Duk Soo Bae

Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial.

BACKGROUND Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. METHODS For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m(2)) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients. FINDINGS 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 [54%] of 452 patients in the placebo group vs 258 [56%] of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 [17%] patients vs 27 [6%], respectively) and higher incidences of oedema (294 [64%] patients had any-grade oedema in the trebananib group vs 127 [28%] patients in the placebo group). Grade 3 or higher adverse events included ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 [17%] vs 46 [10%]). INTERPRETATION Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. FUNDING Amgen.

Single-Port Access Laparoscopic-Assisted Vaginal Hysterectomy: A Novel Method with a Wound Retractor and a Glove

STUDY OBJECTIVE To present our initial experience with single port-access laparoscopic-assisted vaginal hysterectomy (SPA-LAVH) by use of a wound retractor and a glove. DESIGN Continuing, prospective study (Canadian Task Force classification II-3). SETTING University teaching, research hospital, and a tertiary care center. PATIENTS We performed the SPA-LAVH in 24 patients from May 6, 2008, through October 8, 2008. INTERVENTIONS All cases of SPA-LAVH were performed by a single surgeon (T. J. K.). MEASUREMENTS AND MAIN RESULTS We analyzed the data to determine the outcome of SPA-LAVH and compared the initial 10 cases (group A) and the latter 14 cases (group B) to consider the learning curve. Median and range are used to describe non-normal data. A total of 24 consecutive patients have undergone SPA-LAVH, for benign gynecologic conditions, including 16 uterine myomas and 8 cases of adenomyosis, regardless of body mass index or previous abdominal or pelvic surgery. All cases but 3 were performed exclusively through a single port. The median operative time, weight of the uterus, and estimated blood loss were 119 minutes (range 90 to 255 minutes), 347 g (range 225 to 732 g), and 400 mL (range 100 to 1000 mL), respectively. The decline in hemoglobin from before surgery to postoperative day 1 was from 0.7 to 4.3 g/dL, with a median of 2.05 g/dL. The median hospital stay (postoperative day) was 3 days (range 3 to 7). When we compared the operative outcomes between the 2 groups, there was a tendency toward a decreased operative time in group B, although the difference was not significant. However, there was a significant decrease in the estimated blood loss and hospital stay in group B (p = .00, = .04, respectively). CONCLUSION The SPA-LAVH was safe and effective, and the procedure could be learned over a short period of time. Additional experience and continued investigation are warranted.

Single Port Access Laparoscopic Adnexal Surgery

STUDY OBJECTIVE To estimate the feasibility, safety, and operative outcomes for the management of adnexal masses by single port access (SPA) laparoscopy with a wound retractor and a surgical glove. DESIGN A prospective single-center study (Canadian Task Force classification III). SETTING University hospital. PATIENTS Twenty-four well selected patients with adnexal masses on imaging scans recruited from June 2008 through January 2009. INTERVENTIONS Single port access laparoscopic adnexal surgery. MEASUREMENTS AND MAIN RESULTS Single port access laparoscopic adnexal surgery was successfully completed in 22 of 24 patients. The median age of the patients was 45 years (range 23-63 years), and the median body mass index was 22 (range 18-29). The median tumor size was 5 cm (range 3-12 cm). The median operative time was 70 minutes (range 40-128 minutes). The estimated blood loss was minimal (range 10-100mL). The postoperative course was uneventful in all patients. The median postoperative hospital stay was 1 day (range 1-3 days). No postoperative complications were observed at follow-up. The 2 failed cases were as follow: 1 required an additional trocar for adequate adhesiolysis, and the other a staging laparotomy because of the finding of a borderline ovarian malignancy on frozen section pathologic study. CONCLUSION The single port access laparoscopic adnexal surgery was safe and feasible and provided almost no visual scar.

Increased expression of pAKT is associated with radiation resistance in cervical cancer.

