Publications by authors named "Joo Ho Lee"

111 Publications

All-cause and cause-specific mortality of patients with rheumatoid arthritis in Korea: A nation-wide population-based study.

Joint Bone Spine 2021 Sep 14:105269. Epub 2021 Sep 14.

Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea. Electronic address:

Objective: To compare all-cause and cause-specific mortality between rheumatoid arthritis (RA) patients versus the general population of Korea Methods: A nationally representative RA population aged ≥40 years was identified from Korea National Health Insurance Service (KNHIS) database. We estimated age- and sex-adjusted all-cause and cause-specific standardized mortality ratios (SMRs) with 95% confidence intervals (CIs), comparing RA patients to the general population. Subgroup analyses were done by sex, age group, calendar year, and biologics use.

Results: We identified 79,352 RA patients with 6,404 deaths during 2011-2016. The all-cause SMR [95% CI] of RA patients compared to the general population was 1.53 [1.49-1.56]. The top five causes of death were cancer (19.5%), respiratory disease (19.1%), cardiovascular disease (18.8%), systemic rheumatic diseases (9.5%, 9.1% due to RA), and infection (6.1%). Cause-specific SMRs [95% CI] were 0.95 [0.90-1.01] for cancer, 3.34 [3.15-3.52] for respiratory disease, 1.26 [1.18-1.33] for cardiovascular disease, 3.41 [3.08-3.75] for infection, and 4.88 [3.10-6.65] for non-RA systemic rheumatic disease. The SMR of RA population was slightly higher among men than women, and highest in their 60s and 70s. The yearly SMR increased from 1.10 [1.01-1.18] in 2011 to 1.85 [1.75-1.95] in 2016 due to population aging and comorbidity accumulation. Users of biologics showed a higher SMR than non-users (1.82 [1.69-1.96] vs. 1.50 [1.46-1.54]), due to higher RA activity, and more comorbidities despite a younger mean age.

Conclusion: RA patients in Korea experienced 1.5-fold increase in all-cause mortality compared to the general population. Except for cancer, the top five causes of death were associated with excess mortality among RA patients. RA-associated mortality was largely determined by age, RA activity, and comorbidity status.
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http://dx.doi.org/10.1016/j.jbspin.2021.105269DOI Listing
September 2021

Correction to: Short-term changes in the serum metabolome after laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass.

Metabolomics 2021 Sep 14;17(9):85. Epub 2021 Sep 14.

Molecular Recognition Research Center, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea.

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http://dx.doi.org/10.1007/s11306-021-01838-8DOI Listing
September 2021

Short-term changes in the serum metabolome after laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass.

Metabolomics 2021 08 5;17(8):71. Epub 2021 Aug 5.

Molecular Recognition Research Center, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea.

Introduction: Bariatric surgery is known to be the most effective treatment for weight loss in obese patients and for the rapid remission of obesity-related comorbidities. These short-term improvements result from not only limited digestion or absorption but also dynamic changes in metabolism throughout the whole body. However, short-term metabolism studies associated with bariatric surgery in Asian individuals have not been reported.

Objectives: The aim of this study was to investigate the short-term metabolome changes in the serum promoted by laparoscopic sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) and to determine the underlying mechanisms that affect obesity-related comorbidities.

Methods: Serum samples were collected from Korean patients who underwent RYGB or SG before and 4 weeks after the surgery. Metabolomic and lipidomic profiling was performed using UPLC-Orbitrap-MS, and data were analyzed using statistical analysis.

Results: Metabolites mainly related to amino acids, lipids (fatty acids, glycerophospholipids, sphingolipids, glycerolipids) and bile acids changed after surgery, and these changes were associated with the lowering of risk factors for obesity-related diseases such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and atherosclerosis. Interestingly, the number of significantly altered metabolites related to the lipid metabolism were greater in SG than in RYGB. Furthermore, the metabolites related to amino acid metabolism were significantly changed only after SG, whereas bile acid changed significantly only following RYGB.

Conclusion: These differences could result from anatomical differences between the two surgeries and could be related to the gut microbiota. This study provides crucial information to expand the knowledge of the common but different molecular mechanisms involved in obesity and obesity-related comorbidities affected by each bariatric procedure.
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http://dx.doi.org/10.1007/s11306-021-01826-yDOI Listing
August 2021

Radiological assessment schedule for 1p/19q-codeleted gliomas during the surveillance period using parametric modeling.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab069. Epub 2021 May 20.

Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Background: There have been no evidence-based guidelines on the optimal schedule for the radiological assessment of 1p/19q-codeleted glioma. This study aimed to recommend an appropriate radiological evaluation schedule for 1p/19q-codeleted glioma during the surveillance period through parametric modeling of the progression-free survival (PFS) curve.

Methods: A total of 234 patients with 1p/19q-codeleted glioma (137 grade II and 97 grade III) who completed regular treatment were retrospectively reviewed. The patients were stratified into each layered progression risk group by recursive partitioning analysis. A piecewise exponential model was used to standardize the PFS curves. The cutoff value of the progression rate among the remaining progression-free patients was set to 10% at each scan.

Results: Progression risk stratification resulted in 3 groups. The optimal magnetic resonance imaging (MRI) interval for patients without a residual tumor was every 91.2 weeks until 720 weeks after the end of regular treatment following the latent period for 15 weeks. For patients with a residual tumor after the completion of adjuvant radiotherapy followed by chemotherapy, the optimal MRI interval was every 37.5 weeks until week 90 and every 132.8 weeks until week 361, while it was every 33.6 weeks until week 210 and every 14.4 weeks until week 495 for patients with a residual tumor after surgery only or surgery followed by radiotherapy only.

Conclusions: The optimal radiological follow-up schedule for each progression risk stratification of 1p/19q-codeleted glioma can be established from the parametric modeling of PFS.
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http://dx.doi.org/10.1093/noajnl/vdab069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284622PMC
May 2021

Prediction of Prognosis in Glioblastoma Using Radiomics Features of Dynamic Contrast-Enhanced MRI.

Korean J Radiol 2021 09 14;22(9):1514-1524. Epub 2021 Jul 14.

Department of Radiology, Seoul National University Hospital, Seoul, Korea.

Objective: To develop a radiomics risk score based on dynamic contrast-enhanced (DCE) MRI for prognosis prediction in patients with glioblastoma.

