RAD6 promotes DNA repair and stem cell signaling in ovarian cancer and is a promising therapeutic target to prevent and treat acquired chemoresistance.

Ovarian cancer (OC) is the most deadly gynecological cancer and unlike most other neoplasms, survival rates for OC have not significantly improved in recent decades. We show that RAD6, an ubiquitin-conjugating enzyme, is significantly overexpressed in ovarian tumors and its expression increases in response to carboplatin chemotherapy. RAD6 expression correlated strongly with acquired chemoresistance and malignant behavior of OC cells, expression of stem cell genes and poor prognosis of OC patients, suggesting an important role for RAD6 in ovarian tumor progression. Upregulated RAD6 enhances DNA damage tolerance and repair efficiency of OC cells and promotes their survival. Increased RAD6 levels cause histone 2B ubiquitination-mediated epigenetic changes that stimulate transcription of stem cell genes, including ALDH1A1 and SOX2, leading to a cancer stem cell phenotype, which is implicated in disease recurrence and metastasis. Downregulation of RAD6 or its inhibition using a small molecule inhibitor attenuated DNA repair signaling and expression of cancer stem cells markers and sensitized chemoresistant OC cells to carboplatin. Together, these results suggest that RAD6 could be a therapeutic target to prevent and treat acquired chemoresistance and disease recurrence in OC and enhance the efficacy of standard chemotherapy.

A multi-institutional evaluation of factors predictive of toxicity and efficacy of bevacizumab for recurrent ovarian cancer.

While bevacizumab has shown activity in recurrent ovarian cancer, a higher than expected incidence of bowel perforations has been reported in recent trials. We sought to determine factors associated with toxicity and tumor response in patients with relapsed ovarian cancer treated with bevacizumab. A retrospective review of patients with recurrent ovarian cancer treated with bevacizumab was undertaken. Response was determined radiographically and through CA125 measurements. Statistical analysis to determine factors associated with toxicity and response was performed. Sixty-two eligible patients were identified. The cohort had received a median of 5 prior chemotherapy regimens. Single-agent bevacizumab was administered to 12 (19%), while 50 (81%) received the drug in combination with a cytotoxic agent. Grade 3-5 toxicities occurred in 15 (24%) patients, including grade 3-4 hypertension in 4 (7%), gastrointestinal perforations in 7%, and chylous ascites in 5%. Development of chylous ascites and gastrointestinal perforations appeared to correlate with tumor response. The overall response rate was 36% (4 complete response, 17 partial response), with stable disease in 40%. A higher objective response rate was seen in the bevacizumab combination group compared to single-agent treatment (43% vs 10%) (P = 0.07). However, 29 grade 3-5 toxic episodes were seen in the combination group vs only 1 in the single-agent bevacizumab cohort (P = 0.071). We conclude that bevacizumab demonstrates promising activity in recurrent ovarian cancer. The addition of a cytotoxic agent to bevacizumab improved response rates at the cost of increased toxicity. Gastrointestinal perforations occurred in 7%. The perforations occurred in heavily pretreated patients who were responding to therapy.

Outcomes for patients with fallopian tube carcinoma managed with adjuvant chemotherapy following primary surgery: a retrospective university experience.

The aim is to evaluate disease-free (DFS) and overall survival (OS) of patients with fallopian tube carcinoma (FTCA) treated with adjuvant chemotherapy. An Institutional Review Board approved retrospective review identified 38 patients with FTCA that received adjuvant chemotherapy following primary surgery from 1975 to 2001. Median age was 56 (range 36-78) and 95% of patients were white. Twenty patients (53%) had FIGO stage III/IV FTCA. Seventeen patients underwent second-look laparotomy, 8 (47%) patients were found to have disease. Adjuvant chemotherapeutic regimens consisted of melphalan in 11 patients, platinum-based chemotherapy without paclitaxel in 17 patients, and the combination of paclitaxel and platinum in 10 patients. Although DFS was similar for the three chemotherapy cohorts (P= 0.19), patients receiving paclitaxel had superior OS compared to patients receiving either melphalan (P= 0.02) or platinum without paclitaxel (P= 0.04). Of the twenty patients with stage III/IV disease, 55% of patients had optimal cytoreduction performed at their initial surgery. Both median DFS, 68 versus 50 months (P= 0.14) and OS, 73 versus 50 months (P= 0.12) were greater in patients with optimal cytoreduction. When compared to historical chemotherapeutic regimens, the combination of paclitaxel and platinum has superior efficacy for the management of patients with FTCA. Although not statistically significant in our study, optimal cytoreduction likely improves both DFS and OS and should be the goal of all patients surgically managed for FTCA.

Pegfilgrastim for the prevention of febrile neutropenia in patients with epithelial ovarian carcinoma--a cost-effectiveness analysis.

