A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.

OBJECTIVE: Vascular endothelial growth factor (VEGF) receptor-mediated signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression is associated with poor clinical outcomes. We investigated ramucirumab, a fully human anti-VEGFR-2 antibody, in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Primary endpoints were progression-free survival at 6 months (PFS-6) and confirmed objective response rate (ORR). METHODS: Women who received ≥ 1 platinum-based chemotherapeutic regimen and had a platinum-free interval of <12 months with measurable disease were eligible. Patients received 8 mg/kg ramucirumab intravenously every 2 weeks. RESULTS: Sixty patients were treated; one patient remained on study as of September 2013. The median age was 62 years (range: 27-80), and median number of prior regimens was 3. Forty-five (75%) patients had platinum refractory/resistant disease. Thirty-nine patients (65.0%) had serous tumors. PFS-6 was 25.0% (n=15/60, 95% CI: 14.7-37.9%). Best overall response was: partial response 5.0% (n=3/60), stable disease 56.7% (n=34/60), and progressive disease 33.3% (n=20/60). The most common treatment-emergent adverse events possibly related to study drug were headache (65.0%; 10.0% Grade ≥ 3), fatigue (56.7%; 3.3% Grade ≥ 3), diarrhea (28.3%; 1.7% Grade ≥ 3), hypertension (25.0%; 3.3% Grade ≥ 3), and nausea (20.0%; no Grade ≥ 3). Two patients experienced intestinal perforations (3.3% Grade ≥ 3). Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2. CONCLUSIONS: Although antitumor activity was observed, the predetermined efficacy endpoints were not met.

Ovarian Teratoid Carcinosarcoma Is an Aggressive Tumor of Probable Mullerian Derivation with a Carcinosarcomatous and Mixed Germ-Cell Morphology.

Ovarian carcinosarcoma is also referred to as malignant mixed Mullerian tumor (MMMT). It is a rare neoplasm, and although it represents less than 5% of malignant ovarian tumors, it remains generally well-known among clinicians and pathologists. Rarer yet is ovarian teratoid carcinosarcoma, defined as carcinosarcoma with the added feature of immature neuroectodermal tissue, with or without elements of primitive germ cell tumor. To our knowledge, six ovarian teratoid carcinosarcomas have been reported in the literature [Matsuura et al. J Obstet Gynaecol Res. 2010 Aug; 36(4): 907-11]. These tumors resemble nasopharyngeal tumors of the same name. We report a 55-year-old woman seen at Orlando Health's division of gynecological oncology whose pathology showed ovarian teratoid carcinosarcoma, and present what we believe to be a seventh report of this entity.

Glassy Cell Carcinoma of the Endometrium Presenting as an Intracavitary Leiomyoma on Ultrasound.

BACKGROUND Glassy cell carcinoma of the endometrium is an extremely rare variant of adenosquamous carcinoma, and it has a poor prognosis. In postmenopausal women it typically presents as unprovoked, painless uterine bleeding. Tissue sampling is necessary to establish the diagnosis. CASE REPORT A 58-year-old postmenopausal woman on no hormone replacement therapy experienced 2 months of intermittent uterine bleeding. An office transvaginal ultrasound discovered a 1.7-cm intracavitary leiomyoma, but because the endometrial stripe was not visualized, an endometrial biopsy was performed. She was found to have a Stage 1 A endometrial poorly-differentiated adenosquamous carcinoma, glassy cell carcinoma tumor of 1.5 cm in greatest dimension. She underwent a robotic total hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node mapping, and bilateral pelvic lymphadenectomy. CONCLUSIONS Glassy cell carcinoma of the endometrium can present as an intracavitary leiomyoma in postmenopausal women.

Bladder erosion by an intraperitoneal chemotherapy catheter resulting in catheter protrusion through the external urethral meatus.

BACKGROUND: Chemotherapy remains an essential part of the treatment of advanced ovarian cancer. Intraperitoneal (IP) administration has been demonstrated to provide a survival advantage over intravenous chemotherapy in three phase 3 studies. However, IP catheter complications have been a significant factor in aborting IP therapy. CASE: A 42-year-old woman receiving IP chemotherapy for carcinoma of the ovary presented with complaints of incontinence. Examination revealed the catheter protruding through the external urethral meatus. The reservoir was intact, and the catheter was immobile. Laparoscopic and cystoscopic evaluation demonstrated that the catheter tip had eroded through the dome of the bladder. The catheter was re-secured to the abdominal wall, and the bladder was laparoscopically repaired. IP chemotherapy was resumed 16 days postoperatively without incident. CONCLUSION: This is the first report of an IP catheter eroding through the bladder. Increased usage of IP chemotherapy may offer new challenges in the diagnosis and management of catheter-related complications.