Materials And Methods: One hundred and fifty patients (92 male [61.3%]; mean age ± standard deviation, 60.5 ± 13.5 years) with glioblastoma who underwent preoperative MRI were enrolled in the study. Six hundred and forty-two radiomic features were extracted from volume transfer constant (K), fractional volume of vascular plasma space (V), and fractional volume of extravascular extracellular space (V) maps of DCE MRI, wherein the regions of interest were based on both T1-weighted contrast-enhancing areas and non-enhancing T2 hyperintense areas. Using feature selection algorithms, salient radiomic features were selected from the 642 features. Next, a radiomics risk score was developed using a weighted combination of the selected features in the discovery set (n = 105); the risk score was validated in the validation set (n = 45) by investigating the difference in prognosis between the "radiomics risk score" groups. Finally, multivariable Cox regression analysis for progression-free survival was performed using the radiomics risk score and clinical variables as covariates.

Results: 16 radiomic features obtained from non-enhancing T2 hyperintense areas were selected among the 642 features identified. The radiomics risk score was used to stratify high- and low-risk groups in both the discovery and validation sets (both < 0.001 by the log-rank test). The radiomics risk score and presence of isocitrate dehydrogenase (IDH) mutation showed independent associations with progression-free survival in opposite directions (hazard ratio, 3.56; = 0.004 and hazard ratio, 0.34; = 0.022, respectively).

Conclusion: We developed and validated the "radiomics risk score" from the features of DCE MRI based on non-enhancing T2 hyperintense areas for risk stratification of patients with glioblastoma. It was associated with progression-free survival independently of IDH mutation status.
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http://dx.doi.org/10.3348/kjr.2020.1433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390822PMC
September 2021

Radiotherapy Versus Surgery in Early-Stage HPV-positive Oropharyngeal Cancer.

Cancer Res Treat 2021 Jun 23. Epub 2021 Jun 23.

Department of Radiation Oncology, SMG-SNU Boramae Medical Center, Seoul, Korea.

Purpose: To compare the outcomes of primary radiotherapy (RT) versus surgery in early-stage human papilloma virus-positive oropharyngeal squamous cell carcinoma (hpv+OPC), and investigate the preoperative clinical factors that can predict the requirement for postoperative adjuvant treatment.

Materials And Methods: This multicenter study included 166 patients with AJCC 8th edition-Stages I-II hpv+OPC. Sixty (36.1%) and 106 (63.9%) patients underwent primary (CC)RT and surgery, respectively. Seventy-eight (73.6%) patients in the surgery group received postoperative (CC)RT.

Results: With a median follow-up of 45.6 months for survivors, the 2-year overall survival (OS), progression-free survival (PFS), and locoregional control (LC) for radiotherapy/surgery were 97.8%/96.4%, 91.1%/92.0%, and 92.9%/93.3%, respectively. In multivariate analyses, patients with synchronous radiologic extranodal extension and conglomeration (ENEcong) of metastatic LNs showed significantly poorer OS (p=0.047), PFS (p=0.001) and LC (p=0.003). In patients undergoing primary surgery, two or more clinically positive LN metastases (OR, 5.15; p=0.004) and LN metastases with ENEcong (OR, 3.75; p=0.009) were predictors of postoperative chemoradiotherapy. No patient in the primary radiotherapy group demonstrated late severe toxicity whereas 3 (2.8%), 1 (0.9%), and 1 (0.9%) patient in the surgery group showed grade 3 dysphagia, grade 3 xerostomia, and fatal oral cavity bleeding.

Conclusion: We found no differences in OS, PFS, and LC between upfront radiotherapy and surgery in stage I-II hpv+OPC which warrants comparison through a prospective trial in the treatment de-escalation era. However, most early-stage hpv+OPC patients undergoing surgery received adjuvant (CC)RT. Pretreatment LN findings were prognostic and predictive for adjuvant treatment.
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http://dx.doi.org/10.4143/crt.2021.441DOI Listing
June 2021

Differentiation between glioblastoma and primary CNS lymphoma: application of DCE-MRI parameters based on arterial input function obtained from DSC-MRI.

Eur Radiol 2021 May 18. Epub 2021 May 18.

Department of Radiology, Seoul National University College of Medicine, Seoul, Republic of Korea.

Objective: This study aimed to evaluate whether arterial input functions (AIFs) obtained from dynamic susceptibility contrast (DSC)-MRI (AIF) improve the reliability and diagnostic accuracy of dynamic contrast-enhanced (DCE)-derived pharmacokinetic (PK) parameters for differentiating glioblastoma from primary CNS lymphoma (PCNSL) compared with AIFs derived from DCE-MRI (AIF).

Methods: This retrospective study included 172 patients with glioblastoma (n = 147) and PCNSL (n = 25). All patients had undergone preoperative DSC- and DCE-MRI. The volume transfer constant (K), volume of the vascular plasma space (v), and volume of the extravascular extracellular space (v) were acquired using AIF and AIF. The relative cerebral blood volume (rCBV) was obtained from DSC-MRI. Intraclass correlation coefficients (ICC) and ROC curves were used to assess the reliability and diagnostic accuracy of individual parameters.

Results: The mean K, v, and v values revealed better ICCs with AIF than with AIF (K, 0.911 vs 0.355; v, 0.766 vs 0.503; v, 0.758 vs 0.657, respectively). For differentiating all glioblastomas from PCNSL, the mean rCBV (AUC = 0.856) was more accurate than the AIF-driven mean K, which had the largest AUC (0.711) among the DCE-derived parameters (p = 0.02). However, for glioblastomas with low rCBV (≤ 75th percentile of PCNSL; n = 30), the AIF-driven mean K and v were more accurate than rCBV (AUC: K, 0.807 vs rCBV, 0.515, p = 0.004; v, 0.715 vs rCBV, p = 0.045).

Conclusion: DCE-derived PK parameters using the AIF showed improved reliability and diagnostic accuracy for differentiating glioblastoma with low rCBV from PCNSL.

Key Points: • An accurate differential diagnosis of glioblastoma and PCNSL is crucial because of different therapeutic strategies. • In contrast to the rCBV from DSC-MRI, another perfusion imaging technique, the DCE parameters for the differential diagnosis have been limited because of the low reliability of AIFs from DCE-MRI. • When we analyzed DCE-MRI data using AIFs from DSC-MRI (AIF), AIF-driven DCE parameters showed improved reliability and better diagnostic accuracy than rCBV for differentiating glioblastoma with low rCBV from PCNSL.
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http://dx.doi.org/10.1007/s00330-021-08044-zDOI Listing
May 2021

3D Facial Pain Expression for a Care Training Assistant Robot in an Elderly Care Education Environment.

Front Robot AI 2021 29;8:632015. Epub 2021 Apr 29.

