Andrea R. Hagemann

Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis.

The study was undertaken to determine the safety and efficacy of the monoclonal, antivascular endothelial growth factor antibody bevacizumab in combination with cytotoxic chemotherapy for women with platinum‐refractory ovarian cancer.

A Dendritic Cell Vaccine Pulsed with Autologous Hypochlorous Acid-Oxidized Ovarian Cancer Lysate Primes Effective Broad Antitumor Immunity: From Bench to Bedside

Purpose: Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells. Experimental Design: We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo. Results: We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-γ secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate–pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC. Conclusions: This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers. Clin Cancer Res; 19(17); 4801–15. ©2013 AACR.

Risk of occult malignancy in morcellated hysterectomy: a case series.

Uterine morcellation is performed only when significant neoplasia is not anticipated. In this study, we aimed to determine the prevalence of unexpected pathology in a series of low-risk morcellated hysterectomies. We reviewed a series consisting of all patients undergoing hysterectomy with morcellation at a tertiary-care hospital over a 4-yr period (n=101). Patient records were reviewed to retrieve demographics, details of preoperative evaluation (Pap smear, endometrial biopsy, imaging), and surgical pathology diagnoses. The median number of blocks submitted for histology was 6. On final pathology, endometrium was detected in 99% of all cases. No endometrial, myometrial, or cervical neoplasia other than leiomyoma (numerous cases) was present in the morcellated uteri, but in 1 case an atypical trophoblastic nodule with necrosis and myometrial infiltration, suspected to represent epithelioid trophoblastic tumor, was inadvertently morcellated. From this series, the prospective risk of occult malignancy in a low-risk population undergoing morcellation is estimated at 1% (95% confidence interval, <0.01%-5.94%). A subgroup analysis of patients who participated in what we propose as a complete preoperative workup, consisting of nonconcerning Pap smear, endometrial biopsy, and ultrasound or magnetic resonance imaging, showed no significant findings on final histology. Even with a complete workup, however, morcellation of occult uterine malignancy remains a possibility. This risk should be discussed as part of informed consent before morcellation.

Positive peritoneal cytology is an independent risk-factor in early stage endometrial cancer

OBJECTIVE In light of the recent changes in the International Federation of Gynecology and Obstetrics (FIGO) staging system, the objective of this study was to determine the prognostic significance of positive peritoneal cytology (PPC) among patients with early stage endometrial cancer. METHODS Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Only those patients with stage I/II endometrial cancer who had undergone a complete staging procedure (lymph-node removal) were included. Statistical analyses used Chi-square test, Kaplan-Meier log rank, and Cox proportional hazards models. RESULTS A total of 14,704 patients were identified: 14,219 with negative peritoneal cytology (NPC) and 485 with positive peritoneal cytology. More patients with PPC compared to those with NPC were diagnosed with high-risk factors such grade III disease (40.2% vs. 23.8%, p<0.0001), and unfavorable histologic types such as clear cell/serous carcinoma (17.5% vs. 7.5%, p=<0.0001) and carcinosarcoma (9.3% vs. 5.6%, p<0.0001). When compared to patients with negative peritoneal cytology, survival was significantly worse among patients with positive peritoneal cytology (p<0.0001): 5-year disease specific survival 95.1% vs. 80.8% in endometrioid adenocarcinoma; 78.0% vs. 50.4% in clear cell/serous cancer; and 64.7% vs. 32.3% in carcinosarcoma. After adjusting for other contributing factors in the multivariable model, PPC remained an independent predictor of poor survival (p<0.0001) in all histologic types examined. CONCLUSION PPC is an independent risk factor in patients with early stage endometrial cancer. Although, no longer a part of the current FIGO staging criteria, peritoneal cytology status should still be considered for accurate risk-stratification of these patients.

Clinical predictors of bevacizumab-associated gastrointestinal perforation.

