Publications by authors named "Patricia L Judson"

52 Publications

Complementary and Alternative Medicine Use in Individuals Presenting for Care at a Comprehensive Cancer Center.

Integr Cancer Ther 2017 03 21;16(1):96-103. Epub 2016 Jul 21.

1 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Purpose: To define the use of complementary and alternative medicine (CAM) in individuals presenting for care at a comprehensive cancer center.

Patients And Methods: A total of 17 639 individuals presenting to an NCI-designated Comprehensive Cancer Center (and consortium sites) completed a questionnaire regarding CAM use. Data were analyzed using the univariate χ test to assess CAM use associated with a number of variables, including cancer status, age, gender, marital status, ethnicity, race, employment, and education level.

Results: Eighty-seven percent of individuals who completed the CAM survey acknowledged CAM therapy use within the previous 12 months. Of the 5 broad categories of CAM, the most commonly used were biologically based approaches (14 759/17 639 [83.67%]), mind-body interventions (4624/17 485 [26.45%]), manipulative and body-based therapies (3957/17 537 [22.56%]), alternative medical systems (429/15 952 [2.69%]), and energy therapies (270/15 872 [1.7%]). CAM use was more prevalent among women, non-Hispanics, Caucasians, patients 60 to 69 years of age, and those who are married, have a higher level of education, and are employed ( P < .005).

Conclusions: This is the largest report of CAM use in individuals presenting for care at a comprehensive cancer center. Our analysis revealed that a very high percentage of patients utilize CAM. Because many of these CAM interventions are not studied in oncology patients, additional research on safety, efficacy, and mechanisms of action are essential. Furthermore, it is important that oncologists understand CAM modalities and counsel their patients about their use.
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http://dx.doi.org/10.1177/1534735416660384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736072PMC
March 2017

Sensitivity of ovarian cancer cells to acetaminophen reveals biological pathways that affect patient survival.

Mol Clin Oncol 2016 Mar 7;4(3):399-404. Epub 2016 Jan 7.

Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Experimental and epidemiological data support the potential activity of acetaminophen against ovarian cancer (OVCA). In this study, we sought to confirm the activity of acetaminophen in OVCA cell lines and to investigate the molecular basis of response. A total of 16 OVCA cell lines underwent pretreatment (baseline) genome-wide expression measurements and were then treated with and analyzed for acetaminophen sensitivity. Pearson's correlation analysis was performed to identify genes that were associated with OVCA acetaminophen response. The identified genes were subjected to pathway analysis, and the expression of each represented pathway was summarized using principal component analysis. OVCA acetaminophen response pathways were analyzed in 4 external clinico-genomic datasets from 820 women for associations with overall survival from OVCA. Acetaminophen exhibited antiproliferative activity against all tested OVCA cell lines, with half maximal inhibitory concentration values ranging from 63.2 to 403 µM. Pearson's correlation followed by biological pathway analysis identified 13 pathways to be associated with acetaminophen sensitivity (P<0.01). Associations were observed between patient survival from OVCA and expression of the following pathways: Development/angiotensin signaling via β-arrestin (P=0.04), protein folding and maturation/angiotensin system maturation (P=0.02), signal transduction/c-Jun N-terminal kinase (JNK) pathway (P=0.03) and androstenedione and testosterone biosynthesis and metabolism (P=0.02). We confirmed that acetaminophen was active against OVCA cells . Furthermore, we identified 4 molecular signaling pathways associated with acetaminophen response that may also affect overall survival in women with OVCA, including the JNK pathway, which has been previously implicated in the mechanism of action of acetaminophen and is predictive of decreased survival in women with OVCA.
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http://dx.doi.org/10.3892/mco.2016.725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774474PMC
March 2016

Molecular determinants for lymph node metastasis in clinically early-stage endometrial cancer.

Oncol Lett 2016 Jan 6;11(1):323-329. Epub 2015 Nov 6.

Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa Hospital and Clinics, Iowa, IA 52242, USA.

Patients with occult lymph node metastasis in endometrioid-type endometrial cancer (EC) are prone to the development of recurrences and have worse outcomes compared with patients without lymph node metastasis. In the current study, the aim was to identify molecular parameters associated with lymph node metastasis in EC clinically early-stage disease. A univariate analysis of differentially expressed genes, proteins and clinicopathological parameters (including myometrial invasion and tumor grade) was performed, comparing EC patients with and without lymph node metastasis (n=262 patients from The Cancer Genome Atlas). Significant parameters were introduced in a multivariate model and a gene expression pathway analysis. Lymph node metastasis was associated with expression of 268 unique genes (P<0.001), 19 unique proteins (P<0.05), tumor grade and myometrial invasion in univariate analysis. Multivariate analysis demonstrated 10 genes independently associated with lymph node metastasis and 4 independently associated proteins. Myometrial invasion was the only independent clinicopathological parameter associated with lymph node status. The enrichment pathway analysis demonstrated that expression of epidermal growth factor receptor, Bcl2 antagonist of cell death and phosphatase and tensin homolog pathways were significantly involved in lymph node metastasis (P≤0.001). A gene expression signature to predict lymph node status in EC was created for future validation. Few studies have focused on the association between EC's molecular characteristics and nodal metastasis. Defining molecular risk factors for EC lymphatic nodal metastasis may help to individualize treatment and improve patient outcomes.
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http://dx.doi.org/10.3892/ol.2015.3883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726972PMC
January 2016

Micro-RNAs associated with the evolution of ovarian cancer cisplatin resistance.

Gynecol Oncol 2016 Feb 28;140(2):259-63. Epub 2015 Dec 28.

Myriad Genetic Laboratories, Salt Lake City, UT 84108, USA.

Objectives: Ovarian cancer (OVCA) is the leading cause of mortality among women with gynecologic malignancy, in part due to the development of chemoresistance. We sought to identify micro-RNAs (miRNAs) associated with in vitro development of OVCA chemoresistance that may also represent potential targets for therapy.

Methods: In this study, four OVCA cell lines (A2780CP, A2780S, IGROV1, and OVCAR5) were serially treated with cisplatin in parallel with measurements of miRNA expression changes.

Results: Nine miRNAs were found to be associated with increasing cisplatin resistance (IC50) (p<0.01); however, only 5 of these miRNAs have publically available information. Pathway analysis identified 15 molecular signaling pathways that were represented by genes predicted to be targets of the 5 miRNAs (false discovery rate<0.05), 11 of which are associated with the epithelial-mesenchymal transition (EMT). Further analysis identified 2 of those pathways as being associated with overall survival in 218 patients with OVCA.