Advanced Intelligent System Laboratory, Faculty of Information Science and Engineering, Ritsumeikan University, Shiga, Japan.

As the elderly population increases, the importance of the caregiver's role in the quality of life of the elderly has increased. To achieve effective feedback in terms of care and nursing education, it is important to design a robot that can express emotions or feel pain like an actual human through visual-based feedback. This study proposes a care training assistant robot (CaTARo) system with 3D facial pain expression that simulates an elderly person for improving the skills of workers in elderly care. First, in order to develop an accurate and efficient system for elderly care training, this study introduces a fuzzy logic-based care training evaluation method that can calculate the pain level of a robot for giving the feedback. Elderly caregivers and trainees performed the range of motion exercise using the proposed CaTARo. We obtained quantitative data from CaTARo, and the pain level was calculated by combining four key parameters using the fuzzy logic method. Second, we developed a 3D facial avatar for use in CaTARo that is capable of expressing pain based on the UNBC-McMaster Pain Shoulder Archive, and we then generated four pain groups with respect to the pain level. To mimic the conditions for care training with actual humans, we designed the system to provide pain feedback based on the opinions of experts. The pain feedback was expressed in real time by using a projector and a 3D facial mask during care training. The results of the study confirmed the feasibility of utilizing a care training robot with pain expression for elderly care training, and it is concluded that the proposed approach may be used to improve caregiving and nursing skills upon further research.
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http://dx.doi.org/10.3389/frobt.2021.632015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118714PMC
April 2021

Radiomics-based neural network predicts recurrence patterns in glioblastoma using dynamic susceptibility contrast-enhanced MRI.

Sci Rep 2021 05 11;11(1):9974. Epub 2021 May 11.

Seoul National University College of Medicine, Seoul, Republic of Korea.

Glioblastoma remains the most devastating brain tumor despite optimal treatment, because of the high rate of recurrence. Distant recurrence has distinct genomic alterations compared to local recurrence, which requires different treatment planning both in clinical practice and trials. To date, perfusion-weighted MRI has revealed that perfusional characteristics of tumor are associated with prognosis. However, not much research has focused on recurrence patterns in glioblastoma: namely, local and distant recurrence. Here, we propose two different neural network models to predict the recurrence patterns in glioblastoma that utilizes high-dimensional radiomic profiles based on perfusion MRI: area under the curve (AUC) (95% confidence interval), 0.969 (0.903-1.000) for local recurrence; 0.864 (0.726-0.976) for distant recurrence for each patient in the validation set. This creates an opportunity to provide personalized medicine in contrast to studies investigating only group differences. Moreover, interpretable deep learning identified that salient radiomic features for each recurrence pattern are related to perfusional intratumoral heterogeneity. We also demonstrated that the combined salient radiomic features, or "radiomic risk score", increased risk of recurrence/progression (hazard ratio, 1.61; p = 0.03) in multivariate Cox regression on progression-free survival.
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http://dx.doi.org/10.1038/s41598-021-89218-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113258PMC
May 2021

The Role of Postoperative Radiotherapy in Intracranial Solitary Fibrous Tumor/Hemangiopericytoma: A Multi-Institutional Retrospective Study (KROG 18-11).

Cancer Res Treat 2021 Mar 24. Epub 2021 Mar 24.

Department of Radiation Oncology, Seoul National University Hospital, Seoul National University, College of Medicine, Seoul, Korea.

Purpose: To evaluate the role of postoperative radiotherapy (PORT) in intracranial solitary fibrous tumor/hemangiopericytoma (SFT/HPC).

Methods And Materials: A total of 133 patients with histologically confirmed HPC were included from 8 institutions. Gross total resection (GTR) and subtotal resection (STR) were performed in 86 and 47 patients, respectively. PORT was performed in 85 (64%) patients. The prognostic effects of sex, age, performance, WHO grade, location, size, Ki-67, surgical extent, and PORT on local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) were estimated by univariate and multivariate analyses.

Results: The 10-year PFS, and OS rates were 45%, and 71%, respectively. The multivariate analysis suggested that PORT significantly improved LC (p<0.001) and PFS (p<0.001). The PFS benefit of PORT was maintained in the subgroup of GTR (p=0.001), WHO grade II (p=0.001) , or STR (p<0.001). In the favorable subgroup of GTR and WHO grade II, PORT was also significantly related to better PFS (p=0.028). WHO grade III was significantly associated with poor DMFS (p=0.029). In the PORT subgroup, the 0-0.5 cm margin of the target volume showed an inferior LC to a large margin with 1.0-2.0 cm (p=0.021). Time-dependent Cox proportion analysis showed that distant failures were significantly associated with poor OS (p=0.003).

Conclusion: This multicenter study supports the role of PORT in disease control of intracranial SFT/HPC, irrespective of the surgical extent and grade. For LC, PORT should enclose the tumor bed with sufficient margin.
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http://dx.doi.org/10.4143/crt.2021.142DOI Listing
March 2021

Long-Term Outcomes and Sequelae Analysis of Intracranial Germinoma: Need to Reduce the Extended-Field Radiotherapy Volume and Dose to Minimize Late Sequelae.

Cancer Res Treat 2021 Jan 13. Epub 2021 Jan 13.

Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Purpose: We aimed to refine the radiotherapy (RT) volume and dose for intracranial germinoma considering recurrences and long-term toxicities.

Materials And Methods: Total 189 patients with intracranial germinoma were treated with RT alone (n=50) and RT with upfront chemotherapy (CRT) (n=139). All cases were confirmed histologically. RT fields comprised the extended-field and involved-field only for primary site. The extended-field, including craniospinal, whole-brain (WB), and whole-ventricle (WV) for cranial field, is followed by involved-field boost. The median follow-up duration was 115 months.

Results: The relapses developed in 13 patients (6.9%). For the extended-field, cranial RT dose down to 18 Gy exhibited no cranial recurrence in 34 patients. In CRT, 74 patients (56.5%) showed complete response to chemotherapy and no involved-field recurrence with low-dose RT of 30 Gy. WV RT with chemotherapy for the basal ganglia or thalamus germinoma showed no recurrence. Secondary malignancy developed in ten patients (5.3 %) with a latency of 20 years (range, 4-26) and caused mortalities in six. WB or craniospinal field rather than WV or involved-field significantly increased the rate of hormone deficiencies, and secondary malignancy. RT dose for extended-field correlated significantly with the rate of hormone deficiencies, secondary malignancy, and neurocognitive dysfunction.