OBJECTIVES Bevacizumab is a generally well-tolerated drug, but bevacizumab-associated gastrointestinal perforations (BAP) occur in 0 to 15% of patients with ovarian carcinoma. Our goal was to evaluate the clinical predictors of BAP in order to identify factors, which may preclude patients from receiving treatment. METHODS We conducted a review of patients with recurrent epithelial ovarian carcinoma treated with bevacizumab between 2006 and 2009. Demographic and treatment data were collected for statistical analysis. RESULTS Eighty-two patients were identified; perforation occurred in 8 (9.76%). Among patients with perforation, a significantly higher incidence of prior bowel surgeries (p=0.0008) and prior bowel obstruction or ileus (p<0.0001) were found compared to non-perforated patients. The median age at onset of bevacizumab in the perforated group was 3 years younger (60 vs. 63 years, p=0.61). The incidence of thromboembolic events, GI comorbidities, number of prior chemotherapies, and body mass index were similar between the groups. None of the patients in the perforated group developed grade 3 or 4 hypertension, compared to a 32.4% incidence among the non-perforated patients (p=0.09). Upon multivariate analysis, when controlled for age greater or less than 60, prior bowel surgery, obstruction/ileus, and grade 3 or 4 hypertension, only the presence of obstruction/ileus was noted to be a significant predictor of perforation (p=0.04). CONCLUSIONS Predicting BAP remains a challenge. Bowel obstruction or ileus appears to be associated with increased risk of BAP.

Day-4 Myeloid Dendritic Cells Pulsed with Whole Tumor Lysate Are Highly Immunogenic and Elicit Potent Anti-Tumor Responses

“Day-7” myeloid DCs are commonly used in the clinic. However, there is a strong need to develop DCs faster that have the same potent immunostimulatory capacity as “Day-7” myeloid DCs and at the same time minimizing time, labor and cost of DC preparations. Although “2 days” DCs can elicit peptide-specific responses, they have not been demonstrated to engulf, process and present complex whole tumor lysates, which could be more convenient and personalized source of tumor antigens than defined peptides. In this preclinical study, we evaluated the T-cell stimulatory capacity of Day-2, Day-4, and Day-7 cultured monocyte-derived DCs loaded with SKOV3 cell whole lysate prepared by freeze-thaw or by UVB-irradiation followed by freeze-thaw, and matured with lipopolysaccharide (LPS) and interferon (IFN)-gamma. DCs were evaluated for antigen uptake, and following maturation with LPS and IFN-gamma, DCs were assessed for expression of CD80, CD40, CD86, ICAM-1 and CCR7, production of IL-12p70 and IP-10, and induction of tumor-specific T-cell responses. Day-4 and Day-7 DCs exhibited similar phagocytic abilities, which were superior to Day-2 DCs. Mature Day-7 DCs expressed the highest CD40 and ICAM-1, but mature Day-4 DCs produced the most IL-12p70 and IP-10. Importantly, Day-4 and Day-7 DCs derived from ovarian cancer patients stimulated equally strongly tumor-specific T-cell responses. This is the first study demonstrating the highly immunogenic and strong T-cell stimulatory properties of Day-4 myeloid DCs, and provided important preclinical data for rapid development of potent whole tumor lysate-loaded DC vaccines that are applicable to many tumor types.

A prospective, randomized, double-blinded study of assisted hatching in women younger than 38 years undergoing in vitro fertilization

OBJECTIVE To determine whether assisted hatching is beneficial to IVF patients younger than 38 years whose embryos have a thickened zona pellucida (ZP). DESIGN Prospective, randomized, double-blinded, crossover study. SETTING University-based infertility center. PATIENT(S) One hundred twenty-one women less than 38 years of age, undergoing IVF at Washington University between April 2004 and February 2007, with ZP thickness > or =13 microm for any embryos. INTERVENTION(S) Measurement of ZP thickness in embryos undergoing IVF; randomization of women with embryos with ZP thickness > or =13 microm to no procedure or assisted hatching performed by acidic Tyrodes solution. MAIN OUTCOME MEASURE(S) Clinical intrauterine pregnancy rate, implantation rate, spontaneous pregnancy loss, and live birth rate. RESULT(S) Baseline characteristics and ZP thickness were not significantly different between the two study arms (hatched and unhatched). No significant differences were observed between hatched and unhatched patients in the rates of clinical pregnancy (47% vs. 50% respectively) or live birth (46% vs. 45% respectively). Further, no significant differences were noted between hatched and unhatched groups in rates of spontaneous abortions, monozygotic twinning, dizygotic twinning, chromosomal abnormalities, or ectopic gestations. In addition, mean ZP thickness did not have a significant effect on pregnancy. CONCLUSION(S) In patients younger than 38 years with embryos with ZP thickness of > or =13 microm, assisted hatching does not improve the rates of implantation, clinical pregnancy, or live birth, and thus does not appear to offer any benefit to patients in this age group undergoing IVF.

