Jang-Hee Kim

Posttreatment High-Grade Glioma: Usefulness of Peak Height Position with Semiquantitative MR Perfusion Histogram Analysis in an Entire Contrast-enhanced Lesion for Predicting Volume Fraction of Recurrence

PURPOSE To determine whether semiquantitative histogram analysis of the normalized cerebral blood volume (CBV) for an entire contrast material-enhanced lesion could be used to predict the volume fraction of posttreatment high-grade glioma recurrence compared with posttreatment change. MATERIALS AND METHODS The institutional review board approved this retrospective study. Informed consent was obtained. Thirty-nine patients with pathologically proved predominant tumor recurrence (tumor recurrence group, tumor fraction > or =50% [n = 14]), mixed tumor and posttreatment change (mixed group, tumor fraction > or =20% and <50% [n = 10]), and predominant posttreatment change (treatment change group, tumor fraction <20% [n = 15]) were evaluated. Histogram parameters of normalized CBV-histogram width, peak height position (PHP), and maximum value (MV)-were measured in entire contrast-enhanced lesions and used as discriminative indexes. Ordered logistic regression was used to determine independent factors for predicting the diseases of posttreatment contrast-enhanced lesions. Leave-one-out cross-validation was used to determine diagnostic accuracy. RESULTS PHP was an independent predictive factor (P = .003) for differentiating contrast-enhanced lesions in patients with posttreatment gliomas. According to receiver operating characteristic curve analyses, PHP provided sensitivity of 90.2% and specificity of 91.1% for differentiating tumor recurrence from mixed and treatment change groups at an optimum threshold of 1.7 by using leave-one-out cross-validation. MV helped distinguish treatment change group from tumor recurrence and mixed groups at an optimum threshold of 2.6 (sensitivity, 96.5%; specificity, 93.1%). CONCLUSION PHP can be used to predict the volume fraction of posttreatment high-grade glioma recurrence.

Gankyrin is frequently overexpressed in breast cancer and is associated with ErbB2 expression.

Gankyrin is a subunit of the 26S proteasome, and has been known to degrade p53 and retinoblastoma protein and promote the tumorigenicity and metastasis in some malignancies. However, the role of gankyrin in breast cancer has not been explored. In this study, we investigated the expression of gankyrin in breast cancer and evaluated its effect on breast cancer. Representative cancer tissues including normal breasts from 60 patients with breast cancer were stained immunohistochemically for gankyrin, estrogen receptor, progesterone receptor, and ErbB2. We evaluated the relationship between gankyrin expression and clinicopathologic parameters or prognostic markers. We also attempted to clarify the mechanism of gankyrin involved in breast carcinogenesis by using MCF7 breast cancer cells. Gankyrin was weakly expressed in normal breast epithelial cells, however, tumor regions of 37/60 (61.7%) cases showed an overexpression of gankyrin. Gankyrin overexpression was associated with extensive intraductal carcinoma (p=0.014) and ErbB2 positivity (p=0.031) in invasive ductal carcinoma. In MCF7 breast cancer cells, downregulation of gankyrin was associated with a reduction of cell proliferation and tumorigenicity. In conclusion, gankyrin was identified in normal breasts and overexpressed in invasive breast cancers. The overexpression of gankyrin was associated with extensive intraductal carcinoma and ErbB2 expression in breast cancer.

Pathologic Diagnosis of Recurrent Glioblastoma: Morphologic, Immunohistochemical, and Molecular Analysis of 20 Paired Cases

To evaluate the prognostic value of the volume of residual viable tumor versus therapy-induced necrosis in resection material and the diagnostic value of ancillary tests in recurrent glioblastoma (GBM), we conducted a retrospective review of 20 patients whose initial and recurrent specimens were available. Recurrent GBMs were graded according to the extent of histopathologic parameters: recurrent tumor with high-grade, non–high-grade, and pure high-grade tumor components and therapy-related necrosis. We also examined MIB-1 labeling, isocitrate dehydrogenase 1R132H mutation, and epidermal growth factor receptor amplification in primary and recurrent GBMs. To evaluate patient outcomes according to clinical and pathologic parameters, a survival analysis was performed, and correlations between histopathologic parameters and each ancillary test were assessed. Among clinical parameters, age above 60 years was associated with decreased survival (P=0.022), but other clinical parameters showed no significant association with overall survival. Among the 3 histopathologic parameters, the extent of recurrent tumor, including high-grade and non–high-grade components, revealed a significant association with overall survival (P=0.042), but neither the extent of pure high-grade components nor therapy-related necrosis showed any prognostic value. MIB-1 labeling, isocitrate dehydrogenase 1R132H mutation, and epidermal growth factor receptor amplification were useful for the diagnosis of recurrent GBMs but showed no prognostic value. Our data suggest that histopathologic evaluation on the basis of tumor extent in resected recurrent GBM specimens may provide additional prognostic information on the survival of patients with recurrent GBM.

