Jung-Soo Pyo

Overexpressions of Cyclin B1, cdc2, p16 and p53 in human breast cancer: the clinicopathologic correlations and prognostic implications.

Purpose The molecular mechanisms that are responsible for the initiation and progression of breast cancers are largely unknown. This study was to analyze the cyclin B1, cdc2, p53 and p16 tumor suppressor genes in human breast cancer. Materials and Methods To investigate the role of cyclin B1, cdc2, p53 and p16 in the pathogenesis and progression of breast carcinomas, 98 cases of breast cancers were examined by immunohistochemical method. The correlations of cyclin B1, cdc2, p53 and p16 expression with various clinico-pathologic findings were analysed. Results In the normal breast tissues, cyclin B1, cdc2 and p16 were weakly expressed, while p53 was not expressed. On the other hand, cyclin B1, cdc2, p53 and p16 were overexpressed in breast cancer, showing correlation between the expression of cyclin B1 and cdc2 and breast cancers (p=0.00). The overexpressions of cdc2 and p16 were correlated with an infiltrative tumor border pattern and this was statistically significant (p<0.05). In addition, the overexpression of cdc2 was correlated with histologic high grade carcinomas (p=0.00). Conclusion Cyclin B1 and cdc2 appeared to be involved in the genesis or progression of breast cancers. In addition, the overexpressions of p16 and p53 may play important roles in more aggressive tumor and the overexpression of cdc2 is associated with progression of tumor to a higher grade of breast carcinomas. The deranged overexpressions of cyclin B1, cdc2, p16 and p53 may play an important role in human breast carcinogenesis.

Expression patterns of stromal MMP-2 and tumoural MMP-2 and -9 are significant prognostic factors in invasive ductal carcinoma of the breast.

Matrix metalloproteinases (MMPs) are matrix‐degrading enzymes that play a pivotal role in aggressive behaviours, such as rapid tumour growth, invasion, and metastasis, of several types of solid tumours. In particular, stromal MMP‐2 plays important roles in the progression of malignant tumours, but most clinical studies have focused on tumoural MMP‐2 and ‐9 expression, and not stromal MMP‐2 expression. One hundred and seventy‐seven cases diagnosed as invasive ductal carcinoma of the breast between 2000 and 2005 were included in this study. Expressions of tumoural MMP‐2 and ‐9 and stromal MMP‐2 were analysed by immunostaining on a tissue microarray. Subsequently, the associations between those results and various clinicopathological parameters were evaluated. Stromal MMP‐2 expression correlated significantly with clinicopathological parameters such as advanced T category, larger tumour size, high histological grade, tumour necrosis, ER‐ and PR‐negative, and HER‐2‐positive (all p < 0.05). In univariate and multivariate analyses, overall survival was linked with stromal MMP‐2 expression as well as dual expression of stromal MMP‐2 and tumoural MMP‐2 and ‐9 (all p < 0.05). Stromal MMP‐2 expression may play a crucial role in predicting aggressive clinical behaviour in breast cancer patients.

Activation of nuclear factor-κB contributes to growth and aggressiveness of papillary thyroid carcinoma.

Nuclear factor-κB (NF-κB) is involved in proliferation, angiogenesis, and metastasis in various malignancies; however, the role of NF-κB in papillary thyroid carcinoma (PTC) has not been fully elucidated. The purpose of this study was to elucidate the role and clinicopathological significance of the NF-κB signaling pathway in PTC. We investigated NF-κB RelA expression in 122 patients with conventional PTC by immunohistochemistry, and evaluated the correlation between RelA expression and clinicopathological parameters, including BRAF(V600E) mutation. Nuclear expression of NF-κB RelA, regardless of cytoplasmic expression, was identified in 91 of 122 PTCs (74.6%), and was more frequent in PTCs larger than 1cm (overt PTC) (P=0.001). There were significant differences in clinicopathological parameters, such as extrathyroidal extension (P=0.031), nodal metastasis (P=0.021) and BRAF(V600E) mutation (P=0.039), between NF-κB-positive and negative PTCs. Proliferation index was strongly associated with NF-κB activation (P=0.045) but not with BRAF(V600E) mutation (P=0.141). Taken together, our results suggest that NF-κB RelA activation contributes, at least in part, to tumor growth and aggressiveness of PTC after tumor transformation. The expression pattern of NF-κB may serve as a prognostic marker and a potential therapeutic target.

The Prognostic Relevance of Psammoma Bodies and Ultrasonographic Intratumoral Calcifications in Papillary Thyroid Carcinoma

Background Although psammoma bodies (PB) are found in up to 50 % of papillary thyroid carcinomas (PTC), their clinicopathological significance remains uncertain. The aim of the present study was to determine the clinicopathological significance of PB and the correlation between PB and ultrasonographic intratumoral calcification in PTC.

