Yu-Li Chen

Serous ovarian carcinoma patients with high alpha-folate receptor had reducing survival and cytotoxic chemo-response

The alpha‐folate receptor (α‐FR) is highly‐expressed in various non‐mucinous tumors of epithelial origin, including ovarian carcinoma. The aim of this study was to investigate the relationship between alpha‐folate receptor (α‐FR) and the clinico‐pathologic features and outcomes of serous ovarian carcinoma patients and the possible mechanism of α‐FR to chemo‐resistance. Therefore, semi‐quantitative reverse‐transcription polymerase chain reactions for α‐FR expression were performed in the 91 specimens of serous ovarian carcinomas. The expression of α‐FR in each ovarian cancer tissue specimen was defined as the ratio of density of α‐FR to density of glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH). In vitro apoptotic experiments were tested in the original OVCAR‐3 tumor cells and various OVCAR‐3 α‐FR‐transfectants. Patients with an increased α‐FR expression level had poorer responses to chemotherapy (per α‐FR expression level increase: odds ratio (OR): 8.97 (95% confidence interval (CI): 1.40–57.36), p = 0.021). An increased α‐FR expression level was an independently poor prognostic factor for disease free interval (DFI) (per α‐FR expression level increase: hazard ratio (HR): 2.45 (95% CI: 1.16–5.18), p = 0.02) and had a negative impact on overall survival (OS) of these serous ovarian cancer patients (per α‐FR expression level increase: HR: 3.6 (95% CI: 0.93–13.29), p = 0.03) by multivariate analyses. α‐FR inhibited cytotoxic drug‐induced apoptosis in our in vitro apoptotic assays. α‐FR could induce chemo‐resistance via regulating the expression of apoptosis‐related molecules, Bcl‐2 and Bax. Therefore, α‐FR can be a potential biomarker for the prediction of chemotherapeutic responses and clinical prognosis. It also could be the target of ovarian cancer treatment.

Metronomic Chemotherapy Enhances Antitumor Effects of Cancer Vaccine by Depleting Regulatory T Lymphocytes and Inhibiting Tumor Angiogenesis

Although cancer vaccines are emerging as innovative methods for cancer treatment, these alone have limited potential for treating measurable tumor burden. Thus, the importance of identifying anticancer strategies with greater potency is necessary. The chimeric DNA vaccine CTGF/E7 (connective tissue growth factor linked to the tumor antigen human papillomavirus 16 E7) generates potent E7-specific immunity and antitumor effects. We tested immune-modulating doses of chemotherapy in combination with the CTGF/E7 DNA vaccine to treat existing tumors in mice. Metronomic low doses of paclitaxel, not the maximal tolerable dose, are synergistic with the antigen-specific DNA vaccine. Paclitaxel, given in metronomic sequence with the CTGF/E7 DNA vaccine enhanced the vaccines potential to delay tumor growth and decreased metastatic tumors in vivo better than the CTGF/E7 DNA vaccine alone. The two possible mechanisms of metronomic paclitaxel chemotherapy are the depletion of regulatory T cells and the inhibition of tumor angiogenesis rather than direct cancer cell cytolytic effects. Results indicate that combination treatment of metronomic chemotherapy and antigen-specific DNA vaccine can induce more potent antigen-specific immune responses and antitumor effects. This provides an immunologic basis for further testing in cancer patients.

Nationwide Surveillance in Uterine Cancer: Survival Analysis and the Importance of Birth Cohort: 30-Year Population-Based Registry in Taiwan

Introduction Uterine cancer was the most rapidly increasing malignancy and the second most common gynecologic malignancy in Taiwan. Methods We analyzed the secular trend of uterine cancer incidence and compare the survival of women with uterine carcinomas and uterine sarcomas in Taiwan. Data on women diagnosed with uterine cancer between 1979 and 2008 were obtained from the Taiwan cancer registry. Survival data were analyzed by using Kaplan-Meier and Cox proportional hazards regression methods. Results Records of 11,558 women with uterine carcinomas and 1,226 women with uterine sarcomas were analyzed. The age-adjusted incidence rate of endometrioid adenocarcinoma increased from 0.83 per 100,000 women per year between 1979 and 1983 to 7.50 per 100,000 women per year between 2004 and 2008. The 5-year survival rate of women with endometrioid adenocarcinoma (83.2%) was higher than that for women with clear cell carcinoma (58.3%), serous carcinoma (54.4%), and carcinosarcoma (35.2%) (p<0.0001, log-rank test). The 5-year survival rates of women with low grade endometrial stromal sarcoma, endometrial stromal sarcoma, leiomyosarcoma (LMS), and adenosarcoma were 97.5%, 73.5%, 60.1%, and 77.2%, respectively (p<0.0001, log rank test). The histologic type of endometrioid adenocarcinoma, young age, and treatment period after 2000 were independent, favorable prognostic factors in women with uterine carcinomas by multivariate analysis. The histologic type of LMS, old age, and treatment period after 2000 were independent, poor prognostic factors in women with uterine sarcomas by multivariate analysis. Conclusions An increase over time in the number of patients with endometrioid adenocarcinomas was noted in this 30-year, nationwide, population-based study. Histologic type, age and treatment period were survival factors for uterine cancers. A more comprehensive assessment of uterine cancers and patient care should be undertaken on this increasingly common type of cancer.

