Publications by authors named "Jung Il Lee"

321 Publications

Risk assessment of hepatocellular carcinoma and liver-related events using ultrasonography and transient elastography in patients with chronic hepatitis B.

J Viral Hepat 2021 Jun 29. Epub 2021 Jun 29.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

Cirrhosis has prognostic value. We investigated whether the combined use of ultrasonography (US) and transient elastography (TE) to diagnose cirrhosis is beneficial for the risk assessment of hepatocellular carcinoma (HCC) and liver-related events in patients with chronic hepatitis B (CHB). 9,300 patients with CHB who underwent US and TE in two institutions between 2006 and 2018 were enrolled. TE value ≥13 kPa was set to indicate cirrhosis. Patients were divided into four groups: US(+)TE(+) (cirrhosis by US and TE), US(+)TE(-) (cirrhosis by US, but not by TE), US(-)TE(+) (cirrhosis by TE, but not by US), and US(-)TE(-) (non-cirrhosis by US and TE).The patients were predominantly male (n=5,474, 58.9%) with a mean age of 47.5 years. The proportions of patients with cirrhosis diagnosed by US and TE were 17.2% (n=1,595) and 13.2% (n=1,225), respectively. The proportion of patients with discordant results in diagnosing cirrhosis by US and TE was 18.7% (n=1,740). During follow-up (median: 60.0 months), HCC and LRE developed in 481 (5.2%) and 759 (8.2%) patients, respectively. The cumulative incidence rates of HCC and liver-related events were highest in the US(+)TE(+) group, intermediate-high in the US(-)TE(+) group, intermediate-low in the US(+)TE(-) group, and the lowest in the US(-)TE(-) group (overall P<0.001). Cirrhosis assessed using US and TE was a major predictor of HCC and liver-related events development in patients with CHB. Cirrhosis assessed using TE was better in predicting HCC or liver-related events than using US, when cirrhosis diagnosis was discordant by US and TE.
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http://dx.doi.org/10.1111/jvh.13560DOI Listing
June 2021

Functional recovery by colon organoid transplantation in a mouse model of radiation proctitis.

Biomaterials 2021 May 29;275:120925. Epub 2021 May 29.

Department of Microbiology, CHA University School of Medicine, Seongnam, Republic of Korea; CHA Organoid Research Center, CHA University, Seongnam, Republic of Korea; R&D Institute, ORGANOIDSCIENCES LTD., Seongnam, Republic of Korea. Electronic address:

Radiation proctitis is the collateral damage that occurs to healthy cells during radiation treatment of pelvic malignancies. Conservative treatment of radiation proctitis can mitigate inflammatory symptoms, but, to date, no therapeutic options are available for direct recovery of the damaged colonic epithelium. The present study assessed the ability of colon organoid-based regeneration to treat radiation proctitis. Radiation proctitis was induced in mice by irradiating their recta, followed by enema-based transplantation of mouse colon organoids. The transplanted colon organoids were found to successfully engraft onto the damaged rectal mucosa of the irradiated mice, reconstituting epithelial structure and integrity. Lgr5 stem cells were shown to be pivotal to colon organoid mediated regeneration. Endoscopic examination showed the efficacy of localized transplantation of colon organoids with fibrin glue to irradiated sites. These findings provide useful insights into the use of colon organoid-based regenerative therapy for the treatment of radiation proctitis.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120925DOI Listing
May 2021

The effect of body fatness on regional brain imaging markers and cognitive function in healthy elderly mediated by impaired glucose metabolism.

J Psychiatr Res 2021 Aug 11;140:488-495. Epub 2021 Jun 11.

Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Department of Public Health, Yonsei University Graduate School, Seoul, 03722, Republic of Korea; Institute of Human Complexity and Systems Science, Yonsei University, Incheon, 21983, Republic of Korea. Electronic address:

Brain atrophy is related to vascular risk factors and can increase cognitive dysfunction risk. This community-based, cross-sectional study investigated whether glucose metabolic disorders due to body fatness are linked to regional changes in brain structure and a decline in neuropsychological function in cognitively healthy older adults. From 2016 to 2019, 429 participants underwent measurements for cortical thickness and subcortical volume using 3 T magnetic resonance imaging and for cognitive function using the neuropsychological screening battery. The effects of body fatness mediated by impaired glucose metabolism on neuroimaging markers and cognitive function was investigated using partial least square structural equation modeling. Total grey matter volume (β = -0.020; bias-corrected (BC) 95% confidence interval (CI) = -0.047 to -0.006), frontal (β = -0.029; BC 95% CI = -0.063 to -0.005) and temporal (β = -0.022; BC 95% CI = -0.051 to -0.004) lobe cortical thickness, and hippocampal volume (β = -0.029; BC 95% CI = -0.058 to -0.008) were indirectly related to body fatness. Further, frontal/temporal lobe thinning was associated with recognition memory (β = -0.005; BC 95% CI = -0.012 to -0.001/β = -0.005; BC 95% CI = -0.013 to -0.001) and delayed recall for visual information (β = -0.005; BC 95% CI = -0.013 to -0.001/β = -0.005; BC 95% CI = -0.013 to -0.001). Additionally, the smaller the hippocampal volume, the lower the score in recognition memory (β = -0.005; BC 95% CI = -0.012 to -0.001), delayed recall for visual information (β = -0.005; BC 95% CI = -0.012 to -0.001), and verbal learning (β = -0.008; BC 95% CI = -0.017 to -0.002). Our findings indicate that impaired glucose metabolism caused by excess body fatness affects memory decline as well as regional grey matter atrophy in elderly individuals with no neurological disease.
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http://dx.doi.org/10.1016/j.jpsychires.2021.06.011DOI Listing
August 2021

Early hormonal recovery following endoscopic transsphenoidal surgery for silent non-functioning pituitary adenomas with hormone dysfunction.

J Neurooncol 2021 Jun 17;153(2):343-350. Epub 2021 May 17.

Department of Neurosurgery, Brain Tumor Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: The role of transsphenoidal surgery in the recovery of preexisting hormone dysfunction from pituitary tumors remains controversial. This study aimed to investigate the incidence of hormone dysfunction among asymptomatic non-functioning pituitary adenomas and their recovery following endoscopic transsphenoidal surgery.

Methods: Eligibility criteria included age under 80 years, presence of a non-functioning pituitary adenoma compressing the normal gland resulting in deviation of the stalk, absence of visual symptoms, and availability for regular follow-up using MRI and pre- and post-operative endocrinological assessments. 182 patients with silent non-functioning pituitary adenomas were included in this study between March 2014 and December 2018. All patients underwent endoscopic transsphenoidal surgery and complete hormonal evaluation, with basal hormone assays and a combined pituitary function test before and after surgery until the end of last follow-up.

