A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early-stage incident cancers and demonstrates high positive predictive value.

BACKGROUND: A 2-stage ovarian cancer screening strategy was evaluated that incorporates change of carbohydrate antigen 125 (CA125) levels over time and age to estimate risk of ovarian cancer. Women with high-risk scores were referred for transvaginal ultrasound (TVS). METHODS: A single-arm, prospective study of postmenopausal women was conducted. Participants underwent an annual CA125 blood test. Based on the Risk of Ovarian Cancer Algorithm (ROCA) result, women were triaged to next annual CA125 test (low risk), repeat CA125 test in 3 months (intermediate risk), or TVS and referral to a gynecologic oncologist (high risk). RESULTS: A total of 4051 women participated over 11 years. The average annual rate of referral to a CA125 test in 3 months was 5.8%, and the average annual referral rate to TVS and review by a gynecologic oncologist was 0.9%. Ten women underwent surgery on the basis of TVS, with 4 invasive ovarian cancers (1 with stage IA disease, 2 with stage IC disease, and 1 with stage IIB disease), 2 ovarian tumors of low malignant potential (both stage IA), 1 endometrial cancer (stage I), and 3 benign ovarian tumors, providing a positive predictive value of 40% (95% confidence interval = 12.2%, 73.8%) for detecting invasive ovarian cancer. The specificity was 99.9% (95% confidence interval = 99.7%, 100%). All 4 women with invasive ovarian cancer were enrolled in the study for at least 3 years with low-risk annual CA125 test values prior to rising CA125 levels. CONCLUSIONS: ROCA followed by TVS demonstrated excellent specificity and positive predictive value in a population of US women at average risk for ovarian cancer.

Improving breast care: providing, guiding, expertise, and leadership.

Optimal healthcare blends timeless doctor-patient values with state-of-the-art medical knowledge. The physician's role varies from delivering therapies to guiding patients through the healthcare maze to their best decisions. Breast care should not be parceling out of anatomic parts, as if biological relationships do not exist. Instead, it should stem from an understanding of the "total woman"--biological and otherwise--and how important that unity is for quality of life, even when confronting breast cancer. Breast fellowships for gynecologic and general surgeons create superior clinicians and better patient advocates -essential in advancing women-centric care and healthcare leadership.

Addressing clinical trials: can the multidisciplinary Tumor Board improve participation? A study from an academic women's cancer program.

OBJECTIVE: The Tumor Board (TB) allows for an interdisciplinary approach to cancer treatment designed to encourage evidence-based treatment. However, its role in facilitating clinical trial participation has not been reported. We aimed to determine whether a prospective TB is an effective strategy for trial recruitment and to identify steps within the TB process that facilitate discussion of trial eligibility and optimize accrual. METHODS: We conducted a retrospective cross-sectional analysis of women presented to Gynecologic Oncology TB between March and December 2008. Patient demographics, TB recommendations, and post-TB patient discussions were abstracted. These were compared to data derived from the Department of Oncology Research to determine research team awareness of eligible patients and confirm trial enrollment(s). Data analysis was completed with Chi-square test; risk ratios and confidence intervals were calculated as summary measures. RESULTS: We reviewed 1213 case presentations involving 916 women. Overall, 358 TB recommendations (30%) identified eligible patients, of which enrollment consisted of 87 (24%) trials (6% therapeutic trials and 18% non-therapeutic trials). Compared to other types of TB recommendations, those involving trials were discussed less frequently at post-TB patient visits (79% vs. 44%). Documentation of trial discussion at the post-TB visit was more likely to result in trial participation, versus solely relying on the research staff to communicate enrollment eligibility with the treating team (RR 2.5, p=0.006). CONCLUSIONS: Patients identified by the TB were 2.5-times as likely to enroll in a clinical trial, but trials were mentioned only 44% of the time. Interventions that facilitate trial discussions during post-TB meetings are needed to improve trial participation.

A case of Peutz-Jeghers syndrome with breast cancer, bilateral sex cord tumor with annular tubules, and adenoma malignum caused by STK11 gene mutation.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder, and women with this syndrome are at an increased risk of developing intestinal and extraintestinal malignancies including breast and gynecologic malignancies. This case report presents a patient with PJS with a concomitant breast cancer, bilateral stromal tumors with annular tubules of the ovaries, and adenoma malignum of the cervix. CASE: A 43-year-old woman presented with an advanced-stage breast cancer and a pelvic mass. The patient was treated with neoadjuvant chemotherapy followed by laparotomy with a hysterectomy and oophorectomy. Final pathologic examination revealed a concomitant breast cancer with metastasis to the ovaries, bilateral stromal tumors with annular tubules of the ovaries, and adenoma malignum of the cervix. CONCLUSIONS: Patients with PJS are at a high risk for intestinal and extraintestinal malignancies and can present with multiple concomitant malignancies.