The objective is to assess the cost-effectiveness of pegfilgrastim for the prevention of hospitalization due to febrile neutropenia (FN) in patients with epithelial ovarian carcinoma (EOC) receiving taxane/platinum-based chemotherapy. A decision analysis model evaluated a hypothetical cohort of 10,000 patients receiving six cycles of taxane/platinum-based chemotherapy for EOC. Three strategies were analyzed for the prevention of hospitalization due to FN: 1) dose modifications and delays after a hospitalization for FN without the use of granulocyte-colony stimulating factors (G-CSF) (NO G-CSF); 2) all patients receive G-CSF with each chemotherapy cycle (1 degrees PROPHYLAXIS); 3) patients receive G-CSF for all subsequent chemotherapy cycles after a hospitalization for FN (2 degrees PROPHYLAXIS). The model was applied to two patient populations: 1) an average-risk population (FN hospitalization rate = 5%); 2) a high-risk population (FN hospitalization rate = 16%). Using baseline assumptions in an average-risk population, NO G-CSF was the least expensive strategy with a cost of $68 million and resulted in 2,860 hospitalizations for FN. 2 degrees PROPHYLAXIS resulted in 141 fewer hospitalizations than NO G-CSF at a cost of $76,288 per hospitalization prevented. 1 degrees PROPHYLAXIS was the most effective and resulted in 1,689 fewer hospitalizations for FN compared to NO G-CSF at a cost of $47,343 per hospitalization prevented. When this model is applied to a high-risk patient population, 1 degrees PROPHYLAXIS is more effective and less expensive than both NO G-CSF and 2 degrees PROPHYLAXIS. We conclude that in average-risk patients receiving chemotherapy for EOC the use of pegfilgrastim is effective at reducing hospitalizations due to FN, but at a significant cost. However, in high-risk patients, primary prophylaxis is the only cost-effective strategy and should be strongly considered.

Outcomes of gynecologic oncology patients admitted to the intensive care unit following surgery: A university teaching hospital experience.

The objective of this study was to determine the outcomes of gynecological oncology patients requiring intensive care unit (ICU) admission following surgery. A computerized database identified postsurgical ICU admissions from January 1, 1999 to December 31, 2004 at a university hospital. Abstracted data included: demographics, preoperative diagnosis, reason(s) for ICU admission, consultations, interventions, length of stay (LOS), Acute Physiology and Chronic Health Evaluation (APACHE) II score, and 30-day mortality. Statistical analysis was performed with the Student's t-test. A total of 185 surgical gynecological oncology ICU patients was identified. Median age was 60 years (range, 21-92 years), and 63% of patients were white. Only 72% of patients had ovarian, endometrial, or cervical cancer. The most common indications for ICU admission were volume resuscitation (108 patients) and respiratory insufficiency (80 patients). Median ICU LOS was 1 day (range, 1-55 days). Patients surviving their hospital admission had a mean APACHE II score of 11.5 (range, 2-37) compared to a mean of 21.2 (range, 13-44) for patients who died prior to hospital discharge (P < 0.001). The overall mortality rate was 12%. A substantial number of gynecological oncology patients will be admitted to the ICU following surgery. Patient outcomes are favorable if APACHE II scores are low and ICU LOS is short.

Employment of liver tissue slice analysis to assay hepatotoxicity linked to replicative and nonreplicative adenoviral agents.

Whereas virotherapy has emerged as a novel and promising approach for neoplastic diseases, appropriate model systems have hampered preclinical evaluation of candidate conditionally replicative adenovirus agents (CRAds) with respect to liver toxicity. This is due to the inability of human viral agents to cross species. We have recently shown the human liver tissue slice model to be a facile means to validate adenoviral replication. On this basis, we sought to determine whether our ex vivo liver tissue slice model could be used to assess CRAd-mediated liver toxicity. We analyzed and compared the toxicity of a conditionally replicative adenovirus (AdDelta24) to that of a replication incompetent adenovirus (Adnull [E1-]) in mouse and human liver tissue slices. To accomplish this, we examined the hepatic apoptosis expression profile by DNA microarray analyses, and compared these results to extracellular release of aminotransferase enzymes, along with direct evidence of apoptosis by caspase-3 immunhistochemical staining and TUNEL assays. Human and mouse liver tissue slices demonstrated a marked increase in extracellular release of aminotransferase enzymes on infection with AdDelta24 compared to Adnull. AdDelta24-mediated liver toxicity was further demonstrated by apoptosis induction, as detected by caspase-3 immunohistochemical staining, TUNEL assay and microarray analysis. In conclusion, concordance of CRAd-mediated apoptosis in both the human and the mouse liver tissue slice models was demonstrated, despite the limited replication ability of CRAds in mouse liver slices. The results of this study, defining the CRAd-mediated apoptosis gene expression profiles in human and mouse liver, may lay a foundation for preclinical liver toxicity analysis of CRAd agents.