

College of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju 28160, Korea.

Docetaxel (DTX), a taxane-based anticancer drug, and osthol (OTH), a coumarin-derivative compound, have shown anticancer effects against different types of cancers through various mechanisms. However, these drugs have low solubility in water and low oral bioavailability, and thus their clinical application is difficult. To overcome these problems, we encapsulated DTX and OTH in methoxy poly(ethylene glycol)--poly(caprolactone) (mPEG--PCL) and conducted studies in vitro and in vivo. We selected a 1:4 ratio as the optimal ratio of DTX and OTH, through combination index analysis in A549 cancer cells, and prepared micelles to evaluate the encapsulation efficiency, drug loading, particle size, and zeta potential. The in vitro drug-release profile showed that DTX/OTH-loaded mPEG--PCL micelles could slowly release DTX and OTH. In the clonogenic assay, DTX/OTH-loaded mPEG--PCL micelles showed 3.7 times higher inhibitory effect than the DTX/OTH solution. Pharmacokinetic studies demonstrated that micelles in combination with DTX and OTH exhibited increased area under curve and decreased clearance values, as compared with single micelles.
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http://dx.doi.org/10.3390/ijms22010231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794789PMC
December 2020

Unripe Miquel Extract Containing Ellagic Acid Promotes Lipolysis and Thermogenesis In Vitro and In Vivo.

Molecules 2020 Dec 16;25(24). Epub 2020 Dec 16.

Central R&D Center, Bioresources and Technology (B&Tech) Co., Ltd., Gwangju 61239, Korea.

Previously, we demonstrated that a 5% ethanol extract of unripe (5-RCK) and ellagic acid has hypocholesterolemic and antiobesity activity, at least partially mediated by the downregulation of adipogenic and lipogenic gene expression in high-fat diet (HFD)-fed animals. The present study investigated the thermogenic and lipolytic antiobesity effects of 5-RCK and ellagic acid in HFD-induced obese C57BL/6 mice and explored its mechanism of action. Mice fed an HFD received 5-RCK or ellagic acid as a post-treatment or pretreatment. Both post-treated and pretreated mice showed significant reductions in body weight and adipose tissue mass compared to the HFD-fed mice. The protein levels of lipolysis-associated proteins, such as adipose triglyceride lipase (ATGL), phosphorylated hormone-sensitive lipase (p-HSL), and perilipin1 (PLIN1), were significantly increased in both the 5-RCK- and ellagic acid-treated mouse epididymal white adipose tissue (eWAT). Additionally, thermogenesis-associated proteins, such as peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyl transferase-1 (CPT1), uncoupling protein 1 (UCP1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), in inguinal white adipose tissue (ingWAT) were clearly increased in both the 5-RCK- and ellagic acid-treated mice compared to HFD-fed mice. These results suggest that 5-RCK and ellagic acid are effective for suppressing body weight gain and enhancing the lipid profile.
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http://dx.doi.org/10.3390/molecules25245954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766442PMC
December 2020

Open-label, single arm, multicenter phase II study of VIDL induction chemotherapy followed by upfront autologous stem cell transplantation in patients with advanced stage extranodal NK/T-cell lymphoma.

Bone Marrow Transplant 2020 Dec 4. Epub 2020 Dec 4.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

The clinical outcome of advanced-stage Extranodal NK/T cell lymphoma (ENKTL) patients using conventional chemotherapy is extremely poor. The aim of this study was to investigate the outcomes of advanced-stage ENKTL patients treated with non-anthracycline-based chemotherapy followed by upfront autologous stem cell transplant (ASCT). From 8 institutions, 27 patients were recruited from February 2016 to May 2019. Patients were treated with 4 cycles of VIDL induction chemotherapy. Patients who achieved complete response (CR) or partial response (PR) underwent upfront ASCT. This study is registered with clinicaltrial.gov, # NCT02544425. Twenty patients (74.1%) completed 4 cycles of VIDL induction. The overall response rate of VIDL was 74.1%, including 17 (63.0%) with CR and 3 (11.1%) with PR. Primary toxicity of the induction regimen was grade 3 or 4 neutropenia, and no treatment-related mortality was reported. Seventeen patients proceeded with upfront ASCT, and 9 patients relapsed after ASCT, among whom, 4 was central nervous system (CNS) relapse. The median duration of response was 15.2 months (95% CI, 6.3-24.1 months). This study suggested that VIDL induction chemotherapy followed by upfront ASCT is feasible and effective for the treatment of advanced-stage ENKTL. However, CNS relapse prevention is needed in the treatment of advanced-stage ENKTL.
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http://dx.doi.org/10.1038/s41409-020-01160-2DOI Listing
December 2020

Co-infection With Chromosomally-Located and Plasmid-Encoding in Pathogenic in the Republic of Korea.