Phosphorylated AKT (pAKT) is a major contributor to radioresistance in human cancers. The aim of this study was to investigate the association of pAKT expression and radiation resistance in cervical cancer. A retrospective review was made of the records of 27 women who received primary radiation therapy due to locally advanced cervical cancer (LACC) with FIGO stage IIB–IVA. Nine patients regarded as radiation resistant developed local recurrences with a median progression free interval of 9 months. Eighteen patients did not show local recurrences, and were regarded as a radiation-sensitive group. Using pretreatment paraffin-embedded tissues, we evaluated pAKT expression by immunohistochemistry. A significant association was found between the level of pAKT expression and local recurrence. Immunohistochemical staining for pAKT was significantly more frequent in the radiation-resistant than in the radiation-sensitive group (P=0.004). The mean progression-free survival was 86 months for patients with pAKT-negative staining (19 cases) and 44 months for patients with pAKT-positive expression (eight cases) (P=0.008). These results suggest that signalling from phosphatidylinositide 3-kinase/pAKT can lead to radiation resistance, and that evaluation of pAKT may be a prognostic marker for response to radiotherapy in LACC.

Increased expression of Toll‐like receptor 5 during progression of cervical neoplasia

The purpose of this study was to determine whether Toll-like receptor 5 (TLR5) expression was associated with disease progression in cervical neoplasia. TLR5 expression was evaluated by immunohistochemistry (IHC) in 55 formalin-fixed paraffin-embedded cervical tissues; 10 normal cervical specimens, 9 low-grade cervical intraepithelial neoplasias (CINs), 12 high-grade CINs, and 24 invasive squamous cell carcinomas (ISCCs). TLR5 expression was also evaluated at the RNA level, in fresh, frozen cervical carcinoma tissues by real-time quantitative RT-PCR. TLR5 expression, which was mainly observed as cytoplasmic staining, gradually increased in accordance with the histopathologic grade in the following order: low-grade CIN less than high-grade CIN less than ISCC (P< 0.001). Immunohistochemical staining showed that TLR5 expression was undetectable (80%) or weak (20%) in normal cervical squamous epithelial tissues. However, moderate expression was detected in 33.3% of low-grade CIN (3/9), 41.7% of high-grade CIN (5/12), and 45.8% of ISCC (11/24). Strong expression was detected in as much as 33.3% of high-grade CIN (4/12) and 50% of ISCC (12/24). Contrary to IHC results, real-time quantitative RT-PCR revealed that TLR5 expression in tumors was not statistically different compared to normal cervical tissues (P= 0.1452). The IHC result suggests that TLR5 may play a significant role in tumor progression of cervical neoplasia and may represent a useful marker for malignant transformation of cervical squamous cells.

AGR2, a mucinous ovarian cancer marker, promotes cell proliferation and migration

Ovarian cancer is a leading cause of death in women. Early detection of ovarian cancer is essential to decrease mortality. However, the early diagnosis of ovarian cancer is difficult due to a lack of clinical symptoms and suitable molecular diagnostic markers. Thus, identification of meaningful tumor biomarkers with potential clinical application is clearly needed. To search for a biomarker for the early detection of ovarian cancer, we identified human anterior gradient 2 (AGR2) from our systematic analysis of paired normal and ovarian tumor tissue cDNA microarray. We noted a marked overexpression of AGR2 mRNA and protein in early stage mucinous ovarian tumors compared to normal ovarian tissues and serous type ovarian tumors by Western blot analysis and immunohistochemistry. To further elucidate the role of AGR2 in ovarian tumorigenesis, stable 2774 human ovarian cancer cell lines overexpressing AGR2 were established. Forced expression of AGR2 in 2774 cells enhanced the growth and migration of ovarian cancer cells. AGR2 protein was detected in the serum of mucinous ovarian cancer patients by Western blot and ELISA analysis. Thus, AGR2 is a potential biomarker for the diagnosis of mucinous ovarian cancer and an ELISA assay may facilitate the early detection of mucinous ovarian cancer using patient serum.