Loss of FOXO1 promotes gastric tumour growth and metastasis through upregulation of human epidermal growth factor receptor 2/neu expression.

Background:The biological significance of FOXO1, a member of the forkhead box O transcription factor family, in gastric cancer (GC) remains unclear. The present study provides direct evidence of the role of FOXO1 in tumour growth and metastasis of GC in relation to human epidermal growth factor receptor 2 (HER2).Methods:The expressions of FOXO1 and HER2 were modulated in GC cell lines (SNU-638, MKN45, SNU-216 and NCI-N87) by stable transfections. The effects of transfection on GC phenotypes were evaluated in vitro and in animal models. In addition, the relationship between FOXO1 and HER2 was analysed using GC clinical specimens, cell lines and xenografts.Results:FOXO1 silencing in GC cells increased colony formation and mesenchymal transition in vitro, as well as tumour growth and metastasis in nude mice, whereas HER2 silencing induced the opposite results.. Furthermore, an inverse relationship between FOXO1 and HER2 was found in clinical specimens of GC, GC cells and GC xenograft tumours. Although a negative crosstalk between these two molecules was shown, double knockdown of both FOXO1 and HER2 in GC cells revealed that HER2 silencing reversed the FOXO1 shRNA-induced migration and invasion even without the FOXO1 restoration.Conclusions:Our results indicate that loss of FOXO1 promotes GC growth and metastasis by upregulating HER2 expression and that the HER2 expression is more critical to the induction of GC cell metastasis. The present study provides evidence that the FOXO1/HER2 pathway may regulate GC progression in a subgroup of GC patients.

Detection of KIT and PDGFRA mutations in the plasma of patients with gastrointestinal stromal tumor

In subsets of gastrointestinal stromal tumors (GISTs), mutations of the KIT and PDGFRA receptor tyrosine kinases correlate with tumor prognosis and response to tyrosine kinase inhibitors (TKIs). Determining genotypes in TKI-resistant GISTs is challenging due to the potential risks and limitations of repeated biopsies during the course of treatment. We prospectively collected plasma samples from three GIST patients harboring KIT mutations that were detected in tissue DNA. The plasma samples were then analyzed for mutations in KIT, PDGFRA, and BRAF via next-generation sequencing. We were able to identify primary KIT mutations in all plasma samples. Additional mutations, including KIT exon 17 S821F and PDGFRA exon 18 D842V, were detected in the patient-matched plasma samples during follow-up and appeared to result in decreased sensitivity to TKIs. Our results demonstrate an approach by which primary and secondary mutations are readily detected in blood-derived circulating tumor DNA from patients with GIST. These mutations can be used as biomarkers for prediction of treatment response. The identification of a resistance mutation in plasma DNA will allow early change to alternative TKIs or dose escalation of imatinib for optimal patient management.

Detection of Tumor Multifocality Is Important for Prediction of Tumor Recurrence in Papillary Thyroid Microcarcinoma: A Retrospective Study and Meta-Analysis.

Background: The clinicopathological characteristics and conclusive treatment modality for multifocal papillary thyroid microcarcinoma (mPTMC) have not been fully established. Methods: A retrospective study, systematic review, and meta-analysis were conducted to elucidate the clinicopathological significance of mPTMC. We investigated the multiplicity of 383 classical papillary thyroid microcarcinomas (PTMCs) and the clinicopathological significance of incidental mPTMCs. Correlation between tumor recurrence and multifocality in PTMCs was evaluated through a systematic review and meta-analysis. Results: Tumor multifocality was identified in 103 of 383 PTMCs (26.9%). On linear regression analysis, primary tumor diameter was significantly correlated with tumor number (R2=0.014, p=.021) and supplemental tumor diameter (R2=0.117, p=.023). Of 103 mPTMCs, 61 (59.2%) were non-incidental, with tumor detected on preoperative ultrasonography, and 42 (40.8%) were diagnosed (incidental mPTMCs) on pathological examination. Lymph node metastasis and higher tumor stage were significantly correlated with tumor multifocality. However, there was no difference in nodal metastasis or tumor stage between incidental and non-incidental mPTMCs. On meta-analysis, tumor multifocality was significantly correlated with tumor recurrence in PTMCs (odds ratio, 2.002; 95% confidence interval, 1.475 to 2.719, p<.001). Conclusions: Our results show that tumor multifocality in PTMC, regardless of manner of detection, is significantly correlated with aggressive tumor behavior.