Topotecan weekly bolus chemotherapy for relapsed platinum-sensitive ovarian and peritoneal cancers.

OBJECTIVE: Topotecan at a dose of 1.5 mg/m(2) on days 1 to 5 of a 21-day cycle is an approved therapy for recurrent ovarian cancer. However, heavily pretreated patients may be predisposed to hematologic adverse events. This prospective study, therefore, investigates the safety and efficacy of an alternate weekly schedule of topotecan in patients with recurrent ovarian or peritoneal cancer. METHODS: Patients with potentially platinum-sensitive recurrent ovarian or peritoneal cancer were treated with 4.0 mg/m(2) weekly topotecan as tolerated until disease progression. Antitumor response and safety were assessed. Dose reductions, delays, or omissions were implemented for grades 3-4 adverse events. RESULTS: Of the 41 enrolled patients (median age, 62 years; range, 42 to 82 years), 39 patients had ovarian cancer, and 2 patients had peritoneal cancer. The median platinum-free interval was 11.7 months. A median of 9 topotecan cycles (range, 1 to 45 doses) was administered. Weekly topotecan was well tolerated: 7 (17%) patients had grades 3-4 neutropenia, and 9 (22%) had grades 3-4 fatigue. No grade 4 thrombocytopenia or anemia was reported. Of 38 response-evaluable patients, 1 (3%) had a complete response, 8 (21%) had a partial response, 16 (42%) had stable disease, and 13 (34%) had progressive disease. CONCLUSIONS: Weekly topotecan was well tolerated in patients with platinum-sensitive ovarian or peritoneal cancer at first relapse, with a hematologic profile that compared favorably with that of the 5-day topotecan regimen. Moreover, antitumor activity was similar to that reported for the 5-day regimen.

Perception and use of complementary and alternative medicine among gynecologic oncology care providers.

OBJECTIVE: To determine general attitudes and approaches to complementary and alternative medicine (CAM) among physicians who care for gynecologic oncology patients. METHODS: Surveys were mailed to members of the Society of Gynecologic Oncologists and the Michigan Oncology Group. Physicians were asked to rate their general attitude toward CAM. RESULTS: Surveys were obtained from 462 physicians. Gynecologic oncologists and female physicians were more likely to have positive attitudes toward CAM, and to believe that clinical care should integrate conventional and CAM practices, compared with other oncologists and male physicians. CONCLUSION: Discrepancies exist among oncologists regarding attitude and use of CAM in their practice. Education of physicians regarding the safety and efficacy of CAM modalities may ultimately improve patient care.

The Impact of HPV as an Etiological Factor in Gynecological and Oropharyngeal Cancer.

The human papilloma virus (HPV) is one of several viral pathogens linked to human cancer. This article reviews the current worldwide cancer burden related to this pathogen. The article also examines the role of HPV in oropharyngeal and gynecological malignancies, current treatment implications, and future directions in the treatment and prevention of HPV-related disease.

Increased expression of hypoxia-inducible factor 1alpha in type I and type II endometrial carcinomas.

Hypoxia-inducible factor 1alpha (HIF-1alpha) is a nuclear protein that is upregulated in many tumors and triggers biologic events intimately associated with aggressive tumor behavior. The aim of this study was to analyze the expression of HIF-1alpha, vascular endothelial growth factor (VEGF), Ki-67 and p53 in type I and type II endometrial adenocarcinoma. In total, 149 patients diagnosed with endometrial adenocarcinoma in our institute from 1995 to 2001 were included in this study, of which 108 were type I and 41 were type II endometrial adenocarcinoma. Patient demographics, clinical and pathological data were reviewed. Tissue microarrays were prepared from the paraffin blocks and immunohistochemistry was performed for antibodies against HIF-1alpha, VEGF, Ki-67 and p53. High expression of HIF-1alpha, VEGF, Ki-67 and p53 were significantly more frequent in type II than type I endometrial adenocarcinoma (P<0.001). HIF-1alpha expression was highly correlated with VEGF expression in the tumor cells (P=0.001). In type I endometrial adenocarcinoma, high expression of HIF-1alpha showed a significant correlation with higher grade of the tumor, depth of myometrial invasion, adnexal invasion and clinical stage. A similar correlation was not observed in type II endometrial adenocarcinoma. Surgical stage was the only independent prognostic marker for survival. In conclusion, high expression of HIF-1alpha is more frequent in type II than in type I endometrial adenocarcinoma. In type I endometrial adenocarcinoma, HIF-1alpha expression correlates with morphologic features of aggressiveness. In type II endometrial adenocarcinoma, there is no correlation between HIF-1alpha expression and these features. Thus, HIF-1alpha may play an important role in endometrial adenocarcinoma progression, particularly in type I endometrial adenocarcinoma. Additional investigations of HIF-1alpha as a biomarker of aggressive potential and as a novel target for therapeutics in endometrial adenocarcinoma are warranted.