Results: Preoperative assessment of hormonal function revealed that 124 of 182 patients (68.1%) had at least a single hormone dysfunction preoperatively. Among these, 61 of 124 (49.2%) had a dysfunction in a single axis, and 63 (50.8%) had a hormone dysfunction in two or more axes. Overall, the median endocrinological follow-up duration was 15.0 months (6-57 months). At 1 month following surgery, 91 patients (73.4%) with hormone dysfunction experienced improvement in at least a single hormone axis. Prolactin was the most common hormone among those that recovered at the last follow up (92.8% improvement) followed by growth hormone (GH, 50.0%), thyroid stimulating hormone (TSH, 50.0%), gonadotropin (Gn, 46.9%), and adrenocorticotropic hormone (ACTH, 45.0%). Time to recovery varied from 1.1 months (for prolactin) to 2.2 months (for gonadotropin, and ACTH). In patients with preoperative deficiency in GH, and ACTH, postoperative transient diabetes insipidus was associated with poor recovery (GH: HR = 0.50, p = 0.048; ACTH: HR = 0.39, p = 0.023).

Conclusions: Non-functioning pituitary adenomas with silent hormone dysfunction are often overlooked by clinicians and patients. We suggest that even silent hormone dysfunction in patients with non-functioning pituitary adenomas can be improved with effective surgical decompression and these tumors may be potential indications of endoscopic transsphenoidal surgery.
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http://dx.doi.org/10.1007/s11060-021-03774-yDOI Listing
June 2021

Optimal Volume of the Residual Tumor to Predict Long-term Tumor Control Using Stereotactic Radiosurgery after Facial Nerve-preserving Surgery for Vestibular Schwannomas.

J Korean Med Sci 2021 Apr 26;36(16):e102. Epub 2021 Apr 26.

Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: Intended subtotal resection (STR) followed by adjuvant gamma knife radiosurgery (GKRS) has emerged as an effective treatment option for facial nerve (FN) preservation in vestibular schwannomas (VSs). This study aimed to identify the optimal cut-off volume of residual VS to predict favorable outcomes in terms of both tumor control and FN preservation.

Methods: This retrospective study assessed the patients who underwent adjuvant GKRS for residual VS after microsurgery. A total of 68 patients who had been followed up for ≥ 24 months after GKRS were included. Tumor progression was defined as an increase in tumor volume (TV) of ≥ 20%. House-Brackmann grades I and II were considered to indicate good FN function.

Results: The median residual TV was 2.5 cm³ (range: 0.3-27.4). The median follow-up period after the first adjuvant GKRS was 64 months (range: 25.7-152.4). Eight (12%) patients showed tumor progression. In multivariate analyses, residual TV was associated with tumor progression ( = 0.003; hazard ratio [HR], 1.229; 95% confidence interval [CI], 1.075-1.405). A residual TV of 6.4 cm³ was identified as the cut-off volume for showing the greatest difference in progression-free survival (PFS). The 5-year PFS rates in the group with residual TVs of < 6.4 cm³ (54 patients) and that with residual TVs of ≥ 6.4 cm³ (14 patients) were 93.3% and 69.3%, respectively ( = 0.014). A good FN outcome was achieved in 57 (84%) patients. Residual TV was not associated with good FN function during the immediate postoperative period ( = 0.695; odds ratio [OR], 1.024; 95% CI, 0.908-1.156) or at the last follow-up ( = 0.755; OR, 0.980; 95% CI, 0.866-1.110).

Conclusion: In this study, residual TV was associated with tumor progression in VS after adjuvant GKRS following STR. As preservation of FN function is not correlated with the extent of resection, optimal volume reduction is imperative to achieve long-term tumor control. Our findings will help surgeons predict the prognosis of residual VS after FN-preserving surgery.
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http://dx.doi.org/10.3346/jkms.2021.36.e102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076845PMC
April 2021

Safety and Efficacy of Endoscopic Dorsum Sellar Resection for Access to Retroinfundibular or Upper Clival Tumors (Korean Society of Endoscopic Neurosurgery-008).

World Neurosurg 2021 Jun 23;150:e675-e680. Epub 2021 Mar 23.

Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; Pituitary Center, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address:

Objective: The retroinfundibular and upper clival regions are challenging to access using the endoscopic endonasal approach because these regions are obstructed by the dorsum sellae and posterior clinoid processes. We evaluated the safety and clinical efficacy of endoscopic dorsum sellar resection (DSR) and identified the optimal indications for endoscopic DSR in patients with craniopharyngioma.

Methods: A retrospective study was conducted of patients who had undergone treatment with an endoscopic endonasal approach from January 2014 to January 2019. We identified a total of 50 patients who had undergone DSR. The indications for DSR included the following: 1) a tumor involving the upper clivus; 2) a tumor located behind the dorsum sellae; and 3) a tumor involving the interpeduncular or prepontine cistern. We evaluated the clinical outcomes, postoperative endocrinological status, and surgical morbidities.

Results: Of the 50 patients, 16 had been treated for craniopharyngioma, 30 for chordoma, 2 for pituitary adenoma, 1 for schwannoma, and 1 for chondrosarcoma. An extradural approach for DSR with posterior clinoidectomy was performed in 33 patients (66.0%) and an interdural transcavernous approach in 17 patients (34.0%). The overall gross total tumor resection rate was 92.0% (46 of 50 patients). Postoperatively, 28 of 33 patients (84.8%) with normal pituitary function preoperatively showed preservation of hormonal function postoperatively.

Conclusions: DSR with or without posterior clinoidectomy is a challenging procedure that requires considerable effort and advanced surgical techniques. However, it can be safely performed with accumulating experience and a thorough knowledge of the surrounding anatomical structures.
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http://dx.doi.org/10.1016/j.wneu.2021.03.085DOI Listing
June 2021

Clinical outcomes after mini-hook plate fixation for small avulsion fractures around the interphalangeal or metacarpophalangeal joints of the hand.

J Orthop Surg Res 2021 Mar 12;16(1):186. Epub 2021 Mar 12.

Department of Emergency Medicine, Ewha Women's University Mokdong Hospital, Seoul, South Korea.

Background: Mini-hook plate has been described for the treatment of various small avulsion fragments in the hand. This retrospective study aimed to evaluate clinical outcomes after mini-hook plate fixation in patients with an avulsion fracture around the interphalangeal or metacarpophalangeal joints of the hand.

Methods: Nineteen patients with avulsion fractures around the interphalangeal or metacarpophalangeal joints of the hand were included in this study. Seven patients had a mallet fracture, and 12 patients had other phalangeal avulsion fractures including central slip, collateral ligament, volar plate, and flexor avulsion fractures. The osseous union and functional outcomes, including finger joint motion, joint stability, pinching strength, and the disabilities of the arm, shoulder, and hand score, were evaluated.