Conclusions: Collectively, this panel of miRNAs associated with in vitro evolution of OVCA cisplatin resistance and the pathways identified to be associated with EMT and overall patient survival provide a framework for further investigations into EMT as a therapeutic target in patients with OVCA.
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http://dx.doi.org/10.1016/j.ygyno.2015.12.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724442PMC
February 2016

Complementary and Alternative Medicine Use in Women With Gynecologic Malignancy Presenting for Care at a Comprehensive Cancer Center.

Int J Gynecol Cancer 2015 Nov;25(9):1724-30

*Departments of Gynecologic Oncology and †Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Objective: We evaluated complementary and alternative medicine (CAM) practices among women presenting to a National Cancer Institute-designated Comprehensive Cancer Center with a gynecologic malignancy.

Methods: Women with a gynecologic malignancy who had consented to enrollment in our institutional prospective clinical registry between January 2003 and January 2014 and who had completed a questionnaire assessing sociodemographic characteristics, medical histories, quality of life, and CAM use were considered for analysis.

Results: Among the 2508 women identified, responses to questions on CAM use were provided by 534 (21.3%). The majority of CAM question respondents were white (93.5%) and older than 50 years (76%). Overall, 464 women (87% of CAM question respondents) used at least 1 CAM therapy during the previous 12 months. The most commonly used CAM categories were biologically based approaches (83.5%), mind and body interventions (30.6%), and manipulative and body-based therapies (18.8%). The most commonly used individual CAM therapies were vitamins and minerals (78%), herbal supplements (27.9%), spiritual healing and prayer (15.1%), and deep breathing relaxation exercises (13.1%). Complementary and alternative medicine use was greatest in age groups 20 to 30 years and older than 65 years and was more prevalent among those who were widowed (P < 0.005), retired (P = 0.02), and with a higher level of education (P < 0.01). There was no association with cancer type, race, or ethnicity.

Conclusions: Complementary and alternative medicine use is common among women being treated for gynecologic malignancy. Given the potential interactions of some CAM modalities with conventional treatment and the possible benefits in controlling symptoms and improving quality of life, providers should discuss CAM with their patients.
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http://dx.doi.org/10.1097/IGC.0000000000000549DOI Listing
November 2015

BAD-mediated apoptotic pathway is associated with human cancer development.

Int J Mol Med 2015 Apr 5;35(4):1081-7. Epub 2015 Feb 5.

Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive and invasive cancers of different types, such as ovarian, endometrial, breast and colon cancers in order to determine the associations between the BAD-mediated apoptotic pathway and cancer development. Immunofluorescence was used to compare the expression levels of phosphorylated BAD [pBAD (serine-112, -136 and -155)] in immortalized normal and invasive ovarian, colon and breast cancer cells. The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples. The growth-promoting effects of pBAD protein levels in the immortalized normal and cancer cells were assessed using siRNA depletion experiments with MTS assays. The expression of the BAD-mediated apoptotic pathway was associated with the development and/or progression of ovarian (n=106, p<0.001), breast (n=185, p<0.0008; n=61, p=0.04), colon (n=22, p<0.001) and endometrial (n=33, p<0.001) cancers, as well as with ovarian endometriosis (n=20, p<0.001). Higher pBAD protein levels were observed in the cancer cells compared to the immortalized normal cells, whereas PP2C gene expression was lower in the cancer compared to the ovarian tumor tissue samples (n=76, p<0.001). The increased pBAD protein levels after the depletion of PP2C conferred a growth advantage to the immortalized normal and cancer cells. The BAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.
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http://dx.doi.org/10.3892/ijmm.2015.2091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356438PMC
April 2015

The Chinese herb polyphyllin D sensitizes ovarian cancer cells to cisplatin-induced growth arrest.

J Cancer Res Clin Oncol 2015 Feb 28;141(2):237-42. Epub 2014 Aug 28.

Department of Women's Oncology, Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.

Purpose: We evaluated the effects of polyphyllin D (PD), a natural compound with anti-neoplastic activity and a major component of the Chinese herb Paris polyphylla, on ovarian cancer (OVCA) cell line proliferation and platinum sensitivity.

Methods: A panel of 20 OVCA cell lines was subjected to PD treatment, MTS proliferation assays, and determination of IC50. Pre-treatment, baseline genome-wide Affymetrix expression analysis was performed on each cell line, and Pearson's correlation was performed to identify genes associated with OVCA PD sensitivity. Twelve cell lines were treated with PD with and without cisplatin, and the effects of PD on cisplatin IC50 were quantified. Genes associated with OVCA PD sensitivity were evaluated for associations with survival in a publically available clinico-genomic dataset of 218 patients with OVCA.

Results: Our results showed that PD exhibited anti-proliferative effects against all OVCA cell lines tested, with IC50 values ranging from 0.2 to 1.4 μm. Furthermore, in all cell lines, PD treatment significantly decreased cisplatin IC50 (mean IC50 reduction of 2.1 µm; P < 0.02). Pearson's correlation test identified 25 probe sets, representing 18 unique genes to be associated with PD sensitivity (FDR = 0). We found that one of these genes was associated with overall survival in women with OVCA: CLDN4 (P = 0.014).

Conclusion: Our findings highlight the value of PD as a natural product with anti-cancer properties, which may also enhance the activity of existing therapeutic agents.
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http://dx.doi.org/10.1007/s00432-014-1797-xDOI Listing
February 2015

Bladder and bowel symptoms in cervical and endometrial cancer survivors.

Psychooncology 2014 Jun 30;23(6):672-8. Epub 2014 Jan 30.

Health Outcomes and Behavior Program, Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Background: Previous studies likely underestimate the prevalence of bowel and bladder symptoms in gynecologic cancer survivors. We sought to estimate the prevalence of these symptoms in cervical and endometrial cancer survivors who had completed treatment 1 year previously compared with non-cancer controls, and to examine factors associated with more severe symptoms in survivors.

Methods: As part of a larger quality of life study, survivors who were 1-year posttreatment for cervical or endometrial cancer (n = 104) completed measures of bladder and bowel symptoms. An age-matched and race/ethnicity-matched sample of women with no history of cancer was recruited for comparison purposes.

Results: Survivors reported a higher prevalence of bladder symptoms, specifically storage and incontinence symptoms, than non-cancer controls. Prevalence rates for bowel symptoms in survivors were higher than those reported in previous studies. Greater symptom severity was associated with younger age, lower annual incomes, and less education. Other correlates included higher body mass index and history of smoking. As hypothesized, more severe symptoms were associated with radical hysterectomy and pelvic radiation.

Conclusions: Bladder and bowel symptoms are more prevalent in cervical and endometrial cancer survivors than non-cancer controls. Future research should replicate these findings in a larger, prospective study.
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http://dx.doi.org/10.1002/pon.3461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043946PMC
June 2014

Human cancer cell line microRNAs associated with in vitro sensitivity to paclitaxel.

