Young Zoon Kim

Altered Histone Modifications in Gliomas

Gliomas are the most frequently occurring primary brain tumors in adults. Although they exist in different malignant stages, including histologically benign forms and highly aggressive states, most gliomas are clinically challenging for neuro-oncologists because of their infiltrative growth patterns and inherent relapse tendency with increased malignancy. Once this disease reaches the glioblastoma multiforme stage, the prognosis of patients is dismal: median survival time is 15 months. Extensive genetic analyses of glial tumors have revealed a variety of deregulated genetic pathways involved in DNA repair, apoptosis, cell migration/adhesion, and cell cycle. Recently, it has become evident that epigenetic alterations may also be an important factor for glioma genesis. Of epigenetic marks, histone modification is a key mark that regulates gene expression and thus modulates a wide range of cellular processes. In this review, I discuss the neuro-oncological significance of altered histone modifications and modifiers in glioma patients while briefly overviewing the biological roles of histone modifications.

Endoscopic Endonasal Transsphenoidal Resection of Solitary Extramedullary Plasmacytoma in the Sphenoid Sinus with Destruction of Skull Base

Solitary extramedullary plasmacytomas are isolated plasma cell tumors of soft tissue that typically do not metastasize. They are rare and account for 4% of all plasma cell tumors. To our knowledge, only 14 cases of solitary extramedullary plasmacytomas in the sphenoid sinus have been reported. A 32-year-old man presented to our department with complaint of ocular pain in the right eyeball and diplopia. Physical and neurological examinations revealed intact and prompt direct and indirect light reflexes in both pupils and limitation of extraocular muscle movement seen with the lateral gaze of the right eyeball. Magnetic resonance imaging suggested the presence of mucocele or mycetoma, therefore surgical resection was performed with endoscopic endonasal transsphenoidal approach. Histopathology was consistent with plasmacytoma. Systemic work-up did not show any evidence of metastasis and the sphenoid sinus was the sole tumor site, and therefore the diagnosis of solitary extramedullary plasmacytoma was confirmed. We report a rare case of solitary extramedullary plasmacytoma in the sphenoid sinus with successful treatment using the endoscopic endonasal transsphenoidal resection and adjuvant radiotherapy.

Even in Patients with a Small Hemorrhagic Volume, Stereotactic-Guided Evacuation of Spontaneous Intracerebral Hemorrhage Improves Functional Outcome

OBJECTIVE The decision to adopt a conservative or surgical modality for a relatively small volume of spontaneous intracerebral hemorrhage (SICH) is difficult and often controversial, especially when consciousness is tolerable. The authors examined the results of stereotactic-guided evacuation of SICH for relatively small volumes with respect to functional outcome. METHODS This prospective study was performed on 387 patients with SICH who underwent stereotactic-guided evacuation (n = 204, group A) or conservative treatment (n = 183, group B) during the past 8 years. The primary end-point was recovery of functional status, which was estimated using the Modified Barthel Index (MBI) and the modified Rankin Scale (mRS). RESULTS All patients had a Glasgow coma scale (GCS) score of >/= 13 and unilateral hemiparesis of less than motor power grade 3. Group demographic characteristics and initial neurological statuses were similar. In all cases, the volume of SICH involved was < 30 cm(3) and location was limited to basal ganglia and thalamus. At 6-month follow-ups, MBI was 90.9 in group A and 62.4 in group B (p < 0.05), and MRS was 1.2 in group A and 3.0 in group B (p < 0.05). Better motor function and stereotactic-guided evacuation had a significant effect on a functional recovery in regression analyses. CONCLUSION Even in patients with a small volume of SICH, stereotactic-guided evacuation improved functional recovery in activities in daily life than conservative treatment did.

A feedback loop comprising PRMT7 and miR-24-2 interplays with Oct4, Nanog, Klf4 and c-Myc to regulate stemness

Self-renewal and pluripotency are two fundamental characteristics of embryonic stem cells (ESCs) and are controlled by diverse regulatory factors, including pluripotent factors, epigenetic regulators and microRNAs (miRNAs). Although histone methyltransferases are key epigenetic regulators, whether and how a histone methyltransferase forms a network with miRNAs and the core pluripotent factor system to regulate ESC stemness is little known. Here, we show that the protein arginine methyltransferase 7 (PRMT7) is a pluripotent factor essential for the stemness of mouse ESCs. PRMT7 repressed the miR-24-2 gene encoding miR-24-3p and miR-24-2-5p by upregulating the levels of symmetrically dimethylated H4R3. Notably, miR-24-3p targeted the 3′ untranslated regions (UTRs) of the major pluripotent factors Oct4, Nanog, Klf4 and c-Myc, whereas miR-24-2-5p silenced Klf4 and c-Myc expression. miR-24-3p and miR-24-2-5p also targeted the 3′UTR of their repressor gene Prmt7. miR-24-3p and miR-24-2-5p induced mouse ESC differentiation, and their anti-sense inhibitors substantially reversed spontaneous differentiation of PRMT7-depleted mouse ESCs. Oct4, Nanog, Klf4 and c-Myc positively regulated Prmt7 expression. These findings define miR-24-3p and miR-24-2-5p as new anti-pluripotent miRNAs and also reveal a novel epigenetic stemness-regulatory mechanism in which a double-negative feedback loop consisting of PRMT7 and miR-24-3p/miR24-2-5p interplays with Oct4, Nanog, Klf4 and c-Myc to control ESC stemness.