Front Microbiol 2020 11;11:545591. Epub 2020 Nov 11.

Division of Bacterial Diseases, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Chungju, South Korea.

The emergence of third-generation cephalosporin resistance in is increasing at an alarming rate in many countries. Thus, the aim of this study was to analyze co-infecting -producing pathogenic isolates linked to three school outbreaks. Among 66 isolates, 44 were identified as ETEC O25, an ETEC isolate serotype was O2, and the other 21 were confirmed as EAEC O44. Interestingly, six patients were co-infected with EAEC O44 and ETEC O25. For these isolates, molecular analysis [antibiotic susceptibility testing, identification of the β-lactamase gene, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE)] was performed for further characterization. In addition, the transmission capacity of genes was examined by conjugation experiments. Whole-genome sequencing (WGS) was performed on representative EAEC O44 and ETEC O25 isolates associated with co-infection and single-infection. All isolates were resistant to cefotaxime and ceftriaxone. All EAEC isolates carried the gene and all ETEC isolates the gene, as detected by multiplex PCR and sequencing analysis. Sequence type and PFGE results indicated three different patterns depending on the O serotype. WGS results of representative isolates revealed that the ETEC O25 strains harbored located on IncK plasmids associated with the Δ-- transposon. The representative EAEC O44 isolates carried on the chromosome, which was surrounded by the IS-- transposon. To the best of our knowledge, this is the first report of co-infection with chromosomally located and plasmid-encoding in pathogenic . Our findings indicate that resistance genes in clinical isolates can spread through concurrent combinations of chromosomes and plasmids.
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http://dx.doi.org/10.3389/fmicb.2020.545591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686028PMC
November 2020

Recent Advances and Challenges in Controlling the Spatiotemporal Release of Combinatorial Anticancer Drugs from Nanoparticles.

Pharmaceutics 2020 Nov 27;12(12). Epub 2020 Nov 27.

College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea.

To overcome cancer, various chemotherapeutic studies are in progress; among these, studies on nano-formulated combinatorial drugs (NFCDs) are being actively pursued. NFCDs function via a fusion technology that includes a drug delivery system using nanoparticles as a carrier and a combinatorial drug therapy using two or more drugs. It not only includes the advantages of these two technologies, such as ensuring stability of drugs, selectively transporting drugs to cancer cells, and synergistic effects of two or more drugs, but also has the additional benefit of enabling the spatiotemporal and controlled release of drugs. This spatial and temporal drug release from NFCDs depends on the application of nanotechnology and the composition of the combination drug. In this review, recent advances and challenges in the control of spatiotemporal drug release from NFCDs are provided. To this end, the types of combinatorial drug release for various NFCDs are classified in terms of time and space, and the detailed programming techniques used for this are described. In addition, the advantages of the time and space differences in drug release in terms of anticancer efficacy are introduced in depth.
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http://dx.doi.org/10.3390/pharmaceutics12121156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759840PMC
November 2020

Repurposing of Fluvastatin as an Anticancer Agent against Breast Cancer Stem Cells via Encapsulation in a Hyaluronan-Conjugated Liposome.

Pharmaceutics 2020 Nov 24;12(12). Epub 2020 Nov 24.

Research Institute of Pharmaceutical Science, College of Pharmacy, Sookmyung Women's University, Cheongparo 47 gil 100, Yongsan gu, Seoul 04310, Korea.

