Publications by authors named "Hye Jin Kang"

161 Publications

MRI-guided radiotherapy for PVTT in HCC patients: evaluation of the efficacy and safety.

J Cancer Res Clin Oncol 2021 Sep 6. Epub 2021 Sep 6.

Department of Radiation Oncology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Purpose: This study aims to evaluate the efficacy, feasibility, and safety of the magnetic resonance imaging (MRI)-guided tumor tracking hypofractionated radiotherapy (HFRT) and stereotactic body radiation therapy (SBRT) for portal vein tumor thrombus (PVTT) in hepatocellular carcinoma (HCC) patients.

Methods: We retrospectively reviewed the twelve cases of unresectable HCC with tumor thrombus in the main trunk or first branch of the portal vein that were treated with MRI-guided tumor tracking HFRT or SBRT using the ViewRay Linac MRIdian system between June 2019 and January 2021. The HFRT was performed with a total of 50 Gy in 10 fractions, and SBRT performed in a range of 36-50 Gy with 4-5 fractions. The median biologic effective dose (BED) with an a/b ratio of 10 was 75 Gy (range 68.4-100 Gy).

Results: The median follow-up duration was 5.0 months (range 1.9-12.8 months). Ten patients (83.3%) showed an objective response of PVTT. At the time of analysis, ten patients (83.3%) showed local control. The 1-year intrahepatic control rate was 48.9%. Three patients (25%) showed mild gastrointestinal symptoms, and there were no cases of grade 3 or higher toxicity. For hepatic toxicity, there were no cases in which the Child-Pugh score increased by more than two points after RT without disease progression.

Conclusion: MRI-guided tumor tracking HFRT and SBRT was a feasible, effective, and safe treatment option in HCC patients with tumor thrombi in the main trunk or first branch of the portal vein.
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http://dx.doi.org/10.1007/s00432-021-03788-zDOI Listing
September 2021

Multicenter, phase II study of response-adapted lenalidomide-based therapy for transplant-ineligible patients with newly diagnosed multiple myeloma without high-risk features.

Curr Probl Cancer 2021 Aug 21:100788. Epub 2021 Aug 21.

Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea. Electronic address:

Lenalidomide and low-dose dexamethasone (Rd) are a standard treatment for older adults with multiple myeloma (MM). Lenalidomide monotherapy has rarely been evaluated for newly diagnosed transplant-ineligible MM patients. This multicenter phase II trial evaluated a response-adapted strategy for elderly patients with newly diagnosed MM without high-risk features. Patients were administered single-agent lenalidomide for the first 21 days of two 28-day cycles. Patients with progressive disease received Rd. The primary endpoint was progression-free survival using the uniform response assessment from the International Myeloma Working Group . Of the 34 enrolled patients, 28 were included in the efficacy analysis. The overall response rate (ORR, ≥ partial response [PR]) to single-agent lenalidomide or lenalidomide plus prednisone was 64.3%. Ten patients received Rd after disease progression, with an Rd ORR of 70%. The ORR of response-adapted lenalidomide-based therapy was 75%. After the median follow-up of 35.6 months, the median progression-free survival was 33.5 months (95% confidence interval [CI], 16.9-50.2), and the median overall survival was 51.8 months (95% CI, 22.0-81.6). The most common adverse event was neutropenia (46.7%), and 17 patients (56.7%) experienced infection including pneumonia. Response-adapted lenalidomide-based therapy was feasible in newly diagnosed, transplant-ineligible MM patients without high-risk features.
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http://dx.doi.org/10.1016/j.currproblcancer.2021.100788DOI Listing
August 2021

Comprehensive analysis of peripheral T-cell and natural killer/T-cell lymphoma in Asian patients: A multinational, multicenter, prospective registry study in Asia.

Lancet Reg Health West Pac 2021 May 22;10:100126. Epub 2021 Mar 22.

Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, South Korea.

Background: Peripheral T-cell lymphomas (PTCLs) are uncommon and their frequency is regionally heterogeneous. Several studies have been conducted to evaluate the clinical features and treatment outcomes of this disease entity, but the majority of these were conducted in limited areas, making it difficult to comprehensively analyze their relative frequency and clinical features. Furthermore, no consensus treatment for PTCLs has been established. Therefore, we conducted an Asia-specific study to understand the relative frequency of PTCLs and assess treatments and their outcomes in Asian patients.

Methods: We performed a multinational, multicenter, prospective registry of adult patients with PTCLs that was named as the International Cooperative non-Hodgkin T-cell lymphoma prospective registry study where thirty-two institutes from six Asian countries and territories (Korea, China, Taiwan, Singapore, Malaysia, and Indonesia) participated.

Findings: A total of 486 patients were registered between April 2016 and February 2019, and more than a half of patients (57%) had stage III or IV. Extranodal natural killer (NK)/T- cell lymphoma was the most common subtype ( = 139,28.6%), followed by angioimmunoblastic T-cell lymphoma (AITL,  = 120,24.7%), PTCL-not otherwise specified (PTCL-NOS,  = 101,20.8%), ALK-positive anaplastic large cell lymphoma (ALCL,  = 34,6.9%), and ALK-negative ALCL ( = 30,6.2%). The median progression-free survival (PFS) and overall survival (OS) were 21.1 months (95% CI,10.6-31.6) and 83.6 months (95% CI, 56.7-110.5), respectively. Upfront use of combined treatment with chemotherapy and radiotherapy showed better PFS than chemotherapy alone in localized ENKTL whereas consolidation with upfront autologous stem cell transplantation (SCT) provided longer PFS in advance stage ENKTL. In patients with PTCLs other than ENKTL, anthracycline-containing chemotherapies were widely used, but the outcome of those regimens was not satisfactory, and upfront autologous SCT was not significantly associated with survival benefit, either. The treatment outcome of salvage chemotherapy was disappointing, and none of the salvage strategies showed superiority to one another.

