Publications by authors named "Sung Hye Park"

359 Publications

Retained medullary cord and terminal myelocystocele as a spectrum: case report.

Childs Nerv Syst 2021 Sep 17. Epub 2021 Sep 17.

Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, 03080, Seoul, Republic of Korea.

The caudal portion of the spinal cord, the medullary cord, is formed by secondary neurulation. One of the distinctive features of secondary neurulation compared to primary neurulation is that the medullary cord normally degenerates into a filum in humans. Various anomalies have been known to originate from degenerating process errors. One anomaly is terminal myelocystocele (TMCC), which is a closed spinal dysraphism with an elongated caudal spinal cord. The terminal part is filled with cerebrospinal fluid (CSF) and protrudes into the dorsal extradural space. Another anomaly is the retained medullary cord (RMC), which is a nonfunctioning cord-like structure extending to the cul-de-sac. In a 1-month-old boy, we identified an RMC with cystic dilatation of the caudal end extending to the epidural space at the very bottom of the cul-de-sac, resembling a degenerating terminal balloon, which is an essential feature of TMCC. Hence, this case may be considered an intermediate form between TMCC and RMC. This case provides clinical evidence that TMCC and RMC share the same pathoembryogenic origin, namely, failure of the regression phase of secondary neurulation.
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http://dx.doi.org/10.1007/s00381-021-05351-0DOI Listing
September 2021

ZFTA-YAP1 fusion-positive ependymoma can occur in the spinal cord: Letter to the editor.

Brain Pathol 2021 Sep 10:e13020. Epub 2021 Sep 10.

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

We report a case of spinal ependymoma with ZFTA-YAP1 fusion, occurring in a 5-year-old boy who complained of back pain. It was high-grade ependymoma, developed in the spinal cord at the level of T9-12. Since ZFTA-YAP1 fusion-positive ependymoma has never been reported in the spinal cord, this case is exceptional and worth reporting because the anatomical location, genetics, and epigenetics are important parameters in the classification of the ependymal tumor. This is the first case of spinal ependymoma harboring ZFTA-fusion to be diagnosed by NGS and Sanger studies to the best of our knowledge.
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http://dx.doi.org/10.1111/bpa.13020DOI Listing
September 2021

ApoE4 attenuates autophagy via FoxO3a repression in the brain.

Sci Rep 2021 Sep 2;11(1):17604. Epub 2021 Sep 2.

Division of Brain Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Cheongju-si, Chungcheongbuk-do, 28159, Republic of Korea.

Apolipoprotein E (ApoE) plays multiple roles in lipid transport, neuronal signaling, glucose metabolism, mitochondrial function, and inflammation in the brain. It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the ε4 allele of APOE is the highest genetic risk factor for developing late-onset Alzheimer's disease (AD). However, the mechanism by which ApoE4 contributes to the pathogenesis of AD remains unclear. We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the APOE4 allele.
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http://dx.doi.org/10.1038/s41598-021-97117-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413297PMC
September 2021

A second hit somatic (p.R905W) and a novel germline intron-mutation of TSC2 gene is found in intestinal lymphangioleiomyomatosis: a case report with literature review.

Diagn Pathol 2021 Aug 31;16(1):83. Epub 2021 Aug 31.

Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in multiple organs associated with germline mutations in TSC1 and TSC2, including exonic, intronic, or mosaic mutations. Gastrointestinal (GI) tract Lymphangioleiomyomatosis (LAM) is an extremely rare manifestation of TSC, with few reported cases. Herein, we aimed to determine the driver mutation, pathogenesis, and relationship of germline and somatic mutations of LAM through whole-genome sequencing (WGS) of the tumor and blood samples and whole transcriptome sequencing (WTS) analysis.

Case Presentation: A nine-year-old girl with a full-blown TSC presented with abdominal masses detected during a routine check-up. Resected intestinal masses were diagnosed as LAM by thorough pathological examination. Interestingly, the LAM presented a somatic TSC2 gene mutation in exon 24 (p.R905W, c.C2713T), and the patient had intron retention by a novel germline mutation in the intron region of TSC2 (chr16:2126489, C > G).

Conclusion: Our case suggests that intron retention by a single nucleotide intronic mutation of TSC2 is sufficient to develop severe manifestations of TSC, but the development of LAM requires an additional somatic oncogenic mutation of TSC2.
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http://dx.doi.org/10.1186/s13000-021-01138-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406734PMC
August 2021

Revisiting vimentin: a negative surrogate marker of molecularly defined oligodendroglioma in adult type diffuse glioma.