Fluvastatin (FLUVA), which is a common anti-hypercholesterolemia drug, exhibits potential anticancer activity as it suppresses the proliferation, angiogenesis, and metastasis of breast cancer cells via inhibiting 3-hydroxy-methyl glutaryl-coenzyme A (HMG-CoA) reductase. In this study, hyaluronan-conjugated FLUVA-encapsulating liposomes (HA-L-FLUVA) were evaluated for their anticancer efficacy in vitro and in vivo. The particle size, zeta potential, and encapsulation efficiency of HA-L-FLUVA were 158.36 ± 1.78 nm, -24.85 ± 6.26 mV, and 35%, respectively. Growth inhibition of breast cancer stem cells (BCSCs) by HA-L-FLUVA was more effective than that by free FLUVA. The half maximal inhibitory concentration (IC) values of FLUVA, L-FLVUA, and HA-L-FLUVA were 0.16, 0.17, and 0.09 μM, respectively. The in vivo anticancer effect of HA-L-FLUVA in combination with doxorubicin (DOX) was more effective than that of free FLUVA, free DOX, and HA-L-FLUVA. The longest survival of mice was achieved by treatment with FLUVA (15 mg/kg) and HA-L-FLUVA (15 mg/kg) + DOX (3 mg/kg), followed by HA-L-FLUVA (15 mg/kg), Dulbecco's phosphate buffered saline, and DOX (3 mg/kg). No more than 10% body weight loss was observed in the mice injected with FLUVA, indicating that the drug was not toxic. Taken together, these results indicate that HA-L-FLUVA could serve as an effective anticancer drug by inhibiting the growth of both breast cancer cells and cancer stem cells.
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http://dx.doi.org/10.3390/pharmaceutics12121133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760927PMC
November 2020

Association between body image dissatisfaction and poor quality of life and depression among patients with hematopoietic stem cell transplantation.

Support Care Cancer 2020 Nov 25. Epub 2020 Nov 25.

Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea.

Purpose: This study aims to evaluate the association between body image dissatisfaction and quality of life and depression among patients after hematopoietic stem cell transplantation (HSCT).

Methods: We conducted a cross-sectional survey at three university-based HSCT outpatient clinics and the Korea Blood Cancer Association. We assessed the body image using the body image scale; quality of life and depression were measured using the World Health Organization Quality of Life-BREF and the Patient Health Questionnaire 9, respectively. Univariate and multivariate linear regression models were used to find an association between body image, quality of life, and depression.

Results: Among 163 study participants, 71.8% were male, and the mean age of the participants was 48.3 (SD = 11.2). Over 70% of the participants reported that they felt less physically and sexually attractive due to HSCT, and 39.3% of the patients were dissatisfied with their body image. In fully adjusted models, patients with dissatisfied body image had significantly poorer quality of life (- 13.68, 95% confidence interval [CI] = - 18.16, - 9.21). Moreover, patients with body image dissatisfaction were 8.59 times (95% CI = 3.79, 19.48) more likely to have depressive symptoms than patients without it.

Conclusion: The majority of HSCT patients experienced body image dissatisfaction, which was significantly associated with poor quality of life and depression. It would be essential to evaluate body image after HSCT and provide appropriate interventions for preventing further psychological consequences.
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http://dx.doi.org/10.1007/s00520-020-05884-1DOI Listing
November 2020

Incidence and etiology of sudden cardiac arrest in Koreans: A cohort from the national health insurance service database.

PLoS One 2020 25;15(11):e0242799. Epub 2020 Nov 25.

Division of Cardiology, Department of Internal Medicine, Korea University College of Medicine and Korea University Medical Center, Seoul, Republic of Korea.

The incidence of sudden cardiac arrest (SCA) in Asians is lower than that seen in Western populations, but there are few available data on the incidence and associated cardiac etiology of SCA in Asians. From 2002 to 2013, patients with SCA were analyzed using a cohort from the South Korean National Health Insurance Service (NHIS) coded database. Sudden unexplained death syndrome (SUDS) was defined as cryptogenic arrest, excluding that of non-cardiac origin, coronary artery disease (CAD), cardiomyopathy (CM), and valvular heart disease. During the 12-year study period, 5,973 patients (0.53%) from the total cohort of 1,125,691 had a cardiac arrest code. The overall incidence of arrest was 48.7 per 100,000 person-years (95% CI 16.6-18.0). The incidence of primary SCA excluding those of non-cardiac origin was 16.1 per 100,000 person-years (95% CI 15.4-16.8). It was higher in males than in females (18.1 vs. 14.1 per 100,000 person-years). CAD was the most common cause of SCA (59.4%), and followed by CM (13.9%). SUDS accounted for 14.7% of SCA events. The risk of SCA had increased gradually from over 25 years old. Heart failure, atrial fibrillation and hypertension are major factors associated with SCA incidence. Our findings outline epidemiologic data for SCA and the proportion of associated cardiac etiology leads SCA in a large population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242799PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688167PMC
January 2021