An essential role for UTX in resolution and activation of bivalent promoters

Trimethylated histone H3 lysine 27 (H3K27me3) is linked to gene silencing, whereas H3K4me3 is associated with gene activation. These two marks frequently co-occupy gene promoters, forming bivalent domains. Bivalency signifies repressed but activatable states of gene expression and can be resolved to active, H3K4me3-prevalent states during multiple cellular processes, including differentiation, development and epithelial mesenchymal transition. However, the molecular mechanism underlying bivalency resolution remains largely unknown. Here, we show that the H3K27 demethylase UTX (also called KDM6A) is required for the resolution and activation of numerous retinoic acid (RA)-inducible bivalent genes during the RA-driven differentiation of mouse embryonic stem cells (ESCs). Notably, UTX loss in mouse ESCs inhibited the RA-driven bivalency resolution and activation of most developmentally critical homeobox (Hox) a–d genes. The UTX-mediated resolution and activation of many bivalent Hox genes during mouse ESC differentiation were recapitulated during RA-driven differentiation of human NT2/D1 embryonal carcinoma cells. In support of the importance of UTX in bivalency resolution, Utx-null mouse ESCs and UTX-depleted NT2/D1 cells displayed defects in RA-driven cellular differentiation. Our results define UTX as a bivalency-resolving histone modifier necessary for stem cell differentiation.

A Clinical Analysis of Brain Metastasis in Gynecologic Cancer: A Retrospective Multi-institute Analysis

This study analyzes the clinical characteristics of the brain metastasis (BM) of gynecologic cancer based on the type of cancer. In addition, the study examines the factors influencing the survival. Total 61 BM patients of gynecologic cancer were analyzed retrospectively from January 2000 to December 2012 in terms of clinical and radiological characteristics by using medical and radiological records from three university hospitals. There were 19 (31.1%) uterine cancers, 32 (52.5%) ovarian cancers, and 10 (16.4%) cervical cancers. The mean interval to BM was 25.4 months (21.6 months in ovarian cancer, 27.8 months in uterine cancer, and 33.1 months in cervical cancer). The mean survival from BM was 16.7 months (14.1 months in ovarian cancer, 23.3 months in uterine cancer, and 8.8 months in cervical cancer). According to a multivariate analysis of factors influencing survival, type of primary cancer, Karnofsky performance score, status of primary cancer, recursive partitioning analysis class, and treatment modality, particularly combined therapies, were significantly related to the overall survival. These results suggest that, in addition to traditional prognostic factors in BM, multiple treatment methods such as neurosurgery and combined chemoradiotherapy may play an important role in prolonging the survival for BM patients of gynecologic cancer. Graphical Abstract

Results of immunohistochemical staining for cell cycle regulators predict the recurrence of atypical meningiomas

OBJECT The aim of this study was to evaluate the role of certain cell-cycle regulatory proteins in the recurrence of atypical meningiomas. These proteins were analyzed with immunohistochemical staining to identify predisposing factors for the recurrence of atypical meningiomas. METHODS The authors retrospectively reviewed the medical records of patients with atypical meningiomas diagnosed in the period from January 2000 to June 2012 at the Department of Neurosurgery at Samsung Changwon Hospital and Dong-A University Medical Center. Clinical data included patient sex and age at the time of surgery, presenting symptoms at diagnosis, location and size of tumor, extent of surgery, use of postoperative radiotherapy, duration of follow-up, and recurrence. Immunohistochemical staining for cell-cycle regulatory proteins (p16, p15, p21, p27, cyclin-dependent kinase [CDK] 4 and 6, phosphorylated retinoblastoma [pRB] protein, and cyclin D1) and proliferative markers (MIB-1 antigen, mitosis, and p53) was performed on archived paraffin-embedded tissues obtained during resection. The recurrence rate and time to recurrence were assessed using Kaplan-Meier analysis. RESULTS Of the 67 atypical meningiomas eligible for analysis, 26 (38.8%) recurred during the follow-up period (mean duration 47.7 months, range 8.4-132.1 months). Immunohistochemically, there was overstaining for p16 in 44 samples (65.7%), for p15 in 21 samples (31.3%), for p21 in 25 samples (37.3%), for p27 in 32 samples (47.8%), for CDK4 in 38 samples (56.7%), for CDK6 in 26 samples (38.8%), for pRB protein in 42 samples (62.7%), and for cyclin D1 in 49 samples (73.1%). Multivariate analysis using the Cox proportional-hazards regression model showed that incomplete resection (HR 4.513, p < 0.001); immunohistochemical understaining for p16 (HR 3.214, p < 0.001); immunohistochemical overstaining for CDK6 (HR 3.427, p < 0.001), pRB protein (HR 2.854, p = 0.008), and p53 (HR 2.296, p = 0.040); and increased MIB-1 labeling index (HR 2.665, p = 0.013) and mitotic index (HR 2.438, p = 0.024) predicted the recurrence of atypical meningiomas after resection. CONCLUSIONS Findings in this study indicated that p16, CDK6, and pRB protein were associated with the recurrence of atypical meningiomas.

