Publications by authors named "Jae Kyung Won"

87 Publications

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

Systems analysis identifies endothelin 1 axis blockade for enhancing the anti-tumor effect of multikinase inhibitor.

Cancer Gene Ther 2021 Aug 6. Epub 2021 Aug 6.

Laboratory for Systems Biology and Bio-inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.

Multikinase inhibitors, such as sorafenib, are used for the treatment of advanced carcinomas but the response shows limited efficacy or varies a lot with patients. Here we adopted the systems approach combined with high-throughput data analysis to discover key mechanism embedded in the drug response. When analyzing the transcriptomic data from the Cancer Cell Line Encyclopedia (CCLE) database, endothelin 1 (EDN1) was enriched in cancer cells with low responsiveness to sorafenib. We found that the level of EDN1 is higher in the tissue and blood of hepatocellular carcinoma (HCC) patients showing poor response to sorafenib. In vitro experiment showed that EDN1 not only induces activation of angiogenic-promoting pathways in HCC cells but also stimulates proliferation and migration. Moreover, EDN1 is related with poor responsiveness to sorafenib by mitigating unfolded protein response (UPR), which was validated in both transcriptomic data analysis and in silico simulation. Finally, we found that endothelin receptor B (EDNRB) antagonists can enhance the efficacy of sorafenib in both HCC cells and xenograft mouse models. Our findings provide that EDN1 is a novel diagnostic marker for sorafenib responsiveness in HCC and a basis for testing macitentan, which is currently used for pulmonary artery hypertension, in combination with sorafenib in advanced HCC patients.
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http://dx.doi.org/10.1038/s41417-021-00373-xDOI Listing
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

NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake.

J Clin Invest 2021 Sep;131(18)

Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.

BACKGROUNDMolecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (131I-refractory) PTC.METHODSPTC samples from 106 pediatric patients (age range: 4.3-19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983-March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison.RESULTSWe identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAFV600E in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAFV600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAFV600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored 125I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received 131I therapy combined with selpercatinib, resulting in a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity.CONCLUSIONSIn pediatric patients with fusion oncogene PTC who have 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.FUNDINGThe Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830).TRIAL REGISTRATIONTwo patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).
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http://dx.doi.org/10.1172/JCI144847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439610PMC
September 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

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

Sci Rep 2021 May 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

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

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

Expression of Class III Beta-Tubulin Is Associated with Invasive Potential and Poor Prognosis in Thyroid Carcinoma.

J Clin Med 2020 Nov 26;9(12). Epub 2020 Nov 26.

Department of Pathology, Seoul National University Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul 07061, Korea.

Although American Thyroid Association guidelines offer a risk stratification scheme for thyroid cancer patients, there is a continuous need for more sophisticated biomarkers that can predict disease progression. In this study, we aim to evaluate the prognostic value of class III beta-tubulin (TUBB3) and uncover the relationship between TUBB3 and invasive potential in thyroid carcinoma. Immunohistochemistry (IHC) for TUBB3 and E-cadherin was performed on a total of 254 cases of thyroid cancer specimens. Tumor budding at the invasive margin was evaluated. In vitro functional studies were also performed; the protein and mRNA levels of TUBB3 were compared among the five cell types at baseline, with transwell invasion and after blocking of TUBB3 by shRNA. IHC revealed that the levels of TUBB3 were higher in conventional papillary carcinomas (cPTCs) and anaplastic thyroid carcinomas (ATCs). In univariate analysis, high tumor budding and TUBB3 expression were associated with inferior progression-free survival in cPTC. The results of a Western blot and RT-PCR agreed with the IHC finding. The results were further validated through data from The Cancer Genome Atlas database. Our results suggest that high expression of TUBB3 in thyroid carcinoma could predict invasive potential and possibly be linked with epithelial-mesenchymal transition.
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http://dx.doi.org/10.3390/jcm9123830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760790PMC
November 2020

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

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

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

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

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

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

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

H3 G34-mutant high-grade glioma.

Brain Tumor Pathol 2021 Jan 29;38(1):4-13. Epub 2020 Sep 29.