Distinct genetic profile with recurrent population-specific missense variants in Korean adult atypical hemolytic uremic syndrome.

Thromb Res 2020 10 9;194:45-53. Epub 2020 Jun 9.

Department of Internal Medicine, School of Medicine, CHA University, Seongnam, Republic of Korea. Electronic address:

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA), characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and renal failure. In more than half of cases, genetic defects leading to overactivation of the alternative complement system have been identified. In this study, we investigated genetic defects in Korean adult patients with aHUS.

Materials And Methods: Sixty-six Korean adult patients with aHUS were ascertained from the Korean TMA Registry. Genetic variants of 15 aHUS-related genes (eight core genes [CFH, CFB, CFI, CD46, C3, THBD, PLG, and DGKE] and seven candidate genes [CFP, C4BPA, and CHFR1-5]) were analyzed from exome sequencing data. Multiplex ligation-dependent probe amplification of CFH and related genes was performed to detect hybrid genes or large deletions.

Results: Thirty patients (45%) had at least one aHUS-related variant (s) in eight core genes (total 40 variant alleles). The most frequently affected gene was CFH (13/40, 32%), followed by THBD (8/40, 20%) and CD46 (7/40, 18%). The two most common variants were Asp486Tyr of THBD (N = 7) and Tyr1058His-Val1060Leu of CFH (N = 5, linked on the same allele), accounting for 30% (12/40). In seven candidate genes, 19 variants were detected. When combined, 40 patients (61%) had at least one variant in 15 core or candidate genes. No patients had anti-CFH Ab or hybrid gene/CFHR1 homozygous deletions.

Conclusions: The genetic profile of Korean adult aHUS was unique with recurrent missense variants, demonstrating ethnicity- and age-dependent differences in the genetic background of aHUS.
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http://dx.doi.org/10.1016/j.thromres.2020.06.016DOI Listing
October 2020

Busulfan, etoposide, cytarabine, and melphalan as a high-dose regimen for autologous stem cell transplantation in peripheral T-cell lymphomas.

Ann Hematol 2021 Jan 17;100(1):189-196. Epub 2020 Nov 17.

Department of Hematology and Oncology, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.

Given the unsatisfactory survival in patients who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) for peripheral T-cell lymphomas (PTCLs), we conducted a prospective trial of busulfan (Bu), etoposide (E), cytarabine (A), and melphalan (M) (BuEAM), including IV Bu instead of carmustine (BCNU) as in standard BEAM, as a high-dose regimen in such patients. This study evaluated the efficacy and toxicity of BuEAM as a high-dose regimen for ASCT in patients with T-cell lymphomas. The high-dose chemotherapy at seven centers in Korea included Bu (3.2 mg/kg IV qd from day 6 to day 5), E (200 mg/m IV bid on day 4 and day 3), A (1 g/m IV qd on day 4 and day 3), and M (140 mg/m IV qd on day 2). Eighty-one patients were enrolled in this study. The main subtypes were peripheral T-cell lymphoma, not other specified (n = 32, 39.5%), NK/T-cell lymphoma (n = 22, 27.5%), and angioimmunoblastic T-cell lymphoma (n = 12, 14.8%). Upfront and salvage ASCTs were performed in 65 (80.2%) and 16 (19.8%) patients, respectively. The disease status of the patients before ASCT was 54 patients (66.7%) with complete response and 27 patients (33.3%) with partial response. The common grade-III toxicities were anorexia (8.6%), diarrhea (7.4%), and stomatitis (4.9%). No veno-occlusive disorder was noted. Fifty-six (69.1%) and seven (8.6%) patients achieved complete and partial response, respectively, after ASCT, although 17 patients (21.0%) showed progressive disease. At a median follow-up duration of 49.3 months, the estimated 3-year progression-free survival and overall survival were 55.2% and 68.2% in all patients. The BuEAM high-dose regimen for ASCT was well tolerated and seemed to be effective in patients with T-cell lymphomas.
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http://dx.doi.org/10.1007/s00277-020-04309-7DOI Listing
January 2021

Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX.

