Jong-Hyuck Yoon

Syndecan-1 enhances the endometrial cancer invasion by modulating matrix metalloproteinase-9 expression through nuclear factor κB

OBJECTIVES Up-regulated expression of syndecan-1, a member of the transmembranous proteoglycans that serves as a co-receptor for a wide pool of extracellular ligands, has been ascribed to the promotion of growth of various cancers including breast, ovarian, and endometrial cancers. Here, we have extended these observations to gain insight into correlation between the expression level of syndecan-1 and its tumor-promoting characteristics, particularly, cancer invasion, in endometrial cancer. METHODS Human syndecan-1 was stably transfected into three human endometrial cancer cell lines, and its effects were examined with respect to cell survival/proliferation and invasion. In addition, the activation of underlying signaling components, including integrins, focal adhesion kinase (FAK), and nuclear factor kappaB (NF-kappaB) was examined. The activity of NF-kappaB as a transcription factor for matrix metalloproteinase (MMP)-9 was assessed. RESULTS The innate expression level of syndecan-1 was moderate to high in all endometrial cancer cell lines. Overexpression of syndecan-1 promoted tumor cell proliferation concomitant with the activation of NF-kappaB. Furthermore, overexpression of syndecan-1 markedly enhanced the cancer invasion accompanied by enhanced expression of integrin alphav/beta5 and enhanced phosphorylation of FAK. The transcriptional activation of MMP-9 by NF-kappaB was up-regulated in syndecan-1 overexpression. CONCLUSION These findings provide evidence that supports that syndecan-1 may have a critical role in carcinogenic progression, particularly, contributing to the development of proliferative and invasive phenotype through NF-kappaB-mediated MMP-9 gene expression in endometrial cancer.

Prognostic significance of the micropapillary pattern in patients with serous borderline ovarian tumors

Background. The impact of micropapillary histology on survival in patients with serous borderline ovarian tumors is not established. The purpose of this study was to evaluate the significance and influence of micropapillary pattern on clinical outcome of patients with serous borderline ovarian tumors. Methods. Eighty‐five patients who underwent surgery and were diagnosed with serous borderline ovarian tumors were retrospectively studied. Among these patients, 18 patients showed micropapillary pattern on histologic examination, while the remaining 67 patients did not. The significance of the presence of micropapillary pattern and relationship with various clinicopathologic findings and progression‐free survival were evaluated by statistical analysis. Results. No differences with regard to age, parity, body mass index, pretreatment CA‐125 level, tumor size, bilaterality, and the duration of follow‐up were observed between the two groups, but there was a significant difference in terms of FIGO stage (p<0.001), invasive implants (p = 0.004), performing lymphadenectomy (p = 0.009), operation time (p = 0.003), estimated blood loss (p<0.001), residual disease>1 cm (p = 0.001), adjuvant chemotherapy (p<0.001), and the length of hospital stay (p = 0.013). Progression‐free survival was found to be significantly decreased in patients with invasive implants (HR, 5.06; p = 0.025) and micropapillary pattern (HR, 4.20; p = 0.056) on multivariate analysis. Conclusions. Micropapillary serous borderline ovarian tumors were associated with a more aggressive clinical course compared with typical serous borderline ovarian tumor. The presence of invasive implants and micropapillary pattern were significant prognostic factors in patients with serous borderline ovarian tumors.

Para-aortic lymphadenectomy improves survival in patients with intermediate to high-risk endometrial carcinoma

Objective. Surgical staging of endometrial carcinoma is practiced to identify the true extent of disease. The impact of para‐aortic lymphadenectomy (PALD) on survival is unproven. The purpose of this study was to determine if a staging procedure that includes PALD is associated with improved survival in endometrial carcinoma patients who had been surgically staged. Design. Retrospective review of patients’ records. Setting. Ajou University Hospital, a tertiary care hospital in South Korea. Population. One hundred and sixty patients with endometrial carcinoma. Methods. We retrospectively analyzed a total of 160 FIGO stage I–III endometrial carcinoma patients without grossly metastatic para‐aortic lymph nodes, who underwent surgery between 1994 and 2007. Exclusion criteria included presurgical radiation, stage IV disease and sarcomas. Two groups were identified: patients who underwent pelvic lymphadenectomy (PLD) and PALD (n = 85) versus those who underwent PLD alone (n = 75). Survival was analyzed using Kaplan–Meier method and Cox proportional hazards model. Main outcome measures. Disease‐free and overall survival. Results. Overall, patients who underwent PALD demonstrated improved 5‐year disease‐free survival (81.0 vs 91.2%) and overall survival (85.8 vs 96.2%) compared to those who underwent PLD alone (p = 0.019 and p = 0.039, respectively). After multivariate analysis, patients’ age (p = 0.028), FIGO stage (p<0.001) and lymphadenectomy (p = 0.014) were independent prognostic factors. The type of lymphadenectomy did not affect survival of low‐risk patients. In intermediate to high‐risk patients, PALD improved disease‐free survival and showed a trend toward improvement of overall survival. Conclusion. These data demonstrate that PALD has a potentially therapeutic benefit on survival in surgically staged patients with intermediate to high‐risk endometrial carcinoma.