Interpretation: This multinational, multicenter study identified the relative frequency of each subtype of PTCLs across Asian countries, and the survival outcomes according to the therapeutic strategies currently used.

Funding: Samsung Biomedical Research Institute.
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http://dx.doi.org/10.1016/j.lanwpc.2021.100126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315366PMC
May 2021

Synthesis and characteristics of a rebaudioside-A like compound as a potential non-caloric natural sweetener by Leuconostoc kimchii dextransucrase.

Food Chem 2022 Jan 20;366:130623. Epub 2021 Jul 20.

Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address:

Stevioside (ST) is currently considered as a highly-demanded natural and zero-caloric replacer of sucrose with several health-promoting properties. Nonetheless, its bitter aftertaste limits its use in the food industry. Herein, glucosyl steviosides were synthesized using primarily a food-grade lactic acid bacteria, Leuconostoc kimchii dextransucrase and conversion yield (%) was 40.3%. A glucose moiety was transferred stereo-selectively to ST by α-1,6-linkage and this is the first report about obtaining rebaudioside A (Reb-A) like glucosyl stevioside-2 (STG-2). Glucosyl steviosides revealed greatly improved stability up to 120 °C and remained stable over 32.1% and 58.12% in the pH (1.4) compared with 30.55% of ST. Moreover, the glucosylated steviosides improved the stability, reaching 95% after 30 days and Reb-A like compound (STG-2) especially exhibited higher stability in commercial beverages. Furthermore, the glucosyl steviosides showed over 1.92- and 2.24-fold decreases than that of enzymatically modified ST in the glucose generation rate test.
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http://dx.doi.org/10.1016/j.foodchem.2021.130623DOI Listing
January 2022

Autologous EBV-specific T cell treatment results in sustained responses in patients with advanced extranodal NK/T lymphoma: results of a multicenter study.

Ann Hematol 2021 Oct 24;100(10):2529-2539. Epub 2021 Jul 24.

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA.

We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0-23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (P = 0.001) and OS (P = 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.
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http://dx.doi.org/10.1007/s00277-021-04558-0DOI Listing
October 2021

Cutaneous T-cell lymphoma in Asian patients: a multinational, multicenter, prospective registry study in Asia.

Int J Hematol 2021 Sep 24;114(3):355-362. Epub 2021 Jul 24.

Department of Internal Medicine, Division of Hemato-Oncology, Kangdong Sacred Heart Hospital, Hallym University, Seoul, South Korea.

Cutaneous T-cell lymphomas (CTCLs) are a group of T-cell lymphomas with low incidence. Due to their indolent characteristics, treatment strategies have not yet been established for advanced CTCLs. In this study, relative incidence of CTCLs in Asia was estimated and the therapeutic outcomes presented based on various treatments currently used in clinics for advanced CTCLs. As part of a prospective registry study of peripheral T-cell lymphoma (PTCL) conducted across Asia, including Korea, China, Taiwan, Singapore, Malaysia, and Indonesia, subgroup analysis was performed for patients with CTCLs. Among 486 patients with PTCL, 37 with CTCL (7.6%) were identified between April 2016 and February 2019. Primary cutaneous ALK-negative anaplastic large cell lymphoma (ALCL, 35.1%) was the most common subtype. With a median follow-up period of 32.1 months, median progression-free survival (PFS) was 53.5 months (95% CI 0.0-122.5), and overall survival was not reached. 14 patients (48.2%) underwent subsequent treatment after the first relapse, but the response rate was 20% with a PFS of 2.2 months (95% CI 0.3-4.0). Six patients received autologous stem cell transplantation (auto-SCT). However, auto-SCT did not result in better outcomes. Additional studies are needed on standard care treatment of advanced or refractory and relapsed CTCLs.
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http://dx.doi.org/10.1007/s12185-021-03179-7DOI Listing
September 2021

A promising chemical series of positive allosteric modulators of the μ-opioid receptor that enhance the antinociceptive efficacy of opioids but not their adverse effects.

Neuropharmacology 2021 09 18;195:108673. Epub 2021 Jun 18.

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Electronic address:

Positive allosteric modulators (PAMs) of the μ-opioid receptor (MOR) have been proposed to exhibit therapeutic potential by maximizing the analgesic properties of clinically used opioid drugs while limiting their adverse effects or risk of overdose as a result of using lower drug doses. We herein report in vitro and in vivo characterization of two small molecules from a chemical series of MOR PAMs that exhibit: (i) MOR PAM activity and receptor subtype selectivity in vitro, (ii) a differential potentiation of the antinociceptive effect of oxycodone, morphine, and methadone in mouse models of pain that roughly correlates with in vitro activity, and (iii) a lack of potentiation of adverse effects associated with opioid administration, such as somatic withdrawal, respiratory depression, and analgesic tolerance. This series of MOR PAMs holds promise for the development of adjuncts to opioid therapy to mitigate against overdose and opioid use disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410669PMC
September 2021

Incidence and risk factors of urinary tract infections in hospitalised patients with spinal cord injury.

J Clin Nurs 2021 Jul 7;30(13-14):2068-2078. Epub 2021 Apr 7.

Mo-Im Kim Nursing Research Institute, College of Nursing, Yonsei University, Seoul, South Korea.

Aims And Objectives: To investigate the incidence of urinary tract infection and analyse its risk factors among hospitalised patients with spinal cord injury.

Background: While the incidence of urinary tract infection varies widely according to the healthcare setting and patients' clinical characteristics, formal reports are limited in quantity. There has been no consensus regarding the risk factors for urinary tract infection.

Design: A retrospective descriptive study.

Methods: Electronic medical records of 964 subjects between 2010-2017 were reviewed. Urinary tract infection status was examined to identify newly occurred cases. Data included demographic and clinical characteristics, hydration status and length of hospitalisation. The reporting of the study followed the EQUATOR Network's STROBE checklist.