Blood Cancer J 2020 11 3;10(11):111. Epub 2020 Nov 3.

Clínica Universidad de Navarra-Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Centro de Investigación Biomédica en Red de Cáncer, Pamplona, Spain.

High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10) was assessed via the clonoSEQ assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk.
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http://dx.doi.org/10.1038/s41408-020-00375-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643179PMC
November 2020

Human herpesvirus 8-negative effusion-based lymphoma with indolent clinical behavior in an elderly patient: A case report and literature review.

Oncol Lett 2020 Dec 8;20(6):343. Epub 2020 Oct 8.

Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Primary effusion lymphoma (PEL) is a B-cell non-Hodgkin's lymphoma that is usually characterized by lymphomatous effusions in the body cavity without any detectable tumor masses. According to the World Health Organization (WHO) schema for tumor classification, PEL is defined by the presence of human herpesvirus 8 (HHV8) in malignant lymphoid cells. However, a subset of effusion-based B-cell lymphoma is not HHV8-positive and exhibits different clinicopathological characteristics. The 2017 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues does not list HHV8-negative effusion-based lymphoma, which remains an underappreciated B-cell lymphoma, as an individual entity. The present study reports a case of this rare type of lymphoma with indolent clinical behavior in a 75-year-old male patient receiving only symptomatic treatment. Additionally, a review of similar cases reported in the English literature is presented.
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http://dx.doi.org/10.3892/ol.2020.12206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583844PMC
December 2020

Physicochemical, Pharmacokinetic, and Toxicity Evaluation of Soluplus Polymeric Micelles Encapsulating Fenbendazole.

Pharmaceutics 2020 Oct 21;12(10). Epub 2020 Oct 21.

College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea.

Fenbendazole (FEN), a broad-spectrum benzimidazole anthelmintic, suppresses cancer cell growth through various mechanisms but has low solubility and achieves low blood concentrations, which leads to low bioavailability. Solubilizing agents are required to prepare poorly soluble drugs for injections; however, these are toxic. To overcome this problem, we designed and fabricated low-toxicity Soluplus polymeric micelles encapsulating FEN and conducted toxicity assays in vitro and in vivo. FEN-loaded Soluplus micelles had an average particle size of 68.3 ± 0.6 nm, a zeta potential of -2.3 ± 0.2 mV, a drug loading of 0.8 ± 0.03%, and an encapsulation efficiency of 85.3 ± 2.9%. MTT and clonogenic assays were performed on A549 cells treated with free FEN and FEN-loaded Soluplus micelles. The in vitro drug release profile showed that the micelles released FEN more gradually than the solution. Pharmacokinetic studies revealed lower total clearance and volume of distribution and higher area under the curve and plasma concentration at time zero of FEN-loaded Soluplus micelles than of the FEN solution. The in vivo toxicity assay revealed that FEN-loaded Soluplus micelle induced no severe toxicity. Therefore, we propose that preclinical and clinical safety and efficacy trials on FEN-loaded Soluplus micelles would be worthwhile.
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http://dx.doi.org/10.3390/pharmaceutics12101000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589096PMC
October 2020

Atrial Substrate Underlies the Recurrence after Catheter Ablation in Patients with Atrial Fibrillation.

J Clin Med 2020 Sep 30;9(10). Epub 2020 Sep 30.

Division of Cardiology, Department of Internal Medicine, Korea University College of Medicine and Korea University Medical Center, Seoul 02841, Korea.