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

H3F3A G34 (H3.3 G34)-mutant high-grade gliomas (HGG) are rare, and newly recognized infiltrating gliomas of the cerebral hemisphere. Here, we report the clinicopathological and molecular characteristics of four H3.3 G34-mutant gliomas in terms of its biological behavior compared to those of glioblastomas (GBMs) and H3 K27M-mutant diffuse midline gliomas (DMGs) of our hospital. The median age of the four patients with H3.3 G34 HGG was 44.5 years (14-66 years). Three patients had tumors in the cerebral hemisphere, whereas one patient had synchronous double tumors in the cerebral hemisphere and posterior fossa. All these tumors were high-grade glioma, but neither microvascular proliferation nor necrosis. They displayed uniform genetic and epigenetic signatures; ATRX-mutant, MGMT promoter-methylated, Olig2-negative, but IDH- and TERT promoter-wildtype. The median survival rate of H3.3 G34-mutant HGGs, IDH-was 23.5 months. In conclusion, H3.3 G34-mutant gliomas were unique HGGs with uniform genetic and epigenetic abnormalities, which suggested a single phylogenic origin. The median survival of H3.3 G34-mutant HGGs was better than those of IDH-wildtype GBMs and H3 K27M-mutant DMGs, but worse than that of IDH-mutant GBM. The tumor-infiltrating area and resectability may be the crucial parameters for the prognosis of the patients.
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http://dx.doi.org/10.1007/s10014-020-00378-8DOI Listing
January 2021

Clinicopathological findings of pediatric NTRK fusion mesenchymal tumors.

Diagn Pathol 2020 Sep 21;15(1):114. Epub 2020 Sep 21.

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

Background: While ETV6- NTRK3 fusion is common in infantile fibrosarcoma, NTRK1/3 fusion in pediatric tumors is scarce and, consequently, not well known. Herein, we evaluated for the presence of NTRK1/3 fusion in pediatric mesenchymal tumors, clinicopathologically and immunophenotypically.

Methods: We reviewed nine NTRK fusion-positive pediatric sarcomas confirmed by fluorescence in situ hybridization and/or next-generation sequencing from Seoul National University Hospital between 2002 and 2020.

Results: One case of TPR-NTRK1 fusion-positive intracranial, extra-axial, high-grade undifferentiated sarcoma (12-year-old boy), one case of LMNA-NTRK1 fusion-positive low-grade infantile fibrosarcoma of the forehead (3-year-old boy), one case of ETV6-NTRK3 fusion-positive inflammatory myofibroblastic tumor (IMT) (3-months-old girl), and six cases of ETV6-NTRK3 fusion-positive infantile fibrosarcoma (median age: 2.6 months, range: 1.6-5.6 months, M: F = 5:1) were reviewed. The Trk immunopositivity patterns were distinct, depending on what fusion genes were present. We observed nuclear positivity in TPR-NTRK1 fusion-positive sarcoma, nuclear membrane positivity in LMNA-NTRK1 fusion-positive sarcoma, and both cytoplasmic and nuclear positivity in ETV6-NTRK3 fusion-positive IMT and infantile fibrosarcomas. Also, the TPR-NTRK1 fusion-positive sarcoma showed robust positivity for CD34/nestin, and also showed high mitotic rate. The LMNA-NTRK1 fusion-positive sarcoma revealed CD34/S100 protein/nestin/CD10 coexpression, and a low mitotic rate. The IMT with ETV6-NTRK3 fusion expressed SMA. Six infantile fibrosarcomas with ETV6-NTRK3 fusion showed variable coexpression of nestin (6/6)/CD10 (4/5)/ S100 protein (3/6).

Conclusions: All cases of NTRK1 and NTRK3 fusion-positive pediatric tumors robustly expressed the Trk protein. A Trk immunopositive pattern and CD34/S100/nestin/CD10/SMA immunohistochemical expression may suggest the presence of NTRK fusion partner genes. LMNA-NTRK1 fusion sarcoma might be a low-grade subtype of infantile fibrosarcoma. Interestingly, more than half of the infantile fibrosarcoma cases were positive for S100 protein and CD10. The follow-up period of TPR-NTRK1 and LMNA-NTRK1 fusion-positive tumors are not enough to predict prognosis. However, ETV6-NTRK3 fusion-positive infantile fibrosarcomas showed an excellent prognosis with no evidence of disease for an average of 11.7 years, after gross total resection of the tumor.
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http://dx.doi.org/10.1186/s13000-020-01031-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507612PMC
September 2020

A glioneuronal tumor with fusion.

NPJ Genom Med 2020 3;5:24. Epub 2020 Jun 3.