The impact of c-kit and ki-67 expression on patients prognosis in advanced ovarian serous carcinoma.

The transmembrane-tyrosine-kinase receptor, c-kit, is involved in cell differentiation and has been found to be expressed in normal human cell types and solid tumors. This study was designed to investigate the effects of c-kit expression on: 1) tumor proliferation and apoptosis, and 2) survival in patients with high-grade advanced stage ovarian serous carcinoma (OSC). We identified 118 patients with high-grade advanced stage OSC from our files. Clinical data, including demographics and overall survival, were collected. Immunohistochemical panel consisting of c-kit, ki-67, p53, and bcl-2 was performed. C-kit was categorized as positive if any cytoplasmic or membranous staining pattern was identified. Correlation between c-kit expression and the other markers was performed. Survival analysis was performed using COX proportional hazards regression and Kaplan-Meier test. Of 118 cases, 25 (21.2%) expressed c-kit. Of 93 c-kit-negative tumors, 87.1% had a high proliferation index. High p53 and bcl-2 expression was identified in 96 (81.4%) and 59 (50%) cases respectively. No significant statistical correlation was identified between c-kit and apoptosis markers. Tumors lacking c-kit expression showed a trend toward having high proliferation index, but this did not achieve statistical significance (p = 0.07). Of the seven variables included in the multivariate survival analysis, only c-kit (odds ratio, 2.12; 95% confidence interval, 08-4.17; p = 0.02) and ki-67 (odds ratio, 1.9; 95% confidence interval, 1.1-3.1; p = 0.03) showed an independent statistically significant impact on survival. High-grade advanced stage OSC lacking c-kit expression correlates with poor outcome. Interestingly, cases lacking c-kit expression also showed a trend to have high proliferation index.

Clinical update of smooth muscle tumors of the uterus.

Smooth muscle tumors of the uterus represent a spectrum of diseases that range from benign leiomyoma to malignant leiomyosarcoma. The leiomyoma is the most common of these neoplasms. Clinically, it is important to fully understand the differences in clinical presentation, biologic behavior, and management for patients with benign leiomyoma, smooth muscle tumors of uncertain malignant potential, and leiomyosarcoma. The goal of this review is to present the most recent information about common smooth muscle tumors of the uterus including their etiology, histopathology, radiographic and clinical presentations, and available treatment options.

Expression of cyclooxygenase-2 in advanced stage ovarian serous carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, and survival.

OBJECTIVE: Cyclo-oxygenase-2 seems to be involved at various steps in the processes of tumor progression. The objective of this study was to examine the relationship between cyclo-oxygenase-2 expression and tumor proliferation, apoptosis and angiogenesis in patients with advanced stage high-grade ovarian carcinoma. STUDY DESIGN: Specimens from 118 patients with high-grade and advanced stage (III, IV) serous ovarian carcinoma were evaluated by immunohistochemistry for cyclo-oxygenase-2, Ki-67, vascular endothelial growth factor, and bcl-2 expression. Tumor microvessel density was assessed with CD34 immunostaining. We investigated the relationships between cyclo-oxygenase-2 expression and clinicopathologic characteristics, tumor angiogenesis (tumor microvessel density and vascular endothelial growth factor expression), and tumor proliferation and apoptosis. The effect of cyclooxygenase-2 expression on patient survival was determined. RESULTS: There was a significant positive correlation between cyclo-oxygenase-2 expression in tumor cells and markers of tumor proliferation and angiogenesis. In univariate survival analysis, high cyclo-oxygenase-2 and high Ki-67 expression showed a significant impact of on patient survival (P < .001). In multivariate regression analysis, only Ki-67 expression retained its significance as an independent poor prognostic factor (death hazard ratio, 2.0; 95% CI, 1.2-3.3; P < .001). CONCLUSION: Expression of cyclo-oxygenase-2 correlates with tumor proliferation and tumor angiogenesis but not with apoptotic markers (bcl-2 expression) in high-grade, advanced-stage serous ovarian carcinoma.