Conclusion: Reduced dose and volume of extended-field rather than total dose or involved-field will be critical to decrease the late toxicities. Upfront chemotherapy could be beneficial for the patients with complete response to minimize the RT dose down to 30 Gy. Prospective trials focused on de-intensification of the extended-field RT are warranted.
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http://dx.doi.org/10.4143/crt.2020.1052DOI Listing
January 2021

Absolute quantification of tumor-infiltrating immune cells in high-grade glioma identifies prognostic and radiomics values.

Cancer Immunol Immunother 2021 Jul 8;70(7):1995-2008. Epub 2021 Jan 8.

Department of Neurosurgery, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.

Purpose: To understand the tumor immune microenvironment precisely, it is important to secure the quantified data of tumor-infiltrating immune cells, since the immune cells are true working unit. We analyzed unit immune cell number per unit volume of core tumor tissue of high-grade gliomas (HGG) to correlate their immune microenvironment characteristics with clinical prognosis and radiomic signatures.

Methods: The number of tumor-infiltrating immune cells from 64 HGG core tissue were analyzed using flow cytometry and standardized. After sorting out patient groups according to diverse immune characteristics, the groups were tested if they have any clinical prognostic relevance and specific radiomic signature relationships. Sparse partial least square with discriminant analysis using multimodal magnetic resonance images was employed for all radiomic classifications.

Results: The median number of CD45 + cells per one gram of HGG core tissue counted 865,770 cells which was equivalent to 8.0% of total cells including tumor cells. There was heterogeneity in the distribution of immune cell subpopulations among patients. Overall survival was significantly better in T cell-deficient group than T cell-enriched group (p = 0.019), and T8 dominant group than T4 dominant group (p = 0.023). The number of tumor-associated macrophages (TAM) and M2-TAM was significantly decreased in isocitrate dehydrogenase mutated HGG. Radiomic signature classification showed good performance in predicting immune phenotypes especially with features extracted from apparent diffusion coefficient maps.

Conclusions: Absolute quantification of tumor-infiltrating immune cells confirmed the heterogeneity of immune microenvironment in HGG which harbors prognostic impact. This immune microenvironment could be predicted by radiomic signatures non-invasively.
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http://dx.doi.org/10.1007/s00262-020-02836-wDOI Listing
July 2021

Enzymatic Characterization and Comparison of Two Steroid Hydroxylases CYP154C3-1 and CYP154C3-2 from Species.

J Microbiol Biotechnol 2021 Mar;31(3):464-474

Department of Life Science and Biochemical Engineering, Sunmoon University, Asan 31460, Republic of Korea.

Bacterial cytochrome P450 (CYP) enzymes are responsible for the hydroxylation of diverse endogenous substances with a heme molecule used as a cofactor. This study characterized two CYP154C3 proteins from sp. W2061 (CYP154C3-1) and sp. KCCM40643 (CYP154C3-2). The enzymatic activity assays of both CYPs conducted using heterologous redox partners' putidaredoxin and putidaredoxin reductase showed substrate flexibility with different steroids and exhibited interesting product formation patterns. The enzymatic characterization revealed good activity over a pH range of 7.0 to 7.8 and the optimal temperature range for activity was 30 to 37°C. The major product was the C16-hydroxylated product and the kinetic profiles and patterns of the generated hydroxylated products differed between the two enzymes. Both enzymes showed a higher affinity toward progesterone, with CYP154C3-1 demonstrating slightly higher activity than CYP154C3-2 for most of the substrates. Oxidizing agents (diacetoxyiodo) benzene (PIDA) and hydrogen peroxide (HO) were also utilized to actively support the redox reactions, with optimum conversion achieved at concentrations of 3 mM and 65 mM, respectively. The oxidizing agents affected the product distribution, influencing the type and selectivity of the CYP-catalyzed reaction. Additionally, CYP154C3s also catalyzed the C-C bond cleavage of steroids. Therefore, CYP154C3s may be a good candidate for the production of modified steroids for various biological uses.
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http://dx.doi.org/10.4014/jmb.2010.10020DOI Listing
March 2021

Prognostic Value of Alpha-Fetoprotein in Patients Who Achieve a Complete Response to Transarterial Chemoembolization for Hepatocellular Carcinoma.

Yonsei Med J 2021 Jan;62(1):12-20

Liver Center, Pusan National University Yangsan Hospital, Yangsan, Korea.

Purpose: Alpha-fetoprotein (AFP) is a prognostic marker for hepatocellular carcinoma (HCC). We investigated the prognostic value of AFP levels in patients who achieved complete response (CR) to transarterial chemoembolization (TACE) for HCC.

Materials And Methods: Between 2005 and 2018, 890 patients with HCC who achieved a CR to TACE were recruited. An AFP responder was defined as a patient who showed elevated levels of AFP (>10 ng/mL) during TACE, but showed normalization or a >50% reduction in AFP levels after achieving a CR.

Results: Among the recruited patients, 569 (63.9%) with naïve HCC and 321 (36.1%) with recurrent HCC after complete resection were treated. Before TACE, 305 (34.3%) patients had multiple tumors, 219 (24.6%) had a maximal tumor size >3 cm, and 22 (2.5%) had portal vein tumor thrombosis. The median AFP level after achieving a CR was 6.36 ng/mL. After a CR, 473 (53.1%) patients experienced recurrence, and 417 (46.9%) died [median progression-free survival (PFS) and overall survival (OS) of 16.3 and 62.8 months, respectively]. High AFP levels at CR (>20 ng/mL) were independently associated with a shorter PFS [hazard ratio (HR)=1.403] and OS (HR=1.284), together with tumor multiplicity at TACE (HR=1.518 and 1.666, respectively). AFP non-responders at CR (76.2%, n=359 of 471) showed a shorter PFS (median 10.5 months vs. 15.5 months, HR=1.375) and OS (median 41.4 months vs. 61.8 months, HR=1.424) than AFP responders (all =0.001).

Conclusion: High AFP levels and AFP non-responders were independently associated with poor outcomes after TACE. AFP holds clinical implications for detailed risk stratification upon achieving a CR after TACE.
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http://dx.doi.org/10.3349/ymj.2021.62.1.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820452PMC
January 2021

Metabolomic Profiles Predict Diabetes Remission after Bariatric Surgery.

J Clin Med 2020 Dec 1;9(12). Epub 2020 Dec 1.

Division of Foregut Surgery, Korea University College of Medicine, Seoul 02841, Korea.

Background: Amino acid metabolites (AAMs) have been linked to glucose homeostasis and type 2 diabetes (T2D). We investigated whether (1) baseline AAMs predict T2D remission 12 months after bariatric surgery and (2) whether AAMs are superior for predicting T2D remission postoperatively compared with existing prediction models.