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

We report a case of glioneuronal tumor (GNT) with a discovery of novel gene fusion of resulting from aberrant chromosome 7 abnormalities. We executed an elaborate genomic study on this case including whole-exome sequencing and RNA sequencing. Genomic analysis of the tumor revealed aberrations in chromosomes 1 and 7 and a fusion. Further analysis of the upregulated genes revealed substantial connections with MAPK pathway activation. We concluded that the chromosome 7 abnormalities prompted gene fusion which successively leads to MAPK pathway activation. We deliberated that MAPK pathway activation is one of the driver pathways responsible for the oncogenesis of GNT.
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http://dx.doi.org/10.1038/s41525-020-0131-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270112PMC
June 2020

Comparison of liquid-based to tissue-based biopsy analysis by targeted next generation sequencing in advanced non-small cell lung cancer: a comprehensive systematic review.

J Cancer Res Clin Oncol 2020 Aug 27;146(8):2051-2066. Epub 2020 May 27.

Oncology Working Group, Society of Junior Doctors, Athens, Greece.

Purpose: To explore whether targeted next generation sequencing (NGS) of liquid biopsy in advanced non-small cell lung cancer (NSCLC) could potentially overcome the innate problems that arise with standard tissue biopsy, like intratumoral heterogeneity and the inability to obtain adequate samples for analysis.

Methods: The Scopus, Cochrane Library, and MEDLINE (via PubMed) databases were searched for studies with matched tissue and liquid biopsies from advanced NSCLC patients, analyzed with targeted NGS. The number of mutations detected in tissue biopsy only, liquid biopsy only, or both was assessed and the positive percent agreement (PPA) of the two methods was calculated for every clinically relevant gene.

Results: A total of 644 unique relevant articles were retrieved and data were extracted from 38 studies fulfilling the inclusion criteria. The sample size was composed of 2000 mutations tested in matched tissue and liquid biopsies derived from 1141 patients. No studies analyzed circulating tumor cells. The calculated PPA rates were 53.6% (45/84) for ALK, 53.9% (14/26) for BRAF, 56.5% (13/23) for ERBB2, 67.8% (428/631) for EGFR, 64.2% (122/190) for KRAS, 58.6% (17/29) for MET, 54.6% (12/22) for RET, and 53.3% (8/15) for ROS1. We additionally recorded data for 65 genes that are not recommended by current guidelines for mutational testing. An extra category containing results of unspecified genes was added, with a PPA rate of 55.7% (122/219).

Conclusion: Despite many advantages, liquid biopsy might be unable to fully substitute its tissue counterpart in detecting clinically relevant mutations in advanced NSCLC patients. However, it may serve as a helpful tool when making therapeutic decisions. More studies are needed to evaluate its role in everyday clinical practice.
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http://dx.doi.org/10.1007/s00432-020-03267-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456570PMC
August 2020

Prognostication of anaplastic astrocytoma patients: application of contrast leakage information of dynamic susceptibility contrast-enhanced MRI and dynamic contrast-enhanced MRI.

Eur Radiol 2020 Apr 17;30(4):2171-2181. Epub 2020 Jan 17.

Department of Neurology, College of Medicine, Seoul National University, Seoul, South Korea.

Purpose: To examine the applicability of contrast leakage information from dynamic susceptibility contrast-enhanced (DSC) MRI and dynamic contrast-enhanced (DCE) MRI to determine which one is the most valuable surrogate imaging biomarker for predicting disease progression in anaplastic astrocytoma (AA) patients.

Materials And Methods: This study was approved by the institutional review board (IRB), which waived informed consent. A total of seventy-three AA patients who had undergone preoperative DCE and DSC MRI and received standard treatment, including partial resection or biopsy followed by radiation therapy, were included in this retrospective study. Based on Response Assessment in Neuro-Oncology (RANO), patients were sorted into progression (n = 21) and non-progression (n = 52) groups. Tumor boundaries were defined as high-signal intensity (SI) lesions on fluid-attenuated inversion recovery (FLAIR) imaging, where we analyzed mean pharmacokinetic parameters (K, V, and V) from DCE MRI and contrast leakage information (mean extraction fraction (EF)) from DSC MRI.

Results: Mean V and mean EF were significantly higher in patients with progression-free survival (PFS) < 18 months than in those with PFS ≥ 18 months. For distinguishing the group with PFS < 18 months, AUC values were calculated using the mean V value (AUC = 0.716). The Kaplan-Meier survival analysis revealed that mean V value was significantly correlated with PFS. In Cox proportional-hazards regression, only the mean V value was found to be significantly associated with PFS.

