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Abstract Although gliomatosis cerebri (GC) has been removed as an independent tumor type from the WHO classification, its extensive infiltrative pattern may harbor a unique biological behavior. However, the clinical implication of GC in the context of the 2021 WHO classification is yet to be unveiled. This study investigated the incidence, clinicopathologic and imaging correlations, and prognostic implications of GC in adult-type diffuse glioma patients. Retrospective chart and imaging review of 1,211 adult-type diffuse glioma patients from a single institution between 2005 and 2021 was performed. Among 1,211 adult-type diffuse glioma patients, there were 99 (8.2%) patients with GC. The proportion of molecular types significantly differed between patients with and without GC (P = 0.017); IDH-wildtype glioblastoma was more common (77.8% vs. 66.5%), while IDH-mutant astrocytoma (16.2% vs. 16.9%) and oligodendroglioma (6.1% vs. 16.5%) were less common in patients with GC than in those without GC. The presence of contrast enhancement, necrosis, cystic change, hemorrhage, and GC type 2 were independent risk factors for predicting IDH mutation status in GC patients. GC remained as an independent prognostic factor (HR = 1.25, P = 0.031) in IDH-wildtype glioblastoma patients on multivariable analysis, along with clinical, molecular, and surgical factors. Overall, our data suggests that although no longer included as a distinct pathological entity in the WHO classification, recognition of GC may be crucial considering its clinical significance. There is a relatively high incidence of GC in adult-type diffuse gliomas, with different proportion according to molecular types between patients with and without GC. Imaging may preoperatively predict the molecular type in GC patients and may assist clinical decision-making. The prognostic role of GC promotes its recognition in clinical settings.

Abstract Choroid plexus tumors (CPTs) are intraventricular tumors derived from the choroid plexus epithelium and occur frequently in children. The aim of this study was to investigate the genomic and epigenomic characteristics of CPT and identify the differences between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC). We conducted multiomics analyses of 20 CPT patients including CPP and CPC. Multiomics analysis included whole-genome sequencing, whole-transcriptome sequencing, and methylation sequencing. Mutually exclusive TP53 and EPHA7 point mutations, coupled with the amplification of chromosome 1, were exclusively identified in CPC. In contrast, amplification of chromosome 9 was specific to CPP. Differential gene expression analysis uncovered a significant overexpression of genes related to cell cycle regulation and epithelial-mesenchymal transition pathways in CPC compared to CPP. Overexpression of genes associated with tumor metastasis and progression was observed in the CPC subgroup with leptomeningeal dissemination. Furthermore, methylation profiling unveiled hypomethylation in major repeat regions, including long interspersed nuclear elements, short interspersed nuclear elements, long terminal repeats, and retrotransposons in CPC compared to CPP, implying that the loss of epigenetic silencing of transposable elements may play a role in tumorigenesis of CPC. Finally, the differential expression of AK1, regulated by both genomic and epigenomic factors, emerged as a potential contributing factor to the histological difference of CPP against CPC. Our results suggest pronounced genomic and epigenomic disparities between CPP and CPC, providing insights into the pathogenesis of CPT at the molecular level.

Abstract Spinal cord injury (SCI) leads to motor and sensory impairment below the site of injury, thereby necessitating rehabilitation. An enriched environment (EE) increases social interaction and locomotor activity in a mouse model, similar to human rehabilitation. However, the impact of EE on presynaptic plasticity in gene expression levels remains unclear. Hence, this study aimed to investigate the therapeutic potential of EE in an SCI mouse model. Mice with spinal cord contusion were divided into two groups: those housed in standard cages (control) and those in EE conditions (EE). Each group was housed separately for either 2- or 8-weeks post-injury, after which RNA sequencing was performed and compared to a sham group (receiving only a dorsal laminectomy). The synaptic vesicle cycle (SVC) pathway and related genes showed significant downregulation after SCI at both time points. Subsequently, we investigated whether exposure to EE for 2- and 8-weeks post-SCI could modulate the SVC pathway and its related genes. Notably, exposure to EE for 8 weeks resulted in a marked reversal effect of SVC-related gene expression, along with stimulation of axon regeneration and mitigation of locomotor activity loss. Thus, prolonged exposure to EE increased presynaptic activity, fostering axon regeneration and functional improvement by modulating the SVC in the SCI mouse model. These findings suggest that EE exposure proves effective in inducing activity-dependent plasticity, offering a promising therapeutic approach akin to rehabilitation training in patients with SCI.

Background Thyroid-stimulating hormone (TSH)-secreting pituitary neuroendocrine tumor (TSH PitNET) is a rare subtype of PitNET. We investigated the comprehensive characteristics and outcomes of TSH PitNET cases from a single medical center. Also, we compared diagnostic methods to determine which showed superior sensitivity. Methods A total of 17 patients diagnosed with TSH PitNET after surgery between 2002 and 2022 in Samsung Medical Center was retrospectively reviewed. Data on comprehensive characteristics and treatment outcomes were collected. The sensitivities of diagnostic methods were compared. Results Seven were male (41%), and the median age at diagnosis was 42 years (range, 21 to 65); the median follow-up duration was 37.4 months. The most common (59%) initial presentation was hyperthyroidism-related symptoms. Hormonal co-secretion was present in four (23%) patients. Elevated serum alpha-subunit (α-SU) showed the greatest diagnostic sensitivity (91%), followed by blunted response at thyrotropin-releasing hormone (TRH) stimulation (80%) and elevated sex hormone binding globulin (63%). Fourteen (82%) patients had macroadenoma, and a specimen of one patient with heavy calcification was negative for TSH. Among 15 patients who were followed up for more than 6 months, 10 (67%) achieved hormonal and structural remission within 6 months postoperatively. A case of growth hormone (GH)/TSH/prolactin (PRL) co-secreting mixed gangliocytoma-pituitary adenoma (MGPA) was discovered. Conclusion The majority of the TSH PitNET cases was macroadenoma, and 23% showed hormone co-secretion. A rare case of GH/TSH/PRL co-secreting MGPA was discovered. Serum α-SU and TRH stimulation tests showed great diagnostic sensitivity. Careful consideration is needed in diagnosing TSH PitNET. Achieving remission requires complete tumor resection. In case of nonremission, radiotherapy or medical therapy can improve the long-term remission rate.

This study investigated differential gene expression between granulation patterns in growth hormone (GH)-secreting pituitary tumors, aiming to elucidate novel transcriptomes that explain clinical variances in patients with acromegaly. Transcriptome analysis was conducted on 6 normal pituitary tissues and 15 GH-secreting pituitary tumors, including 9 densely granulated somatotroph tumors (DGSTs) and 6 sparsely granulated somatotroph tumors (SGSTs). We identified 3111 differentially expressed genes (DEGs) in tumors compared to normal pituitaries, with 1117 DEGs unique to a specific granulation within tumors. SGST showed enrichment of neuronal development and acute inflammatory response pathways, along with a significant enhancement of JAK–STAT, phosphatidylinositol 3-kinase, and MAPK signaling. The results suggest that granulation-specific gene expression may underpin diverse clinical presentations in acromegaly, highlighting the potential for further investigation into these transcriptomic variations and their roles in disease pathology, particularly the involvement of genes linked to neuronal development, inflammatory response, and JAK–STAT signaling in SGST.