Brain Tumor Pathol 2021 Aug 2. Epub 2021 Aug 2.

Department of Pathology, Seoul National University Hospital, College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, South Korea.

Vimentin is a marker of epithelial-mesenchymal transformation and indicates poor prognosis in various cancers, but its role in diffuse gliomas remains unknown. We investigated the vimentin expression of diffuse gliomas according to the upcoming 2021 WHO classification, its variations due to mutational status, and its prognostic effects. We analyzed vimentin immunohistochemistry in 315 gliomas: a test set (n = 164) and a validation set (n = 151). RNA-seq and mutational information from The Cancer Genome Atlas (TCGA, n = 422) were also used for validation. Vimentin was diffusely positive in astrocytic tumors but negative in oligodendroglial tumors (ODGs) and its expression was significantly higher in isocitrate dehydrogenase (IDH) wild-type tumors. High vimentin expression was correlated with poor prognosis (hazard ratio [HR]: 5.99), but it was dependent on the new WHO grade which reflects both histologic features and genetics (HR: 1.28). Using the significant difference in vimentin expression between ODGs and astrocytic tumors, the positive and negative predictive values of the vimentin-based diagnosis for ODGs were 93.5% and 97.8% in the validation set. Along with additional alpha-thalassemia/mental retardation, X-linked (ATRX) immunohistostaining, the values were 98.3% and 97.8%, respectively. Vimentin is a useful ancillary marker for identifying ODGs when combined with routine histochemistry markers.
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http://dx.doi.org/10.1007/s10014-021-00411-4DOI 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

A case of dermatomyositis in a patient with central core disease: unusual association with autoimmunity and genetic muscle disease.

Pediatr Rheumatol Online J 2021 Jun 30;19(1):100. Epub 2021 Jun 30.

Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.

Background: Dermatomyositis is an inflammatory muscle disease caused by immune-mediated muscle injury, and central core disease (CCD) is a congenital myopathy associated with disturbed intracellular calcium homeostasis and excitation-contraction coupling. To date, CCD has not been reported to have autoantibodies or coexist with inflammatory myopathy.

Case Presentation: Here, we described the case of a 25-year-old woman who had progressive proximal muscle weakness, myalgia, pruritic macular rash, skin ulcers, and calcinosis. Dermatomyositis was initially suspected based on the clinical symptoms accompanied by elevated muscle enzyme levels, electromyography abnormalities, and a positive antinuclear antibody test. However, the patient's muscle biopsy revealed the characteristic findings of both dermatomyositis and CCD, suggesting that dermatomyositis occurred in this patient with previously asymptomatic CCD. The patient did not have any pathogenic gene mutations associated with congenital myopathy, including RYR1 and SEPN1 in targeted next-generation sequencing. She received high-dose glucocorticoid therapy and azathioprine with a significant improvement in muscle strength.

Conclusions: We present a case of rare coexistence of dermatomyositis and CCD. Clinicians should be aware that patients with CCD may have inflammatory myopathy that responds well to immunosuppressive therapy.
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http://dx.doi.org/10.1186/s12969-021-00598-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243539PMC
June 2021

The substantial loss of H3K27me3 can stratify risk in grade 2, but not in grade 3 meningioma.

Hum Pathol 2021 Sep 26;115:96-103. Epub 2021 Jun 26.

Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. Electronic address:

Trimethylation of lysine 27 of histone H3 (H3K27me3) has recently emerged as a crucial epigenetic marker in meningioma. The loss of H3K27me3 expression might predict the early recurrence of grade 1 and 2 meningiomas. However, this is controversial in terms of grade 3 meningioma and the effects of H3K27me3 on the overall survival (OS) of patients with low low-grade meningioma have not been studied. Therefore, we immunohistochemically assessed the prognostic implications of H3K27me3 expression in grade 2 and 3 meningiomas. Whole-slide H3K27me3 immunostaining was evaluated for strict quality control and to confirm a significant correlation (P < .0001) with tissue microarray results. The effects of tissue age on H3K27me3 immunostaining were also evaluated, to select an appropriate cohort for survival analysis. Log-rank tests of 115 grade 2 meningiomas and 26 grade 3 meningiomas showed that the loss of H3K27me3 expression was a prognostic factor for early recurrence (P < .0001) and death (P = .00012) in grade 2, but not in grade 3 meningioma. Multivariate analysis revealed that age, recurrent tumor, and loss of H3K27me3 expression (hazard ratio, 1.264-7.510; P = .0133) were significant for recurrentrecurrence-free survival (RFS), and that recurrent tumor and loss of H3K27me3 expression (hazard ratio, 1.717-120.621; P = .0140) were significant for OS. We concluded that H3K27me3 expression is a significant prognostic factor for the RFS and OS of patients with grade 2 meningioma; it should be considered as an ancillary test for risk stratification of this meningioma.
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http://dx.doi.org/10.1016/j.humpath.2021.06.005DOI Listing
September 2021

Control of neurogenic competence in mammalian hypothalamic tanycytes.

