J. Lesnock

Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells

Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing roles in the immune system. In the present study, we report that the establishment of a positive feedback loop between prostaglandin E(2) (PGE(2)) and cyclooxygenase 2 (COX2), the key regulator of PGE(2) synthesis, represents the determining factor in redirecting the development of CD1a(+) DCs to CD14(+)CD33(+)CD34(+) monocytic MDSCs. Exogenous PGE(2) and such diverse COX2 activators as lipopolysaccharide, IL-1β, and IFNγ all induce monocyte expression of COX2, blocking their differentiation into CD1a(+) DCs and inducing endogenous PGE(2), IDO1, IL-4Rα, NOS2, and IL-10, typical MDSC-associated suppressive factors. The addition of PGE(2) to GM-CSF/IL-4-supplemented monocyte cultures is sufficient to induce the MDSC phenotype and cytotoxic T lymphocyte (CTL)-suppressive function. In accordance with the key role of PGE(2) in the physiologic induction of human MDSCs, the frequencies of CD11b(+)CD33(+) MDSCs in ovarian cancer are closely correlated with local PGE(2) production, whereas the cancer-promoted induction of MDSCs is strictly COX2 dependent. The disruption of COX2-PGE(2) feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses the production of MDSC-associated suppressive factors and the CTL-inhibitory function of fully developed MDSCs from cancer patients. The central role of COX2-PGE(2) feedback in the induction and persistence of MDSCs highlights the potential for its manipulation to enhance or suppress immune responses in cancer, autoimmunity, or transplantation.

Consolidation Paclitaxel is more Cost-Effective than Bevacizumab following Upfront Treatment of Advanced Epithelial Ovarian Cancer

INTRODUCTION Randomized trials have demonstrated significant improvements in progression-free survival (PFS) with consolidation paclitaxel (P) and bevacizumab (B) following cytoreduction and adjuvant carboplatin/paclitaxel (CP) for advanced epithelial ovarian cancer (EOC). We sought to evaluate the cost-effectiveness (C/E) of these consolidation strategies. METHODS A decision model was developed based on Gynecologic Oncology Group (GOG) protocols #178 and #218. Arm 1 is 6 cycles of CP. Arm 2 is 6 cycles of CP followed by 12 cycles of P (CP+P). Arm 3 is 1 cycle of CP, 5 cycles of CPB, and 16 cycles of B (CPB+B). Parameters include PFS, overall survival (OS), cost, complications (neuropathy for P and bowel perforation for B), and quality-of-life utility values. Sensitivity analyses were performed. RESULTS The incremental cost-effectiveness ratio (ICER) for CT+T is

Cervical dysplasia in pregnancy: a multi-institutional evaluation

13,402/quality adjusted life year (QALY) gained compared to CP. For CPB+B compared to CP, the ICER is

Completion of intraperitoneal chemotherapy in advanced ovarian cancer and catheter-related complications

326,530/QALY. When compared simultaneously, CPB+B is dominated, i.e. is more costly and less effective than CP+P. Results were robust to parameter variation. At a willingness to pay threshold of

Palliative care education in gynecologic oncology: a survey of the fellows.

100,000/QALY, CP+P was the preferred option throughout most of the decision space. Sensitivity analyses suggest that CPB+B would become the preferred option if it were to improve OS by 6.1 years over CP+P. CONCLUSIONS In this model, B consolidation for advanced EOC was associated with a modest improvement in effectiveness that is less than that with P consolidation and more costly. A statistically significant improvement in survival may improve the value of B consolidation.

MicroRNA Analysis in Human Papillomavirus (HPV)-Associated Cervical Neoplasia and Cancer

OBJECTIVE This study was undertaken to identify the prognostic indicators associated with postpartum regression of cervical dysplasia diagnosed in pregnancy. STUDY DESIGN A retrospective cohort study of pregnant women referred for colposcopy from 2004-2007 at four academic centers. RESULTS One thousand seventy-nine patients were identified. Colposcopic impression by cervical cytology is detailed later in the text. Of patients who underwent biopsy, results correlated with or were less severe than colposcopic impression in 83% with CIN 1 and 56% with CIN 2/3. Fifty-seven percent had follow-up postpartum, with 61% reverting to normal. Resolution of cervical dysplasia was inversely associated with smoking (P = .002). No progression to cancer occurred during pregnancy. CONCLUSION Colposcopic impression in pregnancy correlated with cervical biopsy results and postpartum colposcopic findings when performed by expert colposcopists. A high proportion of cervical dysplasia regressed postpartum. Cervical biopsies in pregnancy may not be necessary unless invasive cancer is suspected.