Ovarian cancer associated with testosterone supplementation in a female-to-male transsexual patient.

Ovarian cancer is the most fatal gynecologic malignancy. Women often present late and though median survival has improved, a majority of women will succumb to their disease. The incidence of ovarian cancer among female-to-male transsexuals is not known. We report only the second case of ovarian cancer in a female-to-male transsexual while on androgen supplementation therapy. Staining of his tumor for androgen receptors showed abundant expression. Androgen supplementation in this population may be associated with an increased risk of both ovarian cancer and of endometrial cancer. Consideration for bilateral salpingo-oophorectomy as part of gender reassignment surgery should be given, especially in this poorly studied group of patients whose overall risk of ovarian cancer remains unknown.

Phenethyl isothiocyanate (PEITC) inhibits growth of ovarian cancer cells by inducing apoptosis: role of caspase and MAPK activation.

OBJECTIVE: Epithelial ovarian cancer has the highest mortality rate among gynecologic cancers. Chemotherapy is an essential component of its treatment. While isothiocyanates are known to possess chemopreventive effects against various cancers, yet little is known about their chemotherapeutic potential in ovarian cancer (OC). In the present study, we examined the antiproliferative and apoptotic effect of phenethyl isothiocyanate (PEITC), a naturally occurring isothiocyanate on OVCAR-3 cells. METHODS: Cytotoxic activity of PEITC on OVCAR-3 cells was determined using cell proliferation, apoptosis (DNA fragmentation and TUNEL assay) and caspase-activation studies. The role of PARP-1, Bax, and Bcl-2 in apoptosis was analyzed by Western blotting. Activation of JNK1/2, p38, Akt, ERK1/2, and c-Myc was examined by immunoblotting. Specific inhibitors of caspases, JNK1/2, p38, and MEK were used to corroborate these data. RESULTS: PEITC was cytotoxic to OVCAR-3 cells, and inhibited proliferation in a dose-dependent fashion (IC(50) = 23.2 microM). PEITC induced apoptosis by activating caspase-3 and -9, without capsase-8 activation. Anti-apoptotic Bcl-2 levels were suppressed while pro-apoptotic Bax levels were enhanced. PEITC suppressed activation of Akt, ERK1/2, and the expression of transcription factor c-Myc, while simultaneously activating pro-apoptotic p38 and JNK1/2. Specific inhibitors of caspase-3 and -9, JNK1/2, and p38 reversed the cytotoxic effect of PEITC. CONCLUSIONS: These findings demonstrate that PEITC exhibits cytotoxicity towards OVCAR-3 cells and induces apoptosis via caspase-9 and -3 pathways. PEITC inhibits Akt, ERK1/2 survival signaling, and c-Myc while simultaneously activating pro-apoptotic p38 and JNK1/2. Systematic preclinical and clinical trials with PEITC in ovarian cancer are indicated.

The effect of total parenteral nutrition on the survival of terminally ill ovarian cancer patients.

OBJECTIVES: Total parenteral nutrition (TPN) for terminal ovarian cancer patients remains controversial. In this study, we compared survival from time of terminal intestinal obstruction (TIO) diagnosis in patients who received TPN versus those who did not. METHODS: A historical cohort of 55 patients with stage IIIC/IV epithelial ovarian cancer hospitalized for TIO between 1994 and 2002 was studied. All patients were previously treated with paclitaxel/platinum following cytoreductive surgery. Exposure was administration of TPN after TIO. The primary outcome was survival from TIO diagnosis to death. Number of chemotherapy cycles completed after TIO diagnosis, major complications of TPN, and demographics were measured. Survival analysis was performed using Kaplan-Meier methods. RESULTS: The median survival from time of TIO diagnosis was 72 days (range 16-485) for patients receiving TPN and 41.0 days (range 4-133) for those not receiving TPN (P = 0.05), but no difference in survival was observed when adjusting for chemotherapy. Overall survival [median 23 (range 6-67) vs. 35 months (range 8-67), P = 0.03] was shorter for the TPN group. Demographic data were similar in both groups. Patients receiving TPN after obstruction were more likely to undergo concurrent chemotherapy (64 vs. 26%, P = 0.004). One major TPN-related complication was found. CONCLUSIONS: Ovarian cancer patients with TIO receiving TPN had a median survival benefit of 4 weeks. This benefit decreased when patients were treated with concurrent chemotherapy. Issues of cost, quality of life, and human values need to be investigated to assess the full impact of TPN in this patient population.

Two for good measure: six versus eight cycles of carboplatin and paclitaxel as adjuvant treatment for epithelial ovarian cancer.