Low-grade endometrial stromal sarcoma: a single center's experience with 22 cases.

The aim of this retrospective study was to evaluate the clinical behavior and management outcome of low-grade endometrial stromal sarcoma (LGESS). From September 1994, to March 2007, 22 patients with histologically proven stage I LGESS were included in this study. Clinicopathologic variables, recurrence, and management outcomes were reviewed retrospectively. The median age of the 22 patients was 43 years. The most common presenting symptom was abnormal vaginal bleeding. All patients underwent a hysterectomy and had stage I disease. Six patients had adjuvant therapy after the hysterectomy. The median follow-up period was 77 months (range 12–202 months). Ten patients had disease recurrence. The median disease-free survival period was 111 months (range 6–182 months). The pelvis (eight cases) was the most common site of recurrence followed by the lung (four cases) and the liver (one case). Recurrent disease was treated with surgery (one case), surgery plus chemotherapy (five cases), chemotherapy (two cases), and surgery plus radiotherapy (two cases). Two patients died after 25 and 54 months after disease recurrence. Treatment with a bilateral salpingo-oophorectomy or adjuvant chemoradiation did not affect the disease-free interval. LGESS is usually a slow-growing neoplasm with an indolent clinical course. Surgery is the primary treatment for recurrent endometrial stromal sarcoma when feasible. Adjuvant treatment (radiotherapy, chemotherapy, or both) had no effect on the prognosis of patients with stage I disease

Clinicopathologic characteristics of granulosa cell tumors of the ovary: a multicenter retrospective study

Objective To evaluate the clinicopathologic characteristics and prognostic factors of ovarian granulosa cell tumors. Methods Medical records of 113 patients presenting between January 1995 and December 2007 were retrospectively reviewed. Results One-hundred two patients had adult type disease, with a mean age of 46.2 years (range, 18 to 83 years) and a mean follow-up period of 54.7 months (range, 1 to 155 months). The distribution of FIGO stages was 86 patients at stage I, 11 at stage II, and 5 at stage III. During follow-up, ten patients recurred at a mean time of 48 months (range, 4 to 109 months). Among them, three patients died after a mean of 57 months (range, 25 to 103 months). In recurrence analysis, advanced stage (p=0.032) and presence of residual disease (p=0.012) were statistically significant, and age<40 years, premenopause and positive washing cytology were marginally significant (p<0.1). In multivariate analysis, stage was the only factor associated with recurrence; adjuvant chemotherapy and fertility-sparing surgery were not statistically significant. Among 36 patients with fertility-sparing operations, eight patients had nine pregnancies and delivered seven babies. Eleven patients had juvenile type tumors; the mean age was 20.0 years (range, 8 to 45 years) and the mean follow-up period was 69.8 months (range, 20 to 156 months). The distribution of FIGO stage was nine patients at stage I and two at stage III. There were no recurrences or deaths reported. Four patients had seven pregnancies and delivered six babies. Conclusion Stage is the only factor associated with disease-free survival, and fertility-sparing surgery may be a treatment option for women with early-stage disease who want to retain fertility.

Prognostic significance of volume-based metabolic parameters in uterine cervical cancer determined using 18F-fluorodeoxyglucose positron emission tomography.

