Younghye Kim

The association between papillary thyroid carcinoma and histologically proven Hashimoto's thyroiditis: a meta-analysis.

OBJECTIVE No consensus exists on the association between papillary thyroid carcinoma (PTC) and Hashimotos thyroiditis (HT). To resolve this controversy, this study aimed to evaluate the relationship between the two conditions using a meta-analysis. METHODS We searched relevant published studies using citation databases including PubMed, Embase, and ISI Web of Science. The effect sizes of clinicopathologic parameters were calculated by odds ratio (OR), weighted mean difference, or hazard ratio (HR). The effect sizes were combined using a random-effects model. RESULTS Thirty-eight eligible studies including 10 648 PTC cases were selected. Histologically proven HT was identified in 2471 (23.2%) PTCs. HT was more frequently observed in PTCs than in benign thyroid diseases and other carcinomas (OR=2.8 and 2.4; P<0.001). PTCs with coexisting HT were significantly related to female patients (OR=2.7; P<0.001), multifocal involvement (OR=1.5; P=0.010), no extrathyroidal extension (OR=1.3; P=0.002), and no lymph node metastasis (OR=1.3; P=0.041). Moreover, PTCs with HT were significantly associated with long recurrence-free survival (HR=0.6; P=0.001). CONCLUSIONS Our meta-analysis showed that PTC is significantly associated with pathologically confirmed HT. PTC patients with HT have favorable clinicopathologic characteristics compared with PTCs without HT. However, patients with HT need to be carefully monitored for the development of PTC.

MYD88 expression and L265P mutation in diffuse large B-cell lymphoma

Activated B-cell-like subtype of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic active B-cell receptor signaling and a constitutive activation of the nuclear factor κB pathway. As a driving force of nuclear factor κB overactivity, myeloid differentiation primary response gene 88 (MYD88) L265P mutation occurs in activated B-cell-like DLBCL. However, the MYD88 L265P mutation has not yet been studied in conjunction with MYD88 protein expression in DLBCL cases. Thus, we investigated MYD88 expression in 124 DLBCL specimens by immunohistochemistry. In addition, the MYD88 L265P mutation was examined by polymerase chain reaction and direct DNA sequencing. MYD88 was overexpressed in 38.7% (48/124) of DLBCL cases. MYD88 was expressed in the cytoplasm of lymphoma cells. MYD88 overexpression was associated with older age (P = .016) and tumor recurrence (P = .007). In univariate analysis, MYD88 overexpression was correlated with shortened disease-free survival (DFS) of DLBCL (P = .013) and non-germinal center B-cell-like DLBCL (P = .034). In multivariate analysis, MYD88 overexpression was an independent factor for reduced DFS (P = .025). MYD88 L265P mutation was found in 6.5% (8/124) of DLBCL cases. All but 1 case were of non-germinal center B-cell-like subtype. The MYD88 L265P mutation was not associated with MYD88 expression (Spearman ρ = -0.074) and clinicopathologic parameters of DLBCL. The data indicate that high MYD88 expression is significantly associated with tumor recurrence and shortened DFS in patients with DLBCL. In addition, the incidence of MYD88 L265P mutation in Korea is much lower than previously reported. Thus, MYD88 may be crucial for lymphoma progression, independent of MYD88 L265P mutation.

Expression of lactate/H+ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses

Clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau protein, leading to the accumulation of hypoxia-inducible factor-α (HIF-α). HIF-1α induces aerobic glycolysis, the Warburg effect, whereas HIF-2α functions as an oncoprotein. Lactate transport through monocarboxylate transporters (MCTs) and the chaperone CD147 is essential for high glycolytic cancer cell survival. To elucidate the clinical significance of MCT1, MCT4, and CD147 expression, we investigated their expressions by immunohistochemistry in ccRCC specimens and validated the results by an open-access The Cancer Genome Atlas data analysis. Overexpression of MCT1, MCT4, and CD147 was observed in 49.4% (89/180), 39.4% (71/180), and 79.4% (143/180) of ccRCC patients, respectively. High MCT1 expression was associated with older age (P = .017), larger tumor size (P = .015), and advanced TNM stage (P = .012). However, MCT4 overexpression was not related to any variables. CD147 overexpression correlated with high grade (P = .005), tumor necrosis (P = .016), and larger tumor size (P = .038). In univariate analysis, high expression of MCT1 (P < .001), MCT4 (P = .016), and CD147 (P = .02) was linked to short progression-free survival. In multivariate analysis, high MCT1 expression was associated with worse progression-free survival (P = .001). In conclusion, high expression of MCT1 and CD147 is associated with poor prognostic factors. Overexpression of MCT1, MCT4, and CD147 predicts tumor progression. Reversing the Warburg effect by targeting the lactate transporters may be a useful strategy to prevent ccRCC progression.

