Hung-Chun Fu

High immunohistochemical expression of TGF-β1 predicts a poor prognosis in cervical cancer patients who harbor enriched endoglin microvessel density.

Endoglin, a coreceptor for transforming growth factor &bgr;1 (TGF-&bgr;1) in vascular endothelial cells, is highly upregulated in tumor vessels and therefore is a specific biomarker for angiogenesis. Some studies have suggested that assessment of tumor angiogenesis may predict cancer response to chemotherapy and radiotherapy. In this study, we attempted to analyze the immunohistochemical expression of endoglin and TGF-&bgr;1 from 80 patients with different International Federation of Gynecology and Obstetrics (FIGO) stages of cervical cancer before they received concurrent chemoradiation and to investigate their prognostic significance. The median follow-up period was 86 months (range, 2–144 months). Endoglin staining was assessed by microvessel density (MVD), whereas TGF-&bgr;1 expression was semiquantified as negative, weakly, or strongly staining. A receiver operating characteristic curve was established for endoglin MVD in predicting survival; the optimal cutoff value was 11.125. With a Cox regression analysis, we found that an advanced FIGO stage (hazard ratio 4.66; 95% confidence interval 2.10–10.32, P<0.001) and endoglin MVD more than 11.125 (hazard ratio 12.21; 95% confidence interval 3.62–41.16, P=<0.001) were independent factors to predict survival. Interestingly, a strong TGF-&bgr;1 expression was significantly associated with poor survival only when the endoglin MVD value was higher than 10. Our study shows that evaluation of endoglin MVD by immunochemistry can be used as an independent prognostic marker for cervical cancer patients receiving concurrent chemoradiation. TGF-&bgr;1 also had an impact on survival only when endoglin MVD was enriched, suggesting its involvement in tumor progression in the later stage of angiogenesis.

Outcomes of Patients With Surgically and Pathologically Staged IIIA-IVB Pure Endometrioid-type Endometrial Cancer: A Taiwanese Gynecology Oncology Group (TGOG–2005) Retrospective Cohort Study (A STROBE-Compliant Article)

AbstractIn the management of patients with advanced-stage pure endometrioid-type endometrial cancer (E-EC), such as positive lymph nodes (stage III) or stage IV, treatment options are severely limited. This article aims to investigate the outcome of women with FIGO III-IV E-EC (based on FIGO 2009 system).The retrospective cohort study, based on the Taiwanese Gynecologic Oncology Group (TGOG-2005), enrolled patients undergoing staging surgery to have a pathologically confirmed FIGO III-IV E-EC from 22-member hospitals between 1991 and 2010.This cohort included 541 patients (stage III, n = 464; stage IV, n = 77). Five-year overall survival (OS) was 70.4%. Median progression-free survival (PFS) was 43 months (range 0–258 months) and median OS was 52 months (range 1–258 months). Multivariate analysis showed that FIGO stage, >1/2 myometrial invasion (hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.12–2.09; P = 0.007), histological grade 3 (HR 2.0, 95% CI 1.47–2.75; P < 0.001), and metastases of pelvic and para-aortic lymph nodes (PLN and PALN) (HR 2.75, 95% CI 1.13–6.72; P < 0.001) were independent risk factors for PFS. FIGO stage, >1/2 myometrial invasion (HR 1.89, 95% CI 1.34–2.64; P < 0.001), and histological grade 3 (HR 2.42, 95% CI 1.75–3.35; P < 0.001) influenced OS. Complete dissection of PLN and PALN (HR 0.27, 95% CI 0.16–0.45; P < 0.001, and HR 0.14, 95% CI 0.08–0.26; P < 0.001) and the following paclitaxel-based therapy (HR 0.61, 95% CI 0.79–0.92; P = 0.017, and HR 0.48; 95% CI 0.31–0.75; P = 0.001) provided the better PFS and OS, respectively.In management of women with FIGO III-V E-EC, combination of complete staging surgery (complete dissection of PLN and PALN is included) and the following paclitaxel-based therapy could provide the better chance to survive. Patients with tumor >1/2 myometrial invasion and histological grade 3 are risky for disease-related mortality.

