Young Soo Song

Locally Delivered Growth Factor Enhances the Angiogenic Efficacy of Adipose‐Derived Stromal Cells Transplanted to Ischemic Limbs

Ischemia is a potentially fatal medical event that is associated with as many as 30% of all deaths. Stem cell therapy offers significant therapeutic promise, but poor survival following transplantation to ischemic tissue limits its efficacy. Here we demonstrate that nanosphere‐mediated growth factor delivery can enhance the survival of transplanted human adipose‐derived stromal cells (hADSCs) and secretion of human angiogenic growth factors per cell, and substantially improve therapeutic efficacy of hADSCs. In vitro, in hypoxic (1% oxygen) and serum‐deprived conditions that simulate in vivo ischemia, fibroblast growth factor‐2 (FGF2) significantly reduced hADSC apoptosis and enhanced angiogenic growth factor secretion. In vivo, hADSCs delivered intramuscularly into ischemic hind limbs in combination with FGF2 resulted in significant improvements in limb survival and blood perfusion, as well as survival of the transplanted hADSCs and secretion of human angiogenic growth factors (i.e., vascular endothelial growth factor, hepatocyte growth factor, and FGF2). Interestingly, the majority of transplanted hADSCs were localized adjacent to the microvessels rather than being incorporated into them, suggesting that their major contribution to angiogenesis might be to increase paracrine secretion of angiogenic growth factors. This study demonstrates the potential of hADSCs in combination with growth factors for use in the treatment of ischemia. STEM CELLS 2009;27:1976–1986

Clinicopathological significance of nuclear PTEN expression in colorectal adenocarcinoma.

Jang K‐S, Song Y S, Jang S‐H, Min K‐W, Na W, Jang S M, Jun Y J, Lee K H, Choi D & Paik S S
(2010) Histopathology56, 229–239

Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation and metastasis in gastric cancer.

Choi JH, Song YS, Yoon JS, Song KW, Lee YY. Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation and metastasis in gastric cancer. APMIS 2010; 118: 196–202.

Reduced expression of Apaf-1 in colorectal adenocarcinoma correlates with tumor progression and aggressive phenotype.

BackgroundApoptotic protease activating factor-1 (Apaf-1) is one of the key regulators in the mitochondrial apoptotic pathway, and the loss of Apaf-1 leads to cellular resistance against the apoptotic signals. We investigated the expression of Apaf-1 in colorectal tissues corresponding to the multistep carcinogenesis model to determine correlations between the clinicopathologic characteristics and the expression of this molecule and to evaluate the role of Apaf-1 in the development and progression of colorectal adenocarcinoma.MethodsImmunohistochemistry for Apaf-1 was performed on the tissue microarray of 38 normal mucosal tissues, 46 adenomatous polyps, 529 colorectal adenocarcinomas, and 76 metastatic tumors.ResultsNormal colonic mucosa tissues and adenomas were positive for Apaf-1 with no exceptions (100%). However, in colorectal adenocarcinomas, 119 of 529 cases (22.5%) were positive and 410 cases (77.5%) were negative. Moreover, 67 of 76 metastatic cases (88.2 %) were negative and only nine cases (11.8%) were positive for Apaf-1 expression. In the analyses between Apaf-1 expression and clinicopathologic parameters, reduced expression of Apaf-1 correlated with left colon location (p < 0.001), deeper tumor invasion (p < 0.001), frequent lymph node metastasis ( p= 0.021), higher American Joint Committee on Cancer (AJCC) and Dukes’ stage (p = 0.02 and p = 0.001, respectively) and poorer differentiation (p < 0.001). The patient survival was significantly associated with age, histological grade, AJCC stage, and lymphovascular invasion, but not Apaf-1 expression (p = 0.478).ConclusionsThe results suggest that the loss of Apaf-1 expression is a relatively frequent late event and the loss of Apaf-1 expression may play an important role in tumorigenesis and tumor progression in colorectal adenocarcinoma.

