Publications by authors named "Sachin M Apte"

40 Publications

Dual antibiotic prevention bundle is associated with decreased surgical site infections.

Int J Gynecol Cancer 2020 Sep 29;30(9):1411-1417. Epub 2020 Jul 29.

Gynecologic Oncology, H Lee Moffitt Cancer Center and Research Center Inc, Tampa, Florida, USA.

Background: Gynecologic oncology surgery is associated with a wide variation in surgical site infection risk. The optimal method for infection prevention in this heterogeneous population remains uncertain.

Study Design: A retrospective cohort study was performed to compare surgical site infection rates for patients undergoing hysterectomy over a 1-year period surrounding the implementation of an institutional infection prevention bundle. The bundle comprised pre-operative, intra-operative, and post-operative interventions including a dual-agent antibiotic surgical prophylaxis with cefazolin and metronidazole. Cohorts consisted of patients undergoing surgery during the 6 months prior to this intervention (pre-bundle) versus those undergoing surgery during the 6 months following the intervention (post-bundle). Secondary outcomes included length of stay, readmission rates, compliance measures, and infection microbiology. Data were compared with pre-specified one-sided exact test, Chi-square test, Fisher's exact test, or Kruskal-Wallis test as appropriate.

Results: A total of 358 patients were included (178 PRE, 180 POST). Median age was 58 (range 23-90) years. The post-bundle cohort had a 58% reduction in surgical site infection rate, 3.3% POST vs 7.9% PRE (-4.5%, 95% CI -9.3% to -0.2%, p=0.049) as well as reductions in organ space infection, 0.6% POST vs 4.5% PRE (-3.9%, 95% CI -7.2% to -0.7%, p=0.019), and readmission rates, 2.2% POST vs 6.7% PRE (-4.5%, 95% CI -8.7% to -0.2%, p=0.04). Gram-positive, Gram-negative, and anaerobic bacteria were all prevalent in surgical site infection cultures. There were no monomicrobial infections in post-cohort cultures (0% POST vs 58% PRE, p=0.04). No infections contained methicillin-resistant .

Conclusion: Implementation of a dual antibiotic infection prevention bundle was associated with a 58% reduction in surgical site infection rate after hysterectomy in a surgically diverse gynecologic oncology practice.
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http://dx.doi.org/10.1136/ijgc-2020-001515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868167PMC
September 2020

High-dose intensity-modulated chemoradiotherapy in vulvar squamous cell carcinoma: Outcome and toxicity.

Gynecol Oncol 2020 02 23;156(2):349-356. Epub 2019 Nov 23.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

Introduction: To evaluate clinical outcomes, pattern of failure, and toxicity after high-dose intensity-modulated radiation therapy (IMRT) for advanced vulvar cancer.

Methods: In this IRB approved retrospective study, the charts of women with histologically confirmed, non-metastatic vulvar cancer consecutively treated at our institution from 2012 to 2018 were reviewed to identify patients that received high-dose IMRT with curative intent. The treatment compliance, toxicities, and patterns of failure were investigated. Actuarial local, regional and distant recurrence and survival were estimated using Kaplan-Meier method and compared using log rank test.

Results: Twenty-six patients were identified, 23 were unresectable, and 3 refused surgery. Fifteen patients (58%) had inguinal node metastases; 10(38%) had pelvic node metastases. Elective surgical staging of groins was performed in 9-patients. Median tumor dose was 65.4Gy. Concurrent platinum-based chemotherapy was administered in 22(84.6%) patients. Complete response (CR) was achieved in 21/26 (80.7%) patients. Five patients had persistent disease following treatment and one sustained recurrence 5-months following radiotherapy. All persistent or recurrent disease occurred inside the irradiated volume. Median follow-up was 19 months (3-52 months). Actuarial 1-year local, regional and distant controls were 72.4%, 85.4%, and 86%, respectively. One and 2-year overall survivals were 91% and 62%, respectively. Complete response at 3-months was a strong predictor for overall survival (1-yr OS 73% vs 27%, HR 7.1 (95% CI 1.2-44); p = 0.01). Lymph node metastases adversely affected overall survival (2-yr OS 49% vs. 83%, p = 0.09). Grade 3-4 late urinary and soft-tissue toxicity was seen in 5 patients. Tumor doses >66 Gy (p = 0.03) and prior pelvic radiotherapy (p = 0.002) predicted grade 3-4 toxicity.

