Publications by authors named "Linda Duska"

114 Publications

Post hoc analyses of GOG 9923: Does BRCA status affect toxicities?: An NRG oncology study.

Gynecol Oncol 2021 Feb 17. Epub 2021 Feb 17.

Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK, United States of America. Electronic address:

Objective: To evaluate how women with epithelial ovarian cancer (EOC), dichotomized by BRCA status, tolerate intravenous (IV) or intraperitoneal (IP) chemotherapy given with veliparib and bevacizumab (bev) on a GOG phase I study (GOG 9923, NCT00989651).

Methods: This is an unplanned, post hoc analysis of an IRB approved, multi-institutional, prospective study (GOG 9923). Clinical characteristics and toxicity data based on BRCA status were evaluated and descriptive statistics were used to summarize baseline patient characteristics and toxicities. The Kaplan Meier method was used to generate survival estimates.

Results: Four hundred twenty-four patients were evaluable. Patients were treated with IV carboplatin, paclitaxel, and bev every 21 days (regimen 1), weekly IV paclitaxel with carboplatin and bev (regimen 2) or IV paclitaxel and bev with IP cisplatin (regimen 3). Bev was continued as maintenance in all arms. Within each of these regimens, veliparib was given either twice daily for the entirety of each cycle (continuous) or on days -2 to 5 (intermittent). Ten percent of patients treated on regimen 1, 12% on regimen 2, and 19.8% on regimen 3 had BRCA-associated tumors. Patients with BRCA-associated tumors, when compared to wild type, experienced similar rates of anemia, febrile neutropenia (, abdominal pain, colonic perforation, nausea, vomiting, and peripheral sensory neuropathy. Median progression free survival (PFS) was not significantly different between BRCA-associated and wild type cancers (HR 0.96, CI 0.65-1.42), though this study's primary aim was not to evaluate outcomes.

Conclusions: Germline BRCA mutations positively affect chemosensitivity in EOC, but whether differences in toxicities among BRCA-associated and BRCA wild type tumors existed was previously not reported. In this population with newly diagnosed ovarian cancer no differences in reported toxicity between the two groups was observed.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.037DOI Listing
February 2021

Society of Gynecologic Oncology recommendations for fellowship education during the COVID-19 pandemic and beyond: Innovating programs to optimize trainee success.

Gynecol Oncol 2021 01 17;160(1):271-278. Epub 2020 Oct 17.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars Sinai Medical Center, Los Angeles, CA, USA.

In approximately ten months' time, the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 34 million people and caused over one million deaths worldwide. The impact of this virus on our health, relationships, and careers is difficult to overstate. As the economic realities for academic medical centers come into focus, we must recommit to our core missions of patient care, education, and research. Fellowship education programs in gynecologic oncology have quickly adapted to the "new normal" of social distancing using video conferencing platforms to continue clinical and didactic teaching. United in a time of crisis, we have embraced systemic change by developing and delivering collaborative educational content, overcoming the limitations imposed by institutional silos. Additional innovations are needed in order to overcome the losses in program surgical volume and research opportunities. With the end of the viral pandemic nowhere in sight, program directors can rethink how education is best delivered and potentially overhaul aspects of fellowship curriculum and content. Similarly, restrictions on travel and the need for social distancing has transformed the 2020 fellowship interview season from an in-person to a virtual experience. During this time of unprecedented and rapid change, program directors should be particularly mindful of the needs and health of their trainees and consider tailoring their educational experiences accordingly.
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http://dx.doi.org/10.1016/j.ygyno.2020.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568037PMC
January 2021

Urologic Complications Requiring Intervention Following High-dose Pelvic Radiation for Cervical Cancer.

Urology 2020 Sep 20. Epub 2020 Sep 20.

Department of Urology, University of Virginia, Charlottesville, VA.

Objective: To identify the incidence of radiation-induced urologic complication requiring procedural intervention following high-dose radiotherapy for cervical carcinoma, and to identify predictors of complication occurrence.

Materials And Methods: We performed a retrospective chart review of cervical cancer patients undergoing radiotherapy with primary focus on procedural complications (Clavien-Dindo ≥ III). Clinical data were collected including radiation dose, procedure performed, timing of complication, and need for additional procedures. Univariate and multivariate logistic regression modeling was performed to assess predictive value of demographic and clinical variables.