Methods: Among 24 participants undergoing bariatric surgery, 16 diabetes-related AAMs were quantified at baseline and postoperative 3 and 12 months. Existing prediction models included the ABCD, DiaRem, and IMS models.

Results: Baseline L-dihydroxyphenylalanine (L-DOPA) (areas under receiver operating characteristic curves (AUROC), 0.92; 95% confidence interval (CI), 0.75 to 1.00) and 3-hydroxyanthranilic acid (3-HAA) (AUROC, 0.85; 95% CI, 0.67 to 1.00) better predicted T2D remission 12 months postoperatively than the ABCD model (AUROC, 0.81; 95% CI, 0.54 to 1.00), which presented the highest AUROC value among the three models. The superior prognostic performance of L-DOPA (AUROC at 3 months, 0.97; 95% CI, 0.91 to 1.00) and 3-HAA (AUROC at 3 months, 0.86; 95% CI, 0.63 to 1.00) continued until 3 months postoperatively.

Conclusions: The AAM profile predicts T2D remission after bariatric surgery more effectively than the existing prediction models.
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http://dx.doi.org/10.3390/jcm9123897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760750PMC
December 2020

Reactive oxygen species-induced activation of Yes-associated protein-1 through the c-Myc pathway is a therapeutic target in hepatocellular carcinoma.

World J Gastroenterol 2020 Nov;26(42):6599-6613

Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Bundang gu, South Korea.

Background: The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1 (YAP-1). Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis. The levels of reactive oxygen species (ROS) increase during the progression from early to advanced hepatocellular carcinoma (HCC).

Aim: To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway.

Methods: The expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761) was quantified using real-time polymerase chain reaction and immunoblotting. Human HCC cells were treated with HO, which is a major component of ROS in living organisms, and with either YAP-1 small interfering RNA (siRNA) or control siRNA. To investigate the role of YAP-1 in HCC cells under oxidative stress, MTS assays were performed. Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1. Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses.

Results: HO treatment increased the mRNA and protein expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761). Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during HO treatment both and (both < 0.05). The oncogenic action of YAP-1 occurred the activation of the c-Myc pathway, leading to the upregulation of components of the unfolded protein response (UPR), including 78-kDa glucose-regulated protein and activating transcription factor-6 (ATF-6). The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues ( < 0.05) and were positively correlated with the ATF-6 Levels (Pearson's coefficient = 0.299; < 0.05).

Conclusion: This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC. The ROS-induced activation of YAP-1 the c-Myc pathway, which leads to the activation of the UPR pathway, might be a therapeutic target in HCC.
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http://dx.doi.org/10.3748/wjg.v26.i42.6599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673967PMC
November 2020

Clinical and Genomic Characteristics of Adult Diffuse Midline Glioma.

Cancer Res Treat 2021 Apr 9;53(2):389-398. Epub 2020 Nov 9.

Department of Neurosurgery, Seoul National University Hospital, Seoul, Korea.

Purpose: The treatment outcomes and genomic profiles of diffuse midline glioma (DMG) in adult patients are rarely characterized. We performed a retrospective study to evaluate the clinicogenomic profiles of adult patients with brain DMG.

Materials And Methods: Patients aged ≥ 18 years diagnosed with brain DMG at Seoul National University Hospital were included. The clinicopathological parameters, treatment outcomes, survival, and genomic profiles using 82-gene targeted next-generation sequencing (NGS) were analyzed. The 6-month progression-free survival (PFS6) after radiotherapy and overall survival (OS) were evaluated.

Results: Thirty-three patients with H3-mutant brain DMG were identified. The median OS from diagnosis was 21.8 months (95% confidence interval [CI], 13.2 to not available [NA]) and involvement of the ponto-medullary area tended to have poor OS (median OS, 20.4 months [95% CI, 9.3 to NA] vs. 43.6 months [95% CI, 18.2 to NA]; p=0.07). Twenty-four patients (72.7%) received radiotherapy with or without temozolomide. The PFS6 rate was 83.3% (n=20). Patients without progression at 6 months showed significantly prolonged OS compared with those with progression at 6 months (median OS, 24.9 months [95% CI, 20.4 to NA] vs. 10.8 months [95% CI, 4.0 to NA]; p=0.02, respectively). Targeted NGS was performed in 13 patients with DMG, among whom nine (69.2%) harbored concurrent TP53 mutation. Two patients (DMG14 and DMG23) with PIK3CAR38S+E545K and KRASG12A mutations received matched therapies. Patient DMG14 received sirolimus with a PFS of 8.4 months.

Conclusion: PFS6 after radiotherapy was associated with prolonged survival in adult patients with DMG. Genome-based matched therapy may be an encouraging approach for progressive adult patients with DMG.
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http://dx.doi.org/10.4143/crt.2020.694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053865PMC
April 2021

Radiological assessment schedule for high-grade glioma patients during the surveillance period using parametric modeling.

Neuro Oncol 2021 05;23(5):837-847

Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine.

Background: An optimal radiological surveillance plan is crucial for high-grade glioma (HGG) patients, which is determined arbitrarily in daily clinical practice. We propose the radiological assessment schedule using a parametric model of standardized progression-free survival (PFS) curves.

Methods: A total of 277 HGG patients (178 glioblastoma [GBM] and 99 anaplastic astrocytoma [AA]) from a single institute who completed the standard treatment protocol were enrolled in this cohort study and retrospectively analyzed. The patients were stratified into each layered risk group by genetic signatures and residual mass or through recursive partitioning analysis. PFS curves were estimated using the piecewise exponential survival model. The criterion of a 10% progression rate among the remaining patients at each observation period was used to determine the optimal radiological assessment time point.

Results: The optimal follow-up intervals for MRI evaluations of isocitrate dehydrogenase (IDH) wild-type GBM was every 7.4 weeks until 120 weeks after the end of standard treatment, followed by a 22-week inflection period and every 27.6 weeks thereafter. For the IDH mutated GBM, scans every 13.2 weeks until 151 weeks are recommended. The optimal follow-up intervals were every 22.8 weeks for IDH wild-type AA, and 41.2 weeks for IDH mutated AA until 241 weeks. Tailored radiological assessment schedules were suggested for each layered risk group of the GBM and the AA patients.

Conclusions: The optimal schedule of radiological assessments for each layered risk group of patients with HGG could be determined from the parametric model of PFS.
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http://dx.doi.org/10.1093/neuonc/noaa250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099465PMC
May 2021

Exceptional response to radiotherapy in unresectable pleuropulmonary blastoma of a child.