Oncol Rep 2014 Jan 13;31(1):376-83. Epub 2013 Nov 13.

Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Paclitaxel is a mainstay of treatment for many solid tumors, and frequently, clinical outcome is influenced by paclitaxel sensitivity. Despite this, our understanding of the molecular basis of paclitaxel response is incomplete. Recently, it has been shown that microRNAs (miRNAs) influence messenger RNA (mRNA) transcriptional control and can contribute to human carcinogenesis. In the present study, our objective was to identify miRNAs associated with cancer cell line response to paclitaxel and to evaluate these miRNAs as therapeutic targets to increase paclitaxel sensitivity. We measured the expression of 335 unique miRNAs in 40 human cancer cell lines selected from the NCI panel. We then integrated miRNA expression data with publicly available paclitaxel-sensitivity (GI₅₀) data for each of the 40 cell lines to identify miRNAs associated with paclitaxel sensitivity. Ovarian cancer cell lines with differential miRNA expression and paclitaxel sensitivity were transiently transfected with miRNA precursors and inhibitors, and the effects on in vitro cell paclitaxel sensitivity were evaluated. Pearson's correlation identified 2 miRNAs (miR-367 and miR-30a-5p) associated with the NCI40 cell line in vitro paclitaxel response (P<0.0003). Ovarian cancer cells were selected based on the association between paclitaxel sensitivity and miR-367/miR-30a-5p expression. Overexpression of miR-367 in the paclitaxel-sensitive cells [PA1; IC₅₀, 1.69 nM, high miR-367 (2.997), low miR-30a-5p (-0.323)] further increased paclitaxel sensitivity, whereas miR-367 depletion decreased paclitaxel sensitivity. In contrast, overexpression and depletion of miR-30a-5p in the paclitaxel-resistant cells [OVCAR4; IC₅₀, 17.8 nM, low miR-367 (-0.640), high miR-30a-5p (3.270)] decreased and increased paclitaxel sensitivity, respectively. We identified and successfully targeted miRNAs associated with human cancer cell line response to paclitaxel. Our strategy of integrating in vitro miRNA expression and drug sensitivity data may not only aid in the characterization of determinants of drug response but also in the identification of novel therapeutic targets to increase activity of existing therapeutics.
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http://dx.doi.org/10.3892/or.2013.2847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981115PMC
January 2014

Gene expression data reveal common pathways that characterize the unifocal nature of ovarian cancer.

Am J Obstet Gynecol 2013 Dec 9;209(6):576.e1-576.e16. Epub 2013 Aug 9.

Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Objective: The objective of the study was to evaluate the biological validity of ovarian cancer (OVCA) screening and early detection efforts and to characterize signaling pathways associated with human cancer metastasis and patient survival.

Study Design: Using genome-wide expression profiling and deoxyribonucleic acid sequencing, we compared pelvic and matched extrapelvic implants from 30 patients with advanced-stage OVCA for expression of molecular signaling pathways and p53 gene mutations. Differentially expressed pathways were further evaluated in a series of primary or early-stage vs metastatic or recurrent cancer samples from 389 ovarian, prostate, and oral cancer patients. Metastasis pathways were also evaluated for associations with survival in 9 independent clinicogenomic datasets from 1691 ovarian, breast, colon, brain, and lung cancer and leukemia patients. The inhibitory effects of 1 pathway (transforming growth factor [TGF]-WNT) on in vitro OVCA cell migration were studied.

Results: Pelvic and extrapelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations. However, we identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extrapelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral, and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P = .006), colon cancer (1 pathway at P = .005), and leukemia (P = .05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration.

Conclusion: Advanced-stage OVCA has a unifocal origin in the pelvis. Molecular pathways associated with extrapelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease.
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http://dx.doi.org/10.1016/j.ajog.2013.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840156PMC
December 2013

Perifosine, an AKT inhibitor, modulates ovarian cancer cell line sensitivity to cisplatin-induced growth arrest.

Gynecol Oncol 2013 Oct 20;131(1):207-12. Epub 2013 Jul 20.

Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Objectives: AKT, a key regulator of diverse tumor signaling, is associated with progression of many cancers. Here, we investigated 1) the influence of AKT on survival from ovarian cancer (OVCA), 2) the activity of the AKT inhibitor perifosine ± cisplatin, and 3) the molecular determinants of perifosine-response. Phospho-AKT expression values and Affymetrix U133a expression data were downloaded from The Cancer Genome Atlas.

Methods: Pearson correlation was used to determine associations between overall survival from OVCA and therapy response. Genes and represented signaling pathways associated with perifosine-response were explored in OVCA cells (n=10) and the NCI60 cancer cell panel. Pathway expressions, modeled by PCA, were evaluated for influences on survival using publically available clinico-genomic datasets.

Results: Phospho-AKT (serine473) expression correlated with survival from OVCA (P<0.05) and platinum-response (P=0.004). In vitro, perifosine showed anti-proliferative effects against OVCA cells and potentiated cisplatin-induced growth arrest. Perifosine-response was associated with the expression (FDR<0.05) of 7 signaling pathways in OVCA cells and 64 signaling pathways in the NCI60 cell panel. Three pathways were found in common: 1) Cytoskeleton remodeling/cytoskeleton remodeling (cyto), 2) cell adhesion/chemokines and adhesion (chemokines), and 3) cytoskeleton remodeling/TGF-WNT (TGF-WNT). The TGF-WNT was associated with survival from OVCA (P=0.0055).

Conclusions: AKT signaling is an important determinant of OVCA response to chemotherapy and overall patient survival. Our data provide insight into the molecular basis to perifosine activity and identifies pathways associated with perifosine sensitivity and patient clinical outcome.
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http://dx.doi.org/10.1016/j.ygyno.2013.07.088DOI Listing
October 2013

A phase II trial of docetaxel and bevacizumab in recurrent ovarian cancer within 12 months of prior platinum-based chemotherapy.

Gynecol Oncol 2013 Jul 25;130(1):19-24. Epub 2013 Apr 25.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Objectives: The efficacy and safety of bevacizumab and docetaxel were evaluated in women who developed recurrent epithelial ovarian, fallopian, or peritoneal cancer within 12 months of platinum-based therapy.

Methods: Patients received docetaxel (40 mg/m(2)) on days 1 and 8 and bevacizumab (15 mg/kg) on day 1 of a 21-daycycle. Primary endpoint was 6-month progression-free survival (PFS).

