Hyoun Wook Lee

The diagnostic utility of the GNAS mutation in patients with fibrous dysplasia: meta-analysis of 168 sporadic cases

GNAS mutations have been implicated in the development of fibrous dysplasia and multiple endocrinopathies of the Albright-McCune syndrome. To investigate the diagnostic utility of GNAS mutations in patients with fibrous dysplasia, we performed mutational analyses of histologically confirmed fibrous dysplasia and conducted a meta-analysis of the literature. We collected 48 cases of fibrous dysplasia from 3 institutions from 2002 to 2011 and performed polymerase chain reaction and direct bidirectional sequencing of exons 8 and 9 of GNAS using paraffin-embedded tissues. We searched MEDLINE, PubMed, and the KoreaMed databases from 1997 to 2011 and included an additional 155 cases of fibrous dysplasia from 8 representative studies to conduct a meta-analysis. In our sample, 28 (58.3%) of 48 cases showed point mutations of codon 201 at exon 8. Twenty-five cases had a substitution of arginine at codon 201 for histidine (p.R201H), and 3 cases had a substitution for cysteine (p.R201C). One case had a new mutation at codon 224 (p.V224A). The incidence of GNAS mutations was significantly greater in cases that involved long bones than in cases that involved flat bones (P = .017) and was higher in polyostotic cases than in monostotic cases (P = .067). In meta-analysis, 9 studies and 203 patients were included. The overall positive rate of GNAS mutation in fibrous dysplasia was 71.9% (146/203). The major types of mutations were missense mutations such as R201H (66.4%) and R201C (30.8%). As a result, the detection of GNAS mutation could be a valuable adjunct to conventional histopathologic diagnosis of fibrous dysplasia.

Altered expression of microRNA miR‐21, miR‐155, and let‐7a and their roles in pulmonary neuroendocrine tumors

MicroRNA (miRNA) has a critical effect on tumorigenesis through post‐transcriptional modification and is considered to be potential biomarkers for cancer diagnosis and treatment monitoring. We evaluated the expression pattern of three selected miRNAs (miR‐21, miR‐155, and let‐7a) to evaluate their potential roles by quantitative reverse transcription‐polymerase chain reaction using formalin‐fixed and paraffin‐embedded tissues of 63 surgically resected pulmonary neuroendocrine (NE) tumors (19 typical carcinoids (TCs), 6 atypical carcinoids (ACs), 19 large cell NE carcinomas (LCNECs), and 19 small cell lung carcinomas (SCLCs). Control amplification for U6 small nuclear RNA (U6) was performed in all samples. Normalized Ct values were calculated (CtExperimental miRNA‐CtU6) for each case and recorded. The expression levels of miR‐21 and miR‐155 were significantly higher in high‐grade NE carcinomas (LCNECs and SCLCs) than in carcinoid tumors (TCs and ACs) (each P < 0.001). The expression level of miR‐21 in carcinoid tumors with lymph node metastasis was significantly higher than in carcinoid tumors without lymph node metastasis (P= 0.010). To the best of our knowledge, the present study is the first to examine the expression patterns of miR‐21 and miR‐155 as an adjunctive diagnostic tool or clinically relevant biomarkers for pulmonary NE tumors.

Clinical significance of the preoperative platelet count and platelet-to-lymphocyte ratio (PLT-PLR) in patients with surgically resected non-small cell lung cancer

Background The aim of this study was to assess the prognostic significance of the preoperative platelet count (PLT) and platelet-to-lymphocyte ratio (PLR) in patients with surgically resected non-small-cell lung cancer (NSCLC). Patients and Methods We retrospectively reviewed 202 patients treated for NSCLC between January 2002 and December 2007. Preoperative PLT and PLR scores were calculated using data obtained at the time of admission. Patients were assigned a PLT-PLR score of 0, 1, or 2 based upon the presence of thrombocytosis, an elevated PLR, or both. Results Patients with a PLT-PLR score of 2 had a significantly lower median overall survival (OS) [12.715 mo; 95% confidence interval (CI) 1.215-24.215] when compared with patients with PLT-PLR scores of 1 (52.238 mo; 95% CI 17.062-87.414, p = 0.002) or 0 (not reached, p < 0.001). Relapse-free survival (RFS) was also significantly decreased in patients with a PLT-PLR score of 2 (10.107 mo; 95% CI 3.388-16.826) relative to patients with a PLT-PLR score of 1 (27.214 mo; 95% CI 0-56.253, p = 0.002) or 0 (58.893 mo; 95% CI 32.938-84.848, p < 0.001). In multivariate analysis, a PLT-PLR score of 2 was an independent prognostic factor for poor OS (hazard ratio (HR) 3.473; 95% CI 1.765-6.835, p < 0.001) and RFS (HR 2.286; 95% CI 1.243-4.206, p = 0.008) compared with a PLT-PLR score of 0. Conclusions Preoperative PLT-PLR scores can be useful for predicting disease prognosis in patients with surgically resected NSCLC. Further large prospective studies will be necessary to validate our findings.