The Characteristics of Incidental Pituitary Microadenomas in 120 Korean Forensic Autopsy Cases

To investigate the characteristics of incidental pituitary microadenomas, we examined 120 pituitary glands from Korean forensic autopsy cases, from which eight tumors were identified (incidence 6.7%). The average age of the affected subjects was 50 yr (range: 33-96 yr) with a female predominance. The maximum diameters of the tumors ranged from 0.4 to 5.4 mm (mean: 2.8 mm). Immunohistochemical analysis of pituitary hormones revealed three growth hormone-secreting adenomas, one prolactin-producing adenoma, one gonadotropin-producing adenoma, one plurihormonal adenoma, and two null cell adenomas. MIB-1 staining for Ki-67 antigen showed no positive expression. The microvessel density (MVD) of the pituitary microadenomas ranged from 2.3 to 11.6% (mean: 5.3%) and was significantly lower than that of nonneoplastic pituitary glands (11.9-20.1%, mean: 14.8%). Our study provides reference data on incidental pituitary microadenomas in the Korean population.

Silencing of homeobox B9 is associated with down-regulation of CD56 and extrathyroidal extension of tumor in papillary thyroid carcinoma

Papillary thyroid carcinoma is the most common type of thyroid malignancy, and CD56, a neural cell adhesion molecule, is typically down-regulated in almost all cases of papillary thyroid carcinoma. Homeobox B9 is a transcription factor, belongs to the products of the homeobox transcription factor gene family, and has been known to regulate transcription of CD56 and to promote tumorigenicity and metastasis in some malignancies. In this study, we investigated the expression and relation of homeobox B9 to reduced expression of CD56 in papillary thyroid carcinomas and also a relationship between their expression and clinicopathologic parameters. Therefore, we performed CD56 and homeobox B9 immunohistochemical staining on 72 papillary thyroid carcinomas and Western blotting on 31 papillary thyroid carcinomas. CD56 protein staining revealed that it was reduced or absent in 65 papillary thyroid carcinomas (90.3%) and was related to silencing of homeobox B9 (77.8%) (P = .003). The loss of homeobox B9 expression was associated with extrathyroidal extension (P = .002), pathologic stage of tumor (P = .01), and age older than 45 years (P = .032). However, the CD56 staining did not reveal any significant relationship with clinicopathologic features (P > .05). In conclusion, reduced expression of CD56 is associated with homeobox B9 in papillary thyroid carcinomas. Furthermore, silencing of homeobox B9 is more common in older age and is linked to extrathyroidal extension and advanced pathologic stage of papillary thyroid carcinoma.

VE1 Antibody Is Not Highly Specific for the BRAF V600E Mutation in Thyroid Cytology Categories With the Exception of Malignant Cases

OBJECTIVES We evaluated the utility of the VE1 antibody that can detect a mutant protein resulting from the BRAF V600E mutation as a diagnostic tool for thyroid fine-needle aspiration cytology (FNAC). METHODS We performed VE1 immunocytochemistry on 202 FNAC specimens from surgically confirmed thyroid nodules. The results were compared with the molecular analyses of the BRAF mutation in these specimens matched with their corresponding histology. RESULTS Diagnoses of FNAC specimens included benign (9.4%), atypia of undetermined significance/follicular lesion of undetermined significance (11.4%), follicular neoplasm/suspicious for follicular neoplasm (2.0%), suspicious for malignancy (9.4%), and malignancy (65.8%). VE1 immunostaining was positive in 71.3% of FNAC specimens. The overall sensitivity of the VE1 antibody was 88.8%, specificity was 71.2%, positive predictive value was 88.2%, negative predictive value was 72.4%, and diagnostic accuracy was 83.7%. CONCLUSIONS VE1 immunocytochemistry in thyroid FNAC as a screening test for BRAF mutations is highly specific for malignant category cases but can be suboptimal due to its high false-positive rate for the nonmalignant cases.

TSH signaling overcomes B-RafV600E-induced senescence in papillary thyroid carcinogenesis through regulation of DUSP6.

B-RafV600E oncogene mutation occurs most commonly in papillary thyroid carcinoma (PTC) and is associated with tumor initiation. However, a genetic modification by B-RafV600E in thyrocytes results in oncogene-induced senescence (OIS). In the present study, we explored the factors involved in the senescence overcome program in PTC. First of all, we observed down-regulation of p-extracellular signal-regulated kinases 1/2 and up-regulation of dual specific phosphatase 6 (DUSP6) in the PTC with B-RafV600E mutation. DUSP6 overexpression in vitro induced extracellular signal-regulated kinases 1/2 dephosphorylation and inhibited B-RafV600E–induced senescence in thyrocytes. Although DUSP6 protein was degraded by B-RafV600E–induced reactive oxygen species (ROS), thyroid-stimulating hormone (TSH) stabilized DUSP6 protein by increasing Mn superoxide dismutase expression and inhibited B-RafV600E–induced senescence. Although serum TSH was not increased, its receptor was markedly upregulated in PTC with B-RafV600E. Furthermore, TSH together with DUSP6 reactivated Ras signaling, resulted in activation of Ras/AKT/glycogen synthase kinase 3β, and stabilized c-Myc protein by inhibiting its degradation. These observations led us to conclude that increased TSH signaling overcomes OIS and is essential for B-RafV600E–induced papillary thyroid carcinogenesis.