Results: Forty-one patients were evaluable for PFS and 38 for best response; 46% had platinum-free intervals (PFI) of <6 months and 54% between 6 and 12 months. The 6-month PFS was 43.9% (95% confidence interval (CI(95%))=28.6-58.2%). Median PFS (months) was 5.2 (CI(95%)=4.4-7.2) for all patients, 6.2 (CI(95%)=4.1-7.4) for patients with PFI <6 months, and 5.1 (CI(95%)=3.0-7.2) for those with PFI ≥ 6 months. Twenty-two patients showed overall response (CR+PR) (57.9%; CI(95%)=40.8-73.7%), and 32 showed clinical benefit (CR+PR+SD) (84.2%; CI(95%)=68.8-94.0%). For those with complete or partial responses, median duration of response was 4.8 months (0.7-14.5). Median overall survival was 12.4 months (CI(95%)=10.0-21.9). The most common grade 3/4 adverse events (AEs) were neutropenia (14.6% of patients), followed by leukopenia, fatigue, metabolic, and gastrointestinal, with 66% showing any grade 3/4 toxicity. Most common AEs of any grade were gastrointestinal (93%), fatigue (73%), and pain (73%). Four (10%) patients developed hypertension, 1 a gastrointestinal perforation, and another a colovesicular fistula.

Conclusions: Bevacizumab and docetaxel administered in patients with recurrent ovarian cancer is an active regimen without new unanticipated toxicities. This combination should be an option for further study or clinical use in recurrent ovarian cancer.
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http://dx.doi.org/10.1016/j.ygyno.2013.04.049DOI Listing
July 2013

Factors associated with improved toxicity and tolerability of intraperitoneal chemotherapy in advanced-stage epithelial ovarian cancers.

Am J Obstet Gynecol 2013 Jun 15;208(6):501.e1-7. Epub 2013 Mar 15.

Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL, USA.

Objective: We sought to evaluate the toxicity and tolerability of the intraperitoneal/intravenous regimen by comparing the modified regimen that is used at the Moffitt Cancer Center vs the published findings of the Gynecologic Oncology Group Study 172.

Study Design: Using the Moffitt database, we evaluated the outcomes of patients who underwent primary optimal cytoreduction for stage IIC-IV epithelial ovarian, tubal, and peritoneal carcinoma followed by the intent-to-treat with intraperitoneal/intravenous chemotherapy. National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) was used to grade adverse events.

Results: We analyzed patient data from 2006-2011 and identified 69 patients who met our inclusion criteria. The most frequent grade 3/4 toxicities were neutropenia (48%), gastrointestinal (9%), metabolic (9%), and infection (5%). Remaining toxicities occurred in <5% of patients. Patients received a greater number of cycles compared with the Gynecologic Oncology Group Study 172 (4.28 vs 3.66, respectively; P = .0088).

Conclusion: With the use of supportive care and the preemptive management of established side-effects, the associated toxicities and tolerability of intraperitoneal chemotherapy can be improved.
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http://dx.doi.org/10.1016/j.ajog.2013.03.012DOI Listing
June 2013

A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth.

Oncol Rep 2013 May 5;29(5):2011-8. Epub 2013 Mar 5.

Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Elevated serum levels of hepatocyte growth factor (HGF) and high tumor expression of c-Met are both indicators of poor overall survival from ovarian cancer (OVCA). In the present study, we evaluated the role of the HGF signaling pathway in OVCA cell line chemoresistance and OVCA patient overall survival as well as the influence of HGF/c-Met signaling inhibition on the sensitivity of OVCA cells to combinational carboplatin plus paclitaxel therapy. The prevalence of the HGF receptor, c-Met, was determined by immunohistochemistry in primary OVCA samples (n=79) and OVCA cell lines (n=41). The influence of the c-Met-specific inhibitor MK8033 on OVCA cell sensitivity to combinations of carboplatin plus paclitaxel was examined in a subset of OVCA cells (n=8) by CellTiter-Blue cell viability assays. Correlation tests were used to identify genes associated with response to MK8033 and carboplatin plus paclitaxel. Identified genes were evaluated for influence on overall survival from OVCA using principal component analysis (PCA) modeling in an independent clinical OVCA dataset (n=218). Immunohistochemistry analysis indicated that 83% of OVCA cells and 92% of primary OVCA expressed the HGF receptor, c-Met. MK8033 exhibited significant anti-proliferative effects against a panel of human OVCA cell lines. Combination index values determined by the Chou-Talalay isobologram equation indicated synergistic activity in combinations of MK8033 and carboplatin plus paclitaxel. Pearson's correlation identified a 47-gene signature to be associated with MK8033-carboplatin plus paclitaxel response. PCA modeling indicated an association of this 47-gene response signature with overall survival from OVCA (P=0.013). These data indicate that HGF/c-Met pathway signaling may influence OVCA chemosensitivity and overall patient survival. Furthermore, HGF/c-Met inhibition by MK8033 represents a promising new therapeutic avenue to increase OVCA sensitivity to carboplatin plus paclitaxel.
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http://dx.doi.org/10.3892/or.2013.2329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536335PMC
May 2013

Hyperthermic intraperitoneal chemotherapy with carboplatin for optimally-cytoreduced, recurrent, platinum-sensitive ovarian carcinoma: a pilot study.

Gynecol Oncol 2013 Apr 23;129(1):81-5. Epub 2013 Jan 23.

Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN, USA.

Objective: We aimed to evaluate the feasibility and tolerability of hyperthermic intraperitoneal carboplatin (HIPEC-carboplatin) following secondary cytoreduction for recurrent, platinum-sensitive ovarian cancer.

Methods: In a single institution prospective, pilot study, ten patients underwent secondary cytoreductive surgery followed by HIPEC-carboplatin at 1000 mg/m(2). Consolidation (6 cycles) was with platinum-based regimens. Adverse and quality of life were measured throughout treatment.

Results: Twelve patients were enrolled of which 2 were excluded (one each for extra-abdominal disease indentified before surgery and suboptimal cytoreduction). All 10 remaining patients received prescribed HIPEC-carboplatin. There were no intra-operative complications or AEs attributable to HIPEC-therapy. Grade 1/2 nausea was the most common post-operative toxicity (6/10 patients). Two patients had grade 4 post-operative neutropenia and thrombocytopenia but only one experienced transient treatment delay. The median hospital stay was 5.5 days. 69/70 (98%) of planned chemotherapy doses were ultimately delivered with 1 patient electively forgoing her final treatment. At a median (range) follow-up of 16 (6-23) months, three patients have recurred at 8, 14, and 16 months from surgery. The median disease-free and overall survivals have not been reached. Fact-O scores were significantly lower following surgery (126 vs. 108, p<.01), but improved by completion of therapy (108 vs. 113, p=0.27).