Results: A total of 126 patients with FIGO stage 1A2-4B cervical cancer were included in study analysis, with 18 patients experiencing procedural complication (14.3%). A total of 22 complications were identified, representing an average of 1.2 complications per patient with complication. The most common complications were ureteral stricture and radiation cystitis. The most common nononcologic procedures performed in the treatment of these complications were ureteral stenting, percutaneous nephrostomy tube placement, and cystoscopy. Notably, a total of 259 procedures were performed in the treatment of urologic complications, representing 14.4 procedures per patient and 24.6 procedures per patient with ureteral stricture. Logistic regression demonstrated active smoking at the time of diagnosis to be a predictor of procedural complication.

Conclusion: Radiotherapy in the treatment of cervical cancer is associated with a high rate of urologic procedural complication. These complications often require numerous procedures and long-term management given their complexity. These findings suggest a need for awareness and plans for multidisciplinary management of urologic complications in this patient population.
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http://dx.doi.org/10.1016/j.urology.2020.09.011DOI Listing
September 2020

Results of an early safety analysis of a study of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer.

Cancer 2020 Nov 10;126(22):4948-4956. Epub 2020 Sep 10.

Department of Radiation Oncology, University of Virginia School of Medicine, Charlottesville, Virginia.

Background: Immune checkpoint inhibitors are being considered for locally advanced cervical cancer (LACC) together with standard-of-care pelvic chemoradiation (CRT). However, the safety of the combination and its optimal schedule are unknown. Defining the safety of the combination is a primary objective of a study examining concurrent and sequential schedules. This article presents a safety analysis that was fully accrued and met reporting requirements.

Methods: Pembrolizumab was given after CRT (arm 1) or during CRT (arm 2) according to a randomized phase 2 design. Patients who were 18 years old or older and had LACC (stages IB-IVA according to the 2009 International Federation of Gynecology and Obstetrics system) were randomized 1:1 to the treatment regimens. The CRT was identical in the 2 arms. Pembrolizumab was administered every 3 weeks for 3 doses; no maintenance was allowed. All patients receiving any treatment were evaluated for safety. Safety assessments included the incidence and severity of adverse events (AEs) and the occurrence of protocol-defined dose-limiting toxicity (DLT) through 30 days after the last pembrolizumab infusion.

Results: As of August 2019, 52 of the 88 planned patients had completed treatment and were evaluable for toxicity. Treatment-related grade 2 or higher toxicity was experienced by 88%; 11 had at least 1 grade 4 AE, and another 23 had at least 1 grade 3 AE. Grade 1 or higher diarrhea was reported in 34 patients (65%; 50% of these were grade 1), and there was no difference between arms (63% in arm 1 vs 68% in arm 2). Two patients experienced 3 DLTs. Most patients completed cisplatin (100% in arm 1 vs 82% in arm 2); 83% in both arms completed all pembrolizumab.

Conclusions: Preliminary results support the safety and feasibility of adding pembrolizumab to pelvic CRT concurrently or sequentially.

Lay Summary: Pembrolizumab is a humanized antibody against programmed cell death protein 1 that is used in cancer immunotherapy. Preliminary data suggest that pembrolizumab can be safely combined with chemotherapy and pelvic radiation in the treatment of locally advanced cervical cancer. Future studies of the addition of immunotherapy to traditional chemoradiation are planned to determine the best way to deliver the treatment and whether any improvement is seen with the addition of immunotherapy to traditional therapy.
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http://dx.doi.org/10.1002/cncr.33136DOI Listing
November 2020

Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.

Lancet Oncol 2020 07 15;21(7):957-968. Epub 2020 Jun 15.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Background: High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer.

Methods: In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov, NCT02595892, and is active but closed to enrolment.

Findings: Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6-81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2-69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9-72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7-36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33-0·98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 [39%] of 36 patients in the gemcitabine alone group vs 16 [47%] of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] vs eight [24%]). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis.

Interpretation: To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting.

Funding: US National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(20)30180-7DOI Listing
July 2020

Loss of MHC Class I Expression in HPV-associated Cervical and Vulvar Neoplasia: A Potential Mechanism of Resistance to Checkpoint Inhibition.