Prevalence and Prognostic Significance of Epstein–Barr Virus Infection in Classical Hodgkin's Lymphoma: A Meta-analysis

BACKGROUND AND AIMS The prevalence and prognostic significance of Epstein-Barr virus (EBV) infection in classical Hodgkins lymphomas (cHLs) remain elusive. To examine the epidemiological and prognostic differences between EBV-positive and -negative cHLs, we conducted a meta-analysis of 119 published studies including 13,045 cases. METHODS We pooled the results of relevant published studies identified using the PubMed and Embase. The effect sizes of outcome parameters were calculated by prevalence, odds ratio (OR), or hazard ratio using a random-effects model. RESULTS The pooled prevalence of EBV infection in cHL was 47.9%, which was significantly higher in Africa and Central and South America than other regions. EBV-positive cHL showed higher incidence in children than in adults (69.7 vs. 41.1%). EBV-positive cHL was significantly related to male (OR = 1.8, 95% CI: 1.510-2.038; p <0.001), mixed cellularity subtype (OR = 3.8, 95% CI: 3.243-4.451; p <0.001), and advanced clinical stages (OR = 1.2, 95% CI: 1.072-1.369; p = 0.002). However, the presence of EBV in cHL was not associated with overall or event-free survival. CONCLUSIONS The prevalence of EBV differs according to age, sex, region, histologic subtype, and clinical stage of cHL. However, the presence of EBV has little effects on cHL patients survival.

Prognostic significance of lactate/proton symporters mct1, mct4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder

OBJECTIVE To investigate the prognostic significance of lactate/proton monocarboxylate transporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder (UCB). METHODS We examined the expressions of MCT1, MCT4, and CD147 proteins in a total of 360 cases of UCB by immunohistochemistry. The immunohistochemical expressions were quantified using an ImageJ-based analysis program. RESULTS MCT1, MCT4, and CD147 expressions were increased in 130 (36.1%), 168 (46.7%), and 228 (63.3%) UCB cases, respectively. Most tumor cells showed diffuse membranous staining, whereas normal urothelial cells showed negative or weak staining. High levels of MCT1 expression correlated with high World Health Organization grade (P<.001), advanced tumor node metastasis (TNM) stage (P<.001), nonpapillary growth type (P<.001), and lymphatic tumor invasion (P=.010), whereas high levels of MCT4 expression did not significantly correlate with any of these variables. High CD147 expression was associated with high World Health Organization grade (P<.001), advanced tumor node metastatis stage (P<.001), and nonpapillary growth type (P=.003). Univariate analyses revealed that high MCT1 (P<.001) and CD147 (P=.029) expressions were associated with poor overall survival and that high MCT4 expression was correlated with poor recurrence-free survival (P=.036). Multivariate analyses revealed that high MCT1 and MCT4 expressions were independent prognostic factors for poor overall survival and poor recurrence-free survival, respectively, in UCB patients. CONCLUSION Our results indicate that increased MCT1, MCT4, and CD147 expressions have prognostic implications in UCB and suggest their roles in urothelial cancer metabolism.

Stability of DNA, RNA, cytomorphology, and immunoantigenicity in Residual ThinPrep® Specimens

The aim of this study was to evaluate the quality of residual liquid‐based preparation (LBP) sample after cytopathologic diagnosis. Cervical swab, body fluid, and thyroid fine‐needle aspiration (FNA) samples preserved in ThinPrep PreservCyt® solution were tested. Samples kept frozen at −80 °C and stored at room temperature were tested 12 months after the initial sample collection. Gel electrophotography of GAPDH multiplex PCR, RNA integrity number (RIN) values obtained from Agilent bioanalyzer, cytomorphologic changes, and immunohistochemical staining (cytokeratin, thyroid transcription factor‐1 (TTF‐1), and D2‐40) were used for the evaluation of sample quality. All available samples showed successful amplification products in multiplex PCR. However, RNAs in all residual samples were degraded with low RIN values (RIN < 4). RIN values decreased rapidly when samples were stored at room temperature in LBP medium. Cytomorpholoic evaluation and immunohistochemical staining results revealed no change regardless of storage time or storage temperature. In conclusion, RNAs stored in LBP medium degraded quickly at room temperature. Residual alcohol‐based LBP cytologic specimens stored at −80 °C and room temperature showed no change in DNA quality, cytomorphology, and immunoreactivity during at least one year of storage.