Infantile hemangioendothelioma with elevated serum α fetoprotein: report of 2 cases with immunohistochemical analysis

Infantile hemangioendothelioma is the most common benign mesenchymal tumor of the liver presenting during the first 6 months of life. Serum alpha fetoprotein is an important tumor marker for hepatoblastoma, hepatocellular carcinoma, and germ cell tumors. However, it is rarely elevated in patients with hepatic infantile hemangioendothelioma. In such cases, surgery may be done to rule out malignancies when alpha fetoprotein levels are high. The etiology of the elevated alpha fetoprotein level has not yet been elucidated. We report 2 cases of solitary hepatic infantile hemangioendothelioma and demonstrate immunohistochemically that hepatocytes near or entrapped within the tumor were the source of the increased serum levels of alpha fetoprotein explaining the unusual clinical presentation.

Significance of the Extracapsular Spread of Metastatic Lymph Nodes in Papillary Thyroid Carcinoma

Objectives The extracapsular spread (ECS) of metastatic lymph nodes is associated with aggressive tumor behavior, and is regarded as a major risk factor for local recurrence in patients with head and neck squamous cell carcinoma. However, the significance of ECS of metastatic lymph nodes has not been well established in well-differentiated thyroid carcinoma. The purpose of this study was to examine this question. Methods A retrospective review was performed of 335 patients with papillary thyroid carcinoma who underwent total thyroidectomy with lymph node dissection from April 2001 to December 2009. We analyzed various clinical characteristics, pathologic factors, and the size, number, and ECS of foci in metastatic lymph nodes. Results On pathologic review, 201 of the patients (56.6%) had lymph node metastasis. This was significantly related to age and tumor size. ECS was noted in 64 of these 201 patients (31.8%), and was significantly related to male gender, tumor size, presence of extrathyroidal extension, metastatic lymph node size, and focus size. Recurrence occurred in 13 patients (3.9%), and the presence of ECS was significantly related to recurrence. Conclusion ECS of metastatic lymph nodes is an important prognostic factor for loco-regional recurrence in papillary thyroid carcinoma.

Differential Diagnosis of Lupus and Primary Membranous Nephropathies by IgG Subclass Analysis

BACKGROUND AND OBJECTIVES Previous studies showed that the accuracy of IgG subclasses (ISs) in differentiating membranous lupus nephritis (MLN) from primary membranous nephropathy (PMN) is <80%. This study hypothesized that diagnostic accuracy of ISs would be increased if renal compartment measurements and decision tree analysis are applied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Renal biopsy specimens from 41 patients with MLN and 59 patients with PMN between October 2004 and March 2010 were examined, and immunofluorescence staining against IgG1, IgG2, IgG3, and IgG4 as well as C3, C1q, and C4 was evaluated in five different renal compartments (glomerular capillary walls, mesangium, tubules, interstitium, and blood vessels). From IS data, a decision tree to differentiate MLN from PMN was produced (IS decision tree) and its accuracy was compared with that of previous studies. Diagnostic accuracy of the IS decision tree was also compared with that of the complement decision tree as a reference. RESULTS The demographic information and patterns of IS deposition were similar to those of previous studies. The IS decision tree had, as decision markers, IgG1 in the mesangium and IgG2 and IgG4 along the glomerular capillary wall. The IS decision tree showed higher accuracy (88%) than that of previous studies (<80%) and also that of the complement decision tree (81%). CONCLUSIONS Accuracy of ISs was increased due to the study methods, but the same methodology was less effective using complement measurements. Appropriate data analysis may enhance diagnostic value, but the analysis alone cannot achieve the ideal diagnostic value.

MicroRNA Expression Signatures Associated With BRAF-Mutated Versus KRAS-Mutated Colorectal Cancers

