Hee-Sug Ryu

An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer

Background:The cancer stem cell (CSC) hypothesis has important clinical implications for cancer therapeutics because of the proposed role of CSCs in chemoresistance. The aim of this study was to investigate changes in the CSC populations before and after primary systemic therapy (PST) and their prognostic role in human breast cancer.Methods:Paired samples (before and after PST) of breast cancer tissue were obtained from clinical stage II or III patients (n=92) undergoing PST with the regimen of doxorubicin plus docetaxel (AD) (n=50) or doxorubicin plus cyclophosphamide (AC) (n=42) and subsequent breast resection. The proportions of putative CSCs with CD44+/CD24− or aldehyde dehydrogenase 1+ (ALDH1+) phenotypes were determined by immunohistochemistry.Results:A higher proportion of CD44+/CD24− tumour cells and ALDH1 positivity in pre-chemotherapy tissue was correlated with higher histologic grade, oestrogen receptor (ER) negativity, high Ki-67 proliferation index and basal-like subtype of breast cancer. Aldehyde dehydrogenase 1 positivity in pre-chemotherapy biopsy was also associated with a higher rate of pathologic complete response following PST. In comparisons of putative CSC populations before and after PST, the proportions of CD44+/CD24− and ALDH1+ tumour cells were significantly increased after PST. The cases with increased CD44+/CD24− tumour cell populations after PST showed high Ki-67 proliferation index in post-chemotherapy specimens and those with increased ALDH1+ tumour cell population after PST were associated with ER negativity and p53 overexpression. Furthermore, cases showing such an increase had significantly shorter disease-free survival time than those with no change or a reduced number of CSCs, and the survival difference was most notable with regard to the changes of ALDH1+ tumour cell population in the patients who received AC regimen.Conclusion:The present study provides the clinical evidence that the putative CSCs in breast cancer are chemoresistant and are associated with tumour progression, emphasising the need for targeting of CSCs in the breast cancer therapeutics.

Sonographic findings of placental lacunae and the prediction of adherent placenta in women with placenta previa totalis and prior Cesarean section

To investigate the value of transvaginal sonographic findings of intraplacental lacunae for predicting adherent placenta and clinical outcome in patients with placenta previa totalis and a history of Cesarean section.

Clinical characteristics of struma ovarii.

OBJECTIVE To evaluate the clinical characteristics of struma ovarii. METHODS Twenty-five cases of struma ovarii were reviewed retrospectively from June 1994 to April 2007. The presenting clinical, radiologic, and pathologic features of the patients were reviewed. RESULTS The mean age of the patients in this study was 45.3 years. The majority was of premenopausal status. Sixteen patients had clinical symptoms such as low abdominal pain, palpable abdominal mass and vaginal bleeding. Although one patient had an abnormal thyroid function test, the laboratory findings normalized after operative treatment. CA-125 levels were elevated in 6 cases. Diagnosis by preoperative imaging studies were 8 dermoid cysts, while only 3 cases were diagnosed as struma ovarii. There were 4 cases of malignant struma ovarii, and no patients with recurrent disease. CONCLUSION Struma ovarii is a rare tumor. The presented clinical, laboratory and radiological findings of patients are very diverse. The diagnosis was confirmed by pathologic findings. The treatment of benign struma ovarii is surgical resection only. The cases of malignant struma ovarii may need adjuvant treatment, but recurrence is uncommon.

Efficacy of different types of treatment in FIGO stage IB2 cervical cancer in Korea: results of a multicenter retrospective Korean study (KGOG‐1005)

The purpose of this study is to review FIGO stage IB2 cervical cancers in Korea for the past 10 years, and evaluate the most frequently employed and appropriate management strategy, and also assess the survival benefits of neoadjuvant chemotherapy (NAC). This is a retrospective chart review of 727 FIGO stage IB2 patients from 1995 to 2005. Six hundred ninety-two patients were enrolled, and all dates on which the patients died were double checked through the “National Registry of Death Statistics” of the Korea National Statistical Office. Management strategies were divided into five groups according to the primary treatment modality. The most frequently employed primary treatment modality for stage IB2 cervical cancer in Korea during the past 10 years was radical hysterectomy (RH). The next was NAC, followed by radiotherapy (RT) and/or extrafascial hysterectomy, concurrent chemoradiotherapy (CCRT) and/or extrafascial hysterectomy, in descending order. The surgery group showed the best results, with an 89% 5-year disease-free survival rate. However, there was no statistical difference between the surgery, NAC, and CCRT groups. For FIGO stage IB2 cervical cancer during the past 10 years in Korea, RH and adjuvant RT or CCRT was the most frequently employed treatment strategy. As a primary modality, RH, NAC, and CCRT showed similar survival rates. However, RH demonstrated the best survival rate among the above treatment strategies

A well-defined in vitro three-dimensional culture of human endometrium and its applicability to endometrial cancer invasion

A three-dimensional (3-D) endometrium culture was established, in which human endometrial stromal cells embedded in a mixture of collagen I, a major component of extracellular matrix, and matrigel, a basement membrane material, supports the epithelial cells seeded on top of the collagen/matrigel matrix. The biological growth and differentiation of the epithelial cells were studied microscopically and immunohistochemically. Transmission electron microscopy showed a polarized columnar epithelium in monolayer with basally positioned nuclei. Scanning electron microscopy revealed a confluent epithelium with an abundance of microvilli and cilia as well as pinopodes on the apical surface. An immunohistochemical staining showed that integrin alpha1, alpha4, and beta3 were co-localized with cytokeratin, confirming the epithelial origin of the cells. In contrast, immunoreactivity against cyclooxygenase-1 or -2 was positive in both epithelial and stromal cells. When epithelial cells were replaced by KLE cells, an endometrial cancer cell of epithelial origin, invasion of KLE cells into the stromal fraction was observed. The invasion was closely correlated to expression of matrix metalloproteinases and their tissue inhibitors of metalloproteinases in a manner consistent with paracrine fashion. The present 3-D culture imitates the normal endometrium physiologically as well as morphologically, thus provides an excellent in vitro tissue suitable for reproducing in vivo physiological processes, including endometrial cancer invasion.

Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer

Background:Epidermal growth factor receptor (EGFR) is overexpressed in a subset of human epidermal growth factor receptor 2 (HER2)-positive breast cancers, and coexpression of HER2 and EGFR has been reported to be associated with poor clinical outcome. Moreover, interaction between HER2 and EGFR has been suggested to be a possible basis for trastuzumab resistance.Methods:We analysed the clinical significance of EGFR overexpression and EGFR gene copy number alterations in 242 HER2-positive primary breast cancers. In addition, we examined the correlations between EGFR overexpression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab.Results:Of the 242 primary cases, the level of EGFR overexpression was 2+ in 12.7% and 3+ in 11.8%. High EGFR gene copy number was detected in 10.3%. Epidermal growth factor receptor overexpression was associated with hormone receptor negativity and high Ki-67 proliferation index. In survival analyses, EGFR overexpression, but not high EGFR copy number, was associated with poor disease-free survival in all patients, and in the subgroup not receiving adjuvant trastuzumab. In 447 HER2-positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor. However, EGFR overexpression was not associated with trastuzumab response, progression-free survival or overall survival in the metastatic setting.Conclusions:Epidermal growth factor receptor overexpression, but not high EGFR copy number, is a poor prognostic factor in HER2-positive primary breast cancer. Epidermal growth factor receptor overexpression is a predictive factor for trastuzumab response in HER2-positive primary breast cancer, but not in metastatic breast cancer.

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.

Ovarian preservation during the surgical treatment of early stage endometrial cancer: A nation-wide study conducted by the Korean Gynecologic Oncology Group

OBJECTIVES The objective of this study was to determine whether ovarian preservation is feasible in younger endometrial cancer patients. METHODS Endometrial cancer patients who underwent ovary-saving surgery were recruited from the tumor registries of 14 tertiary hospitals under the influence of the Korean Gynecologic Oncology Group (KGOG). Information regarding patient age, preoperative and intraoperative evaluations, pathologic reports, and follow-up results was abstracted from medical records. RESULTS One hundred and seventy five patients were eligible for this study. Mean patient age at the time of surgery was 38.5+/-8.3 years (range 25-57). Ovary-preserving surgery was performed in 101 (57.7%) patients who desired to preserve their ovaries, incidentally in 69 (39.4%) patients with preoperative diagnoses other than endometrial carcinoma, and in 5 patients (2.9%) with unknown reasons. Median duration of follow-up was 55.0 months (range 6.2-180.0 months). Recurrence free survival and overall survival rates were 94.3 and 93.3%, respectively. Seven of the 175 (4.0%) patients had documented recurrence, and no recurrences were observed in stage I patients with endometrioid histology. All 7 recurrences had risk factors that could have reasonably explained recurrence, namely, non-endometrioid histology (4/7), deep myometrial invasion (5/7), cervical stromal invasion (4/7), and inadequate adjuvant treatment (4/7). No metachronous ovarian malignancy occurred during follow-up. Ten (5.8%) deaths occurred during follow-up; five resulted from disease recurrence, and 5 from non-disease related causes. CONCLUSION Our findings suggest that ovarian preservation does not adversely impact the recurrence of early stage endometrial cancer.

A model for prediction of parametrial involvement and feasibility of less radical resection of parametrium in patients with FIGO stage IB1 cervical cancer.

OBJECTIVE The objective of this study was to evaluate the potential risk factors associated with parametrial invasion and to identify preoperatively a subgroup of patients at low risk for parametrial involvement who could be appropriate candidates for less radical surgery in FIGO stage IB1 cervical cancer. METHODS We retrospectively reviewed the medical records of 317 FIGO stage IB1 cervical cancer patients undergoing class III radical hysterectomy and bilateral pelvic lymphadenectomy. Clinocopathologic factors associated with parametrial invasion were analyzed and the risk criteria predicting parametrial involvement were calculated using a logistic regression model. RESULTS Of 317 patients, 17 patients (5.4%) had parametrial involvement. Tumor size >3 cm (OR, 3.80; [95% CI, 1.19-12.06]; p=0.02) and pelvic lymph node metastasis (OR, 3.02; [95% CI, 1.04-8.79]; p=0.04) were independent pathologic factors for parametrial invasion on multivariate analysis. Significant preoperative factors associated with parametrial involvement were tumor size >3 cm (OR, 4.29; [95% CI, 1.43-12.89]; p<0.01) and serum SCC Ag level >1.40 ng/mL (OR, 3.27; [95% CI, 1.11-9.69]; p=0.03). We identified 185 low-risk (tumor size ≤ 3 cm and SCC ≤ 1.4 ng/mL) and 132 high-risk (tumor size>3 cm and/or SCC>1.4 ng/mL) patients. The rates of parametrial involvement in low- and high-risk patients were 1.1% and 11.4%, respectively (p<0.01). CONCLUSIONS In this dataset, a model using tumor size and SCC Ag level is highly predictive of parametrial involvement in patients with stage IB1 cervical cancer and may identify candidates for less radical parametrial resection.