Results: The mean duration of follow-up was 33.8 months. All patients in mallet and other phalangeal avulsion fractures achieved osseous union between the avulsion fragment and phalangeal bone, and there was no joint subluxation. There were no significant differences in the disabilities of the arm, shoulder, and hand scores. However, the patients with mallet fracture have lower mean percentage values of the total active range of motion and pinching strength than other phalangeal avulsion fractures. We abandoned this procedure in mallet fractures because the early results after mini-hook plate fixation in mallet fractures appeared unfavorable.

Conclusion: These results suggest that the mini-hook plate fixation can provide sufficient stability and good clinical outcomes in those with phalangeal avulsion fractures. However, the outcomes for mallet fractures were not as good as those for other phalangeal avulsion fractures.
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http://dx.doi.org/10.1186/s13018-021-02339-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953753PMC
March 2021

Gamma Knife Radiosurgery for Incidental, Symptomatic Unruptured, and Ruptured Brain Arteriovenous Malformations.

Cerebrovasc Dis 2021 2;50(2):222-230. Epub 2021 Mar 2.

Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea,

Background: This study was performed to investigate clinical characteristics and outcome after gamma knife radiosurgery (GKS) in patients with incidental, symptomatic unruptured, or ruptured arteriovenous malformations (AVMs).

Methods: A total of 491 patients with brain AVMs treated with GKS from June 2002 to September 2017 were retrospectively reviewed. All patients were classified into the incidental (n = 105), symptomatic unruptured (n = 216), or ruptured AVM (n = 170) groups.

Results: The mean age at diagnosis of incidental, symptomatic unruptured, and ruptured AVMs was 40.3, 36.7, and 27.6 years, respectively. The mean nidus volume was 3.9, 5.7, and 2.4 cm3, respectively. Deep venous drainage was identified in 34, 54, and 76% patients, respectively. There were no significant differences in obliteration rates after GKS between the 3 groups (64.8, 61.1, and 65.9%, respectively) after a mean follow-up period of 60.5 months; however, patients with incidental AVM had a significantly lower post-GKS hemorrhage rate than patients with symptomatic unruptured or ruptured AVMs (annual hemorrhage rate of 1.07, 2.87, and 2.69%; p = 0.028 and p = 0.049, respectively).

Conclusions: There is a significant difference in clinical and anatomical characteristics between incidental, symptomatic unruptured, and ruptured AVMs. The obliteration rate after GKS is not significantly different between the 3 groups. Meanwhile, an older age at diagnosis and lower hemorrhage rate after GKS in incidental AVMs suggest that they have a more indolent natural course with a lower life-long risk of hemorrhage.
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http://dx.doi.org/10.1159/000513280DOI Listing
March 2021

Ventriculoperitoneal Shunt for CNS Metastasis in Breast Cancer: Clinical Outcomes Based on Intrinsic Subtype.

Clin Breast Cancer 2021 Jan 6. Epub 2021 Jan 6.

Division of Hematology-Oncology, Departments of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address:

Background: Leptomeningeal metastasis (LM) is associated with a grave prognosis in breast cancer (BC) and can be controlled with a ventriculoperitoneal shunt (VPS). Information regarding LM and VPS based on intrinsic subtype is limited; thus, we investigated the clinical outcomes of BC treated with VPS.

Patients And Methods: The present retrospective study comprised 70 patients diagnosed with LM who received a VPS. The patients were divided into 4 groups based on BC subtype: hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2), HR/HER2, HR/HER2, and triple negative BC (TNBC).

Results: The most common indications for VPS were uncontrolled intracranial pressure (57.1%) and uncontrolled headache (55.7%), which improved in 54 (77.1%) of 70 patients after VPS. The median overall survival (OS) after brain or LM and overall survival after VPS were 7.6 and 2.3 months, respectively. Anti-HER2 treatment was a significant prognostic factor for better OS after brain or LM based on multivariate analysis (hazard ratio, 0.15; 95% confidence interval, 0.04-0.57; P = .005), whereas TNBC was correlated with shorter OS after central nervous system metastasis (hazard ratio, 2.82; 95% confidence interval, 1.46-5.48; P = .002).

Conclusions: There were significant differences in clinical outcome based on the intrinsic subtype of patients with BC with LM who received a VPS. Anti-HER2 treatment in patients with HER2 BC was associated with better survival in patients with metastatic BC with VPS insertion compared with those without. Survival of metastatic BC with VPS remained poor, especially in the TNBC subgroup.
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http://dx.doi.org/10.1016/j.clbc.2020.12.013DOI Listing
January 2021

Anti-HBc IgG Levels: A Predictor of HBsAg Seroclearance in Chronic Hepatitis B Patients with Nucleos(t)ide Analogue-Induced HBeAg Seroclearance.

Dig Dis Sci 2021 Jan 30. Epub 2021 Jan 30.

Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273, Korea.

Background/aims: We investigated the efficiency of the indirect ratio of anti-HBc IgG at predicting HBsAg seroclearance in patients with nucleos(t)ide analogue (NA)-induced HBeAg seroclearance.

Methods: We performed a retrospective study that included 366 chronic hepatitis B patients (March 2007 to December 2016) at a single tertiary hospital. These patients were HBsAg seropositive, and experienced NA-induced HBeAg seroclearance. The indirect ratio of light absorbance of anti-HBc IgG levels were measured with chemiluminescent microparticle immunoassay using the Architect Anti-HBc assay (Abbott Laboratories, IL, USA) as a qualitative method prior to antiviral therapy. We calculated the cumulative incidences of HBsAg seroclearance based on the anti-HBc IgG levels.

Results: After a 10-year follow-up, 48 patients experienced HBsAg seroclearance (13.1%). Thirty-three of 179 patients who had an indirect ratio of light absorbance of anti-HBc IgG < 11 RLU (relative light unit) showed HBsAg seroclearance (18.4%); 15 of 187 patients who had an indirect ratio of light absorbance of anti-HBc IgG ≥ 11 RLU showed HBsAg seroclerance (8.0%) (p = 0.003). In multivariate analysis, age, and ALT at the time of HBeAg seroclearance were predictors of HBsAg seroclearance. Especially, the relative risk of HBsAg seroclearance in patients with baseline anti-HBc IgG levels < 11 RLU was 2.213 (95% CI, 1.220-4.014), compared to that in patients with higher levels of anti-HBc IgG at baseline (p = 0.009).

Conclusion: Using an indirect method for anti-HBc IgG levels, baseline anti-HBc IgG levels (< 11RLU), age (≥ 50 years), and ALT (≥ 40 IU/L) might be associated with HBsAg seroclearance in patients with NA-induced HBeAg seroclearance.
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http://dx.doi.org/10.1007/s10620-021-06845-2DOI Listing
January 2021

Purposeful Misalignment of Severed Nerve Stumps in a Standardized Transection Model Reveals Persistent Functional Deficit With Aberrant Neurofilament Distribution.

Mil Med 2021 01;186(Suppl 1):696-703

Department of Orthopaedics and Rehabilitation, Center for Orthopaedic Research and Translational Science, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, USA.