Integrative analysis of congenital muscular torticollis: from gene expression to clinical significance

BackgroundCongenital muscular torticollis (CMT) is characterized by thickening and/or tightness of the unilateral sternocleidomastoid muscle (SCM), ending up with torticollis. Our aim was to identify differentially expressed genes (DEGs) and novel protein interaction network modules of CMT, and to discover the relationship between gene expressions and clinical severity of CMT.ResultsTwenty-eight sternocleidomastoid muscles (SCMs) from 23 subjects with CMT and 5 SCMs without CMT were allocated for microarray, MRI, or imunohistochemical studies. We first identified 269 genes as the DEGs in CMT. Gene ontology enrichment analysis revealed that the main function of the DEGs is for extracellular region part during developmental processes. Five CMT-related protein network modules were identified, which showed that the important pathway is fibrosis related with collagen and elastin fibrillogenesis with an evidence of DNA repair mechanism. Interestingly, the expression levels of the 8 DEGs called CMT signature genes whose mRNA expression was double-confirmed by quantitative real time PCR showed good correlation with the severity of CMT which was measured with the pre-operational MRI images (R2 ranging from 0.82 to 0.21). Moreover, the protein expressions of ELN, ASPN and CHD3 which were identified from the CMT-related protein network modules demonstrated the differential expression between the CMT and normal SCM.ConclusionsWe here provided an integrative analysis of CMT from gene expression to clinical significance, which showed good correlation with clinical severity of CMT. Furthermore, the CMT-related protein network modules were identified, which provided more in-depth understanding of pathophysiology of CMT.

Relation Between F-18 FDG Uptake of PET/CT and BRAFV600E Mutation in Papillary Thyroid Cancer

AbstractBRAFV600E mutation and F-18 fluorodeoxyglucose (FDG) uptake are potential prognostic factors of papillary thyroid cancer (PTC). This study was performed to investigate the relationship between the BRAFV600E mutation and F-18 FDG uptake in PTC.We retrospectively included 169 PTC patients who underwent F-18 FDG positron emission tomography/computed tomography (PET/CT) before thyroidectomy from May 2009 to August 2012. Subjects were classified into overt PTC (>1 cm, n = 76) and papillary thyroid microcarcinoma (PTMC, n = 93) groups. Univariate and multivariate analyses were performed to assess the relationship between maximum standardized uptake value (SUVmax) of the primary tumors and clinicopathologic variables.The BRAFV600E mutation was detected in 82.2% (139/169). In all subjects, the BRAFV600E mutation and tumor size were independently related to SUVmax by multivariate analysis (P = 0.048 and P < 0.001, respectively). SUVmax was significantly higher in tumors with the BRAFV600E mutation than in those with wild-type BRAF (9.4 ± 10.9 vs 5.0 ± 4.1, P < 0.001). Similarly, in overt PTC group, the BRAFV600E mutation and tumor size were independently correlated with SUVmax (P = 0.032 and P = 0.001, respectively). By contrast, in PTMC group, only tumor size was significantly associated with SUVmax (P = 0.010).The presence of the BRAFV600E mutation is independently associated with high F-18 FDG uptake on preoperative PET/CT in patients with overt PTC, but this relationship was not evident in PTMC. This study provides a better understanding of the relationship between F-18 FDG uptake and BRAFV600E mutation in patients with PTC.

B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1

B-RafV600E mutant is found in 40–70% of papillary thyroid carcinoma (PTC) and has an important role in the pathogenesis of PTC. The sodium iodide symporter (NIS) is an integral plasma membrane glycoprotein that mediates active iodide transport into the thyroid follicular cells, and B-RafV600E has been known to be associated with the loss of NIS expression. In this study, we found that B-RafV600E inhibited NIS expression by the upregulation of its promoter methylation, and that specific regions of CpG islands of NIS promoter in B-RafV600E harboring PTC were highly methylated compared with surrounding normal tissue. Although DNA methyltransferase 3a and 3b (DNMT3a,3b) were not increased by B-RafV600E, DNMT1 expression was markedly upregulated in PTC and B-RafV600E expressing thyrocytes. Furthermore, DNMT1 expression was upregulated by B-RafV600E induced NF-κB activation. These results led us to conclude that NIS promoter methylation, which was induced by B-RafV600E, is one of the possible mechanisms involved in NIS downregulation in PTC.