Endometrial cancer invasion depends on cancer-derived tumor necrosis factor-α and stromal derived hepatocyte growth factor

Cancer invasion is an outcome of interactions of the cancer and the host cell. It is now becoming increasingly clear that ovarian hormones have a huge influence on such intercommunications in various types of cancers. Estrogen is known to aggravate the aggressiveness of the endometrial cancer whereas progesterone seems to act as a negative factor. Insight into the mode of ovarian hormonal actions could come from the studies of its regulation of the paracrine interactions between the endometrial cancer and the normal stromal cells during the cancer invasion. In this context, we report here that estrogen promotes the endometrial cancer invasion by inducing humoral interactions between the cancer and the stromal cells, i.e., estrogen stimulates tumor necrosis factor‐α expression from the endometrial cancer cells, which, in turn, induces the stromal expression of hepatocyte growth factor (HGF), conferring the enhanced NK4 (HGF‐antagonist/angiogenesis inhibitor)‐sensitive invasion characteristic of the endometrial cancer cells. Additionally, we demonstrate a close correlation of the invasion of endometrial cancer cells with the expression and dimerization of integrin αvβ5 as well as the activation of focal adhesion kinase as the consequences of paracrine interactions. Thus, understanding of paracrine interactions of cancer cells with host stromal cells can yield new insight into the architecture and function of cancer invasion and metastasis, leading to a development of a new cancer therapeutic intervention.

Uterine Leiomyosarcoma : 14-year Two-center Experience of 31 Cases

PURPOSE The aim of this study was to evaluate the clinicopathological characteristics of uterine leiomyosarcoma (LMS) and possible prognostic factors. MATERIALS AND METHODS This study included 31 patients with histologically proven LMS at Samsung Medical Center and Ajou University Hospital between 1994 and 2007. The medical records and available histological slides were reviewed retrospectively. RESULTS The median age was 46 years (range, 32~63). The most common symptom was vaginal bleeding (11 patients, 35.5%). There were 23 patients with stage I, one patient with stage III, seven patients with stage IV disease. The median follow up time was 29 months (range, 1~94). The most common recurrence site was lung (5 case), followed by pelvis and upper abdomen (2 case). Nine patients died of disease with a 5-year overall survival rate of 63%. Early tumor stage and mitotic count were the prognostic factor in univariate analysis (p<0.0001 and p=0.0031, respectively), but early tumor stage only was associated with prognosis in multivariate analysis (p=0.010 vs p=0.143). Adjuvant treatment for early stage disease did not decrease the recurrence rate (p=0.1075), but high mitotic count (15>10HPF) had a trend for disease recurrence in early stage LMS (p=0.0859). CONCLUSION Mitotic count less than 15/HPF in early stage may be related with longer progression-free interval, but we could not reach the conclusion that adjuvant therapy in early stage LMS be effective.

Does pretreatment HPV viral load correlate with prognosis in patients with early stage cervical carcinoma

OBJECTIVE Recent data suggest that pretreatment HPV (Human papillomavirus) viral load is useful to predict the severity of intraepithelial lesions of the uterine cervix and formulate a treatment plan. However, the relationship between initial HPV viral load and prognosis of cervical cancer patients has not yet been clearly defined. The objective of this study was to determine whether HPV viral load has prognostic significance in patients with early stage cervical carcinoma treated by surgery. METHODS A retrospective review of all patients with early stage cervical carcinoma who underwent radical hysterectomy and pelvic lymphadenectomy at our institution from August 2003 to December 2007 was conducted. Patients were included only if they had pretreatment Hybrid Capture II test for HPV DNA detection. RESULTS We identified 34 patients who met the inclusion criteria. Two groups were identified: patients who had low HPV viral load (</=100 RLU) versus those who had high viral load (>100 RLU). There were no differences in age, FIGO stage, histology, pathologic risk factors - tumor size, deep stromal invasion, lymph-vascular space invasion, parametrial extensions, vaginal margin involvement, and lymph node metastasis - and adjuvant CCRT. There was no significant difference of disease-free survival regard to pretreatment HPV viral load (p=0.7756). CONCLUSION In our study, survival was not significantly different between early stage cervical cancer patients who had low and high pretreatment HPV viral load. It seems that pretreatment HPV viral load may not be of help to predict disease prognosis.

Comparison of concurrent chemoradiation therapy with weekly cisplatin versus monthly fluorouracil plus cisplatin in FIGO stage IIB-IVA cervical cancer.