Results: Of the sample, 31.7% had urinary tract infection (95% confidence interval: 1.288 to 1.347, p < .001). Sex, completeness of injury, type of bladder emptying, detrusor function and urethral pressure were significant factors affecting urinary tract infection. Patients who were male and those with injury classifications A, B and C had higher risk of urinary tract infection. Patients with urinary or suprapubic indwelling catheters, as well as those with areflexic detrusor combined with normotonic urethral pressure or overactive detrusor combined with normotonic urethral pressure, showed higher risk. Length of hospitalisation in patients with urinary tract infection was greater than that in uninfected patients, which implies the importance of prevention of urinary tract infection.

Conclusions: Nurses should carefully assess risk factors to prevent urinary tract infection in patients with spinal cord injury in the acute and sub-acute stages of the disease trajectory and provide individualised nursing care.

Relevance To Clinical Practice: This study contributes evidence for up-to-date clinical nursing practice for the comprehensive management of urinary tract infection. This can lead to improvements in nursing care quality and patient outcomes, including length of hospitalisation.
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http://dx.doi.org/10.1111/jocn.15763DOI Listing
July 2021

The adipokine Retnla deficiency increases responsiveness to cardiac repair through adiponectin-rich bone marrow cells.

Cell Death Dis 2021 03 22;12(4):307. Epub 2021 Mar 22.

Cell Regeneration Research Center, Chonnam National University Hospital, Gwangju, Republic of Korea.

Resistin-like alpha (Retnla) is a member of the resistin family and known to modulate fibrosis and inflammation. Here, we investigated the role of Retnla in the cardiac injury model. Myocardial infarction (MI) was induced in wild type (WT), Retnla knockout (KO), and Retnla transgenic (TG) mice. Cardiac function was assessed by echocardiography and was significantly preserved in the KO mice, while worsened in the TG group. Angiogenesis was substantially increased in the KO mice, and cardiomyocyte apoptosis was markedly suppressed in the KO mice. By Retnla treatment, the expression of p21 and the ratio of Bax to Bcl2 were increased in cardiomyocytes, while decreased in cardiac fibroblasts. Interestingly, the numbers of cardiac macrophages and unsorted bone marrow cells (UBCs) were higher in the KO mice than in the WT mice. Besides, phosphorylated histone H3(+) cells were more frequent in bone marrow of KO mice. Moreover, adiponectin in UBCs was notably higher in the KO mice compared with WT mice. In an adoptive transfer study, UBCs were isolated from KO mice to transplant to the WT infarcted heart. Cardiac function was better in the KO-UBCs transplanted group in the WT-UBCs transplanted group. Taken together, proliferative and adiponectin-rich bone marrow niche was associated with substantial cardiac recovery by suppression of cardiac apoptosis and proliferation of cardiac fibroblast.
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http://dx.doi.org/10.1038/s41419-021-03593-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985519PMC
March 2021

Synthesis and Characterization of [F]JNJ-46356479 as the First F-Labeled PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

Mol Imaging Biol 2021 08 8;23(4):527-536. Epub 2021 Feb 8.

Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, 3rd Avenue, Charlestown, MA, 02129, USA.

Purpose: Metabotropic glutamate receptor 2 (mGluR2) has been implicated in various psychiatric and neurological disorders, such as schizophrenia and Alzheimer's disease. We have previously developed [C]7 as a PET radioligand for imaging mGluR2. Herein, [F]JNJ-46356479 ([F]8) was synthesized and characterized as the first F-labeled mGluR2 imaging ligand to enhance diagnostic approaches for mGluR2-related disorders.

Procedures: JNJ-46356479 (8) was radiolabeled via the copper (I)-mediated radiofluorination of organoborane 9. In vivo PET imaging experiments with [F]8 were conducted first in C57BL/6 J mice and Sprague-Dawley rats to obtain whole body biodistribution and brain uptake profile. Subsequent PET studies were done in a cynomolgus monkey (Macaca fascicularis) to investigate the uptake of [F]8 in the brain, its metabolic stability, as well as pharmacokinetic properties.

Results: JNJ-46356479 (8) exhibited excellent selectivity against other mGluRs. In vivo PET imaging studies showed reversible and specific binding characteristic of [F]8 in rodents. In the non-human primate, [F]8 displayed good in vivo metabolic stability, excellent brain permeability, fast and reversible kinetics with moderate heterogeneity across brain regions. Pre-treatment studies with compound 7 revealed time-dependent decrease of [F]8 accumulation in mGluR2 rich regions based on SUV values with the highest decrease in the nucleus accumbens (18.7 ± 5.9%) followed by the cerebellum (18.0 ± 7.9%), the parietal cortex (16.9 ± 7.8%), and the hippocampus (16.8 ± 6.9%), similar to results obtained in the rat studies. However, the volume of distribution (V) results derived from 2T4k model showed enhanced V from a blocking study with compound 7. This is probably because of the potentiating effect of compound 7 as an mGluR2 PAM as well as related non-specific binding in the tissue data.

Conclusions: [F]8 readily crosses the blood-brain barrier and demonstrates fast and reversible kinetics both in rodents and in a non-human primate. Further investigation of [F]8 on its binding specificity would warrant translational study in human.
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http://dx.doi.org/10.1007/s11307-021-01586-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277681PMC
August 2021

Remarkable variation of visible light photocatalytic activities of M/SnSbO/TiO (M=Au, Ag, Pt) heterostructures depending on the loaded metals.

Chemosphere 2021 Feb 1;265:129160. Epub 2020 Dec 1.