Increased expression of SKP2 is an independent predictor of locoregional recurrence in cervical cancer via promoting DNA-damage response after irradiation

Although radiation therapy was known to be effective to cervical cancer, loco-regional recurrences are frequently found in patients. We aimed to identify a molecular marker predicting the response of cervical cancer to radiotherapy. We included the patients (n = 149) with cervical cancer who had undergone radiotherapy from 2004 to 2006. Tumor samples were collected to examine the association between the expression of S-phase kinase-associated protein 2 (SKP2) and prognosis in cervical cancer. We found higher expression of SKP2 associated with recurrence (HRs: 2.52, p < 0.001), death (HRs: 2.01, p < 0.001) and higher locoregional recurrence rate (HRs: 3.76, p < 0.001). Cervical cancer cell lines with higher expression of SKP2 showed higher colony formation, cell survival rate and fewer DNA damages after irradiation. SKP2-C25, an inhibitor for SKP2 activity, dose-dependently decreased cell viability after irradiation and knockdown of SKP2 impaired DNA-damage response and sensitized the cervical cancer cells to irradiation. Our data showed the SKP2 represents a promising tool to identify patients with cervical cancer who have a higher risk of locoregional recurrence after radiotherapy. Targeting SKP2 may serve as a potential radiosensitizer for developing effective therapeutic strategies against cervical cancer.

Outcome of ovarian preservation during surgical treatment for endometrial cancer: A Taiwanese Gynecologic Oncology Group study.

OBJECTIVE The goal of this study was to investigate the impact of ovarian preservation on the survival of women with early-stage endometrial cancer, particularly young women. MATERIALS AND METHODS A study cohort of 64 patients with histologically confirmed early-stage endometrial cancer was retrospectively collected from 10 member hospitals of the Taiwanese Gynecologic Oncology Group between 1998 and 2009. Survivorship and overall survival were compared between these two groups using a log-rank test. RESULTS All patients who underwent surgery were adult women with a mean age of 40.4 ± 9.2 years (range 24-63 years). Ovary-preserving surgery was performed in 38 (59.4%) patients who desired to preserve their ovaries, incidentally in 19 (29.7%) patients with a preoperative diagnosis other than endometrial carcinoma, and in seven patients (10.9%) with unknown reasons. The 5-year recurrence-free survival rate was 98.3% with a median follow up of 44.6 months (range 1.0-126.9 months). Eight patients required adjuvant treatment (12.5%); one patient had documented local recurrence (1.6%); and no metachronous ovarian malignancy occurred during follow up. CONCLUSION Preservation of bilateral ovaries does not increase cancer-related mortality. A more conservative approach to surgical staging may be considered in premenopausal women with early-stage endometrial cancer without risk factors.

Comparison of clinical outcomes and spectral Doppler indices of uterine and ovarian stromal arteries in women undergoing myomectomy with or without hypogastric arterial ligation.

To compare clinical outcomes and hemodynamic alterations of uterine and ovarian stromal arteries between patients with symptomatic myomas undergoing myomectomy preceded by arterial ligation and those undergoing myomectomy alone.

Difficulty in diagnosis and different prognoses between colorectal cancer with ovarian metastasis and advanced ovarian cancer: An empirical study of different surgical adoptions