Intravesical bacillus Calmette–Guérin (BCG) instillation is an adjuvant treatment for non–muscle-invasive urinary bladder cancer. Although most complications associated with BCG immunotherapy are mild and self-limiting, rare albeit serious complications have been reported. Only a few cases of BCG-related rhabdomyolysis have been reported. In this study, we present the case of a 72-year-old woman who developed severe weakness and hyperCKemia following intravesical BCG instillation. A muscle biopsy was performed, and a diagnosis of drug-induced myopathy was made.

Abstract Accurate identification of molecular alterations in gliomas is crucial for their diagnosis and treatment. Although, fluorescence in situ hybridization (FISH) allows for the observation of diverse and heterogeneous alterations, it is inherently time-consuming and challenging due to the limitations of the molecular method. Here, we report the development of 1p/19qNET, an advanced deep-learning network designed to predict fold change values of 1p and 19q chromosomes and classify isocitrate dehydrogenase (IDH)-mutant gliomas from whole-slide images. We trained 1p/19qNET on next-generation sequencing data from a discovery set (DS) of 288 patients and utilized a weakly-supervised approach with slide-level labels to reduce bias and workload. We then performed validation on an independent validation set (IVS) comprising 385 samples from The Cancer Genome Atlas, a comprehensive cancer genomics resource. 1p/19qNET outperformed traditional FISH, achieving R 2 values of 0.589 and 0.547 for the 1p and 19q arms, respectively. As an IDH-mutant glioma classifier, 1p/19qNET attained AUCs of 0.930 and 0.837 in the DS and IVS, respectively. The weakly-supervised nature of 1p/19qNET provides explainable heatmaps for the results. This study demonstrates the successful use of deep learning for precise determination of 1p/19q codeletion status and classification of IDH-mutant gliomas as astrocytoma or oligodendroglioma. 1p/19qNET offers comparable results to FISH and provides informative spatial information. This approach has broader applications in tumor classification.

Abstract Purpose Glioblastoma (GBM) has a poor prognosis after standard treatment. Recently, metformin has been shown to have an antitumor effect on glioma cells. We performed the first randomized prospective phase II clinical trial to investigate the clinical efficacy and safety of metformin in patients with recurrent or refractory GBM treated with low-dose temozolomide. Methods Included patients were randomly assigned to a control group [placebo plus low-dose temozolomide (50 mg/m2, daily)] or an experimental group [metformin (1000 mg, 1500 mg, and 2000 mg per day during the 1st, 2nd, and 3rd week until disease progression, respectively) plus low-dose temozolomide]. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, overall response rate, health-related quality of life, and safety. Results Among the 92 patients screened, 81 were randomly assigned to the control group (43 patients) or the experimental group (38 patients). Although the control group showed a longer median PFS, the difference between the two groups was not statistically significant (2.66 versus 2.3 months, p = 0.679). The median OS was 17.22 months (95% CI 12.19–21.68 months) in the experimental group and 7.69 months (95% CI 5.16–22.67 months) in the control group, showing no significant difference by the log-rank test (HR: 0.78; 95% CI 0.39–1.58; p = 0.473). The overall response rate and disease control rate were 9.3% and 46.5% in the control group and 5.3% and 47.4% in the experimental group, respectively. Conclusions Although the metformin plus temozolomide regimen was well tolerated, it did not confer a clinical benefit in patients with recurrent or refractory GBM. Trial registration NCT03243851, registered August 4, 2017.

The aluminum composite with dispersed high entropy alloy were developed by stir casting involving the powder-in-tube method. First, Al0.5CoCrCuFeNi high entropy alloy (HEA) powder was made by mechanical alloying, and the powder was extruded in a tube-type aluminum container to form HEA precursor. The extruded HEA precursor was then dispersed in the aluminum matrix via stir casting. As a result, Fe-Cr-Ni based high-entropy phases was uniformly formed in the aluminum matrix, revealing ~158, 166, 235% enhancement of tensile strength by incorporating 1, 3, and 5 wt% HEA particles, respectively.

Abstract Gliomas are the most common primary tumors in the brain and spinal cord. In previous GWASs, SNPs in epidermal growth factor receptor (EGFR) have been reported as risk loci for gliomas. However, EGFR variants associated with gliomas in the Korean population remain unstudied. This study explored the association of EGFR SNPs with the risk of glioma. We genotyped 13 EGFR exon SNPs in a case–control study that included 324 Korean patients diagnosed with glioma and 480 population-based controls. Statistical analyses of the association between EGFR SNPs and glioma risk were conducted using logistic regression. Both stepwise analysis and conditional logistic analysis were performed to identify independent associations among genotyped variants. We confirmed that two SNPs (rs2227983, rs1050171) were significantly associated with glioma (rs2227983: odds ratio = 1.42, P corr = 0.009; rs1050171: odds ratio = 1.68, P corr = 0.005). Additionally, the stepwise analysis and conditional logistic analysis indicated that both SNPs created variants with independent genetic effects. This study is the first to show evidence that functional variants of EGFR, namely, rs2227983 (K521R) and rs1050171 (Q787Q), are associated with an increased risk of glioma in the Korean population. Future work should confirm the functional association between EGFR variants and glioma.

Abstract Chordoma is a malignant bone neoplasm demonstrating notochordal differentiation and it frequently involves axial skeleton. Most of chordomas are conventional type with varying amount of myxoid stroma. Previously known prognostic factors for conventional chordoma are not specific for chordoma: old age, metastasis, tumor extent, and respectability. Here, we aimed to investigate the histologic, radiologic, and transcriptomic differences in conventional chordoma based on the stromal component. A total of 45 patients diagnosed with conventional chordoma were selected between May 2011 and March 2020 from a single institution. Electronic medical records, pathology slides, and pretreatment magnetic resonance imaging (MRI) scans were reviewed. Of the 45 patients, ten cases (4 stroma-rich and 6 stroma-poor tumor) were selected for RNA sequencing, and available cases in the remainder were used for measuring target gene mRNA expression with qPCR for validation. Differential gene expression and gene set analysis were performed. Based on histologic evaluation, there were 25 (55.6%) stroma-rich and 20 (44.4%) stroma-poor cases. No clinical differences were found between the two groups. Radiologically, stroma-rich chordomas showed significant signal enhancement on MRI (72.4% vs 27.6%, p = 0.002). Upregulated genes in stroma-rich chordomas were cartilage-, collagen/extracellular matrix-, and tumor metastasis/progression-associated genes. Contrarily, tumor suppressor genes were downregulated in stroma-rich chordomas. On survival analysis, Kaplan–Meier plot was separated that showed inferior outcome of stroma-rich group, although statistically insignificant. In conclusion, the abundant stromal component of conventional chordoma enhanced well on MRI and possibly contributed to the biological aggressiveness that supported by transcriptomic characteristics. Further extensive investigation regarding radiologic-pathologic-transcriptomic correlation in conventional chordoma in a larger cohort could verify additional clinical significance.