Department of Chemistry and Chemical Engineering, Inha University, Incheon, 22212, Republic of Korea. Electronic address:

SnSbO/TiO (ATO/TiO) heterostructure is a potential visible light photocatalysts that function via an inter-semiconductor hole-transport mechanism. Herein we selectively deposited Au, Ag, or Pt onto the ATO surface of ATO/TiO to investigate charge-trapping behaviors of the noble metals and their effects on photocatalytic performance. We observed that Pt deposition greatly enhanced the photocatalytic activity whereas effects of Au or Ag depositions were not significant. The result of spectroscopic analysis also indicates that Pt is the most effective in scavenging the electrons from the ATO CB. Particularly, Pt/ATO/TiO (ATO:TiO = 15:85 in weight) produced CO of 42 ppmv in 2 h, which is 16 times and 4.8 times that of bare ATO/TiO and nitrogen-doped TiO, respectively. Pt deposition on the ATO seems to suppress two independent charge recombination pathways, that is, recombination of electron-hole pairs in ATO and electron transport from the ATO CB to TiO VB.
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http://dx.doi.org/10.1016/j.chemosphere.2020.129160DOI Listing
February 2021

Design, Synthesis, and Characterization of Benzimidazole Derivatives as Positron Emission Tomography Imaging Ligands for Metabotropic Glutamate Receptor 2.

J Med Chem 2020 10 7;63(20):12060-12072. Epub 2020 Oct 7.

Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, 3rd Avenue, Charlestown, Massachusetts 02129, United States.

Three benzimidazole derivatives (-) have been synthetized as potential positron emission tomography (PET) imaging ligands for mGluR2 in the brain. Of these compounds, exhibits potent binding affinity (IC = 7.6 ± 0.9 nM), positive allosteric modulator (PAM) activity (EC = 51.2 nM), and excellent selectivity against other mGluR subtypes (>100-fold). [C] was synthesized via -[C]methylation of its phenol precursor with [C]methyl iodide. The achieved radiochemical yield was 20 ± 2% ( = 10, decay-corrected) based on [C]CO with a radiochemical purity of >98% and molar activity of 98 ± 30 GBq/μmol EOS biodistribution studies revealed reversible accumulation of [C] and hepatobiliary and urinary excretions. PET imaging studies in rats demonstrated that [C] accumulated in the mGluR2-rich brain regions. Pre-administration of mGluR2-selective PAM, reduced the brain uptake of [C], indicating a selective binding. Therefore, [C] is a potential PET imaging ligand for mGluR2 in different central nervous system-related conditions.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01394DOI Listing
October 2020

Assessment of postoperative acromial and subacromial morphology after arthroscopic acromioplasty using magnetic resonance imaging.

Skeletal Radiol 2021 Apr 25;50(4):761-770. Epub 2020 Sep 25.

Department of Radiology, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Republic of Korea.

Objective: To identify the morphological characteristics of the acromion and subacromial bursal space after arthroscopic acromioplasty using magnetic resonance imaging (MRI).

Materials And Methods: One hundred patients who received arthroscopic rotator cuff repair and acromioplasty each received at least three MRI examinations (preoperative, first immediate postoperative, and second follow-up imaging between 8 months and 1 year postoperatively). Changes over time in the thickness and morphology of the postoperative acromion as well as the subacromial bursal space were assessed. Clinical and radiological parameters were also analyzed to identify any association with changes in acromial morphology.

Results: Despite minimal acromial thinning observed at the first immediate postoperative state, the acromions showed significant thinning at the second postoperative MRI, with a mean reduction of 32%. Along with acromial thinning, an exaggerated concave contour of the acromial undersurface was observed in some patients. In the subacromial space, a loculated fluid collection developed in 91% of the patients at the second postoperative follow-up. No statistically significant association was noted between postoperative acromial thickness change and clinical or radiological factors (P value > 0.05).

Conclusion: A significant delayed reduction in acromial thickness within approximately 1 year of arthroscopic acromioplasty is thought to be a normal postoperative feature. The simultaneous collection of a loculated, cyst-like fluid in the subacromial bursal space may be an important associated factor of postoperative acromial thinning.
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http://dx.doi.org/10.1007/s00256-020-03607-5DOI Listing
April 2021

Pattern of failure and optimal treatment strategy for primary gastric diffuse large B-cell lymphoma treated with R-CHOP chemotherapy.

PLoS One 2020 22;15(9):e0238807. Epub 2020 Sep 22.

Department of Hematology, Catholic University Lymphoma Group, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Purpose: The optimal treatment for primary gastric diffuse large B-cell lymphoma (PG-DLBCL) is still unknown. We evaluated unfavorable prognostic factors and pattern of failure in PG-DLBCL to determine the optimal treatment strategy.

Methods: Between April 2001 and November 2018, 120 patients with complete remission following rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy were retrospectively reviewed. According to the Lugano staging system, 80 patients (66.7%) had localized disease and 40 patients (33.3%) had advanced disease. A total of 93 (77.5%) patients had single gastric lesion and 27 (22.5%) patients had multiple gastric lesions. Ninety patients (75%) were treated with R-CHOP chemotherapy alone and 30 patients (25%) received R-CHOP chemotherapy with additional local treatment for gastric lesions.

Results: The 5-year locoregional failure-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) rates in patients treated with R-CHOP chemotherapy with local treatment were 100%, 100%, and 100%, respectively, whereas the LRFS, PFS, and OS rates in patients treated with R-CHOP chemotherapy alone were 86.3%, 78.2%, and 87.4%, respectively (p = 0.031, p = 0.095, and p = 0.025, respectively). During the follow-up period, 17 patients (14.2%) had disease recurrence. Only 3 of the 17 patients had relapse in a completely new site without relapse in the initial involved site. All, except 2, cases of local recurrence included gastric failure. In the multivariate analysis, performance status and number of gastric lesions were independent prognostic factors for treatment outcome.