Sci Adv 2021 May 28;7(22). Epub 2021 May 28.

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.

Hypothalamic tanycytes, radial glial cells that share many features with neuronal progenitors, can generate small numbers of neurons in the postnatal hypothalamus, but the identity of these neurons and the molecular mechanisms that control tanycyte-derived neurogenesis are unknown. In this study, we show that tanycyte-specific disruption of the NFI family of transcription factors () robustly stimulates tanycyte proliferation and tanycyte-derived neurogenesis. Single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis reveals that NFI (nuclear factor I) factors repress Sonic hedgehog (Shh) and Wnt signaling in tanycytes and modulation of these pathways blocks proliferation and tanycyte-derived neurogenesis in -deficient mice. -deficient tanycytes give rise to multiple mediobasal hypothalamic neuronal subtypes that can mature, fire action potentials, receive synaptic inputs, and selectively respond to changes in internal states. These findings identify molecular mechanisms that control tanycyte-derived neurogenesis, which can potentially be targeted to selectively remodel the hypothalamic neural circuitry that controls homeostatic physiological processes.
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http://dx.doi.org/10.1126/sciadv.abg3777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163082PMC
May 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

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

Tumor Spheroids of an Aggressive Form of Central Neurocytoma Have Transit-Amplifying Progenitor Characteristics with Enhanced EGFR and Tumor Stem Cell Signaling.

Exp Neurobiol 2021 Apr;30(2):120-143

Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03082, Korea.

Central neurocytoma (CN) has been known as a benign neuronal tumor. In rare cases, CN undergoes malignant transformation to glioblastomas (GBM). Here we examined its cellular origin by characterizing differentiation potential and gene expression of CN-spheroids. First, we demonstrate that both CN tissue and cultured primary cells recapitulate the hierarchal cellular composition of subventricular zone (SVZ), which is comprised of neural stem cells (NSCs), transit amplifying progenitors (TAPs), and neuroblasts. We then derived spheroids from CN which displayed EGFR+/ MASH+ TAP and BLBP+ radial glial cell (RGC) characteristic, and mitotic neurogenesis and gliogenesis by single spheroids were observed with cycling multipotential cells. CN-spheroids expressed increased levels of pluripotency and tumor stem cell genes such as and , when compared to their differentiated cells and human NSCs. Importantly, Gene Set Enrichment Analysis showed that gene sets of GBM-Spheroids, EGFR Signaling, and Packaging of Telomere Ends are enriched in CN-spheroids in comparison with their differentiated cells. We speculate that CN tumor stem cells have TAP and RGC characteristics, and upregulation of EGFR signaling as well as downregulation of eph-ephrin signaling have critical roles in tumorigenesis of CN. And their ephemeral nature of TAPs destined to neuroblasts, might reflect benign nature of CN.
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http://dx.doi.org/10.5607/en21004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118755PMC
April 2021

Clinicopathological Features of Primary Solitary Spinal Cord Tumors in Pediatric Patients : A 32-Year Single Institution Experience.

J Korean Neurosurg Soc 2021 Jul 16;64(4):592-607. Epub 2021 Apr 16.

Division of Pediatric Neurosurgery, Department of Neurosurgery, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.

Objective: Few studies exist on primary spinal cord tumors (PSCTs) in pediatric patients. The purpose of this study was to perform descriptive analysis and detailed survival analysis for PSCTs.

Methods: Between 1985 and 2017, 126 pediatric patients (male : female, 56 : 70) with PSCTs underwent surgery in a single institution. We retrospectively analyzed data regarding demographics, tumor characteristics, outcomes, and survival statistics. Subgroup analysis was performed for the intramedullary (IM) tumors and extradural (ED) tumors separately.