Abstract Objectives This study investigated whether radiomic features can improve the prediction accuracy for tumor recurrence over clinicopathological features and if these features can be used to identify high-risk patients requiring adjuvant radiotherapy (ART) in WHO grade 2 meningiomas. Methods Preoperative magnetic resonance imaging (MRI) of 155 grade 2 meningioma patients with a median follow-up of 63.8 months were included and allocated to training (n = 92) and test sets (n = 63). After radiomic feature extraction (n = 200), least absolute shrinkage and selection operator feature selection with logistic regression classifier was performed to develop two models: (1) a clinicopathological model and (2) a combined clinicopathological and radiomic model. The probability of recurrence using the combined model was analyzed to identify candidates for ART. Results The combined clinicopathological and radiomics model exhibited superior performance for the prediction of recurrence compared with the clinicopathological model in the training set (area under the curve [AUC] 0.78 vs. 0.67, P = 0.042), which was also validated in the test set (AUC 0.77 vs. 0.61, P = 0.192). In patients with a high probability of recurrence by the combined model, the 5-year progression-free survival was significantly improved with ART (92% vs. 57%, P = 0.024), and the median time to recurrence was longer (54 vs. 17 months after surgery). Conclusions Radiomics significantly contributes added value in predicting recurrence when integrated with the clinicopathological features in patients with grade 2 meningiomas. Furthermore, the combined model can be applied to identify high-risk patients who require ART.

Purpose This study presents the characteristics of patients with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) with SLC35A2 somatic variants in the brain who underwent epilepsy surgery and showed clinical improvement in seizures. Methods We collected 10 patients with SLC35A2 somatic mutations in the brain who underwent surgery to treat drug-resistant epilepsy at Severance Children’s Hospital from 2014 to 2019 and retrospectively reviewed their genetic profiles, neuropathologic results, clinical features, pre-operative evaluations, and post-operative outcomes. Results Six of the 10 patients with SCL35A2 somatic mutations in the brain had Lennox Gastaut syndrome (LGS) evolving from infantile spasms (IS), three had LGS, and one had IS. The median value of variant allele frequencies (VAFs) was 5.7% (1.7% to 5.8%; range, 1.4% to 22.9%). Nonsense mutations were the most common (50%), followed by missense mutations (40%) and a splicing site mutation (10%). Eight patients (80%) had good post-operative outcomes, with freedom from disabling seizures in five (Engel class I) and rare disabling seizures in three (Engel class II). Four of the eight patients who could be assessed for social quotient (SQ) after surgery showed SQ improvements by 12.2±6.4. Although all patients were finally diagnosed with MOGHE, seven (70%) were initially diagnosed with gliosis, two with mild malformation of cortical development, and one with no abnormality. Conclusion All patients with SCL35A2 brain somatic mutations, even with low VAFs, had refractory epilepsy such as LGS or IS, and were finally diagnosed with MOGHE. This report is the first in Korea to our knowledge.

Abstract Since a potential link between statins and the risk of adverse chronic periodontitis (CP) has been raised, we aimed to validate the association between statin use and the incidence of CP using nationwide cohort data. This longitudinal follow-up study included 169,381 patients prescribed statins who were matched with an equal number of controls using propensity scores from the Korean National Health Insurance Service-Health Screening Cohort database (2002–2015). A Cox proportional hazard model was used to assess the occurrence of CP following statin use after adjusting for multiple covariates. The occurrence of CP was significantly higher in patients who had long-term use (1–3 years, 3–5 years, or > 5 years) than with short-term use (≤ 1 year) of statins. After adjustment, statin users exhibited an occurrence of CP 1.32-fold higher (95% confidence interval 1.30–1.33) than that of the matched nonusers (incidence: 25.0 and 22.0 per 100 person-years, respectively). Subgroup analyses supported the adverse impact of statins on CP independent of age and gender. Statin user odds ratios for developing CP were higher compared to those of nonusers. This was consistent in individuals aged > 40 years in both genders, especially with long-term use.

Abstract Ovarian carcinoma (OC) is the most lethal gynecological malignancy due to frequent recurrence resulting from cisplatin-resistance. ARL6IP5 is a novel gene implicated to suppress cisplatin-resistance by activating apoptosis and inhibiting DNA repair through XRCC1 and PARP1. We investigated the clinicopathological and prognostic significance of the immunohistochemical ARL6IP5 expression on 79 post-chemotherapy OC patient tissue samples; in vitro, the effect of ARL6IP5 overexpression (OE) and knockdown (KD) on cancer hallmark functions and the effect of ARL6IP5 on the expression of DNA repair and apoptosis-related proteins were observed in OC cells and their cisplatin-resistant (CisR) counterparts. ARL6IP5 expression was significantly associated with chemotherapeutic response and was an independent prognosticator of progression-free and overall survival of high-grade serous OC patients. ARL6IP5-OE decreased cellular proliferation, invasion, migration, adhesion, and increased apoptosis (p

Background Radiation-induced organizing hematoma (RIOH) is a sporadic form of cavernous hemangioma (CH) that occurs after cerebral radiation. RIOH lesions are distinct histologically from de novo CH; however, detailed research on this subject is lacking. In the present study, the clinical and histological features of RIOHs were evaluated based on causative lesions. Methods The present study included 37 RIOHs confirmed by surgical excision from January 2009, to May 2020, in Yonsei Severance Hospital. All cases were divided into subgroups based on type of radiation treatment (gamma knife surgery [GKS], n = 24 vs. conventional radiation therapy [RT], n = 13) and pathology of the original lesion (arteriovenous malformation, n = 14; glioma, n = 12; metastasis, n = 4; other tumors, n = 7). The clinicopathological results were compared between the groups. Results Clinical data of multiplicity, latency, and size and wall thickness of the original tumors and RIOHs were analyzed. The GKS group showed shorter latency (5.85 ± 4.06 years vs. 11.15 ± 8.27 years, p = .046) and thicker tumor wall (693.7 ± 565.7 μm vs. 406.9 ± 519.7 μm, p = .049) than the conventional RT group. Significant difference was not found based on original pathology. Conclusions RIOH is more likely to occur earlier with thick tumor wall in subjects who underwent GKS than in patients who underwent conventional RT. These results indicate the clinical course of RIOH differs based on type of treatment and might help determine the duration of follow-up.

This study suggests a new way to modify the size and morphology of Al-Fe phases in modified AA 7075 by using an Fe-Mn solid solution powder as the precursor. When Fe and Mn are added in the form of a solid solution, the diffusion of Fe and Mn toward the Al is delayed, thus altering the chemical composition and morphology of the precipitates. The fine, spherical precipitates are found to provide a good balance between strength and ductility compared to the case where Fe and Mn are separately added.