Prediction of recurrences after catheter ablation of atrial fibrillation (AF) remains challenging. We sought to investigate the long-term outcomes after AF catheter ablation. A total of 2221 consecutive patients who underwent catheter ablation for symptomatic AF were included in this study (mean age 55 ± 11 years, 20.3% women, and 59.0% paroxysmal AF). Extensive ablation, in addition to circumferential pulmonary vein isolation, was more often accomplished in patients with non-paroxysmal AF than in those with paroxysmal AF (87.4% vs. 25.3%, < 0.001). During a median follow-up of 54 months, sinus rhythm (SR) was maintained in 67.1% after index procedure. After redo procedures in 418 patients, 83.3% exhibited SR maintenance. Recurrence rates were similar for single and multiple procedures (17.4% vs. 16.7%, = 0.765). Subanalysis showed that the extent of late gadolinium enhancement (LGE), as assessed by cardiac magnetic resonance, is greater in patients with recurrence than in those without recurrence (36.2 ± 23.9% vs. 21.8 ± 13.7%, < 0.001). Cox-regression analysis revealed that non-paroxysmal AF (hazard ratio (HR) 2.238, 95% confidence interval (CI) 1.905-2.629, < 0.001), overweight (HR 1.314, 95% CI 1.107-1.559, = 0.020), left atrium dimension ≥ 45 mm (HR 1.284, 95% CI 1.085-1.518, = 0.004), AF duration (HR 1.020 per year, 95% CI 1.006-1.034, = 0.004), and LGE ≥ 25% (HR 1.726, 95% CI 1.330-2.239, < 0.001) are significantly associated with AF recurrence after catheter ablation. This study showed that repeated catheter ablation improves the clinical outcomes of patients with non-paroxysmal AF, suggesting that AF substrate based on LGE may underpin the mechanism of recurrence after catheter ablation.
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http://dx.doi.org/10.3390/jcm9103164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601892PMC
September 2020

Effect of body mass index and abdominal obesity on mortality after percutaneous coronary intervention: A nationwide, population-based study.

Korean J Intern Med 2020 Sep 15. Epub 2020 Sep 15.

Departments of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea.

Background/aims: We investigated the impact of obesity on the clinical outcomes following percutaneous coronary intervention (PCI).

Methods: We included South Koreans aged >20 years who underwent the Korean National Health Screening assessment be¬tween 2009 and 2012. Obesity was defined using the body mass index (BMI), according to the World Health Organization's recommendations. Abdominal obesity was defined using the waist circumference (WC), as defined by the Korean Society for Obesity. The odds and hazard ratios in all-cause mortality were calculated after adjustment for multiple covariates. Patients were followed up to the end of 2017.

Results: Among 130,490 subjects who underwent PCI, the mean age negatively correlated with BMI. WC, hypertension, diabetes, dyslipidemia, fasting glucose, total cholesterol, LDL-cholesterol, and TG levels correlated with the increased BMI. The mortality rates were higher in the lower BMI and WC groups than the higher BMI and WC groups. The non-obese with abdominal obesity group showed a mortality rate of 2.11 per 1,000 person-years. Obese with no abdominal obesity group had the lowest mortality rate (0.88 per 1,000 person-years). The mortality showed U-shaped curve with a cut-off value of 29 in case of BMI and 78 cm of WC.

Conclusions: The mortality showed U-shaped curve and the cut-off value of lowest mortality was 29 in case of BMI and 78 cm of WC. The abdominal obesity may be associated with poor prognosis in Korean patients who underwent PCI.
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http://dx.doi.org/10.3904/kjim.2020.099DOI Listing
September 2020

Let-7 miRNA and CDK4 siRNA co-encapsulated in Herceptin-conjugated liposome for breast cancer stem cells.

Asian J Pharm Sci 2020 Jul 7;15(4):472-481. Epub 2019 May 7.

College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.