Conclusions: HIPEC-carboplatin at 1000 mg/m(2) following optimal cytoreduction for ovarian cancer is feasible. Surgical complications were not observed, and post-operative AEs were largely within expected ranges. Consolidation using standard platinum-based regimens was feasible following HIPEC-carboplatin, and preliminary survival data suggests efficacy. Further investigation of HIPEC-carboplatin in the setting of debulkable cancer recurrence is warranted.
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http://dx.doi.org/10.1016/j.ygyno.2013.01.010DOI Listing
April 2013

Is bilateral lymphadenectomy for midline squamous carcinoma of the vulva always necessary? An analysis from Gynecologic Oncology Group (GOG) 173.

Gynecol Oncol 2013 Feb 29;128(2):155-9. Epub 2012 Nov 29.

The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Objective: To determine which patients with near midline lesions may safely undergo unilateral groin dissection based on clinical exam and lymphoscintigraphy (LSG) results.

Methods: Patients participating in GOG-173 underwent sentinel lymph node (SLN) localization with blue dye, and radiocolloid with optional LSG before definitive inguinal-femoral lymphadenectomy (LND). This analysis interrogates the reliability of LSG alone relative to primary tumor location in those patients who had an interpretable LSG and at least one SLN identified. Primary tumor location was categorized as lateral (>2cm from midline), midline, or lateral ambiguous (LA) if located within 2cm, but not involving the midline.

Results: Two-hundred-thirty-four patients met eligibility criteria. Sixty-four had lateral lesions, and underwent unilateral LND. All patients with LA (N=65) and midline (N=105) tumors underwent bilateral LND. Bilateral drainage by LSG was identified in 14/64 (22%) patients with lateral tumors, 38/65 (58%) with LA tumors and in 73/105 (70%) with midline tumors. At mapping, no SLNs were found in contralateral groins among those patients with LA and midline tumors who had unilateral-only LSGs. However, in these patients groin metastases were found in 4/32 patients with midline tumors undergoing contralateral dissection; none were found in 27 patients with LA tumors.

Conclusion: The likelihood of detectable bilateral drainage using preoperative LSG decreases as a function of distance from midline. Patients with LA primaries and unilateral drainage on LSG may safely undergo unilateral SLN.
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http://dx.doi.org/10.1016/j.ygyno.2012.11.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638213PMC
February 2013

Lymphatic mapping and sentinel lymph node biopsy in women with squamous cell carcinoma of the vulva: a gynecologic oncology group study.

J Clin Oncol 2012 Nov 2;30(31):3786-91. Epub 2012 Jul 2.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 440, Houston, TX 77030, USA.

Purpose: To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer.

Patients And Methods: Eligible women had squamous cell carcinoma, at least 1-mm invasion, and tumor size ≥ 2 cm and ≤ 6 cm. The primary tumor was limited to the vulva, and there were no groin lymph nodes that were clinically suggestive of cancer. All women underwent intraoperative lymphatic mapping, sentinel lymph node biopsy, and inguinal femoral lymphadenectomy. Histologic ultra staging of the sentinel lymph node was prescribed.

Results: In all, 452 women underwent the planned procedures, and 418 had at least one sentinel lymph node identified. There were 132 node-positive women, including 11 (8.3%) with false-negative nodes. Twenty-three percent of the true-positive patients were detected by immunohistochemical analysis of the sentinel lymph node. The sensitivity was 91.7% (90% lower confidence bound, 86.7%) and the false-negative predictive value (1-negative predictive value) was 3.7% (90% upper confidence bound, 6.1%). In women with tumor less than 4 cm, the false-negative predictive value was 2.0% (90% upper confidence bound, 4.5%).

Conclusion: Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva.
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http://dx.doi.org/10.1200/JCO.2011.41.2528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478573PMC
November 2012

Characterizing the efficacy of fermented wheat germ extract against ovarian cancer and defining the genomic basis of its activity.

Int J Gynecol Cancer 2012 Jul;22(6):960-7

Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Objective: Most women with advanced-stage epithelial ovarian cancer (OVCA) ultimately develop chemoresistant recurrent disease. Therefore, a great need to develop new, more active, and less toxic agents and/or to optimize the efficacy of existing agents exists.

Methods: In this study, we investigated the activity of Avemar, a natural, nontoxic, fermented wheat germ extract (FWGE), against a range of OVCA cell lines, both alone and in combination with cisplatin chemotherapy and delineated the molecular signaling pathways that underlie FWGE activity at a genome-wide level.

Results: We found that FWGE exhibited significant antiproliferative effects against 12 human OVCA cell lines and potentiated cisplatin-induced apoptosis. Pearson correlation of FWGE sensitivity and gene expression data identified 2142 genes (false discovery rate < 0.2) representing 27 biologic pathways (P < 0.05) to be significantly associated with FWGE sensitivity. A parallel analysis of genomic data for 59 human cancer cell lines matched to chemosensitivity data for 2,6-dimethoxy-p-benzoquinone, a proposed active component of FWGE, identified representation of 13 pathways common to both FWGE and 2,6-dimethoxy-p-benzoquinone sensitivity.

Conclusions: Our findings confirm the value of FWGE as a natural product with anticancer properties that may also enhance the activity of existing therapeutic agents. Furthermore, our findings provide substantial insights into the molecular basis of FWGE's effect on human cancer cells.
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http://dx.doi.org/10.1097/IGC.0b013e318258509dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036555PMC
July 2012

The O-glycan pathway is associated with in vitro sensitivity to gemcitabine and overall survival from ovarian cancer.

Int J Oncol 2012 Jul 26;41(1):179-88. Epub 2012 Apr 26.

Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Ovarian cancer (OVCA) is the most lethal gynecological malignancy. The high mortality rate associated with this disease is due in large part to the development of resistance to chemotherapy; however, the biological basis of this remains unclear. Gemcitabine is frequently used for the treatment of patients with platinum-resistant OVCA. We report molecular signaling pathways associated with OVCA response to gemcitabine. Forty-one OVCA cell lines were subjected to gene expression analysis; in parallel, IC50 values for gemcitabine were quantified using CellTiter-Blue viability assays. Pearson's correlation coefficients were calculated for gene expression and gemcitabine IC50 values. The genes associated with gemcitabine sensitivity were subjected to pathway analysis. For the identified pathways, principal component analysis was used to derive pathway signatures and corresponding scores, which represent overall measures of pathway expression. Expression levels of the identified pathways were then evaluated in a series of clinico-genomic datasets from 142 patients with stage III/IV serous OVCA. We found that in vitro gemcitabine sensitivity was associated with expression of 131 genes (p<0.001). These genes include significant representation of three molecular signaling pathways (p<0.02): O-glycan biosynthesis, Role of Nek in cell cycle regulation and Antiviral actions of Interferons. In an external clinico-genomic OVCA dataset (n=142), expression of the O-glycan pathway was associated with overall survival, independent of surgical cytoreductive status, grade and age (p<0.001). Expression levels of Role of Nek in cell cycle regulation and Antiviral actions of Interferons were not associated with survival (p=0.31 and p=0.54, respectively). Collectively, expression of the O-glycan biosynthesis pathway, which modifies protein function via post-translational carbohydrate binding, is independently associated with overall survival from OVCA. Our findings shed light on the molecular basis of OVCA responsiveness to gemcitabine and also identify a signaling pathway that may influence patient survival.
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http://dx.doi.org/10.3892/ijo.2012.1451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017641PMC
July 2012

OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.