ObjectiveWe compared the prognostic value of volume-based metabolic parameters determined using fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) (18F-FDG PET) (with other prognostic parameters in uterine cervical cancer. MethodsThe subjects were 73 female patients who had an initial diagnosis of uterine cervical cancer and who underwent 18F-FDG PET. Various metabolic or volume-based PET parameters including maximum and average standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) were measured in primary cervical tumors. Survival analysis for disease-free survival or progression-free survival was performed with a Kaplan-Meier method using PET parameters and other clinical variables. For determining independent prognostic factors, Cox regression analysis was performed. ResultsRecurrence or disease progression occurred in 23 patients (31.5%). In univariate analysis, patient age (cutoff, 57 years, P < 0.05), International Federation of Gynecology and Obstetrics stage (P = 0.07), primary tumor size (cutoff, 6.7 cm; P < 0.05), lymph node status on PET (P < 0.005), treatment method (P < 0.01), metabolic tumor volume (cutoff, 82 cm3; P = 0.001), and TLG (cutoff, 7600; P = 0.005) were significant predictors of recurrence or progression. In multivariate analysis, both lymph node status on PET (hazard ratio, 1.042 [negative vs intrapelvic metastasis only], 7.008 [negative vs extrapelvic metastasis]; P < 0.001) and TLG (cutoff, 7600; hazard ratio, 2.981; P < 0.05) were independent prognostic factors for predicting recurrence. ConclusionsIn uterine cervical cancer, TLG, a volume-based metabolic parameter, and lymph node status on PET may be significant independent prognostic factors for event-free survival.Objective We compared the prognostic value of volume-based metabolic parameters determined using fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) (18F-FDG PET) (with other prognostic parameters in uterine cervical cancer. Methods The subjects were 73 female patients who had an initial diagnosis of uterine cervical cancer and who underwent 18F-FDG PET. Various metabolic or volume-based PET parameters including maximum and average standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) were measured in primary cervical tumors. Survival analysis for disease-free survival or progression-free survival was performed with a Kaplan-Meier method using PET parameters and other clinical variables. For determining independent prognostic factors, Cox regression analysis was performed. Results Recurrence or disease progression occurred in 23 patients (31.5%). In univariate analysis, patient age (cutoff, 57 years, P < 0.05), International Federation of Gynecology and Obstetrics stage (P = 0.07), primary tumor size (cutoff, 6.7 cm; P < 0.05), lymph node status on PET (P < 0.005), treatment method (P < 0.01), metabolic tumor volume (cutoff, 82 cm3; P = 0.001), and TLG (cutoff, 7600; P = 0.005) were significant predictors of recurrence or progression. In multivariate analysis, both lymph node status on PET (hazard ratio, 1.042 [negative vs intrapelvic metastasis only], 7.008 [negative vs extrapelvic metastasis]; P < 0.001) and TLG (cutoff, 7600; hazard ratio, 2.981; P < 0.05) were independent prognostic factors for predicting recurrence. Conclusions In uterine cervical cancer, TLG, a volume-based metabolic parameter, and lymph node status on PET may be significant independent prognostic factors for event-free survival.

The interactions between MicroRNA-200c and BRD7 in endometrial carcinoma

OBJECTIVE Increased expression of miR-200c was recently reported in endometrial carcinoma compared with normal tissues. In this study, we evaluated the role of miR-200c in cell growth and drug sensitivity in endometrial carcinoma and investigated the underlying mechanisms. METHODS The expression of miR-200c in human endometrial tissues was detected by quantitative RT-PCR. The transfection with anti-miRNA (anti-miR) or the premature form of miRNA (pre-miR) was performed to regulate the level of expression of miRNA-200c in endometrial carcinoma cells, HEC-1A and Ishikawa. To identify the target genes for miR-200c, we performed mRNA microarray after pre-miR-200c transfection in HEC-1A cells. RESULTS We found that miR-200c expression was increased in endometrial carcinoma compared with normal endometrial tissues. Anti-miR or pre-miR-200c could regulate cell survival, proliferation, and apoptosis and affect cytotoxicity in endometrial cancer cells. Through mRNA microarray analysis, we found that miR-200c inhibits the expression of BRD7, which was recently reported as a potential tumor suppressor gene. MiR-200c regulated the translocation of β-catenin from the cytoplasm to the nucleus via inhibition of BRD7, resulting in increased expression of its transcriptional target genes, cyclinD1 and c-myc. CONCLUSION The interaction between miR-200c and BRD7 might have important roles in controlling growth of endometrial of cancer cells and suggest a novel target pathway for treatment of this cancer.