DKK3, Downregulated in Invasive Epithelial Ovarian Cancer, Is Associated with Chemoresistance and Enhanced Paclitaxel Susceptibility via Inhibition of the ß-Catenin-P-Glycoprotein Signaling Pathway.

Dickkopf-3 (DKK3), a tumor suppressor, is frequently downregulated in various cancers. However, the role of DKK3 in ovarian cancer has not been evaluated. This study aimed to assess aberrant DKK3 expression and its role in epithelial ovarian carcinoma. DKK3 expression was assessed using immunohistochemistry with tissue blocks from 82 patients with invasive carcinoma, and 15 normal, 19 benign, and 10 borderline tumors as controls. Survival data were analyzed using Kaplan-Meier and Cox regression analysis. Paclitaxel-resistant cells were established using TOV-21G and OV-90 cell lines. Protein expression was assessed using Western blotting and immunofluorescence analysis. Cell viability was assessed using the MT assay and 3D-spheroid assay. Cell migration was determined using a migration assay. DKK3 was significantly downregulated in invasive carcinoma compared to that in normal, benign, and borderline tumors. DKK3 loss occurred in 56.1% invasive carcinomas and was significantly associated with disease-free survival and chemoresistance in serous adenocarcinoma. DKK3 was lost in paclitaxel-resistant cells, while ß-catenin and P-glycoprotein were upregulated. Exogenous secreted DKK3, incorporated by cells, enhanced anti-tumoral effect and paclitaxel susceptibility in paclitaxel-resistant cells, and reduced the levels of active ß-catenin and its downstream P-glycoprotein, suggesting that DKK3 can be used as a therapeutic for targeting paclitaxel-resistant cancer.

Fertility-sparing surgery for borderline ovarian tumors: oncologic safety and reproductive outcomes.

INTRODUCTION: To evaluate the oncological safety and reproductive outcomes of patients with borderline ovarian tumors (BOTs) treated with fertility-sparing surgery. METHODS: Patients with BOTs who underwent radical or fertility-sparing surgery between 1997 and 2009 were identified from an institutional database. The recurrence rates were compared between the 2 surgery groups. To compare the reproductive outcomes, all patients who underwent fertility-sparing surgery were interviewed by telephone. RESULTS: One hundred forty-three patients underwent radical surgery, and 155 patients underwent fertility-sparing surgery. After a median interval of 38 months from the initial surgery (range, 10-77 months), 19 patients had a recurrence. The recurrence rate was similar in the radical and fertility-sparing surgery groups (4.9% and 7.7%, respectively; P = 0.280). In the fertility-sparing surgery group, however, the main site of recurrence was the remaining ovary that was successfully salvaged with a second round of fertility-sparing surgery. Of 51 patients who attempted to conceive, 45 patients (88.2%) were successful and resulted in 54 term deliveries. CONCLUSIONS: Fertility-sparing surgery for BOTs is safe and can result in future pregnancies, suggesting that such surgery should be considered for young patients who desire preservation of fertility.

Prognostic value of the copper transporters, CTR1 and CTR2, in patients with ovarian carcinoma receiving platinum-based chemotherapy.

OBJECTIVE: CTR1 and CTR2 are copper transporters that have been associated with platinum sensitivity in several human cancers. We investigated the prognostic significance of CTR1 and CTR2 in women with ovarian carcinoma. MATERIALS AND METHODS: We evaluated the expression of CTR1 and CTR2 using real-time PCR in 40 women with ovarian carcinoma (IIb=2, IIIb=2, IIIc=30, IV=6). We compared the expression of CTR1 and CTR2 with participants' clinicopathological findings. RESULTS: We found lower expression of CTR1 and CTR2 mRNA in ovarian cancer cells against normal ovarian tissue with statistically significant differences (p=0.018 and 0.011, respectively). High CTR1 expression was a prognostic factor for improved survival after adjusting for age, tumor grade, stage, residual tumor, and CTR2 mRNA expression (HR, 0.35; 95% CI, 0.15-0.84). However, CTR2 expression did not exhibit any prognostic significance. Of the 20 women with elevated CTR1 expression, 17 (85%) were sensitive to platinum-based chemotherapy. Of the 7 women with low CTR1 expression and high CTR2 expression, 6 (85.7%) were resistant to platinum-based chemotherapy and had the shortest progression-free survival of all women in our study sample. CONCLUSION: In our sample of 40 women with ovarian carcinoma, high CTR1 expression was significantly associated with sensitivity to platinum-based chemotherapy and longer progression-free survival. Conversely, low CTR1 expression and high CTR2 expression were significantly associated with resistance to platinum-based chemotherapy and the shortest survival.