Conclusions: Patients with complete remission following R-CHOP chemotherapy showed a good prognosis. The main pattern of failure in patients with PG-DLBCL was local recurrence, especially in the stomach. Patients who received local treatment for gastric lesions showed improved gastric control. Therefore, in patients with unfavorable prognostic factors, we recommend R-CHOP chemotherapy with additional local treatment for gastric lesions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238807PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508390PMC
November 2020

Intravenous busulfan and melphalan versus high-dose melphalan as a conditioning regimen for early autologous stem cell transplantation in patients with multiple myeloma: a propensity score-matched analysis.

Leuk Lymphoma 2020 11 25;61(11):2714-2721. Epub 2020 Jun 25.

Seoul National University Hospital, Seoul, Republic of Korea.

We compared the efficacy and toxicity of busulfan and melphalan (BUMEL) and those of high-dose melphalan (HDMEL) as conditioning regimens for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) through a propensity score-matched analysis. No significant difference in the complete response and overall response rate after ASCT was observed between BUMEL and HDMEL. After a median follow-up of 37.3 months in the BUMEL group and 50.8 months in the HDMEL group, the median progression-free survival was calculated to be 32.9 months and 25.2 months ( = 0.995). With respect to non-hematologic toxicities, infections were more frequently reported in the BUMEL group ( < 0.001). Three patients who received BUMEL developed veno-occlusive disease (VOD), and all of them recovered without administration of defibrotide. In conclusion, BUMEL is an effective alternative conditioning regimen in terms of efficacy, but attention should be paid to toxicities.
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http://dx.doi.org/10.1080/10428194.2020.1783448DOI Listing
November 2020

Treatment with intravenous busulfan, melphalan, and etoposide followed by autologous stem cell transplantation in patients with non-Hodgkin's lymphoma: a multicenter study from the consortium for improving survival of lymphoma.

Transpl Int 2020 10 23;33(10):1211-1219. Epub 2020 Jul 23.

Division of Hematology & Oncology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Hospital, Seoul, Korea.

Several high-dose therapy (HDT) conditioning regimens have been used to treat non-Hodgkin's lymphoma (NHL), such as bis-chloroethylnitrosourea (BCNU)/etoposide/cytosine arabinoside/melphalan (BEAM), BCNU/etoposide/cytosine arabinoside/cyclophosphamide (BEAC), and cyclophosphamide/BCNU/etoposide (CBV). BCNU is an active drug in HDT of NHL, but the supply is limited in some countries, including Korea. Busulfan has been used in allogeneic and autologous stem cell transplantation (ASCT). This phase II study evaluated the efficacy of busulfan/melphalan/etoposide (BuME) as a conditioning regimen for HDT in relapsed or high-risk NHL. The regimen consisted of intravenous busulfan (3.2 mg/kg/day) on days -8, -7, and -6, etoposide (400 mg/m /day) on days -5 and -4, and melphalan (50 mg/m /day) on days -3 and -2. A total of 46 patients were included in the study, with 36 (78.3%) achieving a complete response after ASCT. The 2-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 46.7% (95% CI, 31.8-60.4%) and 63.7% (95% CI, 47.7-76.0%), respectively. There was no development of veno-occlusive disease and no treatment-related deaths within 100 days after ASCT. These results indicate that a BuME regimen is well-tolerated and effective for patients with relapsed or high-risk NHL, and may be comparable to some previously used regimens. This regimen may be useful as a substitute for BCNU-containing regimens.
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http://dx.doi.org/10.1111/tri.13664DOI Listing
October 2020

Inhibition of HIF-1α by Atorvastatin During I-RTX Therapy in Burkitt's Lymphoma Model.

Cancers (Basel) 2020 May 11;12(5). Epub 2020 May 11.

Division of RI Application, Korea Institute of Radiological and Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea.

Backgrounds: Radioimmunotherapy (RIT) serves as a targeted therapy for non-Hodgkin lymphomas (NHL). Although HIF(Hypoxia-inducible factors)-1α is an important biomarker during radiation therapy, its role in NHL is unclear. Atorvastatin (ATV) is used as a combination drug for chemotherapy.

Methods: We investigated whether ATV downregulated tumor radio-resistance and enhanced the anticancer effect of I-RTX (rituximab) in Raji xenograft mouse models. First, the increased uptake and enhanced therapeutic effect of I-RTX by ATV was confirmed using molecular imaging in Raji xenograft subcutaneous model and orthotropic model with SPECT and IVIS images. Second, we examined the profile of differentially expressed miRNAs using miRNA array.

Results: We found that miR-346 inhibited HIF-1α/VEGF (Vascular endothelial growth factor) during ATV combination therapy with I-RTX. The underlying mechanism of ATV involved induction of anti-angiogenesis and radiosensitivity by downregulating HIF-1α in Raji cells.

Conclusion: Our findings suggested that combination therapy with ATV and I-RTX is a promising strategy for enhancing the potency of I-RTX therapy in poorly responding patients and those with radio-resistance.
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http://dx.doi.org/10.3390/cancers12051203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281655PMC
May 2020

Synthesis and Characterization of Fluorine-18-Labeled -(4-Chloro-3-((fluoromethyl-)thio)phenyl)picolinamide for Imaging of mGluR4 in Brain.

J Med Chem 2020 03 4;63(6):3381-3389. Epub 2020 Mar 4.

Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, 125 Nashua Street, Suite 660, Boston, Massachusetts 02114, United States.