INTRODUCTION: Although the standard of care for advanced epithelial ovarian cancer (EOC) is six cycles (6C) of platinum-taxane (PT), there have been no studies on the optimal duration of treatment in the era of adjuvant taxanes. At our center, some women receive eight cycles (8C) of PT, based on physician judgment. We were interested in evaluating the outcomes of women treated with 8C of PT for EOC as compared to a cohort who received 6C. METHODS: We retrospectively identified women with Stage III or IV EOC between 1998 and 2003 who received 6C or 8C of PT. The endpoints were disease-free (DFS) and overall survival (OS). CA-125 response was defined as a decrease in CA-125 of 50% in four serial samples or of 75% over three samples. RESULTS: One hundred and twenty-two women met criteria for inclusion; 84 received 6C, and 38 received 8C. Comparing the cohorts receiving 6C versus 8C, 71% versus 26% were optimally debulked (P < 0.01). 79 patients were evaluable by CA-125 (52 6C/27 8C), and all responded. 88% receiving 6C and 81% receiving 8C normalized their CA-125 at end of treatment (P = 0.20). The proportion with a normal CA-125 at Cycle 2 was 29% versus 12%, respectively (P = 0.15) and, at Cycle 4, was 88% versus 36%, respectively (P < 0.01). DFS was 13 months with 6C and 8 months with 8C (P = 0.01). OS was 31 versus 23.5 months (P = 0.02), respectively. When the survival analysis is restricted to suboptimal debulked patients only, the DFS is 12.5 versus 8 months (P = 0.02), and OS is 32 versus 26.5 months (P = 0.15), respectively. CONCLUSIONS: Two further cycles of PT did not improve DFS or OS for patients with advanced EOC. Patients who do not achieve remission after 6C are unlikely to benefit from additional chemotherapy using the same agents and should be considered for clinical trials involving novel agents with different mechanisms of action.

Iron chelators deferoxamine and diethylenetriamine pentaacetic acid induce apoptosis in ovarian carcinoma.

OBJECTIVES: Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Deprivation of iron (Fe), an essential micro-nutrient, by chelation is known to inhibit proliferation of several human cancers but its potential in ovarian cancer treatment remains unknown. We have evaluated the anti-proliferative activities of iron chelators, deferoxamine (DFO), and diethylenetriamine pentaacetic acid (DTPA), in human and rat ovarian cancer cells. METHODS: The effect of DFO and DTPA on CaOV-3 (human) and NUTU-19 (rat) ovarian cancer cells was determined by cell proliferation and apoptosis assays (Hoechst staining, DNA fragmentation, and caspase activation), cell cycle analysis, and Fe supplementation studies. RESULTS: DFO and DTPA were cytotoxic to ovarian cancer cells in a dose- and time-dependent manner. DFO inhibited proliferation of NUTU-19 and CaOV-3 cells (IC(50) at 45 and 280 microM, respectively), while DTPA inhibited proliferation of only NUTU-19 cells (IC(50) at 50 microM), at 48 h. DNA synthesis was inhibited in CaOV-3 cells by DFO (>90% at 200 microM) and in NUTU-19 by both DFO and DTPA (>90% at 50 microM). Fe supplementation effectively reversed the cytotoxic effects of DFO and DTPA. Cell cycle analysis showed a G0/G1- and S-phase block with increased apoptosis. DNA fragmentation analysis confirmed apoptosis. Increase in caspase-3, -8, and -9 activities ( approximately 2.4-fold) was associated with apoptosis. CONCLUSIONS: Our studies show that Fe chelators suppress ovarian cancer growth by inhibiting proliferation and inducing apoptosis. Therefore, Fe chelators can be potentially developed as novel therapeutic agents to treat ovarian cancer.

Cross-sensitivity between paclitaxel and docetaxel in a women's cancers program.

PURPOSE: With the use of steroid premedication, the incidence of severe hypersensitivity reactions (S-HSR) to paclitaxel is estimated to be 2%. For those who develop a S-HSR to paclitaxel, docetaxel has been employed as an alternative agent though the presence of cross-sensitivity has not been established. We sought to define the incidence of S-HSR to docetaxel following a paclitaxel S-HSR in an academic women's cancer program. METHODS: Patients treated with either paclitaxel (P) or docetaxel (D) between 11/1999 and 8/2004 were identified through our pharmacy database. Records were reviewed and data collected on those patients who had a S-HSR, defined as symptoms for which drug was discontinued, to P, D, or both. RESULTS: 718 patients received P and 93 received D. 59 received D following treatment with P. The presence of S-HSR for P was 2.2% (16/718 patients) and for D was 9.7% (9/93 patients). 10 patients with S-HSR to P crossed over to D and all nine patients reacting to D had a prior reaction to T for a cross-sensitivity rate of 90% (9/10 patients). CONCLUSIONS: Cross-sensitivity of D after P was 90% at our institution. Given the different vehicles used in P and D, it is likely attributed to the taxane moiety. Caution is required with re-challenge of patients with docetaxel if they have previously reacted to paclitaxel.