Upper extremity deep vein thrombosis associated with indwelling peripheral venous catheters in gynecology oncology patients.

OBJECTIVE: The goal of this study was to review the clinical presentation, management, and outcome of upper extremity deep vein thrombosis (UEDVT) in women with gynecologic malignancies who had indwelling peripheral venous access catheters. METHODS: From a retrospective review of medical records, we identified 13 patients with various gynecologic malignancies who were diagnosed with UEDVT during their disease course. We obtained tumor data, detailed information regarding the indwelling catheters used, and the diagnosis and management of UEDVT. RESULTS: Two hundred sixty-four women with gynecologic malignancies underwent insertion of an indwelling peripheral catheter by interventional radiology over a 5-year period. A total of 325 catheters were placed in these patients. Thirteen patients developed UEDVTs, and all had a catheter in situ at the time of DVT diagnosis. Eleven of thirteen patients had Peripheral Access System (PAS) Ports and two had peripheral indwelling central catheters (PICCs). The mean age of the patients was 53 years (range, 32-70). At the time of UEDVT diagnosis patients had the following: progressive cancer (n = 8), stable disease (n = 1), no evaluable disease (n = 4), and actively receiving chemotherapy (n = 7). Clinical signs/symptoms at the time of diagnosis included: catheter occlusion (n = 2), arm swelling and pain (n = 10), and superior vena cava syndrome (n = 1). Diagnosis of thrombosis was confirmed using Doppler ultrasound (n = 4), venography (n = 5), and both modalities (n = 4). Management of UEDVT consisted of anticoagulation with warfarin (2-6 months) (n = 9), urokinase infusion (n = 2), intravenous antibiotics for 21 days and heparin for 10 days (n = 1), arm elevation only (n = 1), Lovenox for 60 days (n = 1), and no therapy (n = 1). There were no complications associated with anticoagulation. No patient had a pulmonary embolism. The incidence of UEDVT among our patients with indwelling venous catheters was 5.7%. CONCLUSION: Symptomatic UEDVT is an uncommon complication of indwelling peripheral venous catheters in women with gynecologic malignancies. The risk of pulmonary embolism is low in this patient population.

Vacuum-assisted closure in the treatment of gynecologic oncology wound failures.

OBJECTIVE: Negative pressure wound vacuum therapy can expedite the healing of complex wound failures. Our aim was to evaluate the use of a vacuum-assisted closure (VAC) device to treat complex wound failures in gynecologic oncology patients. METHODS: We retrospectively identified 27 patients with gynecologic malignancies in whom the device was used to treat complex wound failures from January 2001 to May 2002 at our institution. We analyzed operative data and information regarding the diagnosis and management of these complex wound failures and the length of time the device was used. RESULTS: The procedures performed before wound VAC placement were total abdominal hysterectomy with bilateral salpingo-oopherectomy with or without tumor reductive surgery in 14 patients, vulvectomy with or without inguinal lymph node dissection in five patients, skin or myocutaneous grafting in three patients, parastomal herniorrhaphy in two patients, retroperitoneal lymph node dissection in two patients, and incision and drainage of a gluteal abscess after radiation therapy in one patient. Four of the 27 patients had the VAC device placed at the time of a reoperation, while the remaining 23 patients had the VAC device placed postoperatively for wound failures. Wound breakdown occurred at a median of 9 days (range: 0-88 days) postoperatively. Overall, there was a 96% reduction (range: 0-100%) in the median size of wound defects from 330 to 14.0 cm(3) with use of the VAC device. The median number of days of VAC therapy was 32 days (range: 3-88 days). Twenty patients used this device as outpatients, and the charge per day was approximately US$150.00. One patient experienced bleeding, and 26 patients experienced no complications. The only complaint was pain during dressing changes (67% of patients). The mean follow-up was 52 days (range: 0-270 days). At the time of last contact, 26 (96%) of 27 patients had complete wound healing. CONCLUSIONS: VAC therapy is a novel treatment using controlled negative pressure to evacuate wound fluid, stimulate granulation tissue, and to decrease bacterial colonization of the wound. Our experience indicates that this is a safe method to treat complex wound failures in gynecologic oncology patients.