Background: Functional recovery following primary nerve repair of a transected nerve is often poor even with advanced microsurgical techniques. Recently, we developed a novel sciatic nerve transection method where end-to-end apposition of the nerve endings with minimal gap was performed with fibrin glue. We demonstrated that transected nerve repair with gluing results in optimal functional recovery with improved axonal neurofilament distribution profile compared to the end-to-end micro-suture repair. However, the impact of axonal misdirection and misalignment of nerve fascicles remains largely unknown in nerve-injury recovery. We addressed this issue using a novel nerve repair model with gluing.

Methods: In our complete "Flip and Transection with Glue" model, the nerve was "first" transected to 40% of its width from each side and distal stump was transversely flipped, then 20 µL of fibrin glue was applied around the transection site and the central 20% nerve was completely transected before fibrin glue clotting. Mice were followed for 28 days with weekly assessment of sciatic function. Immunohistochemistry analysis of both sciatic nerves was performed for neurofilament distribution and angiogenesis. Tibialis anterior muscles were analyzed for atrophy and histomorphometry.

Results: Functional recovery following misaligned repair remained persistently low throughout the postsurgical period. Immunohistochemistry of nerve sections revealed significantly increased aberrant axonal neurofilaments in injured and distal nerve segments compared to proximal segments. Increased aberrant neurofilament profiles in the injured and distal nerve segments were associated with significantly increased nerve blood-vessel density and branching index than in the proximal segment. Injured limbs had significant muscle atrophy, and muscle fiber distribution showed significantly increased numbers of smaller muscle fibers and decreased numbers of larger muscle fibers.

Conclusions: These findings in a novel nerve transection mouse model with misaligned repair suggest that aberrant neurofilament distributions and axonal misdirections play an important role in functional recovery and muscle atrophy.
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http://dx.doi.org/10.1093/milmed/usaa344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846134PMC
January 2021

Novel Real-time Digital Pressure Sensor Reveals Wide Variations in Current Nerve Crush Injury Models.

Mil Med 2021 01;186(Suppl 1):473-478

Department of Orthopaedics and Rehabilitation, Center for Orthopaedic Research and Translational Science, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, USA.

Introduction: Peripheral nerve crush injury (PNCI) models are commonly used to study nerve damage and the potential beneficial effects of novel therapeutic strategies. Current models of PNCI rely on inter-device and operator precision to limit the variation with applied pressure. Although the inability to accurately quantify the PNCI pressure may result in reduced reproducibility between animals and studies, there is very limited information on the standardization and quantification of applied pressure with PNCI. To address this deficit, we constructed a novel device comprised of an Arduino UNO microcontroller board and Force Sensitive Resistor capable of reporting the real-time pressure applied to a nerve.

Methods: Two forceps and two needle drivers were used to perform 30-second PNCIs to the sciatic nerves of mice (n = 5/group). Needle drivers were set to the first notch, and a jig was used to hold the forceps pinch at a reproducible pressure. The Force Sensitive Resistor was interposed in-series between the nerve and instrument during PNCI.

Results: Data collected from these procedures displayed average needle driver pressures an order of multitude greater than forceps pressures. Additionally, needle driver inter- and intra-procedure pressure remained more consistent than forceps pressure, with needle driver coefficient of variation equal to 14.5% vs. a forceps coefficient of variation equal to 45.4%.

Conclusions: This is the first demonstration of real-time pressure measurements in PNCI models and it reveals that the applied pressures are dependent on the types of device used. The large disparity in pressure represents an inability to apply graded accurate and consistent intermediate pressure gradients in PNCI. These findings indicate a need for documentation of pressure severity as a screening for PNCI in animals, and the real-time pressure sensor could be a useful tool in monitoring and applying consistent pressure, reducing the outcome variability within the same experimental model of PNCI.
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http://dx.doi.org/10.1093/milmed/usaa346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832820PMC
January 2021

Addition of liver stiffness enhances the predictive accuracy of the PAGE-B model for hepatitis B-related hepatocellular carcinoma.

Aliment Pharmacol Ther 2021 04 19;53(8):919-927. Epub 2021 Jan 19.

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

Background: The modified PAGE-B (mPAGE-B) and PAGE-B models reliably predict the risk of developing chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC).

Aim(s): To investigate whether the addition of liver stiffness (LS) value, assessed using transient elastography, enhanced the predictive accuracies of these models METHODS: Patients with CHB who started anti-viral therapy (AVT) between 2007 and 2017 were enrolled. The training (Yonsei University Hospital) and validation (seven Korean referral institutes) cohorts contained 1211 and 973 patients, respectively.

Results: Based on multivariate analysis, older age (hazard ratio [HR] = 1.051, 95% confidence interval [CI] = 1.031-1.071), male sex (HR = 2.265, 95% CI = 1.463-3.506), lower platelet count (HR = 0.993, 95% CI = 0.989-0.997) and greater LS values (HR = 1.015, 95% CI = 1.002-1.028) were independently associated with an increased risk of HCC development (all P < 0.05). Thus, we developed a modified PAGE -B model (maximum score 34) that included age, male sex, platelet count and LS value. The integrated area under the curve of the modified PAGE model was greater than those of the PAGE-B and mPAGE-B models (0.760 vs 0.714 and 0.716, respectively) in the derivation dataset. The cumulative HCC incidence was significantly higher in the high-risk (modified PAGE-B score ≥ 24) group than in the intermediate-risk (modified PAGE -B score 12-24) or low-risk (modified PAGE -B score < 12) group (all P < 0.001). Similar results were observed in the validation cohort.

Conclusions: The predictive accuracies of the PAGE-B and mPAGE-B models were validated in Korean patients with CHB receiving AVT. However, the modified PAGE -B model featuring the addition of LS value showed higher predictability than the PAGE-B and mPAGE-B models.
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http://dx.doi.org/10.1111/apt.16267DOI Listing
April 2021

Biomechanical evaluation of the stability of extra-articular distal radius fractures fixed with volar locking plates according to the length of the distal locking screw.

Comput Methods Biomech Biomed Engin 2021 Jun 21;24(8):922-932. Epub 2020 Dec 21.

Department of Orthopedic Surgery, Hanyang University Guri hospital, Guri, Korea.

Surgeons usually used short screws to avoid extensor tendon problems during volar locking plate fixation in distal radius fracture. However, the stability according to the length of distal locking screws have not been fully understood. We investigated this issue through finite element analysis and compression test using synthetic radius. Our results demonstrated that the bi-cortical full-length fixation does not contribute to the stiffness increase in the axial compression direction, and a reduction in length of up to more than 50% length can still provide similar stability to full-length screws. Our data can support that surgeon should undersize the distal screw.
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http://dx.doi.org/10.1080/10255842.2020.1861254DOI Listing
June 2021

A novel nerve transection and repair method in mice: histomorphometric analysis of nerves, blood vessels, and muscles with functional recovery.