Inhibition of angiogenesis by vitamin D-binding protein: characterization of anti-endothelial activity of DBP-maf.

Angiogenesis is a complex process involving coordinated steps of endothelial cell activation, proliferation, migration, tube formation and capillary sprouting with participation of intracellular signaling pathways. Regulation of angiogenesis carries tremendous potential for cancer therapy. Our earlier studies showed that vitamin D-binding protein-macrophage activating factor (DBP-maf) acts as a potent anti-angiogenic factor and inhibits tumor growth in vivo. The goal of this investigation was to understand the effect of DBP-maf on human endothelial cell (HEC) and the mechanism of angiogenesis inhibition. DBP-maf inhibited human endothelial cell (HEC) proliferation by inhibiting DNA synthesis (IC(50) = 7.8 +/- 0.15 microg/ml). DBP-maf significantly induced S- and G0/G1-phase arrest in HEC in 72 h. DBP-maf potently blocked VEGF-induced migration, tube-formation of HEC in a dose dependent manner. In addition, DBP-maf inhibited growth factor-induced microvessel sprouting in rat aortic ring assay. Moreover, DBP-maf inhibited VEGF signaling by decreasing VEGF-mediated phosphorylation of VEGFR-2 and ERK1/2, a downstream target of VEGF signaling cascade. However, Akt activation was not affected. These studies collectively demonstrate that DBP-maf inhibits angiogenesis by blocking critical steps such as HEC proliferation, migration, tube formation and microvessel sprouting. DBP-maf exerts its effect by inhibiting VEGR-2 and ERK1/2 signaling cascades. Understanding the cellular and molecular mechanisms of anti-endothelial activity of DBP-maf will allow us to develop it as an angiogenesis targeting novel drug for tumor therapy.

Incidence of metastasis to the ovaries from nongenital tract primary tumors.

OBJECTIVES: The purpose of this study was to evaluate the characteristics of metastatic tumors to the ovaries in nongenital tract primaries and to determine the route of dissemination. METHODS: An IRB-approved study retrospectively reviewed patient records from January 1992 to January 2003. A tumor registry and pathology database search identified women with metastatic disease to the ovaries that had undergone surgery for the presence of an adnexal mass. The charts were reviewed for age at diagnosis, presenting symptoms, size of ovarian metastasis, laterality of metastasis, and primary tumor site. Pathology reports and specimen slides were reviewed to confirm the diagnosis and evaluate the tumors for various pathological features. RESULTS: A total of 59 cases of metastasis to the ovary were identified. The median age of the study group was 55 years old (range: 27-78). Primary colon cancer was identified in 19 (32.2%) cases; appendix 12 (20.3%); breast 5 (8.4%); small bowel and gastric each contributed 4 (6.8%) cases. Pancreatic cancer added 3 (5.1%), while gallbladder and urinary bladder each contributed 1 (1.7%) case. Tumors of unknown primary contributed 10 (18.5%) of the cases. Stromal invasion was seen in 56 (95%) of the cases and surface involvement in 9 (15%) cases. Bilateral metastasis was found in 39 (66.1%) patients and unilateral metastasis in 20 (33.9%) patients. CONCLUSIONS: Metastatic lesions to the ovary are more commonly seen from primary colon cancer, appendiceal, and breast carcinomas. The mechanism of metastasis is through hematogenous pathways as opposed to a transserosal route.

Vulvar epithelioid sarcoma in pregnancy.

BACKGROUND: Epithelioid sarcoma is a soft tissue tumor rarely found centrally and even less commonly on the vulva. Vulvar sarcoma in pregnancy is also exceedingly rare with only five cases reported to date, none of which have been an epithelioid sarcoma. CASE: We report a case of a 29-year-old woman presenting with a vulvar epithelioid sarcoma at 36 weeks of gestation. The patient underwent a radical resection 6 weeks postpartum followed by chemotherapy. Despite a radical hemivulvectomy and doxorubicin and ifosfamide chemotherapy, she developed pulmonary metastasis and died of tumor-related pulmonary failure secondary to her disease 612 months after diagnosis. To our knowledge this is the first case of a vulvar epithelioid sarcoma presenting during pregnancy. The English literature is reviewed and a total of 18 previous cases of vulvar epithelioid sarcoma have been reported outside of pregnancy. Insight into the biological behavior and therapeutic management of this disease is discussed. CONCLUSION: The optimal management of vulvar epithelioid sarcoma remains to be determined. However, it would seem that early and aggressive surgical resection provides the best possibility for cure. The role of radiation and/or chemotherapy remains to be determined.