Results: The mean age of the participants was 6.4±5.04 years, and the mean follow-up time was 69.5±46.30 months. The most common compartment was the ED compartment (n=57, 45.2%), followed by the IM (n=43, 34.1%) and intradural extramedullary (IDEM; n=16, 12.7%) compartments. Approximately half of PSCTs were malignant (n=69, 54.8%). The most common pathologies were schwannomas (n=14) and neuroblastomas (n=14). Twenty-two patients (17.5%) died from the disease, with a mean disease duration of 15.8±15.85 months. Thirty-six patients (28.6%) suffered from progression, with a mean period of 22.6±30.81 months. The 10-year overall survival (OS) rates and progression-free survival (PFS) rates were 81% and 66%, respectively. Regarding IM tumors, the 10-year OS rates and PFS rates were 79% and 57%, respectively. In ED tumors, the 10-year OS rates and PFS rates were 80% and 81%, respectively. Pathology and the extent of resection showed beneficial effects on OS for total PSCTs, IM tumors, and ED tumors. PFS was affected by both the extent of removal and pathology in total PSCTs and ED tumors; however, pathology was a main determinant of PFS rather than the extent of removal in IM tumors. The degree of improvement in the modified McCormick scale showed a trend towards improvement in patients with IM tumors who achieved gross total removal (p=0.447).

Conclusion: Approximately half of PSCTs were malignant, and ED tumors were most common. The most common pathologies were schwannomas and neuroblastomas. Both the pathology and extent of resection had a decisive effect on OS. For IM tumors, pathology was a main determinant of PFS rather than the extent of removal. Radical excision of IM tumors could be a viable option for better survival without an increased risk of worse functional outcomes.
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http://dx.doi.org/10.3340/jkns.2020.0243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273779PMC
July 2021

Coexistence of dentatorubral-pallidoluysian atrophy and Parkinson's disease: An autopsy case report.

Neuropathology 2021 Jun 13;41(3):196-205. Epub 2021 Apr 13.

Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.

We report an autopsy case of a 56-year-old male patient with the coexistence of dentatorubral-pallidoluysian atrophy (DRPLA) and Parkinson's disease (PD). He presented with gait instability and dysarthria for 10 years. The removed brain showed general atrophy (988 g) with depigmentation of the substantia nigra. The neocortex and deep gray matter, including the red nucleus, subthalamic nuclei, and globus pallidus, were atrophic, and grumose degeneration of the cerebellar dentate nucleus was observed. Polyglutamine- and p62-positive neuronal inclusions were present and widespread in the areas mentioned above. Interestingly, this case also had brainstem-predominant PD pathology with α-synuclein-positive Lewy bodies and Lewy neurites. Generalized white matter atrophy with patchy loss of astrocytes in the white matter suggested glial dysfunction by elongated CAG repeats in the atrophin 1 gene (atrophin 1). Polymerase chain reaction (PCR) fragment analysis revealed increased CAG repeats (61) on atrophin 1 encoding atrophin 1. The patient had a family history of DRPLA, including his daughter, who was confirmed positive on genetic testing (CAG repeat: 65). His father, brother, and niece were suspected of having the disease. Clinicopathologically, all of the above findings are consistent with the coexistence of DRPLA and PD. So far, various overlapping neurodegenerative disorders have been reported, but the coexistence of DRPLA and PD has never been demonstrated in the published literature. Even though the exact time of PD development is unknown in this case, PD might develop after DRPLA, and the overwhelming symptoms of DRPLA might mask those of PD. Here, we report a clinicopathologically definite case of the coexistence of DRPLA and PD. White matter degeneration with patchy loss of astrocytes was another remarkable finding of this case.
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http://dx.doi.org/10.1111/neup.12720DOI Listing
June 2021

An autopsy-proven case of Corticobasal degeneration heralded by Pontine infarction.

BMC Neurol 2021 Apr 6;21(1):148. Epub 2021 Apr 6.

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

Background: Neurodegenerative disorders are characterized by insidious progression with poorly-delineated long latent period. Antecedent clinical insult could rarely unmask latent neurodegenerative disorders. Here, we report an autopsy-proven case of corticobasal degeneration which was preceded by a lacunar infarction.