Conclusion: We found that the mean V value based on high-SI tumor lesions on FLAIR imaging was capable of predicting outcomes of AA patients as a potential surrogate imaging biomarker.

Key Points: • Mean V(2.152 ± 1.857 vs. 1.173 ± 1.408) was significantly higher in anaplastic astrocytoma patients with PFS < 18 months that in those with PFS ≥ 18 months (p = 0.02). • Cox proportional-hazards regression showed that only mean V(p = 0.034) was significantly associated with PFS, regardless of IDH mutation status, in anaplastic astrocytoma patients.
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http://dx.doi.org/10.1007/s00330-019-06598-7DOI Listing
April 2020

Arterial spin labeling perfusion-weighted imaging aids in prediction of molecular biomarkers and survival in glioblastomas.

Eur Radiol 2020 Feb 29;30(2):1202-1211. Epub 2019 Aug 29.

Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea.

Objectives: Prediction of progression-free survival (PFS) and overall survival (OS) and early identification of molecular biomarkers with prognostic information are clinically important in glioblastoma (GBM) patients. We aimed to explore the utility of arterial spin labeling perfusion-weighted imaging (ASL-PWI) in the prediction of molecular biomarkers and survival in GBM patients.

Methods: We retrospectively analyzed 149 consecutive GBM patients, who had undergone maximal surgical resection or biopsy followed by concurrent chemoradiotherapy and adjuvant chemotherapy using temozolomide between November 2010 and June 2016. On preoperative ASL-PWI, cerebral blood flow (CBF) within contrast-enhancing (CE) and nonenhancing (NE) portions were evaluated both qualitatively (perfusion pattern and perfusion pattern) and quantitatively (nCBF and nCBF). ASL-PWI findings were correlated with molecular biomarkers, including isocitrate dehydrogenase (IDH) and O6-methylguanine-DNA methyltransferase (MGMT) methylation statuses, and survival, using the Mann-Whitney U-test, Spearman rank correlation, Kaplan-Meier analysis, and receiver operating characteristics analysis.

Results: nCBF was significantly higher in the IDH wild-type group than in the IDH mutant group (p = .013) and in the MGMT unmethylated group than in the methylated group (p = .047). Areas under the receiver operating characteristic curve were 0.678 for IDH mutation (p = .022) and 0.601 for MGMT promoter methylation (p = .043). Hyperperfusion was associated with the shortest median PFS for both perfusion pattern (7.6 months) and perfusion pattern (4.0 months). The perfusion pattern remained an independent predictor for PFS and OS even after adjusting for clinical and molecular predictors, unlike perfusion pattern.

Conclusions: ASL-PWI can aid to predict survival and molecular biomarkers including IDH mutation and MGMT promoter methylation statuses in GBM patients.

Key Points: • ASL-PWI can aid to predict survival in GBM patients. • ASL-PWI can aid to predict IDH and MGMT promoter methylation statuses in GBM.
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http://dx.doi.org/10.1007/s00330-019-06379-2DOI Listing
February 2020

Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer.

Nat Commun 2019 06 24;10(1):2764. Epub 2019 Jun 24.

Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, 03080, Republic of Korea.

Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAF and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.
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http://dx.doi.org/10.1038/s41467-019-10680-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591357PMC
June 2019

Association of pathway mutation with survival after recurrence in colorectal cancer patients treated with adjuvant fluoropyrimidine and oxaliplatin chemotherapy.

BMC Cancer 2019 May 6;19(1):421. Epub 2019 May 6.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul, 110-744, South Korea.

Background: Although the prognostic biomarkers associated with colorectal cancer (CRC) survival are well known, there are limited data on the association between the molecular characteristics and survival after recurrence (SAR). The purpose of this study was to assess the association between pathway mutations and SAR.

Methods: Of the 516 patients with stage III or high risk stage II CRC patients treated with surgery and adjuvant chemotherapy, 87 who had distant recurrence were included in the present study. We analyzed the association between SAR and mutations of 40 genes included in the five critical pathways of CRC (WNT, P53, RTK-RAS, TGF-β, and PI3K).