OBJECTIVE To determine the clinical manifestations and optimal management of female patients with advanced colorectal cancer (CRC) metastasis in ovaries mimicking advanced ovarian malignancy. MATERIALS AND METHODS A retrospective medical records review of female patients with primary CRC metastasis to ovaries, which were initially diagnosed as ovarian malignancy, and treated between 2001 and 2013. Clinical presentations, pathologic findings, and treatment outcomes were analyzed. RESULTS In total, 19 cases were collected in the study through a hospital tumor registry. The mean age of the patients at the time of diagnosis was 45 years (range, 28-63 years). The most common symptoms were abdominal pain or increased abdominal girth (63%). None of them had rectal bleeding. The ratio of cancer antigen-125 to carcinoembryonic antigen was available in 13 out 19 patients (less than 25 in 76.9%). Barium enema or colonoscopic exam was only performed in 10 outpatients. None of them had a positive finding. All 19 patients went for surgery, all of them had ovarian metastasis but only eight of them had bilateral involvement, and 14 of them had carcinomatosis. All patients went for either optimal cytoreduction surgery or suboptimal cytoreduction surgery. The patients who received optimal cytoreduction surgery had a significant better progression-free and overall survival than those who did not. CONCLUSION Clinical manifestations of primary CRC with ovarian metastasis may be confused with advanced ovarian cancer. Negative barium enema or colonoscopic exam cannot rule out the possibility of CRC. For patients with a cancer antigen-125 to carcinoembryonic antigen ratio less than 25, 76% are good reference of CRC metastasis to ovaries. Optimal cytoreduction surgery like that used for treating advanced ovarian cancer had a better prognosis than suboptimal cytoreduction colorectal cancer treatment.

The use of weekly topotecan in the treatment of heavily pretreated recurrent epithelial ovarian and primary peritoneal cancer: The Kaohsiung Chang Gung experience

OBJECTIVE We attempted to investigate the safety and efficacy of alternative weekly topotecan dosing in a heavily pretreated Taiwanese population with recurrent epithelial ovarian cancer (EOC) and primary peritoneal carcinoma (PPC). MATERIALS AND METHODS We retrospectively reviewed the medical records of patients with recurrent EOC and PPC who had been treated with weekly topotecan between November 2008 and May 2012. Topotecan was given at a dose of 2.75-4 mg/m(2) via a 30-minute intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity occurred. RESULTS Thirty-two patients were identified and 24 (75%) of them had received at least two previous regimens of chemotherapy; the median number of treatment courses was seven. The main toxicities (Grades 3 and 4) were anemia in seven (21.9%), neutropenia in six (18.8%), and thrombocytopenia in two patients (6.2%). No deaths were attributable to the therapy. Overall, seven patients (21.9%) showed a partial response (PR), while seven patients (21.9%) with stable disease (SD) were observed. Furthermore, we found a favorable response and toxicity profile in patients who received the lowest dose intensity (2.75 mg/m(2)). The median progression-free survival (PFS) and overall survival (OS) were 3 months [95% confidence interval (CI) 2.7-3.2] and 20 months (95% CI 11.1-28.9), respectively. CONCLUSION Topotecan administered as a weekly dosage (2.75-4 mg/m(2)) seems to be a tolerable regimen with modest activity in a Taiwanese population. Although the lower dose schedule showed a higher response with a better toxicity profile, further studies with more cases are needed to confirm this finding.

Pretreatment Factors Associated with Recurrence for Patients with Cervical Cancer International Federation of Gynecology and Obstetrics Stage IB1 Disease

Background: Pretreatment prognostic information is lacking for patients with cervical cancer International Federation of Gynecology and Obstetrics (FIGO) stage IB1 disease. Thus, we attempted to identify a high-risk subgroup among them prior to treatment. Methods: Cervical cancer FIGO stage IB1 patients who had received curative treatment with various modalities in our institute between January 2004 and December 2010 were enrolled. Pretreatment clinical parameters including age, squamous cell carcinoma antigen (SCC-Ag), carcinoembryonic antigen, hemoglobin (Hb) level, platelet count, histological type, and treatment modality were analyzed for treatment outcomes. Results: One hundred ninety-seven patients were included with a median follow-up of 66 months (range 6-119 months). In Cox regression analysis, only SCC histology (HR 0.457, 95% CI 0.241-0.967, p = 0.017) was an independent factor predicting better disease-free survival (DFS). Among SCC histology, patients with an Hb level less than 12 g/dl and a SCC-Ag level more than 3 ng/ml had worse treatment outcomes. The 5-year DFS rates were 89.2, 69.3, and 44.4% for the patients at low-risk (SCC, Hb >12 g/dl, SCC-Ag ≤3 ng/ml), intermediate-risk (non-SCC), and high-risk (SCC, Hb ≤12 g/dl, SCC-Ag >3 ng/ml), respectively (p < 0.001). Conclusion: Non-SCC and SCC histology with both anemia and high pretreatment SCC-Ag level were associated with recurrence. Further validation studies are warranted for clarification.