J Clin Oncol 2012 Jun 23;30(17):2039-45. Epub 2012 Apr 23.

Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.

Purpose: This randomized, multicenter, blinded, placebo-controlled phase III trial tested the efficacy and safety of bevacizumab (BV) with gemcitabine and carboplatin (GC) compared with GC in platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer (ROC).

Patients And Methods: Patients with platinum-sensitive ROC (recurrence ≥ 6 months after front-line platinum-based therapy) and measurable disease were randomly assigned to GC plus either BV or placebo (PL) for six to 10 cycles. BV or PL, respectively, was then continued until disease progression. The primary end point was progression-free survival (PFS) by RECIST; secondary end points were objective response rate, duration of response (DOR), overall survival, and safety.

Results: Overall, 484 patients were randomly assigned. PFS for the BV arm was superior to that for the PL arm (hazard ratio [HR], 0.484; 95% CI, 0.388 to 0.605; log-rank P < .0001); median PFS was 12.4 v 8.4 months, respectively. The objective response rate (78.5% v 57.4%; P < .0001) and DOR (10.4 v 7.4 months; HR, 0.534; 95% CI, 0.408 to 0.698) were significantly improved with the addition of BV. No new safety concerns were noted. Grade 3 or higher hypertension (17.4% v < 1%) and proteinuria (8.5% v < 1%) occurred more frequently in the BV arm. The rates of neutropenia and febrile neutropenia were similar in both arms. Two patients in the BV arm experienced GI perforation after study treatment discontinuation.

Conclusion: GC plus BV followed by BV until progression resulted in a statistically significant improvement in PFS compared with GC plus PL in platinum-sensitive ROC.
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http://dx.doi.org/10.1200/JCO.2012.42.0505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646321PMC
June 2012

BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin.

J Gynecol Oncol 2012 Jan 9;23(1):35-42. Epub 2012 Jan 9.

Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Objective: The BCL2 family proteins are critical mediators of cellular apoptosis and, as such, have been implicated as determinants of cancer cell chemo-sensitivity. Recently, it has been demonstrated that the phosphorylation status of the BCL2 antagonist of cell death (BAD) protein may influence ovarian cancer (OVCA) cell sensitivity to cisplatin. Here, we sought to evaluate how kinase and phosphatase components of the BAD apoptosis pathway influence OVCA chemo-sensitivity.

Methods: Protein levels of cyclin-dependent kinase 1 (CDK1) and protein phosphatase 2C (PP2C) were measured by immunofluorescence in a series of 64 primary advanced-stage serous OVCA patient samples. In parallel, levels of cAMP-dependent protein kinase (PKA), AKT, and PP2C were quantified by Western blot analysis in paired mother/daughter platinum-sensitive/resistant OVCA cell lines (A2008/C13, A2780S/A2780CP, Chi/ChiR). BAD pathway kinase CDK1 was depleted using siRNA transfection, and the influence on BAD phosphorylation and cisplatin-induced apoptosis was evaluated.

Results: OVCA patient samples that demonstrated complete responses to primary platinum-based therapy demonstrated 4-fold higher CDK1 (p<0.0001) and 2-fold lower PP2C (p=0.14) protein levels than samples that demonstrated incomplete responses. Protein levels of PP2C were lower in the platinum-resistant versus that shown in the platinum-sensitive OVCA cell line sub-clones. Levels of PKA were higher in all platinum-resistant than in platinum-sensitive OVCA cell line sub-clones. Selective siRNA depletion of CDK1 increased sensitivity to cisplatin-induced apoptosis (p<0.002).

Conclusion: BAD pathway kinases and phosphatases, including CDK1 and PP2C, are associated with OVCA sensitivity to platinum and may represent therapeutic opportunities to enhance cytotoxic efficacy.
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http://dx.doi.org/10.3802/jgo.2012.23.1.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280065PMC
January 2012

Uterine serous carcinoma: increased familial risk for lynch-associated malignancies.

Cancer Prev Res (Phila) 2012 Mar 13;5(3):435-43. Epub 2012 Jan 13.

Department of Obstetrics and Gynecology, Washington University School of Medicine, 660 South Euclid, St. Louis, MO 63110, USA.

Serous uterine cancer is not a feature of any known hereditary cancer syndrome. This study evaluated familial risk of cancers for patients with serous uterine carcinoma, focusing on Lynch syndrome malignancies. Fifty serous or mixed serous endometrial carcinoma cases were prospectively enrolled. Pedigrees were developed for 29 probands and tumors were assessed for DNA mismatch repair (MMR) abnormalities. Standardized incidence ratios for cancers in relatives were estimated. A second-stage analysis was undertaken using data from Gynecologic Oncology Group (GOG)-210. Incidence data for cancers reported in relatives of 348 patients with serous and mixed epithelial and 624 patients with endometrioid carcinoma were compared. Nineteen of 29 (65.5%) patients in the single-institution series reported a Lynch-related cancer in relatives. Endometrial and ovarian cancers were significantly overrepresented and a high number of probands (6 of 29, 20.7%) reported pancreatic cancers. None of the probands' tumors had DNA MMR abnormalities. There was no difference in endometrial or ovarian cancer incidence in relatives of serous and endometrioid cancer probands in the case-control study. Pancreatic cancers were, however, significantly more common in relatives of patients with serous cancer [OR, 2.39; 95% confidence interval (CI), 1.06-5.38]. We identified an excess of endometrial, ovarian, and pancreatic cancers in relatives of patients with serous cancer in a single-institution study. Follow-up studies suggest that only pancreatic cancers are overrepresented in relatives. DNA MMR defects in familial clustering of pancreatic and other Lynch-associated malignancies are unlikely. The excess of pancreatic cancers in relatives may reflect an as yet unidentified hereditary syndrome that includes uterine serous cancers.
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http://dx.doi.org/10.1158/1940-6207.CAPR-11-0499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294192PMC
March 2012

The BCL2 antagonist of cell death pathway influences endometrial cancer cell sensitivity to cisplatin.