Results: Mutation of genes within the WNT, P53, RTK-RAS, TGF-β, and PI3K pathways were shown in 69(79.3%), 60(69.0%), 57(65.5%), 21(24.1%), and 19(21.8%) patients, respectively. Patients with TGF-β pathway mutation were younger and had higher incidence of mucinous adenocarcinoma (MAC) histology and microsatellite instability-high. TGF-β pathway mutation (median SAR of 21.6 vs. 44.4 months, p = 0.021) and MAC (20.0 vs. 44.4 months, p = 0.003) were associated with poor SAR, and receiving curative resection after recurrence was associated with favorable SAR (Not reached vs. 23.6 months, p <  0.001). Mutations in genes within other critical pathways were not associated with SAR. When MAC was excluded as a covariate, multivariate analysis revealed TGF-β pathway mutation and curative resection after distant recurrence as an independent prognostic factor for SAR. The impact of TGF-β pathway mutations were predicted using the PROVEAN, SIFT, and PolyPhen-2. Among 25 mutations, 23(92.0%)-24(96.0%) mutations were predicted to be damaging mutation.

Conclusions: Mutation in genes within TGF-β pathway may have negative prognostic role for SAR in CRC. Other pathway mutations were not associated with SAR.
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http://dx.doi.org/10.1186/s12885-019-5650-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501409PMC
May 2019

An Autopsy Proven Case of CSF1R-mutant Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) with Premature Ovarian Failure.

Exp Neurobiol 2019 Feb 28;28(1):119-129. Epub 2019 Feb 28.

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

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a progressive degenerative white matter disorder caused by mutations in the tyrosine kinase domain of the gene. ALSP is often misdiagnosed as other diseases due to its rarity and various clinical presentations such as Parkinsonism, pyramidal signs, cognitive impairment and/or psychiatric symptoms. We describe an autopsy case of ALSP with a mutation. A 61-year-old woman presented insidious-onset gait difficulty for 12 years since her age of 49, and premature ovarian failure since her age of 35. At initial hospital visit, brain magnetic resonance imaging revealed hydrocephalus. Initially, Parkinson's syndrome was diagnosed, and she was prescribed L-dopa/carbidopa because of spasticity and rigidity of extremities, which had worsened. Subsequently, severe neuropsychiatric symptoms and cognitive impairment developed and radiologically, features of leukoencephalopathy or leukodystrophy were detected. She showed a down-hill course and died, 12 years after initial diagnosis. At autopsy, the brain showed severe symmetric atrophy of bilateral white matter, paper-thin corpus callosum, thin internal capsule, and marked hydrocephalus. Microscopically, diffuse loss of white matter, relatively preserved subcortical U-fibers, and many eosinophilic bulbous neuroaxonal spheroids were noted, but there was no calcification. Pigmented glia with brown cytoplasmic pigmentation were readily found in the white matter, which were positive for Periodic acid-Schiff, p62, and CD163 stains, but almost negative for CD68. Whole-exome and Sanger sequencing revealed a mutation (c.2539G>A, p.Glu847Lys) which was reported in prior one ALSP case. This example demonstrates that ALSP could be associated with premature ovarian failure.
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http://dx.doi.org/10.5607/en.2019.28.1.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401550PMC
February 2019

Parathyroid adenoma with prominent lymphocytic infiltrate having histological features highly suggestive of IgG4-related disease: a case report and literature review.

Endocr J 2019 Apr 5;66(4):379-385. Epub 2019 Feb 5.

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

Parathyroid adenoma with prominent lymphocytic infiltrate is a rare disease. Until now, 11 patients have been reported. Herein, we report a 57-year-old man who had a neck mass that was incidentally found. Aspiration cytology and subsequent needle biopsy of the tumor were performed and suggested papillary thyroid carcinoma. From the resected specimen, however, the patient was finally diagnosed with parathyroid adenoma with prominent lymphocytic infiltrate, characterized by hyperplastic parathyroid cells with nuclear atypia within fibrotic stroma along with numerous lymphocytes forming germinal centers. Some eosinophils and plasma cells were also observed with some histological features highly suggestive of IgG4-related disease (IgG4-RD), including increased IgG4-positive plasma cells and IgG4/IgG-positive plasma cell ratio, storiform-type fibrosis, and obliterative phlebitis. It turned out that microfollicular or trabecular architecture and cellular atypia with high expression of HBME-1 observed in the aspiration cytology and needle biopsy had been misinterpreted as a thyroid malignancy. This is the first report describing microscopic features of aspiration cytology and needle biopsy of parathyroid adenoma with prominent lymphocytic infiltrate, warning that it can mimic papillary thyroid carcinoma in biopsy specimens. Furthermore, the IgG4-RD-like features of the present case and previous reports imply that parathyroid adenoma with prominent lymphocytic infiltrate may be a type of IgG4-RD.
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http://dx.doi.org/10.1507/endocrj.EJ18-0428DOI Listing
April 2019

Clinicopathological and molecular analysis of multinodular and vacuolating neuronal tumors of the cerebrum.