Sci Rep 2020 12 10;10(1):21637. Epub 2020 Dec 10.

Department of Orthopaedics and Rehabilitation, Center for Orthopaedic Research and Translational Science, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 500 University Drive, Mail Code H089, Hershey, PA, 17033, USA.

Peripheral nerve transection is associated with permanent functional deficit even after advanced microsurgical repair. While it is difficult to investigate the reasons of poor functional outcomes of microsurgical repairs in humans, we developed a novel pre-clinical nerve transection method that allows reliable evaluation of nerve regeneration, neural angiogenesis, muscle atrophy, and functional recovery. Adult male C57BL/6 mice were randomly assigned to four different types of sciatic nerve transection: Simple Transection (ST), Simple Transection & Glue (TG), Stepwise Transection and Sutures (SU), and Stepwise Transection and Glue (STG). Mice were followed for 28 days for sciatic function index (SFI), and sciatic nerves and hind limb muscles were harvested for histomorphological and cellular analyses. Immunohistochemistry revealed more directional nerve fiber growth in SU and STG groups compared with ST and TG groups. Compared to ST and TG groups, optimal neural vessel density and branching index in SU and STG groups were associated with significantly decreased muscle atrophy, increased myofiber diameter, and improved SFI. In conclusion, our novel STG method represents an easily reproducible and reliable model with close resemblance to the pathophysiological characteristics of SU model, and this can be easily reproduced by any lab.
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http://dx.doi.org/10.1038/s41598-020-78481-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729850PMC
December 2020

Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer with Brain Metastasis : The Role of Gamma Knife Radiosurgery.

J Korean Neurosurg Soc 2021 Mar 4;64(2):271-281. Epub 2020 Dec 4.

Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Objective: Immune checkpoint inhibitors (ICIs) are approved for treating non-small-cell lung cancer (NSCLC); however, the safety and efficacy of combined ICI and Gamma Knife radiosurgery (GKS) treatment remain undefined. In this study, we retrospectively analyzed patients treated with ICIs with or without GKS at our institute to manage patients with brain metastases from NSCLC.

Methods: We retrospectively reviewed medical records of patients with brain metastases from NSCLC treated with ICIs between January 2015 and December 2017. Of 134 patients, 77 were assessable for brain responses and categorized into three groups as follows : group A, ICI alone (n=26); group B, ICI with concurrent GKS within 14 days (n=24); and group C, ICI with non-concurrent GKS (n=27).

Results: The median follow-up duration after brain metastasis diagnosis was 19.1 months (range, 1-77). At the last follow-up, 53 patients (68.8%) died, 20 were alive, and four were lost to follow-up. The estimated median overall survival (OS) of all patients from the date of brain metastasis diagnosis was 20.0 months (95% confidence interval, 12.5-27.7) (10.0, 22.5, and 42.1 months in groups A, B, and C, respectively). The OS was shorter in group A than in group C (p=0.001). The intracranial disease progression-free survival (p=0.569), local progression-free survival (p=0.457), and complication rates did not significantly differ among the groups. Twelve patients showed leptomeningeal seeding (LMS) during follow-up. The 1-year LMS-free rate in treated with ICI alone group (69.1%) was significantly lower than that in treated with GKS before ICI treatment or within 14 days group (93.2%) (p=0.004).

Conclusion: GKS with ICI showed no favorable OS outcome in treating brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, compared with ICI alone, GKS with ICI may be associated with a reduced incidence of LMS. Further understanding of the mechanism, which remains unknown, may help improve the quality of life of patients with brain metastasis.
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http://dx.doi.org/10.3340/jkns.2020.0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969051PMC
March 2021

Pharmacokinetics and safety of evogliptin in hepatically impaired patients.

Br J Clin Pharmacol 2021 Jul 16;87(7):2757-2766. Epub 2020 Dec 16.

Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.

Aims: Evogliptin is a potent and selective dipeptidyl peptidase-4 inhibitor for glycaemic control in patients with type 2 diabetes mellitus. Since evogliptin is mainly eliminated through hepatic metabolism, we investigated the pharmacokinetics (PKs) and safety characteristics of evogliptin in Korean patients with mild or moderate hepatic impairment.

Methods: An open-label, parallel-group study was conducted in patients with mild or moderate hepatic impairment and healthy control subjects matched to each patient for sex, age and body mass index. A single dose (5 mg) of evogliptin was administered orally, and serial blood samples were collected over 120 h to assess the PK profile of evogliptin and its main metabolites (M7 and M8).

Results: Patients with mild hepatic impairment and their matched healthy controls showed similar maximum concentration (C ) and area under the concentration-time curve values from 0 to 120 h (AUC ); the geometric mean ratio (GMR) and 90% confidence interval (CI) were 1.04 (0.80, 1.35) and 1.01 (0.90, 1.14), respectively. Exposure to evogliptin (C and AUC ) was increased by about 40% in patients with moderate hepatic impairment-the GMR and 90% CI were 1.37 (1.09, 1.72) and 1.44 (1.18, 1.75), respectively. The metabolic ratios of M7 and M8 were lower in patients with moderate hepatic impairment than in matched healthy controls. Evogliptin was well tolerated by both patients and healthy subjects.

Conclusion: Although evogliptin exposure was increased in patients with moderate hepatic impairment, the increase is unlikely to affect safety and efficacy adversely, and no dose adjustment is warranted.
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http://dx.doi.org/10.1111/bcp.14680DOI Listing
July 2021

Long-Term Ambient Air Pollution Exposures and Brain Imaging Markers in Korean Adults: The Environmental Pollution-Induced Neurological EFfects (EPINEF) Study.

Environ Health Perspect 2020 11 20;128(11):117006. Epub 2020 Nov 20.

Institute of Human Complexity and Systems Science, Yonsei University, Incheon, Republic of Korea.

Background: Only a limited number of neuroimaging studies have explored the effects of ambient air pollution in adults. The prior studies have investigated only cortical volume, and they have reported mixed findings, particularly for gray matter. Furthermore, the association between nitrogen dioxide () and neuroimaging markers has been little studied in adults.

Objectives: We investigated the association between long-term exposure to air pollutants (, particulate matter (PM) with aerodynamic diameters of (PM10) and (PM2.5), and neuroimaging markers.

Methods: The study included 427 men and 530 women dwelling in four cities in the Republic of Korea. Long-term concentrations of PM10, , and PM2.5 at residential addresses were estimated. Neuroimaging markers (cortical thickness and subcortical volume) were obtained from brain magnetic resonance images. A generalized linear model was used, adjusting for potential confounders.

Results: A increase in PM10 was associated with reduced thicknesses in the frontal [ (95% CI: , )] and temporal lobes [ (95% CI: , )]. A increase in PM2.5 was associated with a thinner temporal cortex [ (95% CI: , )]. A 10-ppb increase in was associated with reduced thicknesses in the global [ (95% CI: , 0.00)], frontal [ (95% CI: , )], parietal [ (95% CI: , )], temporal [ (95% CI: , )], and insular lobes [ (95% CI: , 0.00)]. The air pollutants were also associated with increased thicknesses in the occipital and cingulate lobes. Subcortical structures associated with the air pollutants included the thalamus, caudate, pallidum, hippocampus, amygdala, and nucleus accumbens.