We have synthesized and characterized [F]--(4-chloro-3-((fluoromethyl-)thio)phenyl)-picolinamide ([F]) as a potential ligand for the positron emission tomography (PET) imaging of mGluR4 in the brain. Radioligand [F] displays central nervous system drug-like properties, including mGluR4 affinity, potent mGluR4 PAM activity, and selectivity against other mGluRs, as well as sufficient metabolic stability. Radiosynthesis was carried out in two steps. The radiochemical yield of [F] was 11.6 ± 2.9% ( = 7, decay corrected) with a purity of 99% and a molar activity of 84.1 ± 11.8 GBq/μmol. Ex vivo biodistribution studies showed reversible binding of [F] in all investigated tissues including the brain, liver, heart, lungs, and kidneys. PET imaging studies in male Sprague Dawley rats showed that [F] accumulates in the brain regions known to express mGluR4. Pretreatment with the unlabeled mGluR4 PAM compounds (methylthio analogue) and showed significant dose-dependent blocking effects. These results suggest that [F] is a promising radioligand for PET imaging mGluR4 in the brain.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261135PMC
March 2020

Virtual discovery of melatonin receptor ligands to modulate circadian rhythms.

Nature 2020 03 10;579(7800):609-614. Epub 2020 Feb 10.

Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), The State University of New York, Buffalo, NY, USA.

The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT and MT. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep and depression. Despite their importance, few in vivo active MT-selective ligands have been reported, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT- but not in MT-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.
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http://dx.doi.org/10.1038/s41586-020-2027-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7134359PMC
March 2020

Pomalidomide, cyclophosphamide, and dexamethasone for elderly patients with relapsed and refractory multiple myeloma: A study of the Korean Multiple Myeloma Working Party (KMMWP-164 study).

Am J Hematol 2020 04 24;95(4):413-421. Epub 2020 Jan 24.

Department of Internal Medicine, Seoul St. Mary's Hospital, Catholic University of Korea, Seoul, South Korea.

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.
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http://dx.doi.org/10.1002/ajh.25726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983889PMC
April 2020

A phase II study of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx) for patients with refractory or relapsed Hodgkin's lymphoma.

Ann Hematol 2020 Feb 2;99(2):255-264. Epub 2020 Jan 2.

Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea.

We assessed the efficacy and toxicity of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx) combination chemotherapy in patients with refractory or relapsed Hodgkin's lymphoma (HL). This was an open-label, non-randomized, multi-center phase II study. The ESHAOx regimen consisted of intravenous (i.v.) etoposide 40 mg/m on days 1 to 4, i.v. methylprednisolone 500 mg on days 1 to 5, i.v. cytarabine 2 g/m on day 5, and i.v. oxaliplatin 130 mg/m on day 1. Cycles (up to six) were repeated every 3 weeks. In an effort to identify prognostic markers, the serum levels of cytokines including tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and vascular endothelial growth factor (VEGF) were measured at the time of study entry. A total of 37 patients were enrolled, and 36 were available for evaluation of tumor response. The overall response rate was 72.2% (26/36) (complete response, 33.3% [12/36]; partial response, 38.9% [14/36]). The median time to progression was 34.9 months (95% confidence interval, 23.1-46.7 months). The most common grade 3 or 4 hematological adverse events were neutropenia (16/37, 43.2%), followed by thrombocytopenia (10/37, 27.0%). Grade 3 or 4 non-hematological adverse events were nausea (3/37, 8.1%), anorexia (2/37, 5.4%), mucositis (1/37, 2.7%), and skin rash (1/37, 2.7%). There were no treatment-related deaths. High levels of TNF-α and CRP were significantly associated with poorer overall survival (p = 0.00005 for TNF-α, p = 0.0004 for CRP, respectively). The ESHAOx regimen exhibited antitumor activity and an acceptable safety profile in patients with refractory or relapsed HL. Trial Registration: ClinicalTrials.gov. Registered February 21, 2011, https://clinicaltrials.gov/ct2/show/NCT01300156.
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http://dx.doi.org/10.1007/s00277-019-03891-9DOI Listing
February 2020

Clinical features and treatment outcomes of limited-stage mantle cell lymphoma: Consortium for Improving Survival of Lymphoma report.

Ann Hematol 2020 Feb 18;99(2):223-228. Epub 2019 Dec 18.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.

Limited-stage (Ann Arbor stage I or II) mantle cell lymphoma (MCL) is an extremely rare disease. Thus, there is little data on the clinical features and treatment outcomes of patients with early-stage MCL. We examined consecutive stage I or II MCL 41 cases diagnosed between 2000 and 2016 in 16 institutions of the Consortium for Improving Survival of Lymphoma group. All cases were pathologically confirmed and systemic evaluation was performed for staging. The clinical features were reviewed, and the treatment outcomes were analyzed. The median age of patients was 66 years (range 19-85 years); there were more men (n = 31, 75.6%) than women. Most patients (n = 28, 68.3%) had stage 2 disease, and 29 (70.7%) were symptomatic. The elevation of lactate dehydrogenase (n = 2, 4.9%) was not common; thus, 39 patients (95.1%) had a low-risk score (0 or 1) for the International Prognostic Index, and 28 (68.3%) had a low-risk score (1-3) for the MCL International Prognostic Index. Most patients (n = 37, 90.1%) received chemotherapy as the first therapeutic strategy, while some received radiotherapy (n = 2), surgical resection (n = 1), or no treatment (n = 1). Of the patients who received chemotherapy, 23 (56.9%) received a rituximab-containing regimen, and R-CHOP (n = 17) and R-bendamustine (n = 5) were commonly used. The best response was noted in 97.4% (n = 38) of patients, including 32 who showed a complete response (78%). With a median follow-up duration of 40.6 months, the 42 months relapse-free survival was 59.1%, and the 5-year overall survival rate was 80.4%. Limited-state MCL showed indolent clinical and low-risk prognostic features. Chemotherapy could be effective for controlling localized MCL lesions, with high complete response rates.
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http://dx.doi.org/10.1007/s00277-019-03803-xDOI Listing
February 2020

Correction to: Clinical outcomes in patients with diffuse large B cell lymphoma with a partial response to first-line R-CHOP chemotherapy: prognostic value of secondary International Prognostic Index scores and Deauville scores.

Ann Hematol 2020 01;99(1):213

Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, 50-1 Yonsei-ro, Seoul, Seodaemun-gu, 03722, South Korea.