Gynecol Oncol 2012 Jan 26;124(1):119-24. Epub 2011 Oct 26.

Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Objective: To identify pathways that influence endometrial cancer (EC) cell sensitivity to cisplatin and to characterize the BCL2 antagonist of cell death (BAD) pathway as a therapeutic target to increase cisplatin sensitivity.

Methods: Eight EC cell lines (Ishikawa, MFE296, RL 95-2, AN3CA, KLE, MFE280, MFE319, HEC-1-A) were subjected to Affymetrix Human U133A GeneChip expression analysis of approximately 22,000 probe sets. In parallel, endometrial cell line sensitivity to cisplatin was quantified by MTS assay, and IC(50) values were calculated. Pearson's correlation test was used to identify genes associated with response to cisplatin. Genes associated with cisplatin responsiveness were subjected to pathway analysis. The BAD pathway was identified and subjected to targeted modulation, and the effect on cisplatin sensitivity was evaluated.

Results: Pearson's correlation analysis identified 1443 genes associated with cisplatin resistance (P<0.05), which included representation of the BAD-apoptosis pathway. Small interfering RNA (siRNA) knockdown of BAD pathway protein phosphatase PP2C expression was associated with increased phosphorylated BAD (serine-155) levels and a parallel increase in cisplatin resistance in Ishikawa (P=0.004) and HEC-1-A (P=0.02) cell lines. In contrast, siRNA knockdown of protein kinase A expression increased cisplatin sensitivity in the Ishikawa (P=0.02) cell line.

Conclusion: The BAD pathway influences EC cell sensitivity to cisplatin, likely via modulation of the phosphorylation status of the BAD protein. The BAD pathway represents an appealing therapeutic target to increase EC cell sensitivity to cisplatin.
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http://dx.doi.org/10.1016/j.ygyno.2011.09.020DOI Listing
January 2012

A prospective, randomized trial of integrative medicine for women with ovarian cancer.

Gynecol Oncol 2011 Nov 23;123(2):346-50. Epub 2011 Aug 23.

H. Lee Moffitt Cancer Center & Research Institute, Department of Women's Oncology, USA.

Objectives: Despite increased use of integrative medicine in cancer therapy, little data exist on its efficacy. This prospective, randomized, pilot trial sought to evaluate the feasibility of combined modality integrative medicine (CM-IM) in women with ovarian cancer (OvCA) and evaluate its effects on quality of life (QoL), chemotherapy toxicity and immunologic profiles.

Methods: Women with newly diagnosed OvCA requiring chemotherapy were offered enrollment. Those randomized to the experimental arm received hypnosis, therapeutic massage and healing touch with each cycle of chemotherapy. The control arm received chemotherapy without CM-IM. All patients completed QoL questionnaires prior to cycles 1, 3 and 6, and 6-months after chemotherapy. Immunologic profiles were measured. Statistical analysis was based on intent-to-treat. Student's t-test and Fischer's exact-test were used to determine differences.

Results: Forty-three women enrolled. All women randomized to CM-IM were successfully treated. There were no statistical differences between the groups in age, stage, grade, histologic cell type, CA125 levels, or surgical cytoreductive status. There was no difference in overall QoL measurements. Re-hospitalization rates, treatment delays, anti-emetic use, and infection rates were similar. Immunologic profiles revealed no difference between arms for WBC or salivary IgA levels. Women receiving CM-IM had consistently higher levels of CD4, CD8 and NK cells, although this did not reach statistical significance.

Conclusions: Prospective clinical evaluation of integrative medicine for women with gynecologic malignancy is feasible. This first, pilot study of CM-IM in gynecologic oncology demonstrated no improvement in QoL or chemotherapy toxicity. Integrative medicine-associated improvements in immunologic profiles warrant further investigation.
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http://dx.doi.org/10.1016/j.ygyno.2011.07.099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393038PMC
November 2011

BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival.

Clin Cancer Res 2011 Oct 17;17(19):6356-66. Epub 2011 Aug 17.

Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33647, USA.

Purpose: Despite initial sensitivity to chemotherapy, ovarian cancers (OVCA) often develop drug resistance, which limits patient survival. Using specimens and/or genomic data from 289 patients and a panel of cancer cell lines, we explored genome-wide expression changes that underlie the evolution of OVCA chemoresistance and characterized the BCL2 antagonist of cell death (BAD) apoptosis pathway as a determinant of chemosensitivity and patient survival.

Experimental Design: Serial OVCA cell cisplatin treatments were performed in parallel with measurements of genome-wide expression changes. Pathway analysis was carried out on genes associated with increasing cisplatin resistance (EC(50)). BAD-pathway expression and BAD protein phosphorylation were evaluated in patient samples and cell lines as determinants of chemosensitivity and/or clinical outcome and as therapeutic targets.

Results: Induced in vitro OVCA cisplatin resistance was associated with BAD-pathway expression (P < 0.001). In OVCA cell lines and primary specimens, BAD protein phosphorylation was associated with platinum resistance (n = 147, P < 0.0001) and also with overall patient survival (n = 134, P = 0.0007). Targeted modulation of BAD-phosphorylation levels influenced cisplatin sensitivity. A 47-gene BAD-pathway score was associated with in vitro phosphorylated BAD levels and with survival in 142 patients with advanced-stage (III/IV) serous OVCA. Integration of BAD-phosphorylation or BAD-pathway score with OVCA surgical cytoreductive status was significantly associated with overall survival by log-rank test (P = 0.004 and P < 0.0001, respectively).

Conclusion: The BAD apoptosis pathway influences OVCA chemosensitivity and overall survival, likely via modulation of BAD phosphorylation. The pathway has clinical relevance as a biomarker of therapeutic response, patient survival, and as a promising therapeutic target.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-0735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186862PMC
October 2011

Solitary fibrous tumors arising from the female pelvis.

Obstet Gynecol 2011 Aug;118(2 Pt 2):470-474

From the Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology University of Minnesota, Minneapolis, Minnesota.

Background: Solitary fibrous tumor is a rare mesenchymal tumor reported initially in the pleura but that is now reported in widely ranging anatomic sites with a variable clinical course. Solitary fibrous tumor arising from the female genital tract is extremely rare and the management of this condition is controversial.

Cases: We report three cases of female genital tract solitary fibrous tumors displaying different clinical behaviors and review literature with regard to diagnosis, possible prognostic factors, and management of this tumor.