Altered Expression of PTEN and Its Major Regulator MicroRNA-21 in Pulmonary Neuroendocrine Tumors

Background Phosphatase and tensin homolog on chromosome ten (PTEN) is one of the most frequently inactivated tumor suppressors in various tumor types. MicroRNA-21 (miR-21) may affect tumor progression by post-transcriptional repression of expression of tumor suppressors, such as PTEN. This study was conducted to evaluate the significance of PTEN expression in pulmonary neuroendocrine (NE) tumors and to analyze the relationship between PTEN and miR-21 expressions. Methods Expressions of PTEN and miR-21 were investigated by immunohistochemistry and real time reverse transcription-polymerase chain reaction, respectively, in 75 resected pulmonary NE tumors (23 typical carcinoids [TCs], nine atypical carcinoids [ACs], 22 large cell NE carcinomas [LCNECs], and 21 small cell lung carcinomas [SCLCs]). Results Loss of PTEN expression was observed in four of 23 TCs (17.4%), four of nine ACs (44.4%), 16 of 22 LCNECs (72.7%) and nine of 21 SCLCs (42.9%) (p=.025). The expression level of miR-21 was significantly higher in high-grade NE carcinomas than in carcinoid tumors (p<.001). PTEN expression was inversely correlated with miR-21 expression (p<.001). Conclusions This study suggests that aberrant expression of PTEN in relation to miR-21 may represent an important step in the development and progression of pulmonary NE tumors.

Diagnostic Utility of Caveolin-1 and MOC-31 in Distinguishing Chromophobe Renal Cell Carcinoma from Renal Oncocytoma

Purpose Renal tumors consist of heterogeneous groups that frequently show complex and overlapping morphology, thus making it difficult to make a correct diagnosis. One of the most problematic differential diagnoses is to distinguish chromophobe renal cell carcinoma (RCC) from oncocytoma. These should be distinguished by differences in their behavior and clinical outcome. Our study was performed to identify whether caveolin-1 and MOC-31 are useful immunohistochemical markers for differentiating chromophobe RCC from oncocytoma. Materials and Methods We selected 23 chromophobe RCCs, 8 oncocytomas, and 25 clear cell RCCs and performed immunohistochemical staining for caveolin-1 and MOC-31. Results Caveolin-1 was positive in 20 (87%) of 23 chromophobe RCCs, 0 of 8 oncocytomas, and 21 (84%) of 25 clear cell RCCs. MOC-31 was positive in 22 (96%) of 23 chromophobe RCCs, 2 (25%) of 8 oncocytomas, and 14 (56%) of 25 clear cell RCCs. There was a statistically significant difference in the expression of caveolin-1 and MOC-31 between chromophobe RCC and oncocytoma (p<0.001). In addition, clear cell RCC was also significantly different from oncocytoma in the expression of caveolin-1 (p<0.001) and was significantly different from chromophobe RCC in the expression of MOC-31 (p<0.001). Conclusions Caveolin-1 and MOC-31 can be useful markers in the differential diagnosis of chromophobe RCC, oncocytoma, and clear cell RCC.

A Case of Perimenopausal Endometrial Cancer in a Woman with MSH2 Germline Mutation

Lynch syndrome is a genetic malignancy syndrome affecting the colon, endometrium, and other organs. It is difficult to find a Lynch syndrome patient without any family history of cancer. We have recently examined an endometrial cancer patient with a MSH2 gene mutation without a family history of cancer. A 55-year old Korean woman was admitted to a local clinic for vaginal bleeding. An endometrial biopsy revealed the presence of adenocarcinoma (endometrioid type, grade 1). After surgical staging, no further adjuvant therapy was required. Analysis of the tissue using immunohistochemistry (IHC) showed the endometrium stained negatively for MSH2. Microsatellite instability (MSI) was analyzed for five markers. The patient was scored as unstable. Further, additional gene sequencing revealed one missense mutation in c.23C > T (p.Thr8Met). This is the first case of Lynch syndrome endometrial cancer in Korea in which the patient does not have any family history of cancer.

Distal urethral polypropylene sling surgical management for urodynamic stress incontinence in Korean women.

Introduction: The purpose of the present study was to assess the objective and subjective efficacy of the distal urethral polypropylene sling (DUPS) for urodynamic stress incontinence (USI) in Korean women. Patients and Methods: We performed DUPS in 89 consecutive patients with USI. The Incontinence Impact Questionnaire (IIQ-7) and the Urogenital Distress Inventory (UDI-6) were used to evaluate the surgical outcomes. Results: The mean operative time was 29.4 min (range 25–40). Concomitant procedures were performed including rectocele repair (n = 48), laparoscopically assisted vaginal hysterectomy (n = 12) and laparoscopic myomectomy (n = 1). There were no intraoperative complications or major postoperative complications. The average follow-up was 15 months (range 12–18). Both mean IIQ-7 and UDI-6 scores decreased significantly after DUPS. In addition, 87% of the patients reported no symptoms of USI under any circumstances and 95% of the patients reported never or rarely being bothered by USI. Conclusions: DUPS is a safe, inexpensive, simple, and effective surgical method for USI. The procedure provides a high cure rate in Korean women.