Radiat Oncol J 2020 Jun 23;38(2):148-150. Epub 2020 Jun 23.

Department of Radiation Oncology, Seoul National University Hospital, Seoul, Korea.

Pleuropulmonary blastoma (PPB) is a rare intrathoracic neoplasm in children. Although surgery with or without chemotherapy mainly conducted, the response of radiotherapy (RT) has not been evaluated yet. For unresectable tumor, RT might be considered as one option to decrease tumor extent to relieve obstructing symptoms or to facilitate successive treatment. We report one child in whom PPB with DICER1 mutation recurred after surgery and lead to respiratory distress. She emergently received palliative RT with a relatively low dose (20 Gy), and symptoms sufficiently relieved. Even she showed an 84.3% reduction in diameter and maintained the remission status for 1 year. These might reflect possible radiosensitivity of PPB, and further investigations of RT might be necessary for unresectable PPB.
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http://dx.doi.org/10.3857/roj.2020.00290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533407PMC
June 2020

Long-Term Outcomes of Laparoscopic Distal Gastrectomy for Locally Advanced Gastric Cancer: The KLASS-02-RCT Randomized Clinical Trial.

J Clin Oncol 2020 10 20;38(28):3304-3313. Epub 2020 Aug 20.

Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea.

Purpose: It is unclear whether laparoscopic distal gastrectomy for locally advanced gastric cancer is oncologically equivalent to open distal gastrectomy. The noninferiority of laparoscopic subtotal gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer compared with open surgery in terms of 3-year relapse-free survival rate was evaluated.

Patients And Methods: A phase III, open-label, randomized controlled trial was conducted for patients with histologically proven locally advanced gastric adenocarcinoma suitable for distal subtotal gastrectomy. The primary end point was the 3-year relapse-free survival rate; the upper limit of the hazard ratio (HR) for noninferiority was 1.43 between the laparoscopic and open distal gastrectomy groups.

Results: From November 2011 to April 2015, 1,050 patients were randomly assigned to laparoscopy (n = 524) or open surgery (n = 526). After exclusions, 492 patients underwent laparoscopic surgery and 482 underwent open surgery and were included in the analysis. The laparoscopy group, compared with the open surgery group, suffered fewer early complications (15.7% 23.4%, respectively; = .0027) and late complications (4.7% 9.5%, respectively; = .0038), particularly intestinal obstruction (2.0% 4.4%, respectively; = .0447). The 3-year relapse-free survival rate was 80.3% (95% CI, 76.0% to 85.0%) for the laparoscopy group and 81.3% (95% CI, 77.0% to 85.0%; log-rank = .726) for the open group. Cox regression analysis after stratification by the surgeon revealed an HR of 1.035 (95% CI, 0.762 to 1.406; log-rank = .827; for noninferiority = .039). When stratified by pathologic stage, the HR was 1.020 (95% CI, 0.751 to 1.385; log-rank = .900; for noninferiority = .030).

Conclusion: Laparoscopic distal gastrectomy with D2 lymphadenectomy was comparable to open surgery in terms of relapse-free survival for patients with locally advanced gastric cancer. Laparoscopic distal gastrectomy with D2 lymphadenectomy could be a potential standard treatment option for locally advanced gastric cancer.
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http://dx.doi.org/10.1200/JCO.20.01210DOI Listing
October 2020

Hepatocellular carcinoma and death and transplantation in chronic hepatitis B treated with entecavir or tenofovir disoproxil fumarate.

Sci Rep 2020 08 11;10(1):13537. Epub 2020 Aug 11.

Department of Gastroenterology, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, South Korea.

Conflicting results have been reported regarding which of entecavir (ETV) or tenofovir disoproxil fumarate (TDF) is associated with better outcomes. Chronic hepatitis B patients who started ETV or TDF between 2010 and 2015 were analysed. The primary outcomes were hepatocellular carcinoma and death and transplantation. The impact of the treatment on the primary outcomes was analysed using Cox proportional hazards models in the entire and propensity score-matched cohorts. A total of 404 patients (180 and 224 in the ETV and TDF groups, respectively) were analysed. The median duration of follow-up was significantly longer in the ETV group (64.0 vs. 49.1 months; P < 0.001). Virological response (79.4% vs. 68.4%; P = 0.018) and sustained virological suppression (59.7% vs. 45.2%; P = 0.005) were significantly higher in the TDF group. TDF was associated with lower hepatocellular carcinoma [hazard ratio (HR) 0.31, 95% confidence interval (95% CI), 0.12‒0.79; P = 0.014]; however, statistical significance was not reached after adjusting sustained virological suppression using propensity score matching (HR 0.36, 95% CI 0.12‒1.14; P = 0.08). Death and transplantation was comparable. In conclusion, the impact of TDF on the lower hepatocellular carcinoma was blunted after adjusting sustained virological suppression. Further comparison in a larger number of patients who show sustained virological suppression over a longer period of time is needed.
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http://dx.doi.org/10.1038/s41598-020-70433-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419516PMC
August 2020

Microsatellite Instability Correlated Inflammatory Markers and their Prognostic Value in the Rectal Cancer Following Neoadjuvant Chemoradiotherapy: A Hypothesis-generating Study.

In Vivo 2020 Jul-Aug;34(4):2119-2126

Department of Radiation Oncology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea

Background/aim: This study aimed to analyze the correlation between microsatellite instability (MSI) and inflammatory markers during neoadjuvant CRT in rectal cancer and its influence on prognosis.

Patients And Methods: A total of 549 patients with locally advanced rectal cancer underwent neoadjuvant CRT. Complete blood counts before CRT, and 4-8 weeks after CRT were used to measure neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR).

Results: MSI was significantly associated with elevated NLR and PLR after CRT as well as with a change in NLR and PLR during CRT. Neither inflammatory markers nor MSI significantly related to survival. However, in patients with MSI, an increase in NLR and PLR before CRT was significantly correlated with poor overall survival and disease-free survival.

Conclusion: There is correlation between inflammatory markers and MSI during CRT and it influences prognosis. Therefore, inflammatory markers might have a role in assessing the microenvironment related to MSI and the immunologic response in rectal cancer.
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http://dx.doi.org/10.21873/invivo.12017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439872PMC
June 2021

High body mass index hinders fibrosis improvement in patients receiving long-term tenofovir therapy in hepatitis B virus-related cirrhosis.

J Viral Hepat 2020 11 23;27(11):1119-1126. Epub 2020 Jun 23.

Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.

Long-term suppression of hepatitis B virus with tenofovir (TDF) induces fibrosis regression, and repeated liver stiffness (LS) measurement can indicate the improvement of fibrosis. We aimed to investigate predictors for LS improvement assessed by changes in patients receiving long-term TDF therapy in chronic hepatitis B (CHB) with liver cirrhosis. CHB patients with histologically proven liver cirrhosis who received TDF as the first-line therapy from 2012 to 2015 were recruited. LS and controlled attenuation parameter (CAP) measurements were repeated at baseline and 3 years after therapy. Liver stiffness improvement was defined as a drop of LS value ≥30% from the baseline. A total of 131 patients were enrolled (mean age 51.4% and male 64.9%). After 3 years of TDF therapy, the mean LS value significantly improved (from 14.7 to 8.6 kPa, P < .001), and 96 (73.3%) patients have achieved LS improvement. Predictors associated with improvement of LS were low body mass index (BMI), HBeAg positivity, and low CAP value at baseline. In multivariate analysis, low BMI was a single factor independently associated with LS improvement (odds ratio 0.680, 95% CI 0.560-0.825, P < .001). Patients with BMI < 23.5, had a 1.96 times more chance of achieving LS improvement compared to those with BMI ≥ 23.5 (90.1% vs. 46.0%, P = .001). High BMI was a single significant factor hindering the fibrosis improvement in patients receiving long-term TDF therapy in CHB with liver cirrhosis. Life style modification and BMI reduction should be encouraged to enhance fibrosis improvement.
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http://dx.doi.org/10.1111/jvh.13345DOI Listing
November 2020

Dynamics of liver stiffness-based risk prediction model during antiviral therapy in patients with chronic hepatitis B.

Eur J Gastroenterol Hepatol 2021 06;33(6):885-893

Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Bundang.

Objective: The liver stiffness-based risk prediction models predict hepatocellular carcinoma (HCC) development. We investigated the influence of antiviral therapy (AVT) on liver stiffness-based risk prediction model in patients with chronic hepatitis B (CHB).

Methods: Patients with CHB who initiated AVT were retrospectively recruited from 13 referral Korean institutes. The modified risk estimation for hepatocellular carcinoma in chronic hepatitis B (mREACH-B) model was selected for the analysis.

Results: Between 2007 and 2015, 1034 patients with CHB were recruited. The mean age of the study population (639 men and 395 women) was 46.8 years. During AVT, the mREACH-B score significantly decreased from the baseline to 3 years of AVT (mean 9.21 → 7.46, P < 0.05) and was maintained until 5 years of AVT (mean 7.23, P > 0.05). The proportion of high-risk patients (mREACH-B score ≥11) was significantly reduced from the baseline to 2 years of AVT (36.4% → 16.4%, P < 0.001) and was maintained until 5 years of AVT (12.2%, P > 0.05). The mREACH-B scores at baseline and 1 year of AVT independently predicted HCC development (hazard ratio = 1.209-1.224) (all P < 0.05). The cumulative incidence rate of HCC was significantly different at 5 years of AVT among risk groups (high vs. high-intermediate vs. low-intermediate vs. low) from baseline (4.5% vs. 3.2% vs. 1.5% vs. 0.8%) and 1 year (11.8% vs. 4.6% vs. 1.8% vs. 0.6%) (all P < 0.05, log-rank tests).

Conclusions: The mREACH-B score was dynamically changed during AVT. Thus, repeated assessment of the mREACH-B score is required to predict the changing risk of HCC development in patients with CHB undergoing AVT.
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http://dx.doi.org/10.1097/MEG.0000000000001794DOI Listing
June 2021

Decrease in waist-to-hip ratio reduced the development of chronic kidney disease in non-obese non-alcoholic fatty liver disease.

Sci Rep 2020 06 2;10(1):8996. Epub 2020 Jun 2.

Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.

To date, there are few studies that have evaluated the prognostic impact of changes in abdominal obesity or weight on long-term adverse kidney outcomes in non-alcoholic fatty liver disease (NAFLD). We investigated the effect of changes in waist-to-hip ratio (WHR) and body weight (BW) on chronic kidney disease (CKD) development, especially in non-obese NAFLD patients. We included 6,137 participants from a community-based prospective cohort with 12-year follow-up in Korea. NAFLD patients were categorized according to time-averaged percent changes in WHR and BW (≤-5%, >-5% to <5%, and ≥5%). Compared to non-obese controls, non-obese NAFLD was significantly associated with an increased risk of incident CKD (hazard ratio [HR] = 1.238, 95% confidence interval [CI] = 1.006-1.524). In 1,563 NAFLD patients, compared to patients with minimal changes in WHR (>-5% to <5%), patients with a decreased WHR (≤-5%) had a significantly attenuated risk of CKD development (HR = 0.300; 95% CI = 0.194-0.464). Furthermore, risk reduction from decreased WHR for developing CKD remained significant in non-obese NAFLD patients (HR = 0.290; 95% CI = 0.114-0.736). In conclusion, a decrease in WHR of more than 5% significantly reduced the risk of CKD development in NAFLD patients, even in those who were non-obese. Thus, serial monitoring of WHR may be prioritized in the management of NAFLD.
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http://dx.doi.org/10.1038/s41598-020-65940-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265367PMC
June 2020

Reduced-dose whole-brain radiotherapy with tumor bed boost after upfront high-dose methotrexate for primary central nervous system lymphoma.

Radiat Oncol J 2020 Mar 25;38(1):35-43. Epub 2020 Mar 25.

Department of Radiation Oncology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea.

Purpose: This retrospective study compares higher-dose whole-brain radiotherapy (hdWBRT) with reduced-dose WBRT (rdWBRT) in terms of clinical efficacy and toxicity profile in patients treated for primary central nervous system lymphoma (PCNSL).

Materials And Methods: Radiotherapy followed by high-dose methotrexate (HD-MTX)-based chemotherapy was administered to immunocompetent patients with histologically confirmed PCNSL between 2000 and 2016. Response to chemotherapy was taken into account when prescribing the radiation dose to the whole brain and primary tumor bed. The whole brain dose was ≤23.4 Gy for rdWBRT (n = 20) and >23.4 Gy for hdWBRT (n = 68). Patients manifesting cognitive disturbance, memory impairment and dysarthria were considered to have neurotoxicity. A median follow-up was 3.62 years.