Discussion: The findings suggest that long-term exposure to high ambient air pollution may lead to cortical thinning and reduced subcortical volume in adults. https://doi.org/10.1289/EHP7133.
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http://dx.doi.org/10.1289/EHP7133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678746PMC
November 2020

Obligatory role of Schwann cell-specific erythropoietin receptors in erythropoietin-induced functional recovery and neurogenic muscle atrophy after nerve injury.

Muscle Nerve 2021 02 1;63(2):268-272. Epub 2020 Dec 1.

Department of Orthopaedics and Rehabilitation, Center for Orthopaedics and Translational Science, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.

Background: Erythropoietin (EPO) promotes myelination and functional recovery in rodent peripheral nerve injury (PNI). While EPO receptors (EpoR) are present in Schwann cells, the role of EpoR in PNI recovery is unknown because of the lack of EpoR antagonists or Schwann cell-specific EpoR knockout animals.

Methods: Using the Cre-loxP system, we developed a myelin protein zero (Mpz) promoter-driven knockout mouse model of Schwann cell EpoR (MpzCre-EpoR , Mpz-EpoR-KO). Mpz-EpoR-KO and control mice were assigned to sciatic nerve crush injury followed by EPO treatment.

Results: EPO treatment significantly accelerated functional recovery in control mice in contrast to significantly reduced functional recovery in Mpz-EpoR-KO mice. Significant muscle atrophy was found in the injured hindlimb of EPO-treated Mpz-EpoR-KO mice but not in EPO-treated control mice.

Conclusions: These preliminary findings provide direct evidence for an obligatory role of Schwann-cell specific EpoR for EPO-induced functional recovery and muscle atrophy following PNI.
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http://dx.doi.org/10.1002/mus.27121DOI Listing
February 2021

Effects of Statin Use on the Development and Progression of Nonalcoholic Fatty Liver Disease: A Nationwide Nested Case-Control Study.

Am J Gastroenterol 2021 01;116(1):116-124

Biostatistics Collaboration Unit, Yonsei University College of Medicine, Gangnam-Gu, Seoul, South Korea.

Introduction: The use of statins in nonalcoholic fatty liver disease (NAFLD) may reduce cardiovascular morbidity, although their effect on NAFLD itself is not well known. We aimed to investigate the role of statins on the development of de novo NAFLD and progression of significant liver fibrosis.

Methods: This study included 11,593,409 subjects from the National Health Information Database of the Republic of Korea entered in 2010 and followed up until 2016. NAFLD was diagnosed by calculating fatty liver index (FLI), and significant liver fibrosis was evaluated using the BARD score. Controls were randomly selected at a ratio of 1:5 from individuals who were at risk of becoming the case subjects at the time of selection.

Results: Among 5,339,901 subjects that had a FLI < 30 and included in the non-NAFLD cohort, 164,856 subjects eventually had NAFLD developed. The use of statin was associated with a reduced risk of NAFLD development (adjusted odds ratio [AOR] 0.66; 95% confidence interval [CI] 0.65-0.67) and was independent of associated diabetes mellitus (DM) (with DM: AOR 0.44; 95% CI 0.41-0.46, without DM: AOR 0.71; 95% CI 0.69-0.72). From 712,262 subjects with a FLI > 60 and selected in the NAFLD cohort, 111,257 subjects showed a BARD score ≥ 2 and were defined as liver fibrosis cases. The use of statins reduced the risk of significant liver fibrosis (AOR 0.43; 95% CI 0.42-0.44), independent of DM (with DM: AOR 0.31; 95% CI 0.31-0.32, without DM: AOR 0.52; 95% CI 0.51-0.52).

Discussion: In this large population-based study, statin use decreased the risk of NAFLD occurrence and the risk of liver fibrosis once NAFLD developed.
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http://dx.doi.org/10.14309/ajg.0000000000000845DOI Listing
January 2021

Use of endoscopic transorbital and endonasal approaches for 360° circumferential access to orbital tumors.

J Neurosurg 2020 Sep 25:1-10. Epub 2020 Sep 25.

Departments of1Neurosurgery.

Objective: Orbital tumors are often surgically challenging because they require an extensive fronto-temporo-orbital zygomatic approach (FTOZ) and a multidisciplinary team approach to provide the best outcomes. Recently, minimally invasive endoscopic techniques via a transorbital superior eyelid approach (ETOA) or endoscopic endonasal approach (EEA) have been proposed as viable alternatives to transcranial approaches for orbital tumors. In this study, the authors investigated the feasibility of 360° circumferential access to orbital tumors via both ETOA and EEA.

Methods: Between April 2014 and June 2019, 16 patients with orbital tumors underwent either ETOA or EEA at the authors' institution. Based on the neuro-topographic "four-zone model" of the orbit with its tumor epicenter around the optic nerve in the coronal plane, ETOA (n = 10, 62.5%) was performed for tumors located predominantly superolateral to the nerve and EEA (n = 6, 37.5%) for those located predominantly inferomedial to the nerve. Eight patients (50%) presented with intraconal tumors and 8 (50%) with extraconal ones. The orbital tumors included orbital schwannoma (n = 6), cavernous hemangioma (n = 2), olfactory groove meningioma (n = 1), sphenoorbital meningioma (n = 1), chondrosarcoma (n = 1), trigeminal schwannoma (n = 1), metastatic osteosarcoma (n = 1), mature cystic teratoma (n = 1), sebaceous carcinoma (n = 1), and ethmoid sinus osteoma (n = 1). The clinical outcomes and details of surgical techniques were reviewed.

Results: Gross-total resection was achieved in 12 patients (75%), near-total resection in 3 (18.8%), and subtotal resection in 1 (6.2%). Eight (88.9%) of the 9 patients with preoperative proptosis showed improvement after surgery, and 4 (66.7%) of the 6 patients with visual symptoms demonstrated improvement. Four (40%) of the 10 patients treated with ETOA experienced partial third nerve palsy immediately after surgery (3 transient and 1 persistent). There have been no postoperative CSF leaks or infections in this series.

Conclusions: Without transcranial approaches requiring temporalis muscle dissection and orbitozygomatic osteotomy, the selection of ETOA or EEA based on a concept of a four-zone model with its epicenter around the optic nerve successfully provides a minimally invasive 360° circumferential access to the entire orbit with acceptable morbidity.
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http://dx.doi.org/10.3171/2020.6.JNS20890DOI Listing
September 2020

Gamma Knife Radiosurgery as a Primary Treatment for Nonfunctioning Pituitary Adenoma Invading the Cavernous Sinus.