Sodium/iodide symporter expression in primary lung cancer and comparison with glucose transporter 1 expression.

The aim of the present study was to evaluate the expression of sodium/iodide symporter (NIS) and glucose transporter 1 (Glut1) in 139 primary lung cancers on immunohistochemistry, and to determine the diagnostic utility of NIS as an imaging reporter. Immunoreactivity for NIS and Glut1 was noted in 75 (54.0%) and 72 (51.8%) of the 139 cases, respectively. Analysis of NIS expression on Western blot confirmed the immunohistochemistry. NIS expression was significantly higher in the adenocarcinomas than in the other carcinomas, and Glut1 expression was significantly higher in the squamous cell carcinomas than in the other carcinomas (each P < 0.0001). The frequency of NIS expression in those carcinomas lacking Glut1 expression was significantly higher than in those with Glut1 expression (P = 0.012). Among 64 adenocarcinomas, the frequency of the NIS(+)/Glut1(−) phenotype was 61.0%, which was the most frequent expression pattern. By studying the expression pattern of NIS in lung cancer, the present paper provides a helpful foundation for examining the potential utility of NIS‐mediated radioiodide as an alternative diagnostic modality, especially for the management of patients with lung adenocarcinoma lacking Glut1 expression.

Silencing of translation initiation factor eIF3b promotes apoptosis in osteosarcoma cells

Objectives Eukaryotic translation initiation factor 3 (eIF3) is a multi-subunit complex that plays a critical role in translation initiation. Expression levels of eIF3 subunits are elevated or decreased in various cancers, suggesting a role for eIF3 in tumorigenesis. Recent studies have shown that the expression of the eIF3b subunit is elevated in bladder and prostate cancer, and eIF3b silencing inhibited glioblastoma growth and induced cellular apoptosis. In this study, we investigated the role of eIF3b in the survival of osteosarcoma cells. Methods To investigate the effect of eIF3b on cell viability and apoptosis in osteosarcoma cells, we first examined the silencing effect of eIF3b in U2OS cells. Cell viability and apoptosis were examined by the Cell Counting Kit-8 (CCK-8) assay and Western blot, respectively. We also performed gene profiling to identify genes affected by eIF3b silencing. Finally, the effect of eIF3b on cell viability and apoptosis was confirmed in multiple osteosarcoma cell lines. Results eIF3b silencing decreased cell viability and induced apoptosis in U2OS cells, and by using gene profiling we discovered that eIF3b silencing also resulted in the upregulation of tumour necrosis factor receptor superfamily member 21 (TNFRSF21). We found that TNFRSF21 overexpression induced cell death in U2OS cells, and we confirmed that eIF3b silencing completely suppressed cell growth in multiple osteosarcoma cell lines. However, eIF3b silencing failed to suppress cell growth completely in normal fibroblast cells. Conclusion Our data led us to conclude that eIF3b may be required for osteosarcoma cell proliferation by regulating TNFRSF21 expression. Cite this article: Y. J. Choi, Y. S. Lee, H. W. Lee, D. M. Shim, S. W. Seo. Silencing of translation initiation factor eIF3b promotes apoptosis in osteosarcoma cells. Bone Joint Res 2017;6:186–193. DOI: 10.1302/2046-3758.63.BJR-2016-0151.R2.

Frequency of BRAF Mutation and Clinical Relevance for Primary Melanomas

Background This study was conducted to clarify the frequency of the BRAF mutation in primary melanomas and its correlation with clinicopathologic parameters. Methods We analyzed the frequency of BRAF mutation in patients with primary cutaneous melanoma (n=58) or non-cutaneous one (n=27) by performing dual priming oligonucleotide-based multiplex real-time polymerase chain reaction to isolate and to purify the DNA from the formalin-fixed and paraffin-embedded tumors. Results The BRAF mutation was found in 17.2% (10/58) of patients with primary cutaneous melanoma and 11.1% (3/27) of those with non-cutaneous melanoma. The frequency of BRAF mutation was not correlated with any clinicopathologic parameters with the exception of the patient age. The frequency of the BRAF mutation was significantly higher in patients younger than 60 years as compared with those older than 60 years (p=0.005). Conclusions Compared with previous reports, our results showed that the frequency of the BRAF mutation was relatively lower in patients with primary cutaneous melanoma. Besides, our results also showed that the frequency of the BRAF mutation had an inverse correlation with the age. Further studies are warranted to exclude methodological bias, to elucidate the difference in the frequency of the BRAF mutation from the previous reports from a Caucasian population and to provide an improved understanding of the molecular pathogenesis of malignant melanoma.