Induction of cytotoxic T lymphocytes against ovarian cancer-initiating cells.

The majority of patients with stage III/IV ovarian carcinoma that respond initially to standard therapies ultimately undergo relapse due to the survival of small populations of cells with tumor-initiating potential. These ovarian cancer (OVCA)-initiating cells (OCIC) are sometimes called cancer stem cells (CSC) because they express stem cell markers, and can survive conventional therapies such as chemotherapy, which usually target rapidly replicating tumor cells, and give rise to recurrent tumors that are more chemo-resistant and more aggressive. Thus, it would be desirable to develop a therapy that could selectively target OCIC and be used to complement the conventional therapies. In this study, we isolated a subset of OVCA cells with a CD44(+) phenotype in samples from patients with OVCA that possess CSC properties including the formation of spheroids in culture, self-renewal and the ability to be engrafted in immune-compromised mice. We next explored the use of immunotherapy using fusions of dendritic cells and OCIC to specifically target the OCIC subpopulations. Fusion cells (FCs) prepared in this way activated T cells to express elevated levels of IFN-γ with enhanced killing of CD44(+) OVCA cells. We envision a combined approach where conventional therapies such as chemotherapy kill the bulk of tumor cells, whereas OCIC-reactive cytotoxic T lymphocytes target the resistant OCIC fraction. A combined therapy such as this may represent a promising approach for the treatment of OVCA.

Management of melanomas of the female genital tract.

PURPOSE OF REVIEW: The significant increase in cutaneous melanomas over the past 30 years has led to studies resulting in advances in their diagnosis, staging, surgical treatment, and adjuvant therapies. Similar approaches have been investigated in patients with far rarer malignant melanomas of the female genital tract. This review will summarize the current state of knowledge on the incidence, causes, presenting symptoms, prognostic factors, therapeutic approaches, and outcomes, site-by-site, for primary melanomas of the vulva, vagina, urethra, ovary, and the uterine cervix. RECENT FINDINGS: Surgery remains the initial treatment of choice for localized melanomas of the female genital tract, with less radical, organ function preserving resections demonstrating similar control rates compared with more radical surgical approaches in vulva and possibly vaginal melanomas. Radiation therapy may play a role in the treatment of patients with close resection margins, regional nodal metastasis, or unresectable tumors. Sentinel lymph node studies, positron emission tomography and computed tomography scans for staging and evaluation of response, and adjuvant chemo or biochemotherapy warrant further investigation. SUMMARY: The results of treatment for female genital tract melanomas remain poor. Although surgery remains the initial treatment of choice for localized disease, adjuvant local-regional, and systemic therapies are needed.

Vulvar melanoma: a multivariable analysis of 644 patients.

OBJECTIVES: To determine the prognostic factors associated with the survival of vulvar melanoma patients. METHODS: Data were obtained from the Surveillance Epidemiology and End Results database from 1973 to 2003. Kaplan-Meier survival curves and Cox regression models were used for analysis. RESULTS: Of the 644 vulvar melanoma patients, the median age was 68 years. Of these 572 women were white, 28 were Hispanic, 18 were African-American, and 14 were Asian. A total of 302 had localized disease, 168 had regional disease, and 28 had distant disease. Of the participants who underwent surgical resection, 171 (26.6%) had conservative surgery, 164 (25.5%) had radical excision, and 241 (37.5%) had unspecified surgical resections. One hundred seventy-nine (27.8%) had lymph node resections, and 33 patients had concurrent radiation therapy. Nodal metastases were identified in 58 (9%) of the participants. The 5-year disease-specific survival rates for those with localized, regional, and distant disease were 75.5%, 38.7%, and 22.1%, respectively (P<.001). Women aged 68 years or younger had a better survival rate than older patients (72.0% compared with 47.7%; P<.001). Those with 0, 1, and 2 or more positive lymph nodes had survival rates of 68.3%, 29%, and 19.5%, respectively (P<.001). In a multivariable analysis, younger age, localized disease, and negative lymph nodes were independent prognostic factors for improved survival. CONCLUSION: Age, stage, and lymph node involvement were significant factors for survival in vulvar melanoma. LEVEL OF EVIDENCE: III.