Phase II study of belotecan, a camptothecin analogue, in combination with carboplatin for the treatment of recurrent ovarian cancer.

BACKGROUND: Belotecan (CKD602; Camtobell, Chong Keun Dang Corp., Seoul, Korea) is a recently developed camptothecin derivative with antitumor properties. This phase II study was designed to evaluate the toxicity and efficacy of belotecan combined with carboplatin in patients with recurrent epithelial ovarian cancer (EOC). METHODS: Thirty-eight patients with recurrent EOC were treated with belotecan 0.3 mg/m(2) /day (days 1-5) and carboplatin AUC 5 (day 5) every 3 weeks for 6 cycles. The primary objective was to determine the response rate as defined by Response Evaluation Criteria in Solid Tumors and CA-125 response. Other end points included toxicities and progression-free survival (PFS). RESULTS: All 38 patients were assessed for toxicity, and 35 patients were assessed for response. The overall response rate was 57.1%; there were 7 complete responses (20.0%), 13 partial responses (37.1%), 6 patients with stable disease (17.1%), and 9 patients with progressive disease (25.7%). Grades 3 and 4 hematologic toxicities included neutropenia (28.8%), thrombocytopenia (19.8%), and anemia (14.4%), and there were 2 episodes of febrile neutropenia. Median PFS was 7 months, with a median follow-up of 12 months. CONCLUSIONS: The newly developed topoisomerase I inhibitor belotecan (CKD-602) combined with carboplatin is a well-tolerated regimen with activity in recurrent EOC. Further testing of this regimen is warranted to further characterize efficacy and indications for use.

Overexpression of Galectin-3 and its clinical significance in ovarian carcinoma.

BACKGROUND: Galectin-3 (Gal-3) is a ß-galactoside-binding lectin involved in regulating cell growth, angiogenesis, and tumor progression. We investigated the clinical significance of Gal-3 expression including its possible use as a prognostic marker or therapeutic target in epithelial ovarian carcinoma (EOC). METHODS: Gal-3 expression was evaluated by immunohistochemistry in 71 patients with 54 serous, 13 endometrioid, and 4 mucinous ovarian carcinomas. We assessed the correlation of Gal-3 expression with clinical characteristics including histology, optimal debulking, chemosensitivity, and survival. In vitro, Gal-3 was inhibited using siRNA to evaluate its role in cell growth and sensitivity to chemotherapeutic agents in ovarian carcinoma cell lines. RESULTS: Gal-3 protein, which was mainly cytoplasmic in location, was observed in a majority (63/71, 88.7%) of the EOCs but not in normal ovarian tissues (P < 0.001). High Gal-3 expression in EOCs correlated with shorter progression-free survival (PFS) of patients (P = 0.039; 43.1 and 49.5 months, respectively). Moreover, cotreatment with Gal-3 siRNA and paclitaxel showed an enhanced cytotoxic effect compared with control siRNA in SKOV3 cells. CONCLUSION: These findings suggest that Gal-3 expression can be a prognostic factor for PFS and may be involved in regulating the response to paclitaxel-based chemotherapy in the treatment of EOC.

Myxoid malignant fibrous histiocytoma of the ovary: a case report.

A 46-year-old woman presented with whole abdominal discomfort, and imaging revealed a 3-cm-sized ill-defined ovarian mass with extensive peritoneal carcinomatosis. Histologic examination showed malignant fibrous histiocytoma of ovary with predominant myxoid stroma. Microscopic examination showed a highly cellular neoplasm composed of fibroblast-like cells with a predominant myxoid stroma and high pleomorphism and mitotic activity. Immunohistochemically, the tumor was negative for smooth muscle actin, desmin, S-100, pancytokeratin, c-kit, epithelial membrane antigen, and calretinin. Malignant fibrous histiocytoma of ovary is extremely rare, with only six previously reported cases. To the best of our knowledge, the myxoid type of malignant fibrous histiocytoma of ovary has not been previously reported in the English literature except for a case arising in a dermoid cyst of ovary. We present the case and briefly discuss the differential diagnosis.