Conclusion: High-dose IMRT for vulvar cancer achieves high rates of local control with acceptable dose dependent long-term toxicity.
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http://dx.doi.org/10.1016/j.ygyno.2019.11.027DOI Listing
February 2020

Adherence to practice guidelines is associated with reduced referral times for patients with ovarian cancer.

Am J Obstet Gynecol 2018 04 17;218(4):436.e1-436.e7. Epub 2018 Jan 17.

Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Electronic address:

Background: Patients with ovarian cancer tend to receive the highest quality of care at high-volume cancer centers with gynecological oncologists. However, the care that they receive prior to gynecological oncology consult has not been examined. We investigated the quantity and quality of care given to patients with ovarian cancer before being seen by a gynecological oncologist.

Objective: We evaluated the variability, quantity, and quality of diagnostic testing and physician-referral patterns prior to consultation with a gynecological oncologist, in women with suspicious pelvic masses seen on imaging.

Study Design: A chart review was performed on patients treated for ovarian cancer at a single institution from 2001 to 2014. We evaluated their workup in 4 categories, drawn from National Comprehensive Care Network guidelines: provider visits, abdominal/pelvic imaging, chest imaging, and tumor markers. Workup was classified as guideline adherent or guideline nonadherent.

Results: We identified 335 cases that met our criteria. In the provider visit category, 83.9% of patients received guideline-adherent workup: 77% in the abdominal/pelvic imaging, 98.2% in the chest imaging, and 95.2% in the tumor marker categories. Each patient's workup was assessed as a compilation of the 4 categories, yielding 65.7% patients as having received an adherent workup and 34.3% of workup as nonadherent to guidelines. The timeframe to see a gynecological oncologist for patients with guideline-adherent workup was significantly shorter than for those whose workup was nonadherant (20 vs 86 days, P < .001). A suspicious pelvic mass was identified by obstetrics-gynecology in only 23.9% of patients; 42.7% of patients did not have tumor marker testing before a gynecological oncologist consult. When an obstetrics-gynecology specialist discovered the suspicious pelvic mass, the remaining workup was more likely to be guideline adherent prior to gynecological oncologist referral than when initial imaging was not ordered by an obstetrics-gynecology specialist (P = .18). Survival was not significantly different (P = .103).

Conclusion: With a guideline-adherent workup, including tumor marker testing, gynecological oncologist referral times can be shortened, minimizing cost inefficiencies and delays that can compromise the effectiveness of downstream care for patients with ovarian cancer. Guidelines should be disseminated beyond the obstetrics-gynecology field.
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http://dx.doi.org/10.1016/j.ajog.2018.01.015DOI Listing
April 2018

An oncologist's perspective: preparation for new payment models in cancer care.

Authors:
Sachin M Apte

Am J Manag Care 2017 Apr;23(5 Spec No.):SP169-SP172

Associate Chief Medical Officer, Moffitt Cancer Center Magnolia Drive, Tampa, FL 33612. E-mail:

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April 2017

Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers.

BMC Cancer 2017 Jun 8;17(1):407. Epub 2017 Jun 8.

Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33647, USA.

Background: Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers.

Methods: Eligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m) and carboplatin (area under the curve [AUC] 5-6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated.

Results: Thirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1-5 and 8-12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1-12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles.

Conclusions: Treatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1-5 and 8-12) plus day 1 paclitaxel (175 mg/m) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle.

Trial Registration: ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).
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http://dx.doi.org/10.1186/s12885-017-3394-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465458PMC
June 2017

Payment Reform: Unprecedented and Evolving Impact on Gynecologic Oncology.

Front Oncol 2016 15;6:84. Epub 2016 Apr 15.

The Brookings Institution , Washington, DC , USA.