Conclusion: The primary treatment of this disease should be surgical. The rarity and disparate clinical manifestations of this disease preclude a definitive statement on use and optimization of adjuvant therapy. Nevertheless, both pathologic and clinical findings may be useful in gauging risk and assessing the merits of individualized adjuvant therapy.
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http://dx.doi.org/10.1097/AOG.0b013e31821b2037DOI Listing
August 2011

A phase II trial of carboplatin and docetaxel followed by radiotherapy given in a "Sandwich" method for stage III, IV, and recurrent endometrial cancer.

Gynecol Oncol 2011 Apr 15;121(1):112-7. Epub 2011 Jan 15.

Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN, USA.

Objective: To determine feasibility and efficacy of administering docetaxel and carboplatin chemotherapy followed by pelvic radiotherapy and then consolidation chemotherapy in patients with advanced or recurrent endometrial cancer.

Methods: Patients with surgically staged III-IV (excluding IIIA from positive cytology alone) endometrial cancer or biopsy confirmed recurrent disease were eligible. Treatment consisted of 3 cycles of docetaxel (75 mg/m²) and carboplatin (AUC 6) on a q21 day schedule followed by involved field irradiation (45 Gy)± brachytherapy and three additional cycles of docetaxel and carboplatin. Kaplan-Meier (KM) methods estimated overall survival (OS) and progression free survival (PFS).

Results: Forty-two patients enrolled, 7 did not complete therapy. 95% (39/41) had primary disease. Median age=58 years (range: 21-81 years). 78% (32/41)=endometrioid histology. Stages=10 IIIA, 21 IIIC, 1 IVA, 7 IVB, (recurrent=1 IC, 1 IIA). There were 23 non-hematologic and 14 grade 3 and 16 grade 4 hematologic toxicities. Seven patients died following treatment with a median follow-up of 28 months (range: 7-70 months). KM estimates and 95% confidence intervals for OS at 1 year were 95% (82-99%), at 3 years 90% (75-96%), and at 5 years 71% (45-86%). Of the 39 with primary disease, 11 progressed or died within 5 years of study enrollment. KM estimates and 95% confidence intervals for PFS at 1 year were 87% (72-94%), at 3 years 71% (51-83%), and at 5 years 64% (42-80%).

Conclusions: "Sandwiching" radiation between chemotherapy for advanced or recurrent endometrial cancer merits further development based on the reported PFS and OS.
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http://dx.doi.org/10.1016/j.ygyno.2010.12.338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231578PMC
April 2011

Ifosfamide, paclitaxel, and carboplatin, a novel triplet regimen for advanced, recurrent, or persistent carcinoma of the cervix: a phase II trial.

Gynecol Oncol 2011 Feb 8;120(2):265-9. Epub 2010 Dec 8.

Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN 55455, USA.

Objectives: (1) To determine the response rate of advanced, recurrent, or persistent carcinoma of the cervix to ifosfamide, paclitaxel, and carboplatin chemotherapy; (2) to determine the progression free interval and survival rate in patients treated with this regimen; (3) to describe the toxicities associated with this regimen; and (4) to evaluate the quality of life of patients while on treatment.

Methods: Eligible patients had histologically proven stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. Chemotherapy was given on day 1 of a 28-day cycle: mesna (600 mg/m(2)) prior to ifosfamide (2 g/m(2)), paclitaxel (175 mg/m(2)), carboplatin (AUC 5). Response rates were determined according to RECIST criteria. Toxicity was graded according the National Cancer Institute's common toxicity criteria. Quality of life measurements were obtained using the FACT-Cx.

Results: Twenty-eight patients participated in this study, with 21 evaluable for response rate. Overall, 7 patients (33%) had a demonstrated objective response (4 complete responses, 3 partial responses). Stable disease was documented in 3 patients. The overall median survival for all patients was 10 months. Median progression free survival for evaluable patients was 5.0 months. Bone marrow suppression was the most common toxicity. There were no negative effects of this treatment regimen on quality of life assessments.

Conclusion: Ifosfamide, paclitaxel, and carboplatin is an effective regimen in treating advanced or recurrent carcinoma of the cervix and has an acceptable toxicity profile.
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http://dx.doi.org/10.1016/j.ygyno.2010.10.020DOI Listing
February 2011

A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer.

Cytotherapy 2011 Jan 20;13(1):98-107. Epub 2010 Sep 20.

Obstetrics and Gynecology, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.

Background: Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer.

Methods: Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m(2) × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of ≥100 donor-derived NK cells/μL blood 14 days after infusion, based on molecular chimerism and flow cytometry.

Results: Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30-65) years. Mean NK cell dose was 2.16 × 10(7)cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = <0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansion.

Conclusions: Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.
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http://dx.doi.org/10.3109/14653249.2010.515582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760671PMC
January 2011

Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers.

Cancer Immunol Immunother 2010 Dec 5;59(12):1877-1884. Epub 2010 Sep 5.

Department of Medicine, MMC 806 420 Delaware St. SE., University of Minnesota, Minneapolis, MN, 55455 USA.

Background: The primary objective was to study the antitumor activity of prolonged subcutaneous dosing of systemic 852A, a Toll-like receptor-7 agonist (TLR-7), in recurrent breast, ovarian and cervix cancer. Secondary objectives included assessment of safety and immune system activation.

Methods: Adults with recurrent breast, ovarian or cervix cancer failing multiple therapies received 0.6 mg/m(2) of 852A subcutaneously twice weekly for 12 weeks. Doses increased by 0.2 mg/m(2)/week to a maximum of 1.2 mg/m(2). Serum was collected to assess immune activation.

Results: Fifteen patients enrolled: 10 ovarian, 2 cervix and 3 breast. Three completed all 24 injections. There were two grade 2 (decreased ejection fractions), nine grade 3 (1 cardiovascular, 1 anorexia, 3 dehydration, 2 infections, 2 renal) and two grade 4 (hepatic and troponin elevation) unanticipated toxicities. Cardiac toxicities included three cardiomyopathies (2 asymptomatic) and one stress-related non-ST elevated myocardial infarction. Five patients discontinued therapy due to possibly associated side effects. One who had stable disease (SD) following 24 doses received 17 additional doses. A cervix patient with SD following 24 doses received chemotherapy after progressing 3 months later, and remains disease free at 18 months. Immune activation, as evidenced by increased IP-10 and IL-1ra, was observed.

Conclusions: In this first human experience of a TLR-7 agonist delivered subcutaneously using a prolonged dosing schedule, 852A demonstrated sustained tolerability in some patients. Clinical benefit was modest, but immune activation was seen suggesting further study of antitumor applications is warranted. Because of cardiac toxicity; 852A should be used cautiously in heavily pretreated patients.
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http://dx.doi.org/10.1007/s00262-010-0914-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098785PMC
December 2010