Radiation-induced Necrosis Deteriorating Neurological Symptoms and Mimicking Progression of Brain Metastasis after Stereotactic-guided Radiotherapy

PURPOSE Although radiation-induced necrosis (RIN) is not a tumor in itself, the lesion progressively enlarges with mass effects and diffuse peritumoral edema in a way that resembles neoplasm. To identify the RIN that mimics progression of brain metastasis, we performed surgical resections of symptomatic RIN lesions. MATERIALS AND METHODS From June 2003 to December 2005, 7 patients received stereotactic-guided radiotherapy (SRT) for metastatic brain tumor, and they later underwent craniotomy and tumor resection due to the progressive mass effects and the peritumoral edema that caused focal neurological deficit. On MR imaging, a ring-like enhanced single lesion with massive peritumoral edema could not be distinguished from progression of brain metastasis. RESULTS Four patients had non-small cell lung cancer, 2 patients had colorectal cancer and 1 patient had renal cell carcinoma. The mean tumor volume was 8.7 ml (range: 3.0 approximately 20.7 ml). The prescribed dose of SRT was 30 Gy with 4 fractions for one patient, 18 Gy for two patients and 20 Gy for the other four patients. The four patients who received SRT with a dose of 20 Gy had RIN with or without microscopic residual tumor cells. CONCLUSIONS Early detection of recurrent disease after radiotherapy and identifying radiation-induced tissue damage are important for delivering adequate treatment. Therefore, specific diagnostic tools that can distinguish RIN from progression of metastatic brain tumor need to be developed.

Skull Base Invasion of Adenoid Cystic Carcinoma of the Lacrimal Gland : A Case Report

Although adenoid cystic carcinoma (ACC) of the lacrimal gland is a rarely encountered orbital tumor, it invades intracranially more frequently than carcinomas of other glands in the head and neck. A 52-year-old man underwent orbital exenteration and resection of intracranially extended tumor via a fronto-orbito-zygomatic approach in combination with a transfacial approach. Histopathologically, the tumor showed perineural, vascular, and lymphatic invasion. Additionally, he received radiotherapy (60 Gy) and adjuvant systemic cisplatin and 5-fluorouracil chemotherapy due to residual tumor in the orbit and systemic metastases (lung, ribs, and spines). He was free of progression and recurrence at 6 months after treatment. The authors report a case of skull base invasion by an ACC of the lacrimal gland to remind neurosurgeons planning intervention that this disease shows a tendency to invade intracranially.

Clinical Analysis of Patients who Survived for Less than 3 Months After Brain Metastatectomy

In the patients with brain metastasis (BM), it is impossible to determine who will benefit from surgery because of limited survival. In an attempt to identify optimal candidates for brain metastatectomy, we analyzed patients who survived for <3 months after craniotomy for a single BM lesion. Between January 1st, 1997 and July 31st, 2007, 83 patients with a single BM underwent craniotomy. Of these patients, 25 patients (30.1%) died within 3 months of craniotomy. The primary lesions were non-small call lung cancer in 15, colon cancer in 6, and breast cancer, renal cell carcinoma, ovarian cancer, or esophageal cancer in one apiece. Of the 25 patients, 19 (79%) were of tumor stage IV and had extra-cranial metastasis. Eleven (44%) of the 25 primary cancers had a well-controlled status. Twelve patients (48%) had a Karnofsky Performance Scale (KPS) score of <70, and 13 (52%) were of Recursive Partitioning Analysis (RPA) class 3. Primary cancer status, RPA class, and functional status were found to be critical factors for consideration when selecting surgical candidates. In addition, adjuvant therapy was found to have an important role on survival.