Abstract We aimed to identify somatic genetic alterations in pure growth hormone (GH)-secreting pituitary adenomas without GNAS variants. Patients with GH-secreting pituitary adenoma who underwent transsphenoidal adenomectomy at Severance Hospital, Yonsei University College of Medicine were recruited. Somatic genetic alterations were profiled by whole-exome sequencing (WES) and targeted resequencing. WES was performed using DNA from nine GH-secreting pituitary tumors and corresponding blood samples. Absence of GNAS variant was confirmed by Sanger sequencing. For targeted resequencing of 140 fixed tissues, 48 WES-derived candidate genes and 7 GH-secreting pituitary adenoma-associated genes were included. Forty-eight genes with 59 somatic variants were identified by WES. In targeted resequencing, variants in 26 recurrent genes, including MAST4, PRIM2, TNN, STARD9, DNAH11, DOCK4, GPR98, BCHE, DARS, CUBN, NGDN, PLXND1, UNC5B, and COL22A1, were identified, but variants in previously reported genes were not detected. BCHE, DARS, NGDN, and UNC5B variants were associated with increased GH-secreting pituitary tumor biochemical activity, which was confirmed in vitro. Although recurrent point variants were rare, several somatic variants were identified in sporadic pure GH-secreting pituitary adenomas. Several somatic variants may affect pathways involved in the tumorigenesis and biochemical activities of GH-secreting pituitary adenomas.

Background The guanine nucleotide-binding protein, alpha stimulating (GNAS) gene has been associated with growth hormone (GH)-secreting pituitary adenoma. We investigated the prevalence of GNAS mutations in Korean patients with acromegaly and assessed whether mutation status correlated with biochemical or clinical characteristics. Methods We studied 126 patients with acromegaly who underwent surgery between 2005 and 2014 at Severance Hospital. We performed GNAS gene analysis and evaluated age, sex, hormone levels, postoperative biochemical remission, and immunohistochemical staining results of the tumor. Results GNAS mutations were present in 75 patients (59.5%). Patients with and without GNAS mutations showed similar age distribution and Knosp classification. The proportion of female patients was 76.5% and 48.0% in the GNAS-negative and GNAS-mutation groups, respectively (P=0.006). In immunohistochemical staining, the GNAS-mutation group showed higher GH expression in pituitary tumor tissues than the mutation-negative group (98.7% vs. 92.2%, P=0.015). Patients with GNAS mutations had higher preoperative insulin-like growth factor-1 levels (791.3 ng/mL vs. 697.0 ng/mL, P=0.045) and lower immediate postoperative basal (0.9 ng/mL vs. 1.0 ng/mL, P=0.191) and nadir GH levels (0.3 ng/mL vs. 0.6 ng/mL, P=0.012) in oral glucose tolerance tests. Finally, the GNAS-mutation group showed significantly higher surgical remission rates than the mutation-negative group, both at 1 week and 6 months after surgical resection (70.7% vs. 54.9%, P=0.011; 85.3% vs. 82.4%, P=0.007, respectively). Conclusion GNAS mutations in GH-secreting pituitary tumors are associated with higher preoperative insulin-like growth factor-1 levels and surgical remission rates and lower immediate postoperative nadir GH levels. Thus, GNAS mutation status can predict surgical responsiveness in patients with acromegaly.

Abstract The purpose of this study was to establish a high-performing radiomics strategy with machine learning from conventional and diffusion MRI to differentiate recurrent glioblastoma (GBM) from radiation necrosis (RN) after concurrent chemoradiotherapy (CCRT) or radiotherapy. Eighty-six patients with GBM were enrolled in the training set after they underwent CCRT or radiotherapy and presented with new or enlarging contrast enhancement within the radiation field on follow-up MRI. A diagnosis was established either pathologically or clinicoradiologically (63 recurrent GBM and 23 RN). Another 41 patients (23 recurrent GBM and 18 RN) from a different institution were enrolled in the test set. Conventional MRI sequences (T2-weighted and postcontrast T1-weighted images) and ADC were analyzed to extract 263 radiomic features. After feature selection, various machine learning models with oversampling methods were trained with combinations of MRI sequences and subsequently validated in the test set. In the independent test set, the model using ADC sequence showed the best diagnostic performance, with an AUC, accuracy, sensitivity, specificity of 0.80, 78%, 66.7%, and 87%, respectively. In conclusion, the radiomics models models using other MRI sequences showed AUCs ranging from 0.65 to 0.66 in the test set. The diffusion radiomics may be helpful in differentiating recurrent GBM from RN. .

Abstract Focal malformations of cortical development (MCD) are linked to somatic brain mutations occurring during neurodevelopment. Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a newly recognized clinico-pathological entity associated with pediatric drug-resistant focal epilepsy, and amenable to neurosurgical treatment. MOGHE is histopathologically characterized by clusters of increased oligodendroglial cell densities, patchy zones of hypomyelination, and heterotopic neurons in the white matter. The molecular etiology of MOGHE remained unknown so far. We hypothesized a contribution of mosaic brain variants and performed deep targeted gene sequencing on 20 surgical MOGHE brain samples from a single-center cohort of pediatric patients. We identified somatic pathogenic SLC35A2 variants in 9/20 (45%) patients with mosaic rates ranging from 7 to 52%. SLC35A2 encodes a UDP-galactose transporter, previously implicated in other malformations of cortical development (MCD) and a rare type of congenital disorder of glycosylation. To further clarify the histological features of SLC35A2-brain tissues, we then collected 17 samples with pathogenic SLC35A2 variants from a multicenter cohort of MCD cases. Histopathological reassessment including anti-Olig2 staining confirmed a MOGHE diagnosis in all cases. Analysis by droplet digital PCR of pools of microdissected cells from one MOGHE tissue revealed a variant enrichment in clustered oligodendroglial cells and heterotopic neurons. Through an international consortium, we assembled an unprecedented series of 26 SLC35A2-MOGHE cases providing evidence that mosaic SLC35A2 variants, likely occurred in a neuroglial progenitor cell during brain development, are a genetic marker for MOGHE.

Abstract Background Driver genes of GBM may be crucial for the onset of isocitrate dehydrogenase (IDH)-wildtype (WT) glioblastoma (GBM). However, it is still unknown whether the genes are expressed in the identical cluster of cells. Here, we have examined the gene expression patterns of GBM tissues and patient-derived tumorspheres (TSs) and aimed to find a progression-related gene. Methods We retrospectively collected primary IDH-WT GBM tissue samples (n = 58) and tumor-free cortical tissue samples (control, n = 20). TSs are isolated from the IDH-WT GBM tissue with B27 neurobasal medium. Associations among the driver genes were explored in the bulk tissue, bulk cell, and a single cell RNAsequencing techniques (scRNAseq) considering the alteration status of TP53, PTEN, EGFR, and TERT promoter as well as MGMT promoter methylation. Transcriptomic perturbation by temozolomide (TMZ) was examined in the two TSs. Results We comprehensively compared the gene expression of the known driver genes as well as MGMT, PTPRZ1, or IDH1. Bulk RNAseq databases of the primary GBM tissue revealed a significant association between TERT and TP53 (p

Abstract This study was conducted to assess whether levetiracetam (LEV) affects the survival of patients with glioblastoma (GBM) treated with concurrent temozolomide (TMZ) chemotherapy. To this end, from 2004 to 2016, 322 patients with surgically resected and pathologically confirmed isocitrate dehydrogenase (IDH)-wildtype GBM who received TMZ-based chemoradiotherapy were analysed. The patients were divided into two groups based on whether LEV was used as an anticonvulsant both at the time of surgery and the first visit thereafter. The median overall survival (OS) and progression-free survival (PFS) were compared between the groups. The OS was 21.1 and 17.5 months in the LEV (+) and LEV (−) groups, respectively (P = 0.003); the corresponding PFS was 12.3 and 11.2 months (P = 0.017). The other prognostic factors included age, extent of resection, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and Karnofsky Performance Status (KPS) score. The multivariate analysis showed age (hazard ratio [HR], 1.02; P

The heterogeneity of IDH1/2 wild-type glioblastoma limits its prognosis and therapy. Here, the authors show a binary stratification, based on quantitative proteomic analysis of samples from patients with glioblastoma, with different prognosis and therapeutic vulnerabilities.