Malignant ovarian germ cell tumors

Objectives: Fifty patients with malignant ovarian germ cell tumors, which accounts for 10.8% of all ovarian malignancies, were treated from 1977 through 1994. Their cases are reviewed. Methods: The histology includes endodermal sinus tumor (EST) in 15 patients, immature teratoma in 14, dysgerminoma in 13, and mixed germ cell tumor in eight. The mean age at presentation was 21.5 years and mean primary tumor diameter was 16 cm. All patients underwent surgery as the initial treatment, and 10 received more than one operation. Postoperative adjuvant chemotherapy was not given to cases with stage Ia immature teratoma and dysgerminoma. VAC (vincristine, actinomycin D, cyclophosphamide) and BVP (bleomycin, vinblastine, cisplatin) regimens were utilized in early 1980s for EST and advanced‐stage tumors of immature teratoma and dysgerminoma. BEP (bleomycin, etoposide, cisplatin) and EP (etoposide, cisplatin) regimens were applied in advanced‐stage disease and some stage I disease since 1990. VIP (VP‐16, ifosfamide, cisplatin) regimen was employed as salvage regimen in cases where other combinations failed. Results: α‐Fetoprotein (AFP) was elevated in every tumor containing endodermal sinus element, and AFP served as a good indicator for prediction of tumor recurrence. The follow‐up time ranged from 5 to 144 months with the mean of 54.5 months. Conclusions: The survival rate for EST was 54%, that for immature teratoma and dysgerminoma was 85% and 90%, respectively.

Depletion of regulatory T lymphocytes reverses the imbalance between pro- and anti-tumor immunities via enhancing antigen-specific T cell immune responses.

Background The regulatory T cells (Tregs) can actively suppress the immune responses. However, literature about detailed changes of host effective and suppressive immunities before and after depletion of Tregs in ovarian carcinomas, is rare. Materials and Methods Ovarian cancer patients and the ascitogenic animal model were employed. Immunologic profiles with flow cytometric analyses, immunohistochemistric staining, RT-PCR, ELISA, and ELISPOT assays were performed. In vivo depletion of Treg cells with the mAb PC61was also performed in the animal model. Results The cytokines, including IL-4 (p = 0.017) and TNF-α (p = 0.046), significantly decreased while others such as TGF-β (p = 0.013), IL-6 (p = 0.016), and IL-10 (p = 0.018) were elevated in ascites of ovarian cancer patients, when the disease progressed to advanced stages. The ratio of CD8+ T cell/Treg cell in ascites was also lower in advanced diseases than in early diseases (advanced 7.37±0.64 vs. early 14.25±3.11, p = 0.037). The kinetic low-dose CD25 Ab depletion group had significantly lower intra-peritoneal tumor weight (0.20±0.03 g) than the sequential high-dose (0.69±0.06 g) and sequential low-dose (0.67±0.07 g) CD25 Ab deletion groups (p = 0.001) after 49 days of tumor challenge in the animal. The kinetic low-dose CD25 Ab depletion group generated the highest number of IFN-γ-secreting, mesothelin-specific T lymphocytes compared to the other groups (p<0.001). Conclusions The imbalance between effective and suppressive immunities becomes more severe as a tumor progresses. The depletion of Treg cells can correct the imbalance of immunologic profiles and generate potent anti-tumor effects. Targeting Treg cells can be a new strategy for the immunotherapy of ovarian carcinoma.

Concurrent Endometrial Carcinoma in Patients with a Curettage Diagnosis of Endometrial Hyperplasia

BACKGROUND/PURPOSE Endometrial hyperplasia is considered a precursor of endometrial carcinoma, but concurrent endometrial carcinoma in patients with endometrial hyperplasia is seen frequently. Our aim was to examine the risk factors for coexisting endometrial carcinoma in patients with endometrial hyperplasia. METHODS Between January 1996 and September 2006, 77 patients who underwent hysterectomy for endometrial hyperplasia were enrolled retrospectively. We divided the patients into non-endometrial carcinoma and endometrial carcinoma groups, depending on the final pathology of hysterectomy and analyzed the clinical variables of these patients. RESULTS The prevalence rate of concurrent endometrial carcinoma in patients with endometrial hyperplasia was 26%. Those with atypical endometrial hyperplasia had a higher rate of coexisting endometrial carcinoma (54%). In addition to cytologic atypia, body mass index (BMI) was another risk factor. All the patients with concomitant endometrial carcinoma had at least one risk factor, but almost 50% of the cases in the non-endometrial group had no risk factors. Half of the women with cytological atypia and BMI > 25 had coexisting endometrial carcinoma. CONCLUSION When patients are diagnosed with endometrial hyperplasia, surgical intervention should be performed in those with cytological atypia and higher BMI because of the possibility of coexisting endometrial carcinoma.