Concordance rate between HER2 immunohistochemistry and in situ hybridization in gastric carcinoma: systematic review and meta-analysis

Purpose The aim of this study was to investigate the diagnostic accuracy of HER2 immunohistochemistry (IHC) in gastric carcinoma (GC) through a systematic review, meta-analysis and diagnostic test accuracy review. Method The current study included 12,679 GC cases and 181 subsets in 45 eligible studies. We performed concordance analysis between HER2 IHC and in situ hybridization (ISH) in GC. Diagnostic test accuracy was analyzed and the area under the curve (AUC) on the summary receiver operating characteristic (SROC) curve was calculated. Results HER2 amplification rates were 3.0%, 31.8%, and 93.0% in the IHC score 0/1+, 2+, and 3+ groups, respectively. The concordance rates between IHC and ISH were 0.969 (95% confidence interval [CI] 0.962-0.975), 0.393 (95% CI 0.331-0.458) and 0.915 (95% CI 0.882-0.939) in the HER2 IHC score 0/1+, 2+, and 3+ groups, respectively. For all the HER2 IHC score groups, the positive rates were higher in the silver ISH (SISH) subgroup than in the fluorescence ISH (FISH) and chromogenic ISH (CISH) subgroups. In diagnostic test accuracy review, the pooled sensitivity and specificity were 0.86 (95% CI 0.84-0.87) and 0.91 (95% CI 0.90-0.91). The AUC on SROC curve was 0.958. However, there was no significant difference in the values of AUC between the ISH methods. Conclusions Our results showed that HER2 IHC was well concordant with ISH in HER2 IHC score 0/1+ or 3+. Although this meta-analysis showed higher diagnostic accuracy of HER2 IHC, more detailed criteria for HER2 IHC score 2+ cases will be required to predict HER2 status.

Diagnostic and prognostic roles of the mean platelet volume in malignant tumors: a systematic review and meta-analysis

Abstract The aim of this study was to elucidate the diagnostic and prognostic roles of the mean platelet volume (MPV) in various malignant tumors through a systematic review and meta-analysis. The current study included 2,053 patients and 1,396 healthy subjects in 18 eligible studies. We performed a meta-analysis of MPV levels and the mean difference between healthy subjects and pre- and post-treatment patients. Subgroup analysis was conducted based on specific organs and platelet counts. In addition, the correlation between MPV and survival was investigated. The pooled MPVs of healthy subjects, pre-treatment, and post-treatment patients were 8.428 fL (95% confidence interval [CI] 8.118–8.738), 8.831 fL (95% CI 8.582–9.087), and 8.521 fL (95% CI 8.162–8.880), respectively. The mean difference in MPV between healthy subjects and pre-treatment patients was 0.502 (95% CI 0.285–0.719, P < 0.001). However, in lung cancer, the mean difference between pre-treatment patients and healthy subjects was −0.352 (95% CI −0.763–0.060, P = 0.094). The pooled MPV of post-treatment patients was significantly decreased compared to pre-treatment patients. There was no correlation between MPV and disease-free survival rate (hazard ratio 1.033, 95% CI 0.369–2.895). Our results showed that the MPV level was significantly higher in malignant tumors than in healthy subjects and was decreased after treatment. Further cumulative studies will be required before MPV levels can be applied for screening malignant tumors and predicting prognosis.

Forkhead Transcription Factor FOXO1 Inhibits Angiogenesis in Gastric Cancer in Relation to SIRT1.

Purpose We previously reported that forkhead transcription factors of the O class 1 (FOXO1) expression in gastric cancer (GC) was associated with angiogenesis-related molecules. However, there is little experimental evidence for the direct role of FOXO1 in GC. In the present study, we investigated the effect of FOXO1 on the tumorigenesis and angiogenesis in GC and its relationship with SIRT1. Materials and Methods Stable GC cell lines (SNU-638 and SNU-601) infected with a lentivirus containing FOXO1 shRNA were established for animal studies as well as cell culture experiments. We used xenograft tumors in nude mice to evaluate the effect of FOXO1 silencing on tumor growth and angiogenesis. In addition, we examined the association between FOXO1 and SIRT1 by immunohistochemical tissue array analysis of 471 human GC specimens and Western blot analysis of xenografted tumor tissues. Results In cell culture, FOXO1 silencing enhanced hypoxia inducible factor-1α (HIF-1α) expression and GC cell growth under hypoxic conditions, but not under normoxic conditions. The xenograft study showed that FOXO1 downregulation enhanced tumor growth, microvessel areas, HIF-1α activation and vascular endothelial growth factor (VEGF) expression. In addition, inactivated FOXO1 expression was associated with SIRT1 expression in human GC tissues and xenograft tumor tissues. Conclusion Our results indicate that FOXO1 inhibits GC growth and angiogenesis under hypoxic conditions via inactivation of the HIF-1α–VEGF pathway, possibly in association with SIRT1. Thus, development of treatment modalities aiming at this pathway might be useful for treating GC.