BRCA1 deficiency in ovarian cancer is associated with alteration in expression of several key regulators of cell motility – A proteomics study

OBJECTIVE Combination intravenous/intraperitoneal (IV/IP) chemotherapy has been shown in three randomized trials to be superior to IV therapy alone in the treatment of advanced ovarian cancer with respect to overall survival (OS). We sought to evaluate the effect of dose modification of IP therapy on completion rates. METHODS From November 1999 until August 2008, all optimally debulked, advanced stage ovarian cancer patients who received adjuvant IP chemotherapy at a single institution were reviewed. The primary endpoint was completion of 6 cycles of IP chemotherapy. This rate was compared to published results from GOG 172. A secondary analysis evaluated completion of chemotherapy based on IP catheter type. Statistical analysis was performed with a chi square test with a significance level of p<0.05. RESULTS One hundred and three patients received IP chemotherapy during this period. Seventy-five patients received the modified IV/IP chemotherapy regimen. Sixty-two patients (83%) completed all 6 cycles in our cohort compared to 119 patients (42%) reported in GOG 172 (p=0.0001). Fifty-five patients had a fenestrated catheter (F) and 48 had a non-fenestrated (NF) catheter. Eight patients in each cohort discontinued treatment, for a completion rate of 85.5% in NF and 82.3% in F (p=0.79). CONCLUSIONS The dose modifications utilized in this study allowed for completion of 6 cycles of adjuvant IP chemotherapy in 83% of patients. Choice of catheter type did not affect completion rates. Continued monitoring of outcomes is planned to compare PFS and OS. The high completion rate may increase acceptance of IP chemotherapy in the community setting.

Cost-utility comparison of neoadjuvant chemotherapy versus primary debulking surgery for treatment of advanced-stage ovarian cancer in patients 65 years old or older

INTRODUCTION Gynecologic oncologists regularly care for patients at the end of life, yet little is known about their training or preparedness to deal with issues of palliative care. We sought to examine the training provided to gynecologic oncology fellows as well as their perceived preparedness to provide palliative care. METHODS A self-administered survey was distributed to all fellows enrolled in all gynecologic oncology fellowships during the 2009 academic year. The instrument assessed attitudes, training, experience, and preparedness regarding caring for patients at the end of life. Descriptive, bivariate and multivariable analyses were performed. RESULTS Sixty-one percent (103/168) of fellows completed the survey. Most (89%) feel that palliative care is integral to their training, but few (11%) have had any palliative care training, including either a rotation or fellowship. Using a scale of 1-10, fellows rated teaching quality on two common training opportunities, specifically managing postoperative complications (7.8) and endometrial cancer patients (8.7), as significantly higher than teaching on managing patients at the end of life (5.5; p<0.001). Fellows rated the quality of end of life teaching as significantly lower than overall teaching (55% vs. 92%; p=0.001). Their self-assessment regarding overall preparedness to deal with end of life issues was associated with higher end of life teaching quality and experience caring for more than 10 dying patients. CONCLUSIONS The quantity and quality of training in palliative care are lower compared to other common procedural and oncological issues. Gynecologic oncology fellowship programs need to incorporate a palliative care training curriculum.

Upfront treatment of locally advanced cervical cancer with intensity modulated radiation therapy compared to four-field radiation therapy: A cost-effectiveness analysis

Background: MicroRNAs (miRNAs) are ~22 nt single-stranded, non-coding RNAs that generally negatively regulate their target mRNAs at a posttranscriptional level. Differential expression of miRNAs has been observed in many human cancers. Methods: To study their potential role in the pathogenesis of human papillomavirus (HPV) type 16-associated cervical neoplasia and cancer, we analyzed miRNA expression in cervical tissue from the normal cervix, moderate/ severe dysplasia, and invasive squamous cell carcinoma. Results: Using RNA from six cervical cancers, three dysplasias, and four normal samples and the TaqMan® MicroRNA Arrays, we found that 18 miRNAs were overexpressed and 2 underexpressed in cervical cancer compared to normal cervical tissue. We further demonstrated via individual TaqMan® MicroRNA Assays that 8 miRNAs (miRs- 16, 21, 106b, 135b, 141, 223, 301b, and 449a) were significantly overexpressed and 2 miRNAs (miRs-218 and 433) were significantly underexpressed in cervical cancer compared to normal cervical tissue. MiR-21, miR-135b, miR- 223, and miR-301b were overexpressed in cervical cancer compared to both cervical dysplasia and normal tissue. MiR-218 was similarly underexpressed in cervical cancer compared to dysplasia and normal tissue. Conclusions: Our results suggest that ten miRNAs can delineate cervical cancer from normal cervical tissue, and five miRNAs may have potential as markers for progression from dysplasia to invasive cervical disease.

MicroRNA analysis in human papillomavirus (HPV)-associated cervical neoplasia and cancer

Functional loss of expression of breast cancer susceptibility gene 1(BRCA1) has been implicated in genomic instability and cancer progression. There is emerging evidence that BRCA1 gene product (BRCA1) also plays a role in cancer cell migration. We performed a quantitative proteomics study of EOC patient tumor tissues and identified changes in expression of several key regulators of actin cytoskeleton/cell adhesion and cell migration (CAPN1, 14-3-3, CAPG, PFN1, SPTBN1, CFN1) associated with loss of BRCA1 function. Gene expression analyses demonstrate that several of these proteomic hits are differentially expressed between early and advanced stage EOC thus suggesting clinical relevance of these proteins to disease progression. By immunohistochemistry of ovarian tumors with BRCA1+/+ and BRCA1null status, we further verified our proteomic-based finding of elevated PFN1 expression associated with BRCA1 deficiency. Finally, we established a causal link between PFN1 and BRCA1-induced changes in cell migration thus uncovering a novel mechanistic basis for BRCA1-dependent regulation of ovarian cancer cell migration. Overall, findings of this study open up multiple avenues by which BRCA1 can potentially regulate migration and metastatic phenotype of EOC cells.