Recently, breast cancer stem cells (BCSCs) have rapidly emerged as a novel target for the therapy of breast cancer as they play critical roles in tumor growth, maintenance, metastasis, and recurrence. Let-7 miRNA is known to be downregulated in a variety of cancers, especially BCSCs, whereas CDK4 being overexpressed in human epidermal growth factor receptor 2 (HER-2) overexpressing tumor cells. In this study, let-7 miRNA and CDK4-specific siRNA were chosen as therapeutic agents and co-encapsulated in Herceptin-conjugated cationic liposomes for breast cancer therapy. Particle size, zeta potential, and encapsulation efficacy of mi/siRNA-loaded PEGylated liposome conjugated with Herceptin (Her-PEG-Lipo-mi/siRNA) were 176 nm, 28.1 mV, and 99.7% ± 0.1%, respectively. Enhanced cellular uptake (86%) was observed by fluorescence microscopy when SK-BR-3 cells were treated with Her-PEG-Lipo-mi/siRNA. Also, the increased amount of let-7a mRNA and decreased amount of cellular CDK4 mRNA were observed by qRT-PCR when SK-BR-3 cells were treated with Her-PEG-Lipo-mi/siRNA, which was even more so when SK-BR-3 stem cells were used (197 vs 768 times increase for let-7a, 62% vs 68% decrease for CDK4). Growth inhibition (65%) and migration arrest (0.5%) of the cells were achieved by the treatment of the cells with Her-PEG-Lipo-mi/siRNA, but not with mi/siRNA complex or other formulations. In conclusion, an efficient liposomal delivery system for the combination of miRNA and siRNA to target the BCSCs was developed and could be used as an efficacious therapeutic modality for breast cancer.
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http://dx.doi.org/10.1016/j.ajps.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486552PMC
July 2020

Clinical impact of frailty on treatment outcomes of elderly patients with relapsed and/or refractory multiple myeloma treated with lenalidomide plus dexamethasone.

Int J Hematol 2021 Jan 5;113(1):81-91. Epub 2020 Sep 5.

Department of Internal Medicine, Seoul St. Mary's Hospital, Catholic University of Korea, 505, Banpo-dong, Seocho-gu, Seoul, 137-701, South Korea.

We compared efficacy and safety, according to frailty, of elderly patients with relapsed and refractory multiple myeloma (RRMM) treated with lenalidomide and dexamethasone (Rd), for whom bortezomib treatment had failed. Patients, 164 (52.9%) and 146 (47.1%), were classified as non-frail and frail using a simplified frailty scale. The overall response rates (ORR) and survival outcomes were lower in frail than in non-frail patients (ORR: 56.2% vs. 67.7%, P = 0.069; median progression free survival: 13.17 vs. 17.80 months, P = 0.033; median overall survival: 23.00 vs. 36.27 months, P = 0.002, respectively). The number of treatment emergent adverse events in grade 3 or worse was higher in frail than in non-frail patients (41.8% vs. 24.4%, P = 0.002, respectively). In frail patients, independent poor prognostic factors for survival were two or more Charlson comorbidity index (CCI) score, prior to exposure to both bortezomib and thalidomide, and achieved less than partial response In conclusion, frailty could predict clinical outcomes of Rd treatment in elderly patients with RRMM who had failed prior bortezomib. In frail patients, lower CCI in addition to less previous treatment exposure and deep response were associated with better survival.
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http://dx.doi.org/10.1007/s12185-020-02988-6DOI Listing
January 2021

First-Line Treatment for Primary Breast Diffuse Large B-Cell Lymphoma Using Immunochemotherapy and Central Nervous System Prophylaxis: A Multicenter Phase 2 Trial.

Cancers (Basel) 2020 Aug 6;12(8). Epub 2020 Aug 6.

Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju 54907, Korea.

There are limited data from prospective controlled trials regarding optimal treatment strategies in patients with primary breast diffuse large B-cell lymphoma (DLBCL). In this phase 2 study (NCT01448096), we examined the efficacy and safety of standard immunochemotherapy and central nervous system (CNS) prophylaxis using intrathecal methotrexate (IT-MTX). Thirty-three patients with newly diagnosed primary breast DLBCL received six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and four fixed doses of IT-MTX (12 mg). The median age was 50 years (range, 29-75), and all patients were females. According to the CNS-International Prognostic Index, most patients ( = 28) were categorized as the low-risk group. Among the 33 patients, 32 completed R-CHOP, and 31 completed IT-MTX as planned. With a median follow-up of 46.1 months (interquartile range (IQR), 31.1-66.8), the 2-year progression-free and overall survival rates were 81.3% and 93.5%, respectively. Six patients experienced treatment failures, which included the CNS in four patients (two parenchyma and two leptomeninges) and breast in two patients (one ipsilateral and one contralateral). The 2-year cumulative incidence of CNS relapse was 12.5%. Although standard R-CHOP and IT-MTX without routine radiotherapy show clinically meaningful survival outcomes, this strategy may not be optimal for reducing CNS relapse and warrants further investigation.
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http://dx.doi.org/10.3390/cancers12082192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463683PMC
August 2020

Immunosuppressive role of CD11b CD33 HLA-DR myeloid-derived suppressor cells-like blast subpopulation in acute myeloid leukemia.