Results: The 3-year overall survival (OS) and progression-free survival (PFS) were 70.0% and 48.9% with rdWBRT, and 63.2% and 43.2% with hdWBRT. The 3-year OS and PFS among patients with partial response (n = 45) after chemotherapy were 77.8% and 53.3% with rdWBRT, and 58.3% and 45.8% with hdWBRT (p > 0.05). Among patients with complete response achieved during follow-up, the 3-year freedom from neurotoxicity (FFNT) rate was 94.1% with rdWBRT and 62.4% with hdWBRT. Among patients aged ≥60 years, the 3-year FFNT rate was 87.5% with rdWBRT and 39.1% with hdWBRT (p = 0.49). Neurotoxicity was not observed after rdWBRT in patients aged below 60 years.

Conclusion: rdWBRT with tumor bed boost combined with upfront HD-MTX is less neurotoxic and results in effective survival as higher-dose radiotherapy even in partial response after chemotherapy.
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http://dx.doi.org/10.3857/roj.2020.00052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113152PMC
March 2020

Enzymatic Synthesis of Anabolic Steroid Glycosides by Glucosyltransferase from sp. PAMC 23288.

J Microbiol Biotechnol 2020 Apr;30(4):604-614

Department of Life Science and Biochemical Engineering, SunMoon University, Asan 31460, Republic of Korea.

The application of steroids has steadily increased thanks to their therapeutic effects. However, alternatives are required due their severe side effects; thus, studies on the activities of steroid derivatives are underway. Sugar derivatives of nandrolone, which is used to treat breast cancer, as well as cortisone and prednisone, which reduce inflammation, pain, and edema, are unknown. We linked O-glucose to nandrolone and testosterone using UDP-glucosyltransferase (UGT-1) and, then, tested their bioactivities in vitro. Analysis by NMR showed that the derivatives were 17β-nandrolone β-D-glucose and 17β-testosterone β-D-glucose, respectively. The viability was higher and cytotoxicity was evident in PC12 cells incubated with rotenone and, testosterone derivatives, compared to the controls. SH-SY5Y cells incubated with HO and nandrolone derivatives remained viable and cytotoxicity was attenuated. Both derivatives enhanced neuronal protective effects and increased the amounts of cellular ATP.
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http://dx.doi.org/10.4014/jmb.1911.11057DOI Listing
April 2020

Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors.

Cancers (Basel) 2019 Oct 11;11(10). Epub 2019 Oct 11.

Chaum Life Center, CHA University School of Medicine, Seoul 06062, Korea.

In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Compared with cytotoxic T lymphocytes, NK cells take a unique position targeting tumor cells that evade the host immune surveillance by down-regulating self-antigen presentation. Recent findings highlighted that NK cells can even target cancer stem cells. The efficacy of allogeneic NK cells has been widely investigated in the treatment of hematologic malignancies. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. In allogeneic NK cell therapy, the mismatch between the killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) can be harnessed to increase the antitumor activity. However, the allogeneic NK cells cause more adverse events and can be rejected by the host immune system after repeated injections. In this regard, the autologous NK cell therapy is safer. This article reviews the published results of clinical trials and discusses strategies to enhance the efficacy of the NK cell therapy. The difference in immunophenotype of the ex vivo expanded NK cells resulted from different culture methods may affect the final efficacy. Furthermore, currently available standard anticancer therapy, molecularly targeted agents, and checkpoint inhibitors may directly or indirectly enhance the efficacy of NK cell therapy. A recent study discovered that NK cell specific genetic defects are closely associated with the tumor immune microenvironment that determines clinical outcomes. This finding warrants future investigations to find the implication of NK cell specific genetic defects in cancer development and treatment, and NK cell deficiency syndrome should be revisited to enhance our understanding. Overall, it is clear that NK cell therapy is safe and promises a new paradigm for the treatment of solid tumors.
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http://dx.doi.org/10.3390/cancers11101534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826624PMC
October 2019

Glioblastoma Cellular Origin and the Firework Pattern of Cancer Genesis from the Subventricular Zone.

J Korean Neurosurg Soc 2020 Jan 8;63(1):26-33. Epub 2019 Oct 8.

Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Glioblastoma (GBM) is a disease without any definite cure. Numerous approaches have been tested in efforts to conquer this brain disease, but patients invariably experience recurrence or develop resistance to treatment. New surgical tools, carefully chosen samples, and experimental methods are enabling discoveries at single-cell resolution. The present article reviews the cell-of-origin of isocitrate dehydrogenase (IDH)-wildtype GBM, beginning with the historical background for focusing on cellular origin and introducing the cancer genesis patterned on firework. The authors also review mutations associated with the senescence process in cells of the subventricular zone (SVZ), and biological validation of somatic mutations in a mouse SVZ model. Understanding GBM would facilitate research on the origin of other cancers and may catalyze the development of new management approaches or treatments against IDH-wildtype GBM.
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http://dx.doi.org/10.3340/jkns.2019.0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952738PMC
January 2020

Deficiency of glutathione peroxidase-1 and catalase attenuated diet-induced obesity and associated metabolic disorders.

Acta Diabetol 2020 Feb 1;57(2):151-161. Epub 2019 Aug 1.

Department of Microbiology, Ewha Womans University Graduate School of Medicine, Magokdongro 2-25, Gangseo-Gu, Seoul, 07804, Republic of Korea.

Aims: Oxidative stress has been considered to contribute to the development of obesity-related metabolic disorders including insulin resistance. To the contrary, deficiency of an anti-oxidizing enzyme, glutathione peroxidase (GPx)-1, was reported to enhance insulin signaling, suggesting that oxidative stress may inhibit the development of type 2 diabetes. However, the beneficial effects of the absence of GPx-1 in metabolic homeostasis, including body weight control, have not yet been clearly manifested. To clarify the relationship between oxidative stress and obesity-related metabolic disorders, we investigated another mouse deficient with both GPx-1 and catalase (Cat).

Methods: C57BL/6J wild-type and GPx-1 × Cat mice were fed with a high-fat diet (60% fat) or a normal chow diet for 16 weeks and were investigated for metabolic and histological studies.

Results: Body weight gain was significantly reduced, and glucose metabolism as well as hepatic steatosis was obviously improved in the GPx-1 × Cat mice. The serum levels of insulin and total cholesterol were also significantly lowered. For the underlying mechanism, inflammation was attenuated and expression of markers for fat browning was enhanced in the visceral white adipose tissues.

Conclusions: Oxidative stress due to deficiency of GPx-1 and Cat may improve obesity-related metabolic disorders through attenuation of inflammation and fat browning.
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http://dx.doi.org/10.1007/s00592-019-01388-5DOI Listing
February 2020
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