Abstract Background To identify the association between somatic ataxia-telangiectasia mutated (ATM) mutations and improved radio-sensitivity, we retrospectively reviewed next-generation sequencing data from patients diagnosed with isocitrate dehydrogenase (IDH)-wildtype high-grade glioma. Methods We included 39 individuals with (IDH)-wildtype high-grade glioma (diffuse astrocytoma n = 2, anaplastic astrocytoma n = 10, and glioblastoma n = 27) not subjected to gross tumor resection and undergoing radiation therapy with a median total dose of 60 Gy in 30 fractions. The mutational status of the ATM gene was obtained through next-generation sequencing using a TruSight Tumor 170 cancer panel. Disease progression was defined according to the Response Assessment in Neuro-Oncology (RANO) criteria as well as neurologic and clinical findings. Results Among the 39 samples, ATM mutations (ATM mut(+)) were detected in 26% of cases (n = 10). No significant differences were observed in the characteristics of the patients or tumors. Among the 10 patients in the ATM mut(+) group, there were 6 patients with glioblastoma and 4 patients with anaplastic astrocytoma. Most mutations were missense mutations (n = 8, 80%). With a median follow-up of 16.5 mo (interquartile range, 11.4–19.8), ATM mut(+) exhibited 1-year in-field control of 100% compared with 44.1% in the ATM mut(−) group (p = 0.002). There was no difference in the out-field control rate or overall survival between the two groups (p = 0.861 and p = 0.247, respectively). Conclusions Our results demonstrated that ATM mutations might be involved in the increased radio-sensitivity with excellent in-field control despite the aggressive nature of IDH-wildtype high-grade glioma. Further studies are necessary to uncover the potential role of ATM as a biomarker and candidate therapeutic target in high-grade gliomas.

Background The revised 4th 2016 World Health Organization (WHO) classification of tumors of the central nervous system (CNS) classification has adopted integrated diagnosis encompassing the histology and molecular features of CNS tumors. We aimed to investigate the immunohistochemistry, molecular testing, and testing methods for diagnosis of CNS tumors in pathological labs of tertiary centers in Korea, and evaluate the adequacy of tests for proper diagnosis in daily practice. Methods A survey, composed of eight questions concerning molecular testing for diagnosis of CNS tumors, was sent to 10 neuropathologists working in tertiary centers in Korea. Results For diagnosis of astrocytic and oligodendroglial tumors, all 10 centers performed isocitrate dehydrogenase mutations testing and 1p/19q loss of heterozygosity. For glioneuronal tumors, immunohistochemistry (IHC) assays for synaptophysin (n = 9), CD34 (n = 7), BRAF(VE1) (n = 5) were used. For embryonal tumors, particularly in medulloblastoma, four respondents used IHC panel (growth factor receptor bound protein 2-associated protein 1, filamin A, and yes-associated protein 1) for molecular subclassification. Regarding meningioma, all respondents performed Ki-67 IHC and five performed telomerase reverse transcriptase promoter mutation. Conclusions Most tertiary centers made proper diagnosis in line with 2016 WHO classification. As classification of CNS tumors has evolved to be more complex and more ancillary tests are required, these should be performed considering the effect of necessity and justification.

Purpose The 2021 World Health Organization classification includes telomerase reverse transcriptase promoter (TERTp) mutation status as a factor for differentiating meningioma grades. Therefore, preoperative prediction of TERTp mutation may assist in clinical decision making. However, no previous study has applied fractal analysis for TERTp mutation status prediction in meningiomas. The purpose of this study was to assess the utility of three-dimensional (3D) fractal analysis for predicting the TERTp mutation status in grade 2 meningiomas. Methods Forty-eight patients with surgically confirmed grade 2 meningiomas (41 TERTp-wildtype and 7 TERTp-mutant) were included. 3D fractal dimension (FD) and lacunarity values were extracted from the fractal analysis. A predictive model combining clinical, conventional, and fractal parameters was built using logistic regression analysis. Receiver operating characteristic curve analysis was used to assess the ability of the model to predict TERTp mutation status. Results Patients with TERTp-mutant grade 2 meningiomas were older (P = 0.029) and had higher 3D FD (P = 0.026) and lacunarity (P = 0.004) values than patients with TERTp-wildtype grade 2 meningiomas. On multivariable logistic analysis, higher 3D FD values (odds ratio = 32.50, P = 0.039) and higher 3D lacunarity values (odds ratio = 20.54, P = 0.014) were significant predictors of TERTp mutation status. The area under the curve, accuracy, sensitivity, and specificity of the multivariable model were 0.84 (95% confidence interval 0.71–0.93), 83.3%, 71.4%, and 85.4%, respectively. Conclusion 3D FD and lacunarity may be useful imaging biomarkers for predicting TERTp mutation status in grade 2 meningiomas.

BackgroundThe new World Health Organization (WHO) classification system proposed a cell lineage-based classification scheme for pituitary adenomas in which transcription factors (TFs) play a major role as key classifiers. We aimed to evaluate clinical relevance of the new classification system in a clinical setting.MethodsTF staining was retrospectively performed for 153 clinically and histologically well characterized pituitary adenomas. Then, 484 pituitary adenomas were prospectively stained for TFs and then for relevant pituitary hormones. TF and hormone stain-based diagnoses were compared, and differences in clinical manifestations were evaluated.ResultsThe accuracies of antibodies for three TFs were successfully validated and had an overall matching rate was 89.6%. We identified 50 (10.4%) cases with discrepancies between TF and pituitary hormone stains. Gonadotroph adenomas lacking follicle-stimulating hormone and luteinizing hormone stains account for most discrepancies. Null cell adenomas may be more prevalent than reported and may be clinically more aggressive than gonadotroph adenomas.ConclusionThe new WHO classification is mostly well matched with the traditional classification. However, until the new classification is further validated and interpreted in the context of long-term clinical outcomes, routine histological examination should include full slate of immunostains for pituitary hormones as well as TFs.

Abstract Objective Myelinated Schwann cells (SCs) in adult peripheral nerves dedifferentiate into immature cells in demyelinating neuropathies and Wallerian degeneration. This plastic SC change is actively involved in the myelin destruction and clearance as demyelinating SCs (DSCs). In inherited demyelinating neuropathy, pathologically differentiated and dysmyelinated SCs constitute the main nerve pathology. Methods We investigated whether this SC plastic status in human neuropathic nerves could be determined by patient sera to develop disease‐relevant serum biomarkers. Based on proteomics analysis of the secreted exosomes from immature SCs, we traced p75 neurotrophin receptor (p75) and neural cell adhesion molecule 1 (NCAM) in the sera of patients with peripheral neuropathy. Results Enzyme‐linked immunosorbent assay (ELISA) revealed that p75 and NCAM were subtype‐specifically expressed in the sera of patients with peripheral neuropathy. In conjunction with these ELISA data, pathological analyses of animal models and human specimens suggested that the presence of DSCs in inflammatory neuropathy and of supernumerary nonmyelinating or dysmyelinating SCs in inherited neuropathy could potentially be distinguished by comparing the expression profiles of p75 and NCAM. Interpretation This study indicates that the identification of disease‐specific pathological SC stages might be a valuable tool for differential diagnosis of peripheral neuropathies.