Stereotact Funct Neurosurg 2020 16;98(6):371-377. Epub 2020 Sep 16.

Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea,

Objectives: Surgical resection of nonfunctioning pituitary adenoma (NFPA) invading the cavernous sinus (CS) remains a challenging and significant factor associated with incomplete resection. The residual tumor in CS is usually treated with adjuvant stereotactic radiosurgery (SRS), but there is little information concerning SRS as an initial treatment for CS-invading NFPA. In this study, we investigated the tumor control rate and clinical outcomes of the patients who received primary gamma knife radiosurgery (GKRS) for CS-invading NFPA.

Methods: This was a single-institute retrospective analysis of 11 patients. CS invasion of tumor was categorized using the modified Knosp grading system. The median tumor volume and maximal diameter were 1.6 cm3 (range 0.4-6.5) and 17.2 mm (range 11.6-23.3), respectively. The median clinical follow-up period was 48.5 months (range 16.4-177.8). The median prescription dose at tumor margin was 15 Gy (range 11-25) and median prescription isodose was 50% (range 45-50). The maximum radiation dose to optic chiasm and optic nerve were 7.2 Gy (range 3.4-9.2) and 7.5 Gy (range 4.5-11.5), respectively.

Results: Tumor control was achieved in all patients. The median tumor volume and maximal diameter at last follow-up were 0.4 cm3 (range 0.1-2.3) and 11.4 mm (range 4.7-19.5), respectively. The median volume reduction rate was 52% (range 33-88). Six patients showed downgrading of modified Knosp grade after GKRS. No patients developed GKRS-related complications such as hypopituitarism or visual disturbance.

Conclusions: SRS may be an alternative primary treatment option for CS-invading NFPA if there is no urgent and absolute indication for surgery such as optic apparatus compression.
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http://dx.doi.org/10.1159/000508737DOI Listing
May 2021

Stereotactic radiosurgery for orbital cavernous venous malformation: a single center's experience for 15 years.

Acta Neurochir (Wien) 2021 02 15;163(2):357-364. Epub 2020 Sep 15.

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

Background: Stereotactic radiosurgery such as Gamma Knife radiosurgery (GKRS) has been shown to have a good treatment effect for orbital cavernous venous malformation (CVM). However, radiation-induced retinopathy or optic neuropathy is a vision-threatening complication of orbital irradiation. Predicting the post-treatment visual outcome is critical.

Methods: Clinical and radiological outcomes were investigated in 30 patients who underwent GKRS for orbital CVM between July 2005 and February 2020. Measurement of peripapillary retinal nerve fiber layer (pRNFL) thickness using optical coherence tomography (OCT) was obtained in 14 patients.

Results: The median clinical and radiological follow-up periods were 46.6 months (range, 15.9-105.8) and 27.5 months (range, 15.4-105.8), respectively. Twenty-eight patients underwent multisession (4 fractions) GKRS. The median cumulative marginal dose was 20 Gy (range, 16-24). Two patients underwent single-session GKRS. Marginal doses were 15 Gy and 10.5 Gy in each patient. The volume of CVM decreased in 29 (97%) patients. Visual acuity was improved in 6 (20%) patients and was stable in 22 (73%) patients. Visual field defect and exophthalmos were improved in all patients. Serial investigation of OCT showed no statistically significant difference in pRNFL thickness after GKRS. Patients with normal average pRNFL thickness showed better visual recovery than patients with thin average pRNFL thickness.

Conclusions: GKRS is an effective and safe treatment option for orbital CVM. The pRNFL thickness before GKRS can be a prognostic indicator for visual recovery in orbital CVM after GKRS.
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http://dx.doi.org/10.1007/s00701-020-04575-4DOI Listing
February 2021

Risk factors for osteonecrosis of the femoral head in brain tumor patients receiving corticosteroid after surgery.

PLoS One 2020 3;15(9):e0238368. Epub 2020 Sep 3.

Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Purpose: Non-traumatic osteonecrosis of the femoral head (ONFH) is a plausible complication in brain tumor patients. Frequent use of corticosteroid therapy, chemotherapy, and oxidative stress for managing brain tumors may be associated with the development of ONFH. However, there is little knowledge on the prevalence and risk factors of ONFH from brain tumor. This study aimed to investigate the prevalence and risk factors of ONFH in patients with primary brain tumors.

Methods: This retrospective cohort study included data from consecutive patients between December 2005 and August 2016 from a tertiary university hospital in South Korea. A total of 73 cases of ONFH were identified among 10,674 primary brain tumor patients. After excluding subjects (25 out of 73) with missing data, history of alcohol consumption or smoking, history of femoral bone trauma or surgery, comorbidities such as systemic lupus erythematosus (SLE), sickle cell disease, cancer patients other than brain tumor, and previous diagnosis of contralateral ONFH, we performed a 1:2 propensity score-matched, case-control study (ONFH group, 48; control group, 96). Risk factors of ONFH in primary brain tumor were evaluated by univariate and multivariate logistic regression analyses.

Results: The prevalence of ONFH in patients with surgical resection of primary brain tumor was 683.9 per 100,000 persons (73 of 10,674). In this cohort, 55 of 74 patients (74.3%) underwent THA for ONFH treatment. We found that diabetes was an independent factor associated with an increased risk of ONFH in primary brain tumor patients (OR = 7.201, 95% CI, 1.349-38.453, p = 0.021). There was a significant difference in univariate analysis, including panhypopituitarism (OR = 4.394, 95% CI, 1.794-11.008, p = 0.002), supratentorial location of brain tumor (OR = 2.616, 95% CI, 1.245-5.499, p = 0.011), and chemotherapy (OR = 2.867, 95% CI, 1.018-8.069, p = 0.046).

Conclusions: This study demonstrated that the prevalence of ONFH after surgical resection of primary brain tumor was 0.68%. Diabetes was an independent risk factor for developing ONFH, whereas corticosteroid dose was not. Routine screening for brain tumor-associated ONFH is not recommended; however, a high index of clinical suspicion in these patients at risk may allow for early intervention and preservation of the joints.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238368PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470295PMC
October 2020

Functional recovery with histomorphometric analysis of nerves and muscles after combination treatment with erythropoietin and dexamethasone in acute peripheral nerve injury.

PLoS One 2020 3;15(9):e0238208. Epub 2020 Sep 3.

Department of Emergency Medicine, Ewha Women's University Mokdong Hospital, Seoul, South Korea.

Introduction: Peripheral nerve injury (PNI) often leads to significant functional loss in patients and poses a challenge to physicians since treatment options for improving functional outcomes are limited. Recent studies suggest that erythropoietin and glucocoticoids have beneficial effects as mediators of neuro-regenerative processes. We hypothesized that combination treatment with erythropoietin and glucocoticoids would have a synergistic effect on functional outcome after PNI.