CD74 expression is increased in high-grade, invasive urothelial carcinoma of the bladder

This study aimed to identify the clinicopathological features of bladder cancer patients with high CD74 expression, as milatuzumab humanized anti‐CD74 antibody is being evaluated in clinical trials for hematological malignancies. Expression of CD74 was examined in 342 urothelial carcinomas of the bladder, and two urothelial carcinoma cell lines by immunohistochemistry and western blotting, respectively. CD74 was overexpressed in 192 (56.1%) of the 342 cancer tissues, although it was not expressed in the cancer cell lines. CD74 staining was intense in tumor cells and inflammatory cells in the tumor stroma, but not in normal urothelium. CD74 expression was significantly associated with older age at diagnosis (≥68 years, P = 0.048), high World Health Organization grade (P = 0.019), advanced stages (P = 0.001) and non‐papillary growth pattern (P = 0.040). CD74 expression was also correlated with the absence of tumor‐infiltrating inflammatory cells (P < 0.001) and the presence of tumor‐associated inflammatory cells (P = 0.017). However, CD74 expression was not related to recurrence‐free and overall survivals in primary and subgroup analyses. In conclusion, urothelial bladder carcinomas with high CD74 expression are characterized by older age, high World Health Organization grade, non‐papillary growth and advanced stages.

MAD2 and CDC20 are upregulated in high-grade squamous intraepithelial lesions and squamous cell carcinomas of the uterine cervix.

Abnormal expression of the spindle assembly checkpoint proteins causes tumor cell aneuploidy, which has been reported in various malignancies. The expression of mitotic arrest deficient 2 (MAD2) and cell-division cycle 20 homolog (CDC20), the key spindle assembly checkpoint proteins, has not been studied in cervical carcinogenesis. In this study, we compared the expression of MAD2 and CDC20 in 332 cases, including normal cervical tissues, low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions (HSILs), and invasive squamous cell carcinomas (SCCs). Both MAD2 and CDC20 were overexpressed in the nuclei or cytoplasm of dysplastic and malignant tumor cells. The frequency of MAD2 overexpression was markedly increased from undetectable (0/100) in normal cervical tissues and 2% (1/50) in low-grade squamous intraepithelial lesions to 67.1% (53/79) in HSILs and 52.4% (54/103) in SCCs. Similarly, CDC20 was overexpressed in 49.4% (39/79) of HSILs and 22.3% (23/103) of SCCs, whereas CDC20 was not detectable (0/100) in normal cervical tissues and overexpressed only in 8.0% (4/50) of low-grade squamous intraepithelial lesions. In SCC cases, MAD2 overexpression correlated with a patient age of less than 60 yr (P=0.043), nonkeratinizing histologic type (P=0.018), and a lesser degree of stromal invasion (P=0.026). In conclusion, MAD2 and CDC20 overexpression was increased in HSILs and SCCs, suggesting their involvement in the initiation of cervical cancers. Controlling CDC20 and MAD2 expression may be a therapeutic strategy for cervical cancer.

Clinicopathological Significance of Plasminogen Activator Inhibitor-1 Promoter 4G/5G Polymorphism in Breast Cancer: A Meta-analysis

BACKGROUND AND AIMS Plasminogen activator inhibitor type 1 (PAI-1) is associated with poor prognosis in breast cancer. Transcriptional expression of the PAI-1 can be controlled by PAI-1 promoter 4G/5G polymorphism. However, the significance of PAI-1 promoter 4G/5G polymorphism in breast cancer patients is contentious. To address this controversy, we conducted a meta-analysis for the relationships between PAI-1 promoter polymorphism and clinicopathological characteristics of breast cancer. METHODS Relevant published studies were identified using a search of PubMed, Embase, and the ISI Web of Science. The effect sizes of PAI-1 promoter 4G/5G polymorphism on breast cancer risk, lymph node metastasis, histologic grade, and overall survival were calculated by odds ratio (OR) or hazard ratio. The effect sizes were combined using a random-effects model. RESULTS Individuals with 4G/4G genotype had a higher risk of breast cancer than those with the combined 4G/5G and 5G/5G genotypes (OR = 1.388; p = 0.031). Breast cancer patients with the 5G/5G genotype displayed lymph node metastasis more than patients with either the combined other genotypes (OR = 1.495; p = 0.027) or with the 4G/4G genotype (OR = 1.623; p = 0.018). However, the PAI-1 promoter 4G/5G polymorphism was not associated with histological grade or overall survival. CONCLUSIONS PAI-1 promoter 4G/5G polymorphism is associated with a relatively increased risk of breast cancer development and lymph node metastasis.

The clinical performance of primary HPV screening, primary HPV screening plus cytology cotesting, and cytology alone at a tertiary care hospital.

Algorithms for primary human papillomavirus (HPV) screening, primary HPV screening plus cytology cotesting, and cytology alone were evaluated previously in large cohort trials for cervical cancer detection, although the quality of cytology in those studies was controversial. To investigate whether these 3 algorithms would be applicable in routine practice at a tertiary care hospital, the authors compared their clinical performance. In addition, the prevalence of HPV genotypes was determined.