Abstract Background Immunotherapy is currently being examined as a treatment modality for glioblastoma. Maintaining an optimal total lymphocyte count (TLC) after radiotherapy (RT) and using temozolomide may be beneficial in optimizing immunotherapy. However, conventional temozolomide-based chemoradiation is known to induce immunosuppressive effects, including lymphopenia. Therefore, this study aimed to identify potential clinical predictors of acute severe lymphopenia (ASL) in patients receiving chemoradiation for glioblastoma. Methods We identified patients with glioblastoma treated with RT plus temozolomide from 2006 to 2017. ASL was defined as a TLC of

Hyalinizing trabecular tumor (HTT) is a rare thyroid tumor with low to minimal malignant potential. HTT is often misinterpreted as other thyroid tumors, including papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC), on fine-needle aspiration (FNA) cytology, because of its overlapping cytologic features, such as nuclear grooves and intranulcear pseudoinclusions. Although cytopathologists cannot definitely conclude HTT by FNA cytology, suspicion of HTT is necessary to avoid misdiagnosing HTT as PTC or MTC and to avoid unnecessary aggressive treatment. Here, we report a case of HTT with novel cytologic features in CellPrep liquid based cytology that was diagnosed as suspicious for papillary carcinoma by FNA and finally diagnosed as HTT in the surgical specimen.

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine carcinoma of the skin that shows locoregional or distant metastasis. Metastasis of MCC to body cavity effusion is extremely rare; only three cases have been reported so far. Metastatic MCC in effusion cytology shows small blue round cells with fine stippled chromatin like other small blue round cell tumors such as small cell lung carcinoma or lymphoma. The diagnosis of metastatic MCC can grant patients good chances at recently advanced therapeutic options. Here, we present a case of metastatic MCC to pleural effusion with characteristic single file-like pattern.

Abstract Background Recent progress in molecular analysis has advanced the understanding of medulloblastoma (MB) and is anticipated to facilitate management of the disease. MB is composed of 4 molecular subgroups: WNT, SHH, Group 3, and Group 4. Macrophages play a crucial role in the tumor microenvironment; however, the functional role of their activated phenotype (M1/M2) remains controversial. Herein, we investigate the correlation between tumor-associated macrophage (TAM) recruitment within the MB subgroups and prognosis. Methods Molecular subgrouping was performed by a nanoString-based RNA assay on retrieved snap-frozen tissue samples. Immunohistochemistry (IHC) and immunofluorescence (IF) assays were performed on subgroup identified samples, and the number of polarized macrophages was quantified from IHC. Survival analyses were conducted on collected clinical data and quantified macrophage data. Results TAM (M1/M2) recruitment in SHH MB was significantly higher compared to that in other subgroups. A Kaplan-Meier survival curve and multivariate Cox regression demonstrated that high M1 expressers showed worse overall survival (OS) and progression-free survival (PFS) than low M1 expressers in SHH MB, with relative risk (RR) values of 11.918 and 6.022, respectively. Conclusion M1 rather than M2 correlates more strongly with worse outcome in SHH medulloblastoma.

Concerns about the hazards of statins on the development and mortality of stomach cancers remain controversial. Here, we investigated the likelihood of incident gastric cancers and related mortality depending on statin exposure, statin type, and the duration of use. This nested case–control-designed study was composed of 8798 patients who were diagnosed with gastric cancer and matched with 35,192 controls at a 1:4 ratio based on propensity scores of age, sex, residential area, and income from the Korean National Health Insurance Service—Health Screening Cohort database (2002–2015). Propensity score overlap weighting was adjusted to balance the baseline covariates. Overlap propensity score-weighted logistic regression analyses were assessed to determine associations of the prior use of statins (any statin, hydrophilic statins vs. lipophilic statins) with incident gastric cancer and its mortality depending on the medication duration (545 days) after adjusting for multiple covariates. After adjustment, the use of any statin, hydrophilic statins, or lipophilic statins showed significant associations with lower odds for incident stomach cancer when used for a short-term period (180–545 days) (OR = 0.88, 95% CI = 0.81–0.86, p = 0.002; OR = 0.78, 95% CI = 0.66–0.92, p = 0.004; and OR = 0.91, 95% CI = 0.84–0.99, p = 0.039, respectively) compared to the control group. Hydrophilic statin use for 180–545 days was associated with 53% lower overall mortality (OR = 0.47; 95% CI = 0.29–0.77). In subgroup analyses, beneficial effects on both cancer development and mortality persisted in patients ≥65 years old, patients with normal blood pressure, and patients with high fasting glucose levels. There were no such associations with long-term statin use (>545 days). Thus, the current nationwide cohort study suggests that prior short-term statin use may have anti-gastric cancer benefits in elderly patients with hyperglycemia.

Melanotic schwannoma (MS) is a rare variant of nerve sheath neoplasm that shows ultrastructural and immunophenotypical features of Schwann cells but also has cytoplasmic melanosomes and is reactive for melanocytic markers as well. Unlike conventional schwannoma, which is totally benign, MS has an unpredictable prognosis and is thought to have low-malignant potential. Herein, we present a rare case of recurrent MS in lumbar spine of a 59-year-old male.

The superior cervical sympathetic ganglion, the largest and most cranial of the three cervical sympathetic ganglia, transfers sympathetic signals to specific targets on the head and neck. This ganglion is located just lateral to the retropharyngeal space along the medial margin of the carotid sheath. Located thus, an enlarged superior cervical sympathetic ganglion can mimic a metastatic lymph node in the retropharyngeal space of the suprahyoid neck in head and neck cancer patients. However, this is often disregarded by radiologists due to lack of interest in its anatomic location. We present a case of an enlarged superior cervical sympathetic ganglion mimicking a retropharyngeal metastatic lymph node in a 42-year-old man with oral tongue cancer.

Cryptococcus neoformans is the most common microorganism found in cerebrospinal fluid (CSF) cytology and causes life-threatening infections in immunocompromised hosts. Although its cytomorphologic features in conventional smear cytology have been well described, those in liquid-based cytology have rarely been. A 73-year-old woman with diffuse large B-cell lymphoma presented with mental confusion and a spiking fever. To rule out infectious conditions, CSF examination was performed. A cytology slide that was prepared using the ThinPrep method showed numerous spherical yeast-form organisms with diameters of 4–11 μm and thick capsules. Occasional asymmetrical, narrow-based budding but no true hyphae or pseudohyphae were observed. Gomori methenamine silver staining was positive. Cryptococcosis was confirmed in blood and CSF through the cryptococcal antigen test and culture. Liquid-based cytology allows for a clean background and additional slides for ancillary testing, facilitating the detection of microorganisms in CSF specimens, particularly when the number of organisms is small.