With the signing of the Medicare Access and CHIP Reauthorization Act in April 2015, the Centers for Medicare and Medicaid Services (CMS) is now positioned to drive the development and implementation of sweeping changes to how physicians and hospitals are paid for the provision of oncology-related services. These changes will have a long-lasting impact on the sub-specialty of gynecologic oncology, regardless of practice structure, physician employment and compensation model, or local insurance market. Recently, commercial payers have piloted various models of payment reform via oncology-specific clinical pathways, oncology medical homes, episode payment arrangements, and accountable care organizations. Despite the positive results of some pilot programs, adoption remains limited. The goals are to eliminate unnecessary variation in cancer treatment, provide coordinated patient-centered care, while controlling costs. Yet, meaningful payment reform in oncology remains elusive. As the largest payer for oncology services in the United States, CMS has the leverage to make cancer services more value based. Thus far, the focus has been around pricing of physician-administered drugs with recent work in the area of the Oncology Medical Home. Gynecologic oncology is a unique sub-specialty that blends surgical and medical oncology, with treatment that often involves radiation therapy. This forward-thinking, multidisciplinary model works to keep the patient at the center of the care continuum and emphasizes care coordination. Because of the breadth and depth of gynecologic oncology, this sub-specialty has both the potential to be disrupted by payment reform as well as potentially benefit from the aspects of reform that can align incentives appropriately to improve coordination. Although the precise future payment models are unknown at this time, focused engagement of gynecologic oncologists and the full care team is imperative to assure that the practice remains patient centered, embodies the highest quality in research and education, yet transforms into a sustainable and agile sub-specialty to pro-actively and effectively manage the immense and relentless financial pressures and regulatory expectations that will be faced over the next decade.
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http://dx.doi.org/10.3389/fonc.2016.00084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831975PMC
May 2016

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

Therapeutic Dilemma: Prognostic Factors and Outcome for Neuroendocrine Tumors of the Cervix.

Int J Gynecol Cancer 2016 Mar;26(3):553-60

*Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute; and †Department of Oncologic Sciences, Morsani School of Medicine, University of South Florida, Tampa, FL.

Objectives: The aim of this study was to review treatment and outcomes for neuroendocrine tumors (NETs) of the cervix at a National Cancer Institute-designated Comprehensive Cancer Center.

Materials And Methods: Data for women with NET of the cervix treated at our institution, since 1999, were collected. Progression-free survival (PFS) and overall survival (OS) were assessed with respect to age, tumor size, tobacco use, lymph node status, stage of disease, and type of treatment.

Results: Among 18 patients (median age, 44 years), 9 (50%) had tumors larger than 5 cm and advanced-stage disease (IB2-IV). Seven recurrences were noted (39%). Median PFS was not reached, and median OS was 72.2 months. Surgery was the only factor significantly associated with both PFS and OS (3-year PFS, 90% vs 30%, P = 0.01; 3-year OS: 89% vs 18%, P = 0.019). Age 40 years or younger and absence of lymph node metastases correlated significantly with PFS, with a trend toward improved OS. Recurrences were less likely with stage IA to IB1 compared with stages IB2 to IVA and IVB (hazards ratio, 0.33; P = 0.054), with median OS of 72.2, 19.2, and 7.4 months, respectively (P = 0.002). Although patients with tumors 4 cm or smaller had better outcomes, this factor did not reach statistical significance. Chemotherapy, radiation therapy, and tobacco use were not associated with survival.

Conclusions: Neuroendocrine tumors of the cervix present at a relatively young age, with bulky tumors and advanced-stage disease. Surgery, younger age, smaller tumor size, early stage, and absence of lymph node involvement seem to be associated with improved survival. Nonetheless, optimal management is yet to be determined, and multimodality treatment is advocated.
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http://dx.doi.org/10.1097/IGC.0000000000000631DOI Listing
March 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

Metastatic VIPoma presenting as an ovarian mass.

Int J Surg Case Rep 2015 23;17:167-9. Epub 2015 Nov 23.

H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA. Electronic address:

Introduction: Pancreatic VIPomas are exceedingly rare, with an annual incidence of less than 1 per million. Most VIPomas are metastatic at diagnosis, with the liver being the most common site of spread.

Presentation Of Case: We describe a highly unusual case of a metastatic pancreatic VIPoma to an ovary in a 54 year-old patient. She was ten years out from her initial diagnosis when routine CT scan showed an enlarging left adnexal mass. After having both ovaries removed laparoscopically the final pathology was consistent with her pancreatic primary. To our knowledge, there has been only one other such case described in the literature.