Treatment outcomes of patients with stage II pure endometrioid-type endometrial cancer: a Taiwanese Gynecologic Oncology Group (TGOG-2006) retrospective cohort study

Objective Choice of hysterectomy and adjuvant treatment for International Federation of Gynecology and Obstetrics (FIGO) 2009 stage II endometrioid endometrial cancer (EEC) is still controversial. Aims of this study were to evaluate survival benefits and adverse effects of different hysterectomies with or without adjuvant radiotherapy (RT), and to identify prognostic factors. Methods The patients at 14 member hospitals of the Taiwanese Gynecologic Oncology Group from 1992 to 2013 were retrospectively investigated. Patients were divided into simple hysterectomy (SH) alone, SH with RT, radical hysterectomy (RH) alone, and RH with RT groups. Endpoints were recurrence-free survival (RFS), overall survival (OS), disease-specific survival (DSS), adverse effects and prognostic factors for survival. Results Total of 246 patients were enrolled. The 5-year RFS, OS, DSS and recurrence rates for the entire cohort were 89.5%, 94.3%, 96.2% and 10.2%, respectively. Patients receiving RH had more adverse effects including blood loss (p<0.001), recurrent urinary tract infections (p=0.013), and leg lymphedema (p=0.038). Age over 50-year (HR=9.2; 95% confidence interval [CI], 1.2–70.9) and grade 3 histology (HR=7.28; 95% CI, 1.45–36.6) were independent predictors of OS. Grade 3 histology was an independent predictor of RFS (HR=5.13; 95% CI, 1.38–19.1) and DSS (HR=5.97; 95% CI, 1.06–58.7). Patients receiving adjuvant RT had lower locoregional recurrence (p=0.046), but no impact on survival. Conclusion Different treatment modalities yield similar survival outcomes. Patients receiving SH with RT had lower locoregional recurrent with acceptable morbidity. Age and tumor grading remained significant predictors for survival among patients with FIGO 2009 stage II EEC.

Clinicopathologic Features and Treatment Outcomes in Patients with Stage I, High-Risk Histology or High-Grade Endometrial Cancer after Primary Staging Surgery: A Taiwanese Gynecologic Oncology Group Study

To investigate the clinicopathological features and treatment outcomes in patients with stage I, high-risk endometrial cancer. Patients with International Federation of Gynecology and Obstetrics stage I, papillary serous, clear cell, or grade 3 endometrioid carcinoma treated between 2000 and 2012 were analyzed for the clinical and pathological factors in relation to prognosis. A total of 267 patients (stage IA; n = 175, stage IB; n = 92) were included. Among the clinicopathological features, stage and age were significant prognostic factors. The recurrence rate and overall survival for stage IB versus IA were 22.8% versus 9.1% (p = 0.003) and 149.7 months versus 201.8 months (p < 0.001), respectively. The patients >60 years of age also had a higher recurrence rate (21.7% versus 9.7%, p = 0.008) and poorer survival (102.0 months versus 196.8 months, p = 0.001) than those ≤60 years of age. Distant recurrence (64.9%) occurred more frequently than local recurrence (24.3%) and local combined with distant recurrence (10.8%) (p < 0.001). The postoperative treatment modality had no impact on tumor recurrence rate, recurrence site, or overall survival. Distant recurrence is a major cause of treatment failure in patients with stage I, high-risk endometrial cancer. However, current adjuvant treatment appeared to have little effect in preventing its occurrence.