Case Presentation: A 58-year-old man presented with acute ataxia associated with a lacunar infarction in the right paramedian pons. His ataxia persisted with additional progressive gait difficulty and left arm clumsiness. Six months later, a follow-up neurological examination showed asymmetrical bradykinesia, apraxia, dystonic posturing, postural instability, and mild ataxia of the left limbs. Cognitive examination revealed frontal executive dysfunction and visuospatial difficulties. Dopamine transporter imaging scan demonstrated bilateral reduced uptakes in mid-to-posterior putamen, more prominent on the right side. Levodopa-unresponsive parkinsonism, asymmetric limb dystonia, and ideomotor apraxia became more conspicuous, while limb ataxia gradually vanished. The patient became unable to walk without assistance after 1 year, and died 4 years after the symptom onset. Autopsy findings showed frontoparietal cortical atrophy, ballooned neurons, and phosphorylated tau-positive astrocytic plaques and neuropil threads with gliosis and neuronal loss, confirming the corticobasal degeneration.

Conclusions: The case illustrates that precedent clinical events such as stroke might tip a patient with subclinical CBS into overt clinical manifestations.
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http://dx.doi.org/10.1186/s12883-021-02178-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022434PMC
April 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

Stage IV Classical Hodgkin Lymphoma-type Posttransplant Lymphoproliferative Disorder in a Pediatric Liver Transplant Patient: A Case Report and Review of the Literature.

J Pediatr Hematol Oncol 2021 Oct;43(7):e1015-e1019

Departments of Pediatrics.

Posttransplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases with abnormal proliferation of lymphoid tissue and classical Hodgkin lymphoma (CHL) type PTLD is a very rare subtype. We describe a successfully diagnosed and treated CHL-PTLD stage IV pediatric patient, 8 years after liver transplantation. The patient was treated with standard CHL (Children's Cancer Group 5942 group 3) chemotherapy, rituximab and reduction of immunosuppressant. The patient remains in complete remission after 3 years with stable graft function. To our best knowledge, this is the first pediatric case report of a successfully treated stage IV CHL-PTLD after a liver transplant.
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http://dx.doi.org/10.1097/MPH.0000000000002121DOI Listing
October 2021

Methylation and molecular profiles of ependymoma: Influence of patient age and tumor anatomic location.

Mol Clin Oncol 2021 May 5;14(5):88. Epub 2021 Mar 5.

Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.

Ependymomas are tumors of the central nervous system that can occur in patients of all ages. Guidelines from the World Health Organization (WHO) for the grading of ependymomas consider patient age, tumor resection range, tumor location and histopathological grade. However, recent studies have suggested that a greater focus on both tumor location and patient age in terms of transcriptomic, genetic, and epigenetic analyses may provide a more accurate assessment of clinical prognosis than the grading system proposed by WHO guidelines. The current study identified the differences and similarities in ependymoma characteristics using three different molecular analyses and methylation arrays. Primary intracranial ependymoma tissues were obtained from 13 Korean patients (9 adults and 4 children), after which whole-exome sequencing (WES), ion-proton comprehensive cancer panel (CCP) analysis, RNA sequencing, and Infinium HumanMethylation450 BeadChip array analysis was performed. Somatic mutations, copy number variations, and fusion genes were identified. It was observed that the methylation status and differentially expressed genes were significantly different according to tumor location and patient age. Several novel gene fusions and somatic mutations were identified, including a fusion mutation in a child with a good prognosis. Moreover, the methylation microarray revealed that genes associated with neurogenesis and neuron differentiation were hypermethylated in the adult group, whereas genes in the homeobox gene family were hypermethylated in the supratentorial (ST) group. The results confirmed the existence of significantly differentially expressed tumor-specific genes based on tumor location and patient age. These results provided valuable insight into the epigenetic and genetic profiles of intracranial ependymomas and uncovered potential strategies for the identification of location- and age-based ependymoma-related prognostic factors.
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http://dx.doi.org/10.3892/mco.2021.2250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976387PMC
May 2021

Perspective of mesenchymal transformation in glioblastoma.

Acta Neuropathol Commun 2021 03 24;9(1):50. Epub 2021 Mar 24.

Department of Neurosurgery, Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, Korea.