Materials And Methods: Sciatic nerve crush injury was simulated in ten-week-old male C57BL/6 mice. The mice were divided into four groups according to the type of drugs administered (control, erythropoietin, dexamethasone, and erythropoietin with dexamethasone). Motor functional recovery was monitored by walking track analysis at serial time points up to 28 days after injury. Morphological analysis of the nerve was performed by immunofluorescent staining for neurofilament (NF) heavy chain and myelin protein zero (P0) in cross-sectional and whole-mount nerve preparations. Additionally, morphological analysis of the muscle was performed by Hematoxylin and eosin staining.

Results: Combination treatment with erythropoietin and dexamethasone significantly improved the sciatic functional index at 3, 7, 14, and 28 days after injury. Fluorescence microscopy of cross sectional nerve revealed that the combination treatment increased the ratio of P0/NF-expressing axons. Furthermore, confocal microscopy of the whole-mount nerve revealed that the combination treatment increased the fluorescence intensity of P0 expression. The cross-sectional area and minimum Feret's diameter of the muscle fibers were significantly larger in the mice which received combination treatment than those in the controls.

Conclusion: Our results demonstrated that combination treatment with erythropoietin and dexamethasone accelerates functional recovery and reduces neurogenic muscle atrophy caused by PNI in mice, which may be attributed to the preservation of myelin and Schwann cell re-myelination. These findings may provide practical therapeutic options for patients with acute PNI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238208PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470391PMC
October 2020

Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma.

Genome Biol 2020 08 26;21(1):216. Epub 2020 Aug 26.

Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages.

Results: We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCO TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCO TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments.

Conclusions: Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.
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http://dx.doi.org/10.1186/s13059-020-02140-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448990PMC
August 2020

Ethnic delineation of primary glioblastoma genome.

Cancer Med 2020 10 13;9(19):7352-7359. Epub 2020 Aug 13.

Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.

Glioblastoma (GBM) is the most malignant primary brain tumor in adults with substantial genomic alterations. The median survival is approximately 14.6 months, despite aggressive therapeutic intervention, which comprised of surgical resection, radiotherapy, and chemotherapy. Recent studies on cancer genomic have revealed crucial insights into dynamic molecular subgroups within GBM, which govern distinct clinical response and sensitivity of each individual to therapy. In the present study, we analyzed genomic composition of primary GBMs between two ethnic groups [IRCR (Institute of Refractory Cancer Research), and TCGA (The Cancer Genome Atlats)] to explore genomic and molecular features that constitute malignant behavior of glioblastoma based on distinct ethnicity. We identified enrichments of MAPK and p53 pathways in IRCR patients, while aberrant activation of Receptor Tyrosine Kinases (RTKs) were predominant in TCGA cohort. We also discovered differential clinical prognosis between two groups and explored essential features that present such diversity.
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http://dx.doi.org/10.1002/cam4.3370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541127PMC
October 2020

Association between exposure to polycyclic aromatic hydrocarbons and brain cortical thinning: The Environmental Pollution-Induced Neurological EFfects (EPINEF) study.

Sci Total Environ 2020 Oct 9;737:140097. Epub 2020 Jun 9.

Institute of Human Complexity and Systems Science, Yonsei University, Seoul, Republic of Korea; Institute for Environmental Research, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background: Although some studies have suggested that exposure to polycyclic aromatic hydrocarbons (PAHs) induces neurodevelopmental disturbances in children and neurodegeneration in animals, the neurotoxic effect of PAH exposure is unclear in adults. The aim was to examine the associations of PAH exposure with brain structure and neuropsychological function in adults without known neurological diseases.

Methods: This study included 421 men and 528 women dwelling in four cities in the Republic of Korea. Urinary concentrations of four PAH metabolites (1-hydroxypyrene, 2-naphthol, 1-hydroxyphenanthrene, and 2-hydroxyfluorene) were obtained. Participants underwent brain 3 T magnetic resonance imaging and neuropsychological tests. Cortical thickness and volume were estimated using the region-of-interest method. Separate generalized linear models were constructed for each sex, adjusting for age, years of education, cohabitation status, income, tobacco use, alcohol consumption, and vascular risk factors.

Results: The mean (standard deviation) age was 68.3 (6.6) years in men and 66.4 (6.1) years in women. In men, those in quartile 4 (versus quartile 1, the lowest) of urinary 2-naphthol concentration had cortical thinning in the global (β = -0.03, P = .02), parietal (β = -0.04, P = .01), temporal (β = -0.06, P < .001), and insular lobes (β = -0.05, P = .02). Higher quartiles of urinary 2-naphthol concentration were associated with cortical thinning in the global (P = .01), parietal (P = .004), temporal (P < .001), and insular lobes (P = .01). In women, those in quartile 4 (versus quartile 1) of urinary 1-hydroxypyrene concentration had cortical thinning in the frontal (β = -0.03, P = .006) and parietal lobes (β = -0.03, P = .003). Higher quartiles of urinary 1-hydroxypyrene concentration were associated with cortical thinning in the frontal (P = .006) and parietal lobes (P = .001). In both sexes, verbal learning and memory scores significantly declined with an increase in quartile of urinary 1-hydroxypyrene concentration.

Conclusions: PAH exposure was associated with cortical thinning and decline in verbal learning and memory function in cognitively healthy adults. This suggests PAHs as an environmental risk factor for neurodegeneration.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140097DOI Listing
October 2020

A Modified Protocol of Diethylnitrosamine Administration in Mice to Model Hepatocellular Carcinoma.

Int J Mol Sci 2020 Jul 30;21(15). Epub 2020 Jul 30.

Department of Biomedical Sciences, School of Medicine, Inha University, Incheon 22212, Korea.

We aimed to create an animal model for hepatocellular carcinoma (HCC) with a short time, a high survival rate, as well as a high incidence of HCC in both males and females than previously reported. The Diethylnitrosamine (DEN) model has an age-related effect. A single dose of DEN treatment is not enough in young mice up to 50 weeks. The same pattern is shown in an adult with multiple-dose trials whether or not there is some promotion agent. In this study, two-week old C57BL6 mice were given a total of eight doses of DEN, initially 20mg/kg body weight, and then 30mg/kg in the third week, followed by 50mg/kg for the last six weeks. The first group is DEN treatment only and the other two groups received thioacetamide (TAA) treatment for four or eight weeks after one week of rest from the last DEN treatment. An autopsy was performed after 24 weeks of the initial dose of DEN in each group. The cellular arrangement of HCC in the entire group was well-differentiated carcinoma and tumor presence with no significant impact on the survival of mice. Increased levels of the biochemical markers in serum, loss of tissue architecture, hepatocyte death, and proliferation were highly activated in all tumor-induced groups. This finding demonstrates an improved strategy to generate an animal model with a high occurrence of tumors combined with cirrhosis in a short time regardless of sex for researchers who want to investigate liver cancer-related.
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http://dx.doi.org/10.3390/ijms21155461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432842PMC
July 2020
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