AimAlthough the atheroprotective effects of statins and angiotensin II receptor blockers (ARBs) are well-established, little is known about their additive effects, especially during the early period of atherosclerosis. The aim of this study was to investigate whether combination of a statin and an ARB exerts synergistic anti-atherosclerotic effects, and to elucidate the mechanisms of combined effects.MethodsAtherosclerotic plaques were developed in arteries of 23 rabbits using a high-cholesterol diet (HCD) and intra-arterial balloon inflation. Rabbits received one of five different treatment strategies for 4 weeks: positive control [n = 5, HCD]; negative control [n = 3, regular chow diet]; statin [n = 5, HCD and rosuvastatin 10 mg]; ARB [n = 5, HCD and olmesartan 20 mg]; and combination [n = 5, HCD and statin+ARB].ResultsHistological analysis demonstrated that development of atherosclerotic plaques was inhibited more in combination group than in statin group (P = 0.001). Although macrophage infiltration identified by RAM11 staining was not significantly different between combination and individual treatment groups (31.76±4.84% [combination] vs. 38.11±6.53% [statin; P = 0.35] or 35.14±2.87% [ARB; P = 0.62]), the relative proportion of pro-inflammatory M1-macrophages was significantly lower in combination group than in ARB group (3.20±0.47% vs. 5.20±0.78%, P = 0.02). Furthermore, M2-macrophage polarization was higher in combination group than in statin group (17.70±3.04% vs. 7.86±0.68%, P = 0.001).ConclusionCombination treatment with a statin and an ARB produced synergistic protective effects for atherosclerosis initiation and progression, which may be attributed to modulation of macrophage characteristics in the early period of atherosclerosis.

Stooped posture, which is usually aggravated during walking, is one of the typical postural deformities in patients with parkinsonism. However, the degree of stooped posture is difficult to quantitatively measure during walking. Furthermore, continuous feedback on posture is also difficult to provide. The purpose of this study is to measure the degree of stooped posture during gait and to investigate whether vibration feedback from sensor modules can improve a patient’s posture. Parkinsonian patients with stooped posture were recruited for this study. Two wearable sensors with three-axis accelerometers were attached, one at the upper neck and the other just below the C7 spinous process of the patients. After being calibrated in the most upright posture, the sensors continuously recorded the sagittal angles at 20 Hz and averaged the data at every second during a 6 min walk test. In the control session, the patients walked with the sensors as usual. In the vibration session, sensory feedback was provided through vibrations from the neck sensor module when the sagittal angle exceeded a programmable threshold value. Data were collected and analyzed successfully in a total of 10 patients. The neck flexion and back flexion were slightly aggravated during gait, although the average change was

Long-term hormone replacement therapy due to panhypopituitarism can lead to serious complications and thus, pituitary transplantation is considered a more desirable. We investigated functional restoration after allotransplatation of the pituitary gland. We transplanted extracted pituitary gland into the omentum of an hypophysectomized rat. Two experiments were performed: (1) to confirm the hypophysectomy was successful and (2) to assess functional restoration after pituitary transplantation. Pituitary hormone level and weight change were consecutively assessed. Electron microscopic (EM) examinations were performed to identify morphological changes at 3 days after transplantation. We confirmed that pituitary gland was properly extracted from 6 rats after sacrifice. The findings showed (1) a weight loss of more than 3% or (2) a weight change of less than 2% along with a decreased growth hormone (GH) level by more than 80% at 2 weeks post-hypophysectomy. A further four rats underwent pituitary transplantation after hypophysectomy and were compared with the previously hypophysectomized rats. All showed rapid weight gain during the two weeks after transplantation. The thyroid-stimulating hormone, prolactin, and GH levels were restored at one week post-transplantation and maintained for 10 weeks. Hypophyseal tissue architecture was maintained at 3 days after transplantation, as indicated by EM. These data suggest that a transplanted pituitary gland can survive in the omentum with concomitant partial restoration of anterior pituitary hormones.

Purpose To describe imaging features of infratentorial desmoplastic infantile or non-infantile tumors (DIT/DNIT). Materials and Methods Four cases with infratentorial DIT/DNIT from our hospital and 5 cases from literature review were analyzed. Clinical data and MR imaging features were evaluated including location, size, shape, margin, composition, dural attachment, perilesional edema, and metastasis or multiplicity. Results The mean age was 9.2 years (range, 1–18 years). Most of the patients presented with headache or vomiting (4/9, 44.4%) and had no underlying disease (8/9, 88.9%). The major pathologic subtype was astrocytoma (6/9, 66.7%). On MR, majority of the tumors involved cerebellum and/or spinal cord (8/9, 88.9%) and the mean size of the tumors was 4.2 cm (range, 3.2–5 cm). The tumors were mainly solid (4/9, 44.4%) or mixed (4/9, 44.4%) in composition with lobulated shape (7/9, 77.8%) and well-defined margin (7/9, 77.8%). Two cases (2/7, 28.6%) showed dural attachment and all the cases had no or minimal perilesional edema (100%). Metastasis or multiplicity was frequently seen in 44.4% (4/9). Conclusion Infratentorial DIT/DNIT occurred in relatively older children and the major tumor type was astrocytoma. They also had atypical imaging features showing mainly solid or mixed in composition with frequent metastasis or multiplicity.

Previous studies have identified multiple loci for inherited susceptibility to glioma development, including the regulator of telomere elongation helicase 1 (RTEL1). However, the association between RTEL1 variants and risk of glioma has not been well understood. Therefore, we sought to comprehensively examine the genetic interaction between RTEL1 variants and risk of glioma with respect to defined histological and molecular subtypes. We employed a case-control study involving 250 adult glioma patients with previous molecular alterations and 375 population-based controls within Korean populations. Statistical analyses on the association between RTEL1 single nucleotide polymorphisms (SNPs) and glioma risk were conducted using unconditional logistic regression. Additional conditional and stepwise analyses were performed on significant RTEL1 SNPs. We detected significant associations (Bonferroni P < .05) between six SNPs (rs6089953, rs3848669, rs6010620, rs3787089, rs6062302, and rs115303435) and risk of glioma in the Korean subjects. The two coding variants, rs6062302 (D664D) and rs115303435 (A1059T), were plausibly causal variants and were independent among the significantly associated RTEL1 variants. The glioma subgroup analyses showed that the causal variants (rs6062302 and rs115303435) may be associated with increased risk of glioma regardless of histological grades and molecular alterations. This study provides a deeper understanding of relationships between RTEL1 variants and risk of glioma. Further studies are required to ascertain the impact of those variants on glioma susceptibility.

Myoclonus epilepsy with ragged-red fibers (MERRFs), an inherited mitochondrial disorder, has characteristic morphological changes of ragged-red fibers (RRFs) in muscle biopsy, in the absence of which mitochondrial etiology is usually not considered in patients with phenotypes suggestive of MERRF. In these circumstances, MERRF can only be diagnosed using genetic analyses. The symptoms, pathological findings, and imaging results being age dependent, we can construct a protocol based on these characteristics to understand the disease’s natural course and to manage patients more effectively. The absence of RRFs should not preclude a MERRF diagnosis.