Immuno-Modulatory Gene Polymorphisms and Outcome in Breast and Ovarian Cancer

Breast and ovarian cancer continue to be a significant source of morbidity and mortality. Improved understanding of signalling pathways related to growth and apoptosis has led to targeted treatments and modest improvement in long term outcomes. However, it has become increasingly clear that tumor factors alone are not the sole determinants of outcome in patients with breast and ovarian cancer. The tumor microenvironment and other immunologic host processes play an integral role in the overall interactions between disease, host and treatment. Cytokines play a major role in the immune response to tumors. Single nucleotide polymorphisms (SNPs) in the regulatory or coding regions of many cytokine genes lead to functional alterations in the transcriptional regulation of these genes or the proteins they encode. This review examines the current literature linking functional variants in cytokine and other immune genes to outcomes in breast and ovarian cancer. We have focused on those involved in the proinflammatory response (IL-6, TNF-alpha), apoptosis (TGF-beta, Fas, FasL, C1QA), angiogenesis (IL-8) and autoimmunity (IL-10). While much remains to be learned about the mechanisms underlying these variants and their impact on tumor behavior, this area holds promise for future development of prognostic profiles and therapeutics exploiting the immune response.

Vaginal intraepithelial neoplasia (VAIN) after radiation therapy for gynecologic malignancies: A clinically recalcitrant entity

OBJECTIVES Vaginal dysplasia is associated with prior radiation therapy (RT) for gynecologic malignancies. We reviewed our institutions experience with VAIN in patients who were treated with radiation therapy for a gynecologic malignancy. METHODS A retrospective review of patients treated for VAIN was performed. All cases of patients followed and treated for VAIN after radiation therapy were identified (n=10), along with a cohort of patients with VAIN who did not have radiation therapy (n=23). RESULTS Mean follow-up after initial diagnosis of VAIN was 37.6 months (range: 12 to 72). Cytologic screening events after diagnosis of VAIN (n=105) showed that patients with prior RT were more than twice as likely to have recurrent dysplasia (OR 3.625, 95% CI=from 1.454 to 9.0376) after treatment. Of patients who recurred, the mean time to first recurrence was 12.3 months in cases and 15.3 months in controls, which was not statistically significant (p=0.31). Screening practices at our institution ranged from 3 month to 12 month intervals. 3 patients in the RT group and 1 patient in the control group developed invasive squamous cell cancer of the vagina. CONCLUSIONS Vaginal dysplasia after radiation therapy is more refractory to treatment than dysplasia not associated with radiation therapy, more likely to recur after surgical and ablative therapy, and may also be more likely to progress to invasive cancer. These data support the need for further study to determine the optimal follow-up screening interval and whether aggressive surgical or ablative treatment stems disease progression in this clinical scenario.

Phase II study of bevacizumab and pemetrexed for recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer

OBJECTIVE We aimed to evaluate the efficacy and safety of combination bevacizumab/pemetrexed for the treatment of recurrent epithelial ovarian cancer (EOC). METHODS Platinum-sensitive or -resistant patients with recurrent or persistent EOC were eligible if they had received up to 2 prior chemotherapy regimens, including a platinum/taxane regimen without prior bevacizumab. Pemetrexed 500 mg/m(2) IV and bevacizumab 15 mg/kg IV were administered every 3 weeks. The primary endpoint was 6-month progression-free survival (PFS); other endpoints included toxicities, PFS and overall survival (OS). RESULTS Thirty-four patients received a median of 7 treatment cycles (range, 2-26). Median follow-up was 25.7 months (range, 3.0-47.2). Six month progression-free survival (PFS) was 56% (95% CI: 38-71). The following response rates were documented (%; 95% CI): 0 complete response, 14 partial responses (41%; 25-59), 18 stable disease (53%; 35-70) and 2 progressive disease (6%; 1-20). Median PFS was 7.9 months (95% CI, 4.6-10.9), with a median OS of 25.7 months (95% CI, 15.4-29.8). Twenty-two patients (64.7%) had a platinum-free interval (PFI) of >6 months prior to enrollment. Grade 3-4 hematologic toxicities included neutropenia (50%), leukopenia (26%), thrombocytopenia (12%) and anemia (9%). Non-hematologic grade 3-4 toxicities included metabolic (29%), constitutional (18%), pain (18%) and gastrointestinal (15%). Two patients developed hematologic malignancies within one year of treatment. CONCLUSIONS Combination bevacizumab/pemetrexed is an active option for both platinum-sensitive and -resistant recurrent EOC. Further investigation of cost and novel toxicities associated with this regimen may be warranted.