Hum Pathol 2019 04 11;86:203-212. Epub 2018 Dec 11.

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

Multinodular and vacuolating neuronal tumor (MVNT) of the cerebrum is a recently recognized rare neuronal tumor, and its pathogenesis is unclear. We analyzed 7 cases of histologically typical MVNT: 6 were adults (mean age, 43.0 years [range, 23-56 years]) and 1 was a child (age, 10 years). The most common symptoms were seizures (n = 4) and headache (n = 2). The tumors were supratentorial (temporal, 5; frontal lobes, 2) in origin as reported. Vacuolated tumor cells were robustly positive for α-INA and Olig2 and at least partly positive for synaptophysin and MAP2, but negative for Neu-N, nestin and CD34. GFAP and vimentin were expressed in reactive astrocytes but not in tumor cells. Negative results were obtained for p53, IDH-1, BRAF, H3 K27M, EGFR, Lin28A, and L1CAM. ATRX, BRG1, INI-1, and TMHH were retained. The Ki-67 labeling index was very low (<1%), and pHH3 revealed no mitotic figure. Ultrastructural features of tumor cells were comparable with those of immature neuronal cells, with several intracytoplasmic myelin-like autophagosomes and pericellular vacuolization. No IDH1/IDH2 and BRAF mutations were found upon direct sequencing. Whole-exome sequencing revealed FGFR2-ZMYND11 gene fusion in 1 case. After gross total resection, all patients were alive without seizures. There was no tumor recurrence during an average period of 68 months (range, 23-101 months). The analysis of 7 typical cases of MVNT suggested that these lesions may be clonal tumors because FGFR2-ZMYND11 fusion was found (1 case).
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http://dx.doi.org/10.1016/j.humpath.2018.11.028DOI Listing
April 2019

Comprehensive Transcriptomic and Genomic Profiling of Subtypes of Follicular Variant of Papillary Thyroid Carcinoma.

Thyroid 2018 11 16;28(11):1468-1478. Epub 2018 Oct 16.

1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital , Seoul, Korea.

Background: Among subtypes of follicular variant of papillary thyroid carcinoma (FVPTC), encapsulated FVPTC (EFVPTC) shows more indolent behavior than infiltrative FVPTC (IFVPTC). In particular, noninvasive EFVPTC, now designated as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), tends to have an excellent prognosis. However, it remains unclear whether the molecular pathogenesis or signature of the various forms of FVPTC is different. By massively parallel sequencing analysis, this study comprehensively characterized the transcriptional and mutational landscape of FVPTC and established correlations with phenotypic subtypes.

Methods: This study included 48 FVPTCs: 17 NIFTPs, 13 invasive EFVPTCs (I-EFVPTCs), and 18 IFVPTCs. For comparison, 55 classical papillary thyroid carcinomas (cPTCs) harboring a BRAF mutation, six follicular adenomas (FAs), and 15 minimally invasive follicular thyroid carcinomas (miFTCs) with RAS mutations were also included.

Results: In NIFTP, the BRAF mutation was not found, but RAS and other alterations were present in 64.7% and 17.6% of cases, respectively. However, in I-EFVPTC and IFVPTC, the proportions of BRAF mutation (38.5% and 38.9%, respectively) and of RAS mutations (38.5% and 38.9%, respectively) or other alterations (15.4% and 16.7%, respectively) were similar. On a molecular level, RAS-mutated FVPTCs were all RAS-like except for one IFVPTC case. Transcriptomic profiles of NIFTP, I-EFVPTC, and FA/miFTC were comparable, although the profile of RAS-mutated IFVPTC was altered to activate molecular pathways involved in cell adhesion and invasion. Interestingly, 80% of BRAF-mutated I-EFVPTCs were also classified as RAS-like, whereas all BRAF-mutated IFVPTCs were BRAF-like and indistinguishable from cPTC. Molecular pathways associated with cell adhesion and invasion were also differentially activated in BRAF-mutated IFVPTC.