BackgroundMultiple endocrine neoplasia type 1 (MEN1) is a familial syndrome characterized by the parathyroid, pancreas and pituitary tumors. Parathyroid tumors are the most common clinical manifestations, occurring in more than 90% of MEN1 patients. Heterozygous germline mutations of the MENIN gene underlie the tumorigenesis in MEN1 and epigenetic alterations along with germline mutations may contribute to tumorigenesis. Here, we investigated the associations between genotype and phenotype in Korean MEN1 patients.MethodsWe analyzed medical records from 14 unrelated MEN1 patients who had newly confirmed MENIN germline mutations, together with 14 previous reports in Korea. Aberrant DNA methylations were also examined in MEN1-related parathyroid tumors using the Infinium HumanMethylation 450 BeadChip.ResultsTotal 28 germline mutations of MENIN were relatively highly concentrated in exons 7 and 8 compared to previous reports from Western countries. Six mutations (c.111dupT/p.S38Ffs*79, c.225_226insT/p.T76Yfs*41, c.383_398del16/p.S128Tfs*52, c.746dupT/p.H250Afs*20, c.1150G>T/p.E384*, and c.1508G>A/p.G503N) were newly found in the present study. Of interest, four patients (15%) showed unusual initial presentations and three patients were diagnosed incidentally at the general medical checkup. We also found three distinct sites in exon 2 of MENIN were significantly hypomethylated in the MEN1 parathyroid tumors, comparing correspondent blood samples.ConclusionWe also have found a lack of genotype/phenotype correlation in Korean MEN1 patients. There were not a few unusual initial manifestations in MEN1 patients, thus, genetic testing for the MENIN germline mutations can provide important information for the better prognosis. Further studies are warranted to investigate altered DNA methylations in the MENIN gene involved in tumorigenesis.

Eosinophils are one of the polymorphonuclear granulocytes derived from bone marrow stem cells, and they contain many small cytoplasmic granules that stain bright red with eosin or brick-red with Romanowsky staining. Eosinophilic infiltration is also present in various human central nervous system (CNS) diseases such as parasitic infection, transverse myelitis, vasculitis, Langerhans cell histiocytosis, glioblastoma and etc... Due to the morphologic and functional characteristics, the presence of eosinophils in certain lesions may provide useful diagnostic clues in the right clinical setting. Consideration of this finding may facilitate the diagnosis of CNS pathologic lesions, especially in a small specimen such as a stereotactic biopsy.

To identify prognostic factors and define the optimal management of patients with supratentorial primitive neuroectodermal tumors (sPNETs), we investigated treatment outcomes and explored the prognostic value of specific molecular markers.A total of 47 consecutive patients with pathologically confirmed sPNETs between May 1985 and June 2012 were included. Immunohistochemical analysis of LIN28, OLIG2, and Rad51 expression was performed and correlated with clinical outcome.With a median follow-up of 70 months, 5-year overall survival (OS) and progression-free survival (PFS) was 55.5% and 40%, respectively, for all patients. Age, surgical extent, and radiotherapy were significant prognostic factors for OS and PFS. Patients who received initially planned multimodal treatment without interruption (i.e., radiotherapy and surgery (≥subtotal resection), with or without chemotherapy) showed significantly higher 5-year OS (71.2%) and PFS (63.1%). In 29 patients with available tumor specimens, tumors with high expression of either LIN28 or OLIG2 or elevated level of Rad51 were significantly associated with poorer prognosis.We found that multimodal treatment improved outcomes for sPNET patients, especially when radiotherapy and ≥subtotal resection were part of the treatment regimen. Furthermore, we confirmed the prognostic significance of LIN28 and OLIG2 and revealed the potential role of Rad51 in sPNETs.

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor, and the prognosis remains poor. Rearrangement of ROS1 gene, which was shown to have an oncogenic potential, was previously discovered in GBM cell lines. In this pilot study, we aimed to identify the incidence of ROS1 rearrangement in GBM patient tissues to explore novel biomarkers for therapeutic strategy. Formalin-fixed and paraffin-embedded (FFPE) tissue sections from 109 patients with GBM were screened for ROS1 rearrangement by anti-ROS immunohistochemistry (IHC) and ROS1 break-apart fluorescent in situ hybridization (FISH) assays. O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation and Isocitrate dehydrogenase 1 (IDH1) mutation status were also assessed. All samples were interpreted by two experienced pathologists who were blinded to the clinical data. A total of 109 samples were collected and all samples were examined for ROS1 rearrangement by IHC and FISH assays, and none was found to harbor ROS1 rearrangement. MGMT gene methylation was found in 42 (39.2%) cases, and IDH1 mutation was found in 6 (5.5%) cases. In this study, ROS1 rearrangement was not identified in GBM patients, and thus it is difficult to classify ROS1 rearrangement as a novel molecular subset in GBM patients for now.

Aminoacyl-tRNA synthetases (ARSs) and ARS-interacting multifunctional proteins (AIMPs) exhibit remarkable functional versatility beyond their catalytic activities in protein synthesis. Their non-canonical functions have been pathologically linked to cancers. Here we described our integrative genome-wide analysis of ARSs to show cancer-associated activities in glioblastoma multiforme (GBM), the most aggressive malignant primary brain tumor. We first selected 23 ARS/AIMPs (together referred to as ARSN), 124 cancer-associated druggable target genes (DTGs) and 404 protein-protein interactors (PPIs) of ARSs using NCI's cancer gene index. 254 GBM affymetrix microarray data in The Cancer Genome Atlas (TCGA) were used to identify the probe sets whose expression were most strongly correlated with survival (Kaplan-Meier plots versus survival times, log-rank t-test

Background: The grade of tracheal collapse (TC) is assessed by the diameter of the narrowed lumen. However, studies on the relationship between TC grade and clinical symptom severity are lacking. Objectives: To investigate the clinical characteristics of small-breed dogs diagnosed with TC and determine if fluoroscopic grading correlates with cough severity. Methods: We retrospectively reviewed medical records from 2022 to 2024. TC diagnosis was confirmed using fluoroscopic examination. Multiple linear regression was employed to investigate factors influencing cough severity, with a significance level set at p < 0.05. Results: A total of 132 dogs with TC were identified, of which 22 were excluded. The final cohort consisted of 110 dogs, aged between 2-19 years, with no significant sex differences. The majority (97.2%) of dogs had a BCS of =4. Among the top four breeds (Maltese, Pomeranian, Poodle, and Chihuahua), the most severe collapse was observed in the carinal region. The grade of collapse on fluoroscopy was mostly related to high BCS (p < 0.007) and low body weight (p < 0.001). However, interestingly, fluoroscopic findings of collapse location and grade did not correlate with cough severity (p = 0.350). Notably, clinical symptoms improved in 86.6% of cases following interventions such as weight reduction, environmental changes, and pharmacotherapy. Conclusions and clinical relevance: In small-breed dogs, the severity of cough was not associated with the region or grade of TC diagnosed by fluoroscopy. [ABSTRACT FROM AUTHOR]