Objective Concurrent chemoradiation therapy (CCRT) is the standard treatment for locally advanced cervical cancer. Although the optimal chemotherapeutic regimen is not yet defined, previous randomized trials have demonstrated that 5-fluorouracil (5-FU) plus cisplatin every 3 weeks and weekly cisplatin are the most popular regimens. The purpose of this study was to compare the outcomes of weekly CCRT with cisplatin and monthly CCRT with 5-FU plus cisplatin for locally advanced cervical cancer. Methods We retrospectively reviewed data from 255 patients with FIGO stage IIB-IVA cervical cancer. Patients were classified into two CCRT groups according to the concurrent chemotherapy: weekly CCRT group, consisted of CCRT with weekly cisplatin for six cycles; and monthly CCRT group, consisted of CCRT with cisplatin and 5-FU every 4 weeks for two cycles followed by additional consolidation chemotherapy for two cycles with the same regimen. Results Of 255 patients, 152 (59.6%) patients received weekly CCRT and 103 (40.4%) received monthly CCRT. The mean follow-up period was 39 months (range, 1 to 186 months). Planned CCRT was given to 130 (85.5%) patients in weekly CCRT group and 84 (81.6%) patients in monthly CCRT group, respectively. Severe adverse effects were more common in the monthly CCRT group than in the weekly CCRT group. There were no statistically significant differences in progression-free survival and overall survival between the two groups (p=0.715 and p=0.237). Conclusion Both weekly CCRT and monthly CCRT seem to have similar efficacy for patients with locally advanced cervical cancer, but the weekly cisplatin is better tolerated.

Young girls with malignant ovarian germ cell tumors can undergo normal menarche and menstruation after fertility-preserving surgery and adjuvant chemotherapy

Objective. To evaluate the long‐term outcome and ovarian function in premenarchal and adolescent patients with malignant ovarian germ cell tumors after fertility‐preserving surgery and adjuvant chemotherapy. Design. Retrospective review of medical records. Setting. Ajou University Hospital, a tertiary care hospital in South Korea. Population. Forty‐five patients with malignant ovarian germ cell tumors. Methods. A retrospective analysis of patients with malignant ovarian germ cell tumors was conducted and a statistical analysis was performed. Main outcome measures. There were 9 premenarchal and 16 adolescent patients; the median ages at diagnosis were 7 and 18 years, respectively. All patients were treated with fertility‐preserving surgery. Seventeen of the patients received adjuvant chemotherapy with bleomycin, etoposide, and cisplatin (68.0%). There were no disease recurrences or deaths. Of the nine premenarchal patients, eight (88.9%) subsequently had normal menarche. Among the 16 adolescent patients, 15 (93.8%) resumed normal menstruation and 1 had premature ovarian failure. Conclusion. Premenarchal and adolescent patients with malignant ovarian germ cell tumors have excellent survival with fertility‐preserving surgery and adjuvant chemotherapy. The majority of these patients can have normal menarche and menstruation.

A validation study of new risk grouping criteria for postoperative treatment in stage IB cervical cancers without high-risk factors: Rethinking the Gynecologic Oncology Group criteria

OBJECTIVE The aim of this study was to verify whether the Gynecologic Oncology Group (GOG) criteria are valid in a different cohort of patients and to investigate simplified new criteria tailoring adjuvant radiation therapy in patients with intermediate-risk factors after radical hysterectomy. STUDY DESIGN We analyzed the data of 332 patients with FIGO stage IB cervical cancer who underwent radical hysterectomy between 1994 and 2007. Two hundred and twenty-five patients without high-risk factors (lymph node metastasis, parametrial invasion, or positive surgical margins) were identified and were classified into low-risk and high-risk groups according to the GOG criteria and new criteria based on combinations of intermediate-risk factors (large tumor size, deep stromal invasion, lymph-vascular space invasion). We evaluated the prognostic significance of both criteria. RESULTS We identified 140 low-risk patients and 85 high-risk patients in the application of the GOG criteria. Low-risk patients had significantly better disease-free survival (DFS) (P=0.001) and overall survival (OS) (P=0.013) than high-risk patients. There were 145 low-risk patients and 80 high-risk patients on applying the new criteria. Low-risk patients had significantly better DFS (P=0.001) and OS (P=0.013) than high-risk patients. The receiver operating characteristic (ROC) curves showed that both criteria had similar performance for predicting which patients would have help from adjuvant therapy. CONCLUSION This study demonstrated that the GOG criteria were still valid in the different population, the simplified new criteria were convenient to apply in practice, and the performance of the new criteria was as good as the GOGs.

Value of Sonohysterography in Preoperative Assessment of Myometrial Invasion for Patients With Endometrial Cancer

Objective. The aims of this study were to compare the diagnostic performance of sonohysterography (SH) with that of magnetic resonance imaging (MRI) in estimation of myometrial invasion and to evaluate the influence of SH on peritoneal cytologic results for patients with endometrial cancer. Methods. Seventy‐four patients with endometrial cancer were included. Sonohysterography and MRI were performed before surgery. All patients had complete staging procedures, including peritoneal cytologic analyses. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined for SH and MRI. Results. The concordance rates of myometrial invasion for SH and MRI were 82.4% and 81.1%, respectively. The sensitivity, specificity, PPV, and NPV for identification of deep myometrial invasion were 64.7%, 87.7%, 61.1%, and 89.3% on SH and 70.6%, 84.2%, 57.1%, and 90.6% on MRI. Two patients (2.7%) were found to have positive results for malignant cells on peritoneal cytologic analyses. Conclusions. Sonohysterography appears to be a useful preoperative method for predicting myometrial invasion, comparable to MRI.