Discussion: In this case, pathology revealed metastatic neuroendocrine tumor involving both the left and right ovaries despite only the right ovary apparently enlarging. In our literature search, only two other cases of metastatic PNET to the ovaries have been reported. One case was a glucagonoma and the other a VIPoma. We recommend that clinicians consider referral of patients with metastatic NET and ovarian metastases to gynecologic surgery for consideration of surgical resection.

Conclusion: In conclusion, this case proves that although uncommon, PNET can show metastases in both ovaries even a decade after initial diagnosis.
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http://dx.doi.org/10.1016/j.ijscr.2015.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701860PMC
January 2016

Uterine Sarcoma, Version 1.2016: Featured Updates to the NCCN Guidelines.

J Natl Compr Canc Netw 2015 Nov;13(11):1321-31

From Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; University of Washington/Seattle Cancer Care Alliance; Memorial Sloan Kettering Cancer Center; Moffitt Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; University of Michigan Comprehensive Cancer Center; Fox Chase Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; Vanderbilt-Ingram Cancer Center; Massachusetts General Hospital Cancer Center; Stanford Cancer Institute; The University of Texas MD Anderson Cancer Center; University of Colorado Cancer Center; Roswell Park Cancer Institute; Huntsman Cancer Institute at the University of Utah; City of Hope Comprehensive Cancer Center; Yale Cancer Center/Smilow Cancer Hospital; University of Alabama at Birmingham Comprehensive Cancer Center; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Mayo Clinic Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Fred & Pamela Buffet Cancer Center at The Nebraska Medical Center; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; Duke Cancer Institute; UC San Diego Moores Cancer Center; and National Comprehensive Cancer Network.

The NCCN Guidelines for Uterine Neoplasms provide interdisciplinary recommendations for treating endometrial carcinoma and uterine sarcomas. These NCCN Guidelines Insights summarize the NCCN Uterine Neoplasms Panel's 2016 discussions and major guideline updates for treating uterine sarcomas. During this most recent update, the panel updated the mesenchymal tumor classification to correspond with recent updates to the WHO tumor classification system. Additionally, the panel revised its systemic therapy recommendations to reflect new data and collective clinical experience. These NCCN Guidelines Insights elaborate on the rationale behind these recent changes.
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http://dx.doi.org/10.6004/jnccn.2015.0162DOI Listing
November 2015

Robotic-Assisted Surgery in Gynecological Oncology.

Cancer Control 2015 Jul;22(3):307-13

Department of Gynecologic Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.

Background: Robotic-assisted surgery is a technological advancement, and its use is rapidly expanding into the field of gynecological oncology. However, a paucity of evidence exists to prove its superiority over standard laparoscopy. Its cost is also high and it lacks haptic feedback.

Methods: A systematic review of the relevant literature was undertaken to understand the use of robotic-assisted surgery in gynecological oncology.

Results: Robotic-assisted surgery is being used for select cases of endometrial cancer and has resulted in the increased utilization of minimally invasive surgery for such patients. Use of robotic-assisted surgery among patients who are obese has led to decreased complication rates. Robotic-assisted surgery appears to be more expensive than traditional laparoscopy; however, there are potential cost savings to robotic-assisted surgery, including shorter hospital stays and fewer complications, compared with laparotomy.

Conclusions: The gynecological oncology community is rapidly accepting the use of robotic-assisted surgery. Although randomized controlled trials are lacking, the technology appears to be safe and effective, and it has equivalent oncological outcomes in this patient population.
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http://dx.doi.org/10.1177/107327481502200308DOI Listing
July 2015

Cervical Cancer, Version 2.2015.

J Natl Compr Canc Netw 2015 Apr;13(4):395-404; quiz 404

From Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; University of Washington/Seattle Cancer Care Alliance; Memorial Sloan Kettering Cancer Center; Moffitt Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; University of Michigan Comprehensive Cancer Center; Fox Chase Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; Vanderbilt-Ingram Cancer Center; Stanford Cancer Institute; The University of Texas MD Anderson Cancer Center; University of Colorado Cancer Center; Roswell Park Cancer Institute; Huntsman Cancer Institute at the University of Utah; City of Hope Comprehensive Cancer Center; University of Alabama at Birmingham Comprehensive Cancer Center; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Fred & Pamela Buffett Cancer Center; Stanford Cancer Institute; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; Duke Cancer Institute; UC San Diego Moores Cancer Center; and National Comprehensive Cancer Network.