Despite aggressive multimodal treatment, glioblastoma (GBM), a grade IV primary brain tumor, still portends a poor prognosis with a median overall survival of 12-16 months. The complexity of GBM treatment mainly lies in the inter- and intra-tumoral heterogeneity, which largely contributes to the treatment-refractory and recurrent nature of GBM. By paving the road towards the development of personalized medicine for GBM patients, the cancer genome atlas classification scheme of GBM into distinct transcriptional subtypes has been considered an invaluable approach to overcoming this heterogeneity. Among the identified transcriptional subtypes, the mesenchymal subtype has been found associated with more aggressive, invasive, angiogenic, hypoxic, necrotic, inflammatory, and multitherapy-resistant features than other transcriptional subtypes. Accordingly, mesenchymal GBM patients were found to exhibit worse prognosis than other subtypes when patients with high transcriptional heterogeneity were excluded. Furthermore, identification of the master mesenchymal regulators and their downstream signaling pathways has not only increased our understanding of the complex regulatory transcriptional networks of mesenchymal GBM, but also has generated a list of potent inhibitors for clinical trials. Importantly, the mesenchymal transition of GBM has been found to be tightly associated with treatment-induced phenotypic changes in recurrence. Together, these findings indicate that elucidating the governing and plastic transcriptomic natures of mesenchymal GBM is critical in order to develop novel and selective therapeutic strategies that can improve both patient care and clinical outcomes. Thus, the focus of our review will be on the recent advances in the understanding of the transcriptome of mesenchymal GBM and discuss microenvironmental, metabolic, and treatment-related factors as critical components through which the mesenchymal signature may be acquired. We also take into consideration the transcriptomic plasticity of GBM to discuss the future perspectives in employing selective therapeutic strategies against mesenchymal GBM.
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http://dx.doi.org/10.1186/s40478-021-01151-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992784PMC
March 2021

Analysis of α-synuclein levels related to LRRK2 kinase activity: from substantia nigra to urine of patients with Parkinson's disease.

Anim Cells Syst (Seoul) 2021 Feb 17;25(1):28-36. Epub 2021 Feb 17.

InAm Neuroscience Research Center, Gunpo, Republic of Korea.

Research on Parkinson's disease (PD) has been focused on the development of PD diagnostic tools as much as the development of PD therapeutics. Several genetic culprits of PD, including DJ-1, Leucine-rich repeat kinase 2 (LRRK2), and α-synuclein (α-syn), have been investigated as markers of PD in human biofluids. Unfortunately, the approaches to develop PD diagnostic tools are impractical, and there is a considerable demand for an appropriate marker of PD. The measurement of α-syn in biofluids has recently been made more accurate by examining monomers and aggregates separately using enzyme-linked immunosorbent assay (ELISA). Previously, we reported on the development of two types of sandwich ELISA for total α-syn and MJFR-14-6-4-2 antibody-specific α-syn fibrillar oligomers. The pathogenic LRRK2 G2019S mutation is related to increased α-syn secretion in the extracellular space. We tested our established ELISA using differentiated SH-SH5Y cells transfected with LRRK2 G2019S. The secretory levels of fibrillar oligomeric α-syn divided by total α-syn were significantly increased in LRRK2 G2019S-expressing cells. Additionally, substantia nigra lysates or concentrated urine from PD patients and non-PD subjects were analyzed. We observed ambiguous changes in the levels of total or fibrillar oligomeric α-syn and their ratio between PD and non-PD. Despite the insignificant increase in the relative levels of fibrillar oligomeric α-syn to total α-syn in PD, the duration of disease progression after diagnosis significantly corresponded to the relative levels of fibrillar oligomeric α-syn to total α-syn in the urine. These results might provide greater understanding for the next stage of development of α-syn ELISAs.
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http://dx.doi.org/10.1080/19768354.2021.1883735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935126PMC
February 2021

Intracranial juvenile xanthogranuloma in an infant.

Childs Nerv Syst 2021 Mar 4. Epub 2021 Mar 4.

Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, Korea.

Juvenile xanthogranuloma (JXG) is a type of non-Langerhans cell histiocytosis that most commonly manifests as a solitary cutaneous lesion of the head and neck in children. Intracranial JXG is extremely rare. Although it is widely known that JXG skin lesions gradually disappear over time without treatment, treatment guidelines for intracranial JXG have not been established. It is very difficult to predict whether an intracranial lesion is JXG with only a pre-operative imaging work-up without pathologic confirmation. We report a case of the youngest, a 3-month-old male infant with an intracranial extra-axial mass with rapid growth for 2 months. Additionally, we suggest characteristic MRI findings for intracranial extra-axial JXG of a low T2 signal and a kidney bean shape.
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http://dx.doi.org/10.1007/s00381-021-05088-wDOI 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

Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma.

Brain 2021 03;144(2):636-654

Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea.

As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.
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http://dx.doi.org/10.1093/brain/awaa408DOI Listing
March 2021

Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation.

Mol Psychiatry 2021 Jan 15. Epub 2021 Jan 15.

School of Biological Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.