Single-port access (SPA) laparoscopic surgery in gynecology: a surgeon's experience with an initial 200 cases.

OBJECTIVE: To report our initial two hundred single-port access (SPA) gynecologic surgeries and present the perioperative outcomes. STUDY DESIGN: This is a prospective single-center study (Canadian Task Force classification II-2). Two hundred selected patients with gynecological disease were recruited for the study from May 2008 through December 2009 at Samsung Medical Center. RESULTS: Two hundred patients underwent SPA gynecological surgery (105 a total hysterectomy; 11 a subtotal hysterectomy; 43 an oophorectomy; 31 an ovarian cystectomy; 5 a salpingectomy; 2 a myomectomy; 3 adhesiolysis only). The median age and body mass index were 45.5 and 22.9 kg/m(2), respectively. SPA surgery was successfully completed in 187 patients, without the need for ancillary ports (93.5%). Two cases required a conventional multiport, and nine cases needed one additional port. Two patients were converted to a laparotomy. One intra- and five post-operative complications occurred. The complication rate was 3.2% (6/187). The median operative time was 120 min (54-250) for a total hysterectomy, 180 (150-345) for a subtotal hysterectomy, 60 (27-245) for an oophorectomy, 105 (50-185) for a cystectomy, and 60 (30-115) for a salpingectomy. CONCLUSION: Single-port surgery was safe and feasible for gynecological indications. Further study of single-port surgery is required to determine whether it has significant benefits compared to conventional techniques.

Peritoneal tuberculosis: a retrospective review of 20 cases and comparison with primary peritoneal carcinoma.

INTRODUCTION: To evaluate the clinical features of peritoneal tuberculosis (TB) and to compare them with those of primary peritoneal carcinoma (PPC). METHODS: We conducted a retrospective review of women with peritoneal TB who were managed at Samsung Medical Center from January 1996 to October 2006. As a control sample, patients with a diagnosis of PPC during the same period were also selected for comparison. RESULTS: During the study period, we identified 20 female patients with peritoneal TB. The median age was 39 years (range, 23-69 years), and the median cancer antigen 125 (CA-125) level was 448 U/mL (range, 32-1725 U/mL). Seventeen patients with PPC whom we examined were older, with a median age of 63 years (range, 50-73 years); their median CA-125 level was higher at 1848 U/mL (range, 42-14,380 U/mL). Compared with those of PPC, the radiologic findings of peritoneal TB indicated less severe involvement of the omentum and the mesentery (P = 0.03). Among the 20 patients who underwent operations, 6 (30%) underwent exploratory laparotomy; 12 (60%), diagnostic laparoscopy; and 2 (10%), laparoscopy converted to laparotomy because of severe adhesion. Frozen tissue sections revealed chronic granulomatous tissue reaction in 15 (83.3%) of 18 women with peritoneal TB. CONCLUSIONS: Maintaining a high index of suspicion is very important for the successful treatment of peritoneal TB, especially in developing countries. Age, CA-125 level, and omental involvement as identified by computed tomography may be helpful for the differential diagnosis of peritoneal TB and PPC.

Sequence-dependent hematologic side effects of topotecan and cisplatin in persistent or recurrent cervical cancer.