Analysis of phase II studies on targeted agents and subsequent phase III trials: what are the predictors for success?

PURPOSE: To identify the characteristics of phase II studies that predict for subsequent "positive" phase III trials (those that reached the proposed primary end points of study or those wherein the study drug was superior to the standard regimen investigating targeted agents in advanced tumors. METHODS: We identified all phase III clinical trials of targeted therapies against advanced cancers published from 1985 to 2005. Characteristics of the preceding phase II studies were reviewed to identify predictive factors for success of the subsequent phase III trial. Data were analyzed using the chi(2) test and logistic regression models. RESULTS: Of 351 phase II studies, 167 (47.6%) subsequent phase III trials were positive and 184 (52.4%) negative. Phase II studies from multiple rather than single institutions were more likely to precede a successful trial (60.4% v 39.4%; P < .001). Positive phase II results were more likely to lead to a successful phase III trial (50.8% v 22.5%; P = .003). The percentage of successful trials from pharmaceutical companies was significantly higher compared with academic, cooperative groups, and research institutes (89.5% v 44.2%, 45.2%, and 46.3%, respectively; P = .002). On multivariate analysis, these factors and shorter time interval between publication of phase II results and III study publication were independent predictive factors for a positive phase III trial. CONCLUSION: In phase II studies of targeted agents, multiple- versus single-institution participation, positive phase II trial, pharmaceutical company-based trials, and shorter time period between publication of phase II to phase III trial were independent predictive factors of success in a phase III trial. Investigators should be cognizant of these factors in phase II studies before designing phase III trials.

Margin distance and other clinico-pathologic prognostic factors in vulvar carcinoma: a multivariate analysis.

OBJECTIVES: To determine the importance of margin status and other prognostic factors associated with the recurrence and survival of patients with squamous cell vulvar carcinoma. METHODS: Data were analyzed using Kaplan-Meier methods and Cox proportional hazards regression. All slides were re-reviewed by two gynecologic pathologists. RESULTS: Ninety patients (median age: 69) were treated for vulvar carcinoma from 1984 to 2002, including 28 FIGO stage I, 20 stage II, 26 stage III and 16 with stage IV disease. Sixty-three (70%) patients underwent complete radical vulvectomies and 27 (30%) had modified radical vulvectomies. Nineteen (20%) patients received adjuvant radiotherapy. Five-year disease-specific survival rates were 100%, 100%, 86% and 29% for stages I-IV, respectively. None of the 30 patients with a pathologic margin distance >8 mm had local recurrence. Of the 53 women with tumor-free pathologic margin of <8 mm, 12 (23%) had a local recurrence. Moreover, women with >2 positive groin nodes had significantly higher recurrence risk compared to those with <2 metastatic groin nodes (p<0.001). On multivariate analysis, positive groin nodes and margin distance were important prognostic factors for recurrence. Moreover, stage, tumor size, margin distance, and depth of invasion were significant independent predictors for disease-specific survival. The median follow-up was 58 months (range: 2-188). CONCLUSIONS: Pathologic margin distance is an important predictor of local vulvar recurrence. Our data suggest that a > or =8-mm pathologic margin clearance leads to a high rate of loco-regional control.

Conservative clitoral preservation surgery in the treatment of vulvar squamous cell carcinoma.

OBJECTIVE: To determine the safety and efficacy of clitoral-sparing surgery in women with squamous cell carcinoma (SCCA) of the anterior vulva not involving the clitoris. METHODS: Patients with vulvar SCCA diagnosed between 1984 and 2000 were identified and data collected. In this descriptive analysis, women treated with complete radical vulvectomy were compared to those treated with clitoral-sparing modified radical vulvectomy. All slides were re-reviewed. RESULTS: Of the 41 women with vulvar carcinoma, 13 had clitoral-sparing modified vulvectomies (group A) while the remaining 28 underwent complete radical vulvectomies (group B). The 13 patients in group A included, 8 with stage I, 2 stage II, 2 stage III, and 1 with stage IV disease. The two groups had similar demographic and pathologic prognostic factors. After a median follow-up of 59 months, no patients in group A had loco-regional failure. CONCLUSION: Clitoral-sparing vulvar cancer surgery does not compromise the rate of loco-regional control in patients and may be offered to selected women.