An additional affiliation for the first author was not indicated. Hyewon Lee is also affiliated with: Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, South Korea.
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http://dx.doi.org/10.1007/s00277-019-03868-8DOI Listing
January 2020

Ruxolitinib shows activity against Hodgkin lymphoma but not primary mediastinal large B-cell lymphoma.

BMC Cancer 2019 Nov 10;19(1):1080. Epub 2019 Nov 10.

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

Background: The upregulated expression of the JAK/STAT pathway promotes tumor growth in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL). Based on the hypothesis that JAK2 is a therapeutic target, we performed a prospective pilot study using ruxolitinib.

Methods: Relapsed or refractory patients with HL or PMBCL were eligible for this study, and JAK2 amplification was assessed by fluorescence in situ hybridization. Ruxolitinib was administered orally at a dose of 20 mg twice daily for a 28-day cycle. Treatment was continued for up to 16 cycles or until progressive disease or intolerability. The primary objective was to assess the overall disease control rate comprising complete response (CR), partial response (PR), or stable disease (SD).

Results: We analyzed 13 HL patients and six PMBCL patients. All responders (one CR, five PR, and one SD) had HL whereas all cases of PMBCL progressed after first or second cycle. The disease control rate for HL was 54% (7/13) with median response duration of 5.6 months. JAK2 amplification was present in six of nine patients tested (four HL, two PMBCL), and three of these HL patients showed PR (n = 2) or SD (n = 1). None of the three HL patients shown to not have JAK2 amplification responded to ruxolitinib. Most treatment-related adverse events were grade 1 or 2 and manageable.

Conclusions: Ruxolitinib has single-agent activity against HL but does not act against PMBCL with or without JAK2 amplification.

Trial Registration: The study population was patients who had relapsed or refractory HL or PMBCL, and patients were registered for our pilot study after providing written informed consent between November 2013 and November 2015 (CilinicalTrials.gov: NCT01965119).
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http://dx.doi.org/10.1186/s12885-019-6303-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842512PMC
November 2019

Comparisons of I-rituximab treatment responses in patients with aggressive lymphoma and indolent lymphoma.

Ann Nucl Med 2019 Dec 30;33(12):881-890. Epub 2019 Sep 30.

Department of Nuclear Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75, Nowon-ro, Nowon-gu, Seoul, Korea.

Objective: We evaluated the changes in treatment response over time after single I-rituximab radioimmunotherapy (RIT) according to non-Hodgkin lymphoma (NHL) types.

Methods: Fifteen aggressive and 21 indolent lymphoma cases undergoing RIT were evaluated. All patients underwent F-FDG-PET-CT before and 5 days, 1, and 3 months after RIT. The maximum standardized uptake value (SUV) and the sum of the products of the longest perpendicular diameters of tumours (SPD) were evaluated. Treatment responses were evaluated 1 and 3 months after RIT RESULTS: In aggressive lymphoma, SUV decreased at 5 days after RIT but increased after that. SPD decreased at 1 month but significantly increased at 3 months. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) at 1 month after RIT were changed to PD at 3 months after RIT. In indolent lymphoma, the SUV decreased continuously until 1 month after RIT. The SPD significantly decreased at 1 month and tended to further decrease to 3 months. CR, PR, SD, and PD at 1 month after RIT were achieved in 0, 8, 13, and 0 cases, respectively. Among the 13 SD cases, one changed to CR, three changed to PR, and nine had not changed at 3 months after RIT.

Conclusions: The treatment response to single RIT differed depending on NHL type. These findings suggest a need to establish an optimal treatment regimen based on NHL aggressiveness.
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http://dx.doi.org/10.1007/s12149-019-01401-5DOI Listing
December 2019

Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation.

Nat Commun 2019 09 9;10(1):4078. Epub 2019 Sep 9.

Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA.

Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish.
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http://dx.doi.org/10.1038/s41467-019-11936-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733874PMC
September 2019

Efficacy of Brentuximab Vedotin in Relapsed or Refractory High-CD30-Expressing Non-Hodgkin Lymphomas: Results of a Multicenter, Open-Labeled Phase II Trial.

Cancer Res Treat 2020 Apr 13;52(2):374-387. Epub 2019 Aug 13.

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

Purpose: The treatment outcome of brentuximab vedotin (BV) has not been related with CD30 expression in previous studies enrolling patients with a wide range of CD30 expression level. Thus, this study explored the efficacy of BV in high-CD30-expressing non-Hodgkin lymphoma (NHL) patients most likely to benefit.

Materials And Methods: This phase II study (Clinicaltrials.gov: NCT02280785) enrolled relapsed or refractory high-CD30-expressing NHL, with BV administered intravenously at 1.8 mg/kg every 3 weeks. The primary endpoint was > 40% disease control rate, consisting of complete response (CR), partial response (PR), or stable disease. We defined high CD30 expression as ≥ 30% tumor cells positive for CD30 by immunohistochemistry.

Results: High-CD30-expressing NHL patients (n=33) were enrolled except anaplastic large cell lymphoma. The disease control rate was 48.5% (16/33) including six CR and six PR; six patients (4CR, 2PR) maintained their response over 16 completed cycles. Response to BV and survival were not associated with CD30 expression levels. Over a median of 29.2 months of follow-up, the median progression-free and overall survival rates were 1.9 months and 6.1 months, respectively. The most common adverse events were fever (39%), neutropenia (30%), fatigue (24%), and peripheral sensory neuropathy (27%). In a post-hoc analysis for the association of multiple myeloma oncogene 1 (MUM1) on treatment outcome, MUM1- negative patients showed a higher response (55.6%, 5/9) than MUM1-positive patients (13.3%, 2/15).

Conclusion: BV performance as a single agent was acceptable in terms of disease control rates and toxicity profiles, especially MUM1-negative patients.
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http://dx.doi.org/10.4143/crt.2019.198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176958PMC
April 2020

Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair.