Conclusions: Molecular profiles of NIFTP and I-EFVPTC may be shared with FA/miFTC, while IFVPTC seems to be associated with a similar profile as cPTC. Activation of cell adhesion and invasion pathways may play a key role in the development of invasive phenotypes of FVPTC.
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http://dx.doi.org/10.1089/thy.2018.0198DOI Listing
November 2018

Novel cytomorphologic characteristics suggesting human papillomavirus infection in patients diagnosed as negative for intraepithelial lesion or malignancy and a comparison of diagnostic performance of three human papillomavirus tests.

Diagn Cytopathol 2018 Oct 25;46(10):833-839. Epub 2018 Aug 25.

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

Background: Although the Papanicolaou (Pap) test is the first-line screening method for cervical cancer, it has low sensitivity for detection of human papillomavirus (HPV)-infected cervical lesion compared to the HPV test. The aims of this study are to determine novel cytomorphologic parameters for HPV infection in patients previously diagnosed as negative for intraepithelial lesion or malignancy (NILM) and to comparatively analyze the detection performance of 3 HPV tests: nested PCR, the DNA Chip test, and the Liquid Beads Microarray (LBMA) assay.

Methods: In total, 232 patients diagnosed with NILM were enrolled and assessed using 8 cytomorphologic parameters.

Results: Six non-classical cytomorphologic features were identified as novel characteristics suggesting HPV infection in patients initially diagnosed with NILM. A combination of these 6 variables showed the best predictive performance for HPV infection (area under the curve, 0.722). In terms of diagnostic ability, the LBMA assay showed better performance in detection of HPV infection (39.7%) in NILM cases compared to the other tests.

Conclusions: Our results suggest that the novel cytomorphologic features used in this study can be used as supportive morphologic parameters to increase the sensitivity of cytological screening tests. The LBMA assay could be used as an advanced method for HPV detection.
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http://dx.doi.org/10.1002/dc.24049DOI Listing
October 2018

Association Between Fusobacterium nucleatum, Pathway Mutation, and Patient Prognosis in Colorectal Cancer.

Ann Surg Oncol 2018 Oct 30;25(11):3389-3395. Epub 2018 Jul 30.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul, 110-744, Korea.

Background: There is a close link between Fusobacterium nucleatum and colorectal cancer (CRC) tumorigenesis and chemoresistance. However, the genetic characteristics and clinical significance of CRC related with F. nucleatum remains unclear. This study evaluated the relationship between F. nucleatum, pathway mutation, and patient prognosis.

Methods: Fusobacterium nucleatum amount in the tumor tissue and adjacent normal tissue were measured by quantitative polymerase chain reaction in adjuvant (N = 128) and metastatic (N = 118) cohorts. Patients were divided into binary (F. nucleatum-high and F. nucleatum-low) according to F. nucleatum amount. Targeted next-generation sequencing of 40 genes included in the 5 critical pathways (WNT, P53, RTK-RAS, PI3 K, and TGF-β) was performed in the adjuvant cohort.

Results: Patients with MSI-H and CIMP-H had higher amount of F. nucleatum in tumor tissue. Fusobacterium nucleatum-high patients had higher rates of transition mutation and C to T (G to A) nucleotide change regardless of MSI status. In addition, mutation rate of AMER1 and ATM genes, and TGF-β pathway was higher in F. nucleatum-high patients. Fusobacterium nucleatum-high was associated with poor overall survival (OS) in the palliative cohort (26.4 vs. 30.7 months, p = 0.042). Multivariate analysis revealed F. nucleatum-high as an independent negative prognostic factor for OS [adjusted hazard ratio of 1.69 (95% confidence interval 1.04-2.75), p = 0.034]. However, F. nucleatum amount was not associated with recurrence in the adjuvant cohort.

Conclusions: F. nucleatum-high was associated with poor survival in metastatic CRC. In addition, we identified mutational characteristics of colorectal cancer according to F. nucleatum amount.
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http://dx.doi.org/10.1245/s10434-018-6681-5DOI Listing
October 2018

Pheochromocytoma and paraganglioma in Fontan patients: Common more than expected.

Congenit Heart Dis 2018 Jul 22;13(4):608-616. Epub 2018 Jul 22.