OBJECTIVE: This retrospective study evaluates the efficacy and toxicity of topotecan, followed by cisplatin, in patients with persistent or recurrent cervical cancer. METHODS: Twenty-four patients were included in the study. Ninety-two cycles of chemotherapy were administered during the study period. Topotecan (0.75 mg/m(2)) was administered as a 30-minute infusion on 3 consecutive days, and cisplatin was given intravenously at a dose of 50 mg/m(2) over 1h on day 3 of every third week. RESULTS: The median number of cycles administered was 3, with a range of 1-8 cycles per patient. There were 4 (16.7%) complete responses, 3 (12.5%) partial responses, and 5 (20.8%) stable disease. All of the patients with a complete response had received palliative radiation or surgery for pain or an isolated solitary recurrence prior to chemotherapy. There were no treatment delays of >7 days per cycle due to hematologic toxicity. There were 59 days of delay (average, 0.6 days per cycle) in 21 of 92 (22.8%) cycles and two episodes of dose reduction (cisplatin, 50% reduction) in 2 patients due to low creatinine clearance (30-60 mL/min). Overall, grade 3/4 anemia, thrombocytopenia, and neutropenia were experienced in 13.1%, 1.1%, and 18.5% of the courses, or 33.4%, 4.2%, and 45.8% of the patients, respectively. CONCLUSION: Combination chemotherapy, consisting of topotecan on days 1-3 and cisplatin on day 3, showed a relatively low rate of hematologic toxicity, as compared with the regimen of topotecan on days 1-3 and cisplatin on day 1, as used in previous studies.

Low dynamin 2 expression is associated with tumor invasion and metastasis in invasive squamous cell carcinoma of cervix.

Dynamin 2 is known as a protein involved in cell migration and endocytosis. We aimed to investigate the association between dynamin 2 expressions and tumor progression in early cervical carcinoma (IB1-IIA). Dynamin 2 expression was evaluated at protein level in thirty seven paraffin-embedded, formalin-fixed tissues including four normal cervix tissues and compared with pathologic risk factors for recurrence after surgery in thirty three patients with squamous cell carcinoma of the cervix. The expression of dynamin 2 was not different according to clinical stage and lympho-vascular space invasion. However, there were inverse correlations between dynamin 2 expression and the depth of invasion in cervix (p = 0.003) and lymph node (LN) metastasis (p = 0.001). To evaluate the mechanism of dynamin 2 in tumor invasion and metastasis, we performed an in vitro experiment with dynamin 2 siRNA using several cervical carcinoma cell lines such as HeLa, MS751 and SiHa cells. We found the inhibition of dynamin 2 using specific siRNA enhanced the expression of matrix metalloproteinase-2. These results suggested that dynamin 2 might be involved in preventing tumor invasion and LN metastasis, possibly in relation with extracellular matrix degradation, and may be a prognostic marker for these risk factors in early squamous cell carcinoma of the cervix.

Single port access laparoscopic adnexal surgery versus conventional laparoscopic adnexal surgery: a comparison of peri-operative outcomes.

OBJECTIVE: The objective of the study was to compare the peri-operative outcomes of single port access (SPA) laparoscopic adnexal surgery and conventional laparoscopic adnexal surgery. STUDY DESIGN: This is a retrospective case-control study matched by body mass index (BMI; kg/m(2)). A single surgeon (T-JK) performed 17 SPA laparoscopic adnexal surgeries (cases) consecutively between December 2008 and March 2009; 34 conventional laparoscopic adnexal surgeries (controls) were performed by another surgeon who had similar surgical skill at our hospital during the same time period. Data on the SPA laparoscopic adnexal surgery cases were collected prospectively into our data registry after Institutional Review Board (IRB) approval and we reviewed the data on the controls from the electronic medical records with IRB approval. RESULTS: In both groups all procedures were performed without failure. Among preoperative baseline characteristics there was no difference between the two groups including preoperative size of ovarian tumor and bilaterality. The pathology findings were similar; a mature cystic teratoma was the most common pathological feature in both groups. The two groups were comparable with regard to operative outcomes according the surgery type. There were no differences between SPA and conventional groups in median operation time (64 min vs. 57.5 min, p=0.252), the number of patients that requested additional parenteral non-steroidal anti-inflammatory drugs (7 patients vs. 19 patients, p=0.597), and the absolute decrease (1.3mg/dl vs. 1.1mg/dl, p=0.640) from preoperative hemoglobin to postoperative day 1 measurements. No patient from either cohort required a blood transfusion. There were no complications in either group including umbilical incision complications in the SPA group. CONCLUSION: Our study demonstrated that SPA laparoscopic adnexal surgery had comparable operative outcomes to conventional laparoscopic adnexal surgery. A prospective comparison is needed for confirmation and to define the role of SPA in gynecological adnexal surgery.