JCI Insight 2019 08 22;4(16). Epub 2019 Aug 22.

Cell Regeneration Research Center, Chonnam National University Hospital, Gwangju, Korea.

Mesenchymal stem cells (MSCs) can suppress pathological inflammation. However, the mechanisms underlying the association between MSCs and inflammation remain unclear. Under coculture conditions with macrophages, MSCs highly expressed angiopoietin-like 4 (ANGPTL4) to blunt the polarization of macrophages toward the proinflammatory phenotype. ANGPTL4-deficient MSCs failed to inhibit the inflammatory macrophage phenotype. In inflammation-related animal models, the injection of coculture medium or ANGPTL4 protein increased the antiinflammatory macrophages in both peritonitis and myocardial infarction. In particular, cardiac function and pathology were markedly improved by ANGPTL4 treatment. We found that retinoic acid-related orphan receptor α (RORα) was increased by inflammatory mediators, such as IL-1β, and bound to ANGPTL4 promoter in MSCs. Collectively, RORα-mediated ANGPTL4 induction was shown to contribute to the antiinflammatory activity of MSCs against macrophages under pathological conditions. This study suggests that the capability of ANGPTL4 to induce tissue repair is a promising opportunity for safe stem cell-free regeneration therapy from a translational perspective.
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http://dx.doi.org/10.1172/jci.insight.125437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777833PMC
August 2019

Radiologic serosal invasion sign as a new criterion of T4a gastric cancer on computed tomography: diagnostic performance and prognostic significance in patients with advanced gastric cancer.

Abdom Radiol (NY) 2020 10;45(10):2950-2959

Department of Radiology, Kyung Hee University Hospital, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.

Purpose: To investigate the diagnostic performance and prognostic significance of a new criterion for radiologic T4a staging on computed tomography (CT) in patients with advanced gastric cancer (AGC).

Methods: Between January 2010 and April 2019, 101 patients with pathologically confirmed gastric cancer were collected. Among them, 53 patients with pathologic T3 and T4a cancers were included in this study. Three reviewers assessed preoperative CT scans for radiologic T staging in two sessions, independently and in consensus at a 2-week interval, while blinded about the pathologic T stage. The radiologic serosal invasion sign was defined as a nodular extension from the outer gastric wall reaching beyond the perigastric vascular plane and adopted as a new CT criterion for T4a cancer. We evaluated the diagnostic performance, interobserver agreement, and prognostic significance of this sign for the postoperative recurrence.

Results: There were 46 pathologic T3 cancers (86.7%) and seven pathologic T4a cancers (13.2%). The diagnostic performance of the radiologic serosal invasion sign in the differentiation between T3 and T4a cancers was as follows: sensitivity, 91.3%; specificity, 71.43%; and accuracy, 88.68% for R1 and sensitivity, 78.26%; specificity, 85.71%; and accuracy, 79.25% for R2. The k-value was 0.64. Among the clinical and pathologic variables, radiologic T4a sign [hazard ratio (HR): 7.96; 95% confidence interval (CI) 2.36-26.86, p = 0.001], pathologic T4a (HR 9.82, 95% CI 2.35-40.95, p = 0.002), tumor size (HR 1.18, 95% CI 1.02-1.35, p = 0.026), and lymphovascular invasion (HR 6.39, 95% CI 1.42-28.75, p = 0.015) were the significant factors for postoperative recurrence.

Conclusions: Radiologic serosal invasion sign is reliable as a new CT criterion for T4a cancer staging in patients with advanced gastric cancer, demonstrating 80% to 88% accuracy. Radiologic serosal invasion sign can also serve as a prognostic factor for postoperative recurrence as well as pathologic T4a stage.
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http://dx.doi.org/10.1007/s00261-019-02156-3DOI Listing
October 2020

Synergistic Effect of Lymphatic Invasion and Venous Invasion on the Risk of Lymph Node Metastasis in Patients with Non-Curative Endoscopic Resection of Early Gastric Cancer.

J Gastrointest Surg 2020 07 16;24(7):1499-1509. Epub 2019 Jul 16.

Department of Internal Medicine and Liver Research Institute, College of Medicine, Seoul National University, Seoul, South Korea.

Background: Although additive radical surgery is recommended for patients with non-curative endoscopic resection for early gastric cancer (EGC), lymph node (LN) metastasis or remnant tumor is detected in only about 10% of patients. Therefore, we aimed to identify patients who required surgery by identifying significant risk factors for LN metastasis and evaluate long-term outcomes in patients with non-curative endoscopic resection.

Methods: We retrospectively analyzed the database of Seoul National University Hospital to identify patients who underwent endoscopic resection for EGC from June 2005 to December 2016.

Results: Three hundred and twenty-nine patients did not meet the criteria for curative resection after endoscopic resection. Among them, 140 patients underwent additional surgery and 171 patients refused surgery and regularly received follow-up. In the surgery group, LN metastasis was found in 12.1% of patients. Logistic regression analysis revealed that the rate of LN metastasis was significantly higher in patients with lymphatic invasion (LI) (odds ratio [OR] 5.84, p = 0.014) and venous invasion (VI) (OR 5.66, p = 0.006). We analyzed LN metastasis based on LI and VI in the surgical group. LN metastasis was significantly increased in the positive LI and VI groups compared with the negative LI and VI groups (OR 68.32; 95% confidence interval, 4.74-984.82; p = 0.002).

Conclusions: Both LI and VI were significant predictors of LN metastasis. The risk of LN metastasis was augmented when both LI and VI were positive. Therefore, LI and VI should be evaluated separately in patients with non-curative endoscopic resection. Additive surgery should be recommended for patients with LI and/or VI.
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http://dx.doi.org/10.1007/s11605-019-04302-0DOI Listing
July 2020
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