Cancer Med 2020 Oct 11;9(19):7007-7017. Epub 2020 Aug 11.

Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, South Korea.

Objective: Myeloid-derived suppressor cells (MDSCs) facilitate tumor growth and development by suppressing T cell function; however, their role in acute myeloid leukemia (AML) remains unclear. Here, we investigated the immunosuppressive role and prognostic value of blasts with an MDSC-like phenotype.

Methods: CD11b CD33 HLA-DR MDSC-like blasts from bone marrow mononuclear cells of patients with AML were analyzed. To investigate their T cell-suppressing function, MDSC-like blasts were isolated using flow cytometry and co-cultured with CD8 cytotoxic T cells and NB4 leukemic cells. Treatment outcomes were then compared between the MDSC-like blasts low (≤9.76%) and high (>9.76%) groups to identify clinical significance.

Results: MDSC-like blasts showed higher expression of arginase-1 and inducible nitric oxide synthase. Isolated MDSC-like blasts significantly suppressed CD8 T cell proliferation induced by phytohemagglutinin A. NB4 cell proliferation was significantly suppressed upon co-culture with CD8 cytotoxic T cells and partially restored upon co-culture with MDSC-like blasts. Patients with high MDSC-like blasts at diagnosis showed substantially shorter overall survival and leukemia-free survival relative to low MDSC-like blasts patients, with subgroup analysis showing statistically significant differences in patients not receiving allogeneic hematopoietic stem cell transplantation.

Conclusion: We demonstrated that MDSC-like blasts drive AML-specific immune-escape mechanisms by suppressing T cell proliferation and restoring T cell-suppressed NB4 cell proliferation, with clinically higher fractions of MDSC-like blasts at diagnosis resulting in poor prognosis.
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http://dx.doi.org/10.1002/cam4.3360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541151PMC
October 2020

Long-Term Exposure to Urban Particulate Matter on the Ocular Surface and the Incidence of Deleterious Changes in the Cornea, Conjunctiva and Retina in Rats.

Int J Mol Sci 2020 Jul 14;21(14). Epub 2020 Jul 14.

Central R&D Center, Bioresources and Technology (B&Tech) Co., Ltd., Gwangju 61239, Korea.

We investigated the time-dependent deleterious ocular changes induced by urban particulate matter (UPM) in vitro and in vivo. UPM treatment decreased human corneal epithelial cell migration and survival. Fluorescein scores were consistently increased by UPM application for 16 weeks. One week of rest at 2 or 4 weeks led to a recovery trend, whereas two weeks of rest at 8 weeks induced no change. UPM treatment decreased the tear film break-up time at 2 weeks, which was thereafter maintained until 16 weeks. No changes were found after periods of rest. UPM-treated eyes exhibited greater corneal epithelium thickness than normal eyes at 2 weeks, which recovered to normal at 4 and 8 weeks and was significantly decreased at 16 weeks. Apoptotic cell number in the epithelium was increased at 2 weeks, which remained constant except at 8 weeks. IL-6 expression in the cornea of the right eye continually increased for 16 weeks, and significant recovery was only observed at 8 weeks after 2 weeks of rest. Ocular pressure was significantly increased in the right eye at 12 and 16 weeks. Topical UPM application to the eye induced deleterious changes to various closely related parts of the eye.
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http://dx.doi.org/10.3390/ijms21144976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404123PMC
July 2020

Horizontal transfer of bla-carrying IncX3 plasmid between carbapenem-resistant Enterobacteriaceae in a single patient.

J Infect 2020 Nov 13;81(5):816-846. Epub 2020 Jul 13.

Infectious Diseases Team, Seoul Metropolitan Government Research Institute of Public Health and Environment, Gyeonggi-do, Republic of Korea.

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http://dx.doi.org/10.1016/j.jinf.2020.07.013DOI Listing
November 2020