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

Objective: Pheochromocytoma and paraganglioma (extra-adrenal pheochromocytoma) are rare neuroendocrine tumors that arise from the neuroendocrine cells. Chronic hypoxia is known as a possible cause, and a strong link between cyanotic congenital heart disease and these tumors has been reported. However, reports of phechromocytoma/paraganglioma in Fontan patients were scarce. We herein report seven cases of phechromocytoma/paraganglioma after Fontan operation at a single tertiary center.

Methods: We retrospectively reviewed medical records and imaging studies who diagnosed as phechromocytoma/paraganglioma after Fontan operation in Seoul National University Children's Hospital.

Results: Seven patients were identified during follow-up after Fontan operation, and the prevalence was 2.5% among Fontan patients greater than 10 years old on active follow-up. Three patients were diagnosed as phechromocytoma and 4 patients as paraganglioma. Median time interval between Fontan operation and diagnosis of pheochromocytoma/paraganglioma was 21.4 years (range, 10.4-29.7 years). Resting percutaneous oxygen saturation varied from 77% to 94%. All patients underwent complete tumor resection. Phechromocytoma recurred in two patients, of whom one patient died at the age of 18 years due to the tumor progression with multiple metastasis and aggravation of heart failure with profound cyanosis. Pheochromocytoma/paraganglioma developed after hepatocellular carcinoma in two patients.

Conclusion: Phechromocytoma/paraganglioma could occur in Fontan patients more than expected. Because it is curable by tumor resection during its early phase, early diagnosis and treatment of pheochromocytoma are crucial in Fontan patients not to make hemodynamic deterioration and aggravation of heart failure.
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http://dx.doi.org/10.1111/chd.12625DOI Listing
July 2018

Acute invasive fungal rhinosinusitis: MR imaging features and their impact on prognosis.

Neuroradiology 2018 Jul 17;60(7):715-723. Epub 2018 May 17.

Department of Radiology, GangNeung Asan Hospital, GangNeung, South Korea.

Purpose: Acute invasive fungal rhinosinusitis (AIFRS) is a life-threatening disease that is difficult to diagnose. Its overall imaging features have not been evaluated and the prognostic impact is unclear. The purpose of our study was to present MR imaging features and their impact on prognosis of AIFRS.

Methods: MR images and clinical records of 23 patients with AIFRS were retrospectively evaluated to identify the imaging features and to determine the factors affecting patients' survival. A multivariable Cox proportional hazard model was used to estimate the hazard ratio of the prognostic factors, and Kaplan-Meier survival curves were compared by using a log-rank test.

Results: All cases showed extra-sinonasal involvement and the orbit was the most common (65.2%, 15/23) location. The lesion enhancement pattern was classified into lack of contrast enhancement (LoCE) (47.8%, 11/23) and homogeneous (34.8%, 8/23) and heterogeneous (17.4%, 4/23) enhancement. Although LoCE showed variable signal intensity (SI), homogeneously or heterogeneously enhancing lesions showed exclusively low SI (100%, 12/12) on T2WI. Among various clinical and imaging factors, LoCE was correlated with coagulation necrosis, probably provoked by numerous fungal hyphae, and was found to be a sole independent prognostic factor for disease-specific mortality (hazard ratio = 16.819; 95% CI, 1.646-171.841, p = 0.017). In addition, patients with LoCE showed worse survival than patients without LoCE (p = 0.008).

Conclusion: AIFRS showed frequent extra-sinonasal involvement and variable MR enhancement patterns. An enhancement pattern of LoCE was seen in about half of the cases and was a unique prognostic factor among the various clinico-radiologic factors.
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http://dx.doi.org/10.1007/s00234-018-2034-0DOI Listing
July 2018

Recent Advancement of the Molecular Diagnosis in Pediatric Brain Tumor.

J Korean Neurosurg Soc 2018 May 1;61(3):376-385. Epub 2018 May 1.

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

Recent discoveries of brain tumor-related genes and fast advances in genomic testing technologies have led to the era of molecular diagnosis of brain tumor. Molecular profiling of brain tumor became the significant step in the diagnosis, the prediction of prognosis and the treatment of brain tumor. Because traditional molecular testing methods have limitations in time and cost for multiple gene tests, next-generation sequencing technologies are rapidly introduced into clinical practice. Targeted sequencing panels using these technologies have been developed for brain tumors. In this article, focused on pediatric brain tumor, key discoveries of brain tumor-related genes are reviewed and cancer panels used in the molecular profiling of brain tumor are discussed.
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http://dx.doi.org/10.3340/jkns.2018.0057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957317PMC
May 2018
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