Proteinopathy in neurodegenerative diseases is typically characterized by deteriorating activity of specific protein aggregates. In tauopathies, including Alzheimer's disease (AD), tau protein abnormally accumulates and induces dysfunction of the affected neurons. Despite active identification of tau modifications responsible for tau aggregation, a critical modulator inducing tau proteinopathy by affecting its protein degradation flux is not known. Here, we report that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, is crucial for the tau-mediated AD pathology. ALK caused abnormal accumulation of highly phosphorylated tau in the somatodendritic region of neurons through its tyrosine kinase activity. ALK-induced LC3-positive axon swelling and loss of spine density, leading to tau-dependent neuronal degeneration. Notably, ALK activation in neurons impaired Stx17-dependent autophagosome maturation and this defect was reversed by a dominant-negative Grb2. In a Drosophila melanogaster model, transgenic flies neuronally expressing active Drosophila Alk exhibited the aggravated tau rough eye phenotype with retinal degeneration and shortened lifespan. In contrast, expression of kinase-dead Alk blocked these phenotypes. Consistent with the previous RNAseq analysis showing upregulation of ALK expression in AD [1], ALK levels were significantly elevated in the brains of AD patients showing autophagosomal defects. Injection of an ALK.Fc-lentivirus exacerbated memory impairment in 3xTg-AD mice. Conversely, pharmacologic inhibition of ALK activity with inhibitors reversed the memory impairment and tau accumulation in both 3xTg-AD and tauC3 (caspase-cleaved tau) transgenic mice. Together, we propose that aberrantly activated ALK is a bona fide mediator of tau proteinopathy that disrupts autophagosome maturation and causes tau accumulation and aggregation, leading to neuronal dysfunction in AD.
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http://dx.doi.org/10.1038/s41380-020-01003-yDOI Listing
January 2021

The Role of ZEB2 Expression in Pediatric and Adult Glioblastomas.

Anticancer Res 2021 Jan;41(1):175-185

Department of Pathology, Seoul National University Hospital, College of Medicine, Seoul, Republic of Korea

Background/aim: Both pediatric glioblastoma (pGB) and adult glioblastoma (aGB) are clinically devastating, and are known to have different molecular pathogenesis. Here, we focused on the role of ZEB2 in pGB and aGB.

Materials And Methods: Following transfection with ZEB2 siRNA into pGB cells (KNS42) and aGB cells (U87 and U373), cell proliferation, migration and invasion, and cell cycle progression were evaluated.

Results: Targeted inhibition of ZEB2 induced up-regulation of E-cadherin expression and down-regulation of vimentin expression. Furthermore, it reduced invasion and migration of both pGB and aGB cells. Interestingly, in pGB cells, but not in aGB cells, silencing of ZEB2 reduced cell proliferation and viability, and affected the cell cycle progression of tumor cells.

Conclusion: Inhibition of ZEB2 altered the mesenchymal features and reduced the migration and invasive ability of both pGB and aGB cells. ZEB2 effects were different in pGB and aGB cells regarding proliferation and cell cycle progression, suggesting that different underlying molecular mechanisms drive progression in these two types of tumors.
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http://dx.doi.org/10.21873/anticanres.14763DOI 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

The prognostic significance of p16 expression pattern in diffuse gliomas.

J Pathol Transl Med 2021 Mar 23;55(2):102-111. Epub 2020 Dec 23.

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

Background: CDKN2A is a tumor suppressor gene that encodes the cell cycle inhibitor protein p16. Homozygous deletion of the CDKN2A gene has been associated with shortened survival in isocitrate dehydrogenase (IDH)-mutant gliomas. This study aimed to analyze the prognostic value of p16 and to evaluate whether p16 immunohistochemical staining could be used as a prognostic marker to replace CDKN2A genotyping in diffuse gliomas.

Methods: p16 immunohistochemistry was performed on tissue microarrays of 326 diffuse gliomas with diagnoses that reflected IDH-mutations and 1p/19q codeletion status. The results were divided into three groups (negative, focal expression, overexpression) according to the presence and degree of p16 expression. Survival analysis was performed to assess the prognostic value of p16 expression.