The NCCN Guidelines for Cervical Cancer provide interdisciplinary recommendations for treating cervical cancer. These NCCN Guidelines Insights summarize the NCCN Cervical Cancer Panel's discussion and major guideline updates from 2014 and 2015. The recommended systemic therapy options for recurrent and metastatic cervical cancer were amended upon panel review of new survival data and the FDA's approval of bevacizumab for treating late-stage cervical cancer. This article outlines relevant data and provides insight into panel decisions regarding various combination regimens. Additionally, a new section was added to provide additional guidance on key principles of evaluation and surgical staging in cervical cancer. This article highlights 2 areas of active investigation and debate from this new section: sentinel lymph node mapping and fertility-sparing treatment approaches.
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http://dx.doi.org/10.6004/jnccn.2015.0055DOI Listing
April 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

Uterine neoplasms, version 1.2014.

J Natl Compr Canc Netw 2014 Feb;12(2):248-80

Adenocarcinoma of the endometrium (also known as endometrial cancer or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. An estimated 49,560 new uterine cancer cases will occur in 2013, with 8190 deaths resulting from the disease. Uterine sarcomas (stromal/mesenchymal tumors) are uncommon malignancies, accounting for approximately 3% of all uterine cancers. The NCCN Guidelines for Uterine Neoplasms describe malignant epithelial carcinomas and uterine sarcomas; each of these major categories contains specific histologic groups that require different management. This excerpt of these guidelines focuses on early-stage disease.
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http://dx.doi.org/10.6004/jnccn.2014.0025DOI Listing
February 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

Cervical cancer.

J Natl Compr Canc Netw 2013 Mar;11(3):320-43

Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance, USA.

These NCCN Clinical Practice Guidelines in Oncology for Cervical Cancer focus on early-stage disease, because it occurs more frequently in the United States. After careful clinical evaluation and staging, the primary treatment of early-stage cervical cancer is either surgery or radiotherapy. These guidelines include fertility-sparing and non-fertility-sparing treatment for those with early-stage disease, which is disease confined to the uterus. A new fertility-sparing algorithm was added for select patients with stage IA and IB1 disease..
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http://dx.doi.org/10.6004/jnccn.2013.0043DOI Listing
March 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

Comparing the retrospective reports of fatigue using the Fatigue Symptom Index with daily diary ratings in women receiving chemotherapy for gynecologic cancer.

J Pain Symptom Manage 2013 Aug 15;46(2):282-8. Epub 2012 Nov 15.

Department of Health Outcomes and Behavior, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.

Context: Fatigue, one of the most common side effects of chemotherapy, is typically assessed via retrospective recall (e.g., over the past week). It is unknown how such retrospective recall of fatigue correlates with daily ratings among people receiving chemotherapy.

Objectives: The current study compared fatigue recorded in daily diaries with retrospective ratings using the Fatigue Symptom Inventory (FSI) in patients receiving chemotherapy for gynecologic cancer.

Methods: During the week before and the week after their first infusion of chemotherapy, patients completed daily diaries at 10 AM, 2, and 6 PM and the FSI at the end of each week.

Results: FSI and diary ratings of peak, lowest, and average fatigue were significantly correlated (P < 0.001). When peak, end, average, and variance diary ratings were regressed separately on the average FSI item, each was significant pre-chemotherapy (P < 0.01) and post-chemotherapy (P < 0.05). However, when entered into a stepwise regression model, only the average fatigue diary rating was retained, explaining 52% of the variance pre-chemotherapy and 54% of the variance post-chemotherapy average FSI item (P < 0.001).

Conclusion: The FSI keyed to the past week accurately reflects daily ratings of fatigue among patients receiving chemotherapy. This study has important implications, as completing retrospective ratings of fatigue may be less burdensome for cancer patients than daily assessments.
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http://dx.doi.org/10.1016/j.jpainsymman.2012.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3735814PMC
August 2013

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

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

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

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