AbstractBRAF and KRAS genes are known to play a similar role in the activation of RAS-RAF-MEK-ERK signaling pathway in colorectal tumorigenesis. However, BRAF-mutated colorectal cancers (CRCs) have distinct clinicopathologic characteristics different from those of the KRAS mutated ones as in comparison the BRAF-mutated CRCs are associated with a much worse prognosis for the afflicted patients. This study aimed to determine the different miRNA expression signatures associated with BRAF-mutated CRCs in comparison to KRAS-mutated ones, and to identify the specific miRNAs possibly mediating the aggressive phenotype of the BRAF-mutated CRCs.We screened 535 formalin-fixed paraffin-embedded CRC tissue samples for the BRAF V600E mutation, and selected 7 BRAF-mutated and 7 KRAS-mutated CRCs that were tumor size, stage, and microsatellite status-matched. Affymetrix GeneChip® miRNA 4.0 Array was used for detection of miRNA expression differences in the selected samples. We validated the array results by quantitative reverse transcription polymerase chain reaction (qRT-PCR) for selected miRNAs.A total of 10 differentially expressed (DE) miRNAs associated with BRAF-mutated CRCs were obtained, including miR-31-5p, miR-877-5p, miR-362-5p, and miR-425-3p. miR-31-5p showed the highest fold change (8.3-fold) among all of the miRNAs analyzed. From the analyses of GO biological processes, the DE-miRNAs were functionally relevant to cellular proliferation such as positive regulation of gene expression (P = 1.26 × 10−10), transcription (P = 9.70 × 10−10), and RNA metabolic process (P = 1.97 × 10−9). Bioinformatics analysis showed that the DE-miRNAs were significantly enriched in cancer-associated pathways including neutrophin signaling (P = 6.84 × 10−5), pathways in cancer (P = 0.0016), Wnt signaling (P = 0.0027), and MAPK signaling pathway (P = 0.0036).Our results suggest that the DE-miRNAs in BRAF-mutated CRCs in comparison to KRAS-mutated CRCs are implicated in the aggressive phenotype of the BRAF-mutated CRCs. Further experimental validation is required to confirm these results.

High MicroRNA-370 Expression Correlates with Tumor Progression and Poor Prognosis in Breast Cancer

Purpose Deregulation of microRNA-370 (miR-370) has been reported in various cancers, in which it can act as either an oncogene or a tumor suppressor gene. However, the clinicopathologic significance of miR-370 expression in breast cancer has not been studied. Methods The expression of miR-370 was determined with quantitative real-time polymerase chain reaction in 60 formalin-fixed, paraffin-embedded primary breast cancer tissues. Additionally, the protein expression levels of previously known targets of miR-370, such as FOXM1, FOXO1, and FOXO3a, were detected using immunohistochemistry. Finally, we analyzed its correlation with target protein expression, clinicopathologic features, and clinical outcome. Results High levels of miR-370 expression correlated with lymph node metastasis (p=0.009), advanced stage (p=0.002), and frequent perineural invasion (p=0.042). Moreover, patients with high miR-370 expression had poor disease-free survival compared with the low-expression group. However, no correlation was observed between miR-370 and its target protein expression. Conclusion Our results indicate that upregulation of miR-370 in breast cancer is correlated with breast cancer progression and that it might be a potential biomarker for predicting clinical outcomes.

An unusual case of bronchogenic cyst mimicking thyroid cystic tumor.

Bronchogenic cysts are rare congenital anomalies of the ventral foregut and are related to abnormal budding of the tracheobronchial tree during embryological development. The majority of these occur in the mediastinum or within the pulmonary parenchyma and rarely in the neck. Those existing in the cervical region, especially in the thyroid or perithyroid area, are quite rare. To the best of our knowledge, there are only few other cases cited in the English-language literature. We herein describe a rare case of bronchogenic cyst that mimicks a thyroid tumor. A 40-year-old woman was admitted to our hospital for further evaluation of thyroid mass incidentally diagnosed at a local clinic. She had a history of dysphagia for three months. Results of routine laboratory tests including complete blood cell count, electrolytes, and urine analysis were within normal limits. There was no evidence of endocrine or metabolic abnormalities. A simple chest x-ray showed an increased soft tissue density in the left upper paratracheal area. A cervical computed tomogram (CT) showed a homogeneous cystic mass that measured 5 4 cm in cross diameters in the lower pole of the left thyroid gland (Fig 1). The left thyroid gland and trachea were deviated to the right side. Cervical lymph nodes were not enlarged. A preoperative fine needle aspiration cytology was performed, but the cytology was not diagnostic. The exact nature of the mass was questionable, and because a tumor in the left thyroid gland could not be ruled out, thyroid resection was scheduled. The patient underwent surgical exploration of the neck. The cystic mass showed fibrous adhesion to the lower pole of the left thyroid gland. A resection of the left lobe of the thyroid gland with the cystic mass was performed. Grossly, the mass presented a tan, smooth, and glistening outer surface, and the unilocular cyst contained thick brownish mucoid material. Microscopically, the cyst revealed only a lining of pseudostratified ciliated columnar epithelium. The stratified squamous epithelium was not noted. The cyst wall showed fibrous connective