Results: A loss of p16 expression predicted a significantly worse outcome in all glioma patients (n=326, p<.001), in the IDH-mutant glioma patients (n=103, p=.010), and in the IDH-mutant astrocytoma patients (n=73, p=.032). However, loss of p16 expression did not predict the outcome in the IDH-wildtype glioma patients (n=223, p=.121) or in the oligodendroglial tumor patients with the IDH-mutation and 1p/19q codeletion (n=30, p=.457). Multivariate analysis showed the association was still significant in the IDH-mutant glioma patients (p=.008; hazard ratio [HR], 2.637; 95% confidence interval [CI], 1.295 to 5.372) and in the IDH-mutant astrocytoma patients (p=.001; HR, 3.586; 95% CI, 1.649 to 7.801). Interestingly, patients who presented with tumors with p16 overexpression also had shorter survival times than did patients with tumors with p16 focal expression in the whole glioma (p< .001) and in IDH-mutant glioma groups. (p=.046).

Conclusions: This study suggests that detection of p16 expression by immunohistochemistry can be used as a useful surrogate test to predict prognosis, especially in IDH-mutant astrocytoma patients.
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http://dx.doi.org/10.4132/jptm.2020.10.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987518PMC
March 2021

Risk factors of progression to endometrial cancer in women with endometrial hyperplasia: A retrospective cohort study.

PLoS One 2020 1;15(12):e0243064. Epub 2020 Dec 1.

Department of Obstetrics and Gynecology, Inha University Hospital, Inha University School of Medicine, Incheon, Republic of Korea.

Objective: This study aimed to investigate risk factors of progression to endometrial cancer (EC) in women with non-atypical and atypical endometrial hyperplasia (EH).

Methods: The data of 62,333 women with EH diagnostic codes from 2007 to 2018 were sourced from the Korean Health Insurance Review and Assessment Service databases. The data from 11,525 women with non-atypical EH and 2,219 women with atypical EH who met the selection criteria were extracted for analysis.

Results: Risk of EC in women with EH decreased in 40-49 year olds compared to other ages (non-atypical EH: [≤39 vs. 40-49 years] HR, 0.557; 95% CI, 0.439-0.708; P<0.001; [≤39 vs. ≥50 years] P = 0.739; atypical EH: [≤39 vs. 40-49 years] HR, 0.391; 95% CI, 0.229-0.670; P = 0.001; [≤39 vs. ≥50 years] P = 0.712). Risk of EC increased with increase in number of follow-up biopsies in women with non-atypical EH (1 biopsy: HR, 1.835; 95% CI, 1.282-2.629; P = 0.001; ≥2 biopsies: HR, 3.644; 95% CI, 2.585-5.317; P<0.001) and in women receiving ≥2 follow-up biopsies with atypical EH (HR, 3.827; 95% CI, 1.924-7.612; P = 0.001). Time of progression to EC decreased in women ≥50 years old with non-atypical EH compared to other ages (P = 0.004) and showed no differences among ages in women with atypical EH (P = 0.576). Progestational agents were a protective factor for EC in women with non-atypical EH (HR, 0.703; 95% CI, 0.565-0.876; P = 0.002).

Conclusions: In this claim data analysis, women ≤39 and ≥50 years old with EH were at a high risk for progression to EC, and repeat follow-up biopsy after a diagnosis of EH increased detection of EC. Progestational agents were an effective modality to prevent EC in women with non-atypical EH.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243064PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707482PMC
January 2021

Clinical Outcomes and Complications of Pituitary Blastoma.

J Clin Endocrinol Metab 2021 01;106(2):351-363

Minneapolis, Minnesota, USA.

Context: Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome.

Objective: This work aims to describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases.

Design And Setting: A multi-institutional case series is presented from tertiary pediatric oncology centers.

Patients: Patients included children with pituitary blastoma.

Interventions: Genetic testing, surgery, oncologic therapy, endocrine support are reported.

Outcome Measures: Outcome measures included survival, long-term morbidities, and germline and tumor DICER1 genotypes.

Results: Seventeen pituitary blastoma cases were studied (10 girls and 7 boys); median age at diagnosis was 11 months (range, 2-24 months). Cushing syndrome was the most frequent presentation (n = 10). Cushingoid stigmata were absent in 7 children (2 with increased adrenocorticotropin [ACTH]; 5 with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n = 7), subtotal resection (n = 9), and biopsy (n = 1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, 9 patients were alive; 8 patients died of the following causes: early medical/surgical complications (n = 3), sepsis (n = 1), catheter-related complication (n = 1), aneurysmal bleeding (n = 1), second brain tumor (n = 1), and progression (n = 1). Surgery was the only intervention for 5 of 9 survivors. Extent of resection, but neither Ki67 labeling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n = 8), visual (n = 4), and neurodevelopmental (n = 3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities.

Conclusions: Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.
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http://dx.doi.org/10.1210/clinem/dgaa857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823240PMC
January 2021
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