Submucous Myoma Induces Uterine Inversion

OBJECTIVE Inversion of the uterus is indeed a rarity for a gynecologist. The puerperal variety is associated with pregnancy, including term pregnancy and abortion. The nonpuerperal condition may be tumor-induced or idiopathic. We present a nonpuerperal uterine inversion and discuss a reasonable plan for its management. CASE REPORT A 42-year-old, unmarried woman without sexual experience and any systemic diseases noted a mass outside of the vaginal introitus combined with massive vaginal bleeding and abdominal pain of sudden onset after taking laxative agents for colonoscopic preparation. Then she had voiding difficulty with distended bladder. A suprapubic urinary catheter was inserted and 800 mL urine was drained out. The patient received emergency tumor resection and subtotal hysterectomy. The diagnosis of uterine inversion was confirmed during operation. The postoperative course was uneventful and she was discharged without complication. CONCLUSION Nonpuerperal inversion of the uterus is rarely encountered by gynecologists. Diagnosis of uterine inversion is often not easy and imaging studies might be helpful. Surgical treatment is the method of choice in nonpuerperal uterine inversion.

Interferon-gamma in ascites could be a predictive biomarker of outcome in ovarian carcinoma

OBJECTIVE The ovarian cancer-associated ascites is an ideal material for evaluating the interaction between the host immune system and cancer cells in the tumor micro-environment. The aim of this study was to investigate whether the selected target cytokine expression levels in ascites could serve as an immune biomarker for predicting outcomes in ovarian cancer. METHODS Eighty-eight specimens of ovarian cancer-associated ascites were evaluated to select the target cytokine by a cytokine profiling kit. The 144 total samples were subsequently analyzed for this target cytokine. The correlation between the target cytokine and clinical characteristics was analyzed. RESULTS Interferon-gamma (IFN-γ) was identified as the target cytokine. Higher levels of IFN-γ in the ascites of the tumor micro-environment were associated with advanced disease (p=0.012), higher tumor histological grading (p=0.004), and sub-optimal surgical status (p=0.040). By multivariate analysis, the adjusted hazard ratios (HRs) were 2.74 (95% confidence interval (CI) 1.85-4.05, p<0.001) for disease-free survival (DFS) and 1.72 (95% CI 1.01-2.93, p=0.048) for overall survival (OS) for a 10-fold increase in IFN-γ concentration in the ascites. An inverse dose-response relationship between IFN-γ level and survival was also noted (Ptrend<0.001 for DFS and Ptrend<0.042 for OS). CONCLUSIONS Patients with ovarian cancer and higher IFN-γ expression levels in cancer-associated ascites will have shorter DFS and OS. IFN-γ levels in the ascites may be a prognostic marker and a potential reference for immunotherapy targeting IFN-γ.

Prognostic factors in women with early stage small cell carcinoma of the uterine cervix.

Small cell carcinoma of the uterine cervix (SCCUC) is an uncommon, aggressive disease accounting for less than 5% of all cervical cancers. Due to its rarity, definitive treatment strategies have not been developed. Our aim was to analyze the clinical factors, treatment modalities, sites of relapse, and overall survival of women with early stage SCCUC and thus determine prognostic factors. The clinical records of 18 women diagnosed with stage IB1 to IIA SCCUC were reviewed, and patient characteristics and treatment modalities were analyzed to determine the prognostic factors for disease-free survival (DFS) and overall survival (OS). DFS and OS were 39% and 44% at 2 years. Lymph node metastasis was a significant prognostic factor of DFS. International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis were significant prognostic factors of OS as determined by multivariate analysis (p < 0.05). Radical hysterectomy followed by adjuvant chemotherapy resulted in higher 2-year survival rates compared to radical hysterectomy followed by adjuvant radiotherapy (62.5% vs. 16.7%); however, the difference was not statistically significant due to the small sample size. FIGO stage and lymph node metastasis are significant indicators of OS in patients with early stage SCCUC. Further larger scale analysis is warranted to determine whether adjuvant chemotherapy may facilitate a better prognosis than adjuvant radiotherapy.

Metronomic chemotherapy and immunotherapy in cancer treatment

Systemic chemotherapy given at maximum tolerated doses (MTD) has been the mainstay of cancer treatment for more than half a century. In some chemosensitive diseases such as hematologic malignancies and solid tumors, MTD has led to complete remission and even cure. The combination of maintenance therapy and standard MTD also can generate good disease control; however, resistance to chemotherapy and disease metastasis still remain major obstacles to successful cancer treatment in the majority of advanced tumors. Metronomic chemotherapy, defined as frequent administration of chemotherapeutic agents at a non-toxic dose without extended rest periods, was originally designed to overcome drug resistance by shifting the therapeutic target from tumor cells to tumor endothelial cells. Metronomic chemotherapy also exerts anti-tumor effects on the immune system (immunomodulation) and tumor cells. The goal of immunotherapy is to enhance host anti-tumor immunities. Adding immunomodulators such as metronomic chemotherapy to immunotherapy can improve the clinical outcomes in a synergistic manner. Here, we review the anti-tumor mechanisms of metronomic chemotherapy and the preliminary research addressing the combination of immunotherapy and metronomic chemotherapy for cancer treatment in animal models and in clinical setting.