Am J Surg Pathol 2020 09;44(9):1184-1191

Department of Pathology, Division of Anatomic Pathology.

Tumor cell expression of major histocompatibility complex (MHC) class I is required for antigen presentation and adaptive immune recognition. Absent or diminished MHC class I expression is thought to contribute to immunotherapeutic resistance in some epithelial tumors but has not been previously studied in cervical and vulvar carcinoma. Given that anti-programmed cell death 1 (PD-1) checkpoint inhibition is deployed for programmed cell death ligand 1 (PD-L1)-positive recurrent and metastatic cervical squamous carcinomas, identifying tumors with loss of MHC class I is of clinical interest to optimize the selection of immunotherapeutic candidates. Immunohistochemistry for PD-L1 and MHC class I combined A, B, and C heavy chains (MHC class I) was assessed in 58 human papillomavirus-associated cervical and vulvar lesions, including 27 squamous intraepithelial lesions (SILs) and 31 invasive squamous cell carcinoma (SCC). Although 84% of SCC and 22% of SIL were PD-L1-positive, 35.5% (11/31) of SCC and 18.5% (5/27) of SIL also showed clonal or complete loss of MHC class I. Loss of MHC class I expression was more common in PD-L1-positive (10/26, 38%) versus PD-L1-negative SCC (1/5, 20%). In summary, over one third of human papillomavirus-associated cervical and vulvar SCC show clonal or complete loss of MHC class I expression, including many PD-L1-positive cases. This suggests that the efficacy of checkpoint inhibitors targeting the PD-1/PD-L1 axis may be limited in a subset of cervical and vulvar squamous neoplasms due to an impaired ability to engage with the adaptive immune system related to loss of MHC class I expression.
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http://dx.doi.org/10.1097/PAS.0000000000001506DOI Listing
September 2020

Are ethnic and racial minority women less likely to participate in clinical trials?

Gynecol Oncol 2020 05 3;157(2):323-328. Epub 2020 Apr 3.

Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA, United States of America.

Objectives: Given the disparity that exists in enrollment of minorities to oncology clinical trials, the objective of our study was to assess whether race is associated with willingness to participate in gynecologic oncology clinical trials in a rural Southern academic medicine setting. Our secondary aim was to determine whether willingness to participate is impacted by an educational intervention.

Methods: A single institution prospective survey study was performed at an academic medical center. Women presenting to the gynecologic oncology clinic with a current or prior diagnosis of gynecologic malignancy were approached to participate. The validated Attitudes to Randomized Trials Questionnaire (ARTQ) assessed willingness to participate in clinical trials. Relevant demographic and clinical data were abstracted. Characteristics were compared between those willing and unwilling to participate in clinical trials with a chi-square test for categorical variables and Wilcoxon rank sum tests for continuous data.

Results: We enrolled 156 participants (50% White, 50% non-White) from May 2017 to January 2018. The minority group included 35% non-Hispanic Black, 9% Hispanic, 4% Asian, and 2% other. Median age was 63 years with endometrial cancer being the most common diagnosis (48%). On initial screen, only 35% were willing to participate in a clinical trial. Willingness to participate did not differ between race, age, marital status, education level, cancer type, stage, or mode of treatment. Rates improved to 82% after being provided additional educational information. Following education, White women and those with more education were significantly more willing to participate in clinical trials than their minority and less educated counterparts.

Conclusions: Willingness to participate improved among all sub-categories following an educational intervention. The increase in willingness was less robust among racial and ethnic minorities, suggesting that different tools are needed for recruitment of minorities to gynecologic oncology clinical trials.
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http://dx.doi.org/10.1016/j.ygyno.2020.01.040DOI Listing
May 2020

Validation of the surprise question in gynecologic oncology: A one-question screen to promote palliative care integration and advance care planning.

Gynecol Oncol 2020 06 12;157(3):754-758. Epub 2020 Mar 12.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado, Denver, CO, USA.

Objective: The "surprise question" ("Would you be surprised if this patient died in the next year?") has been shown to be predictive of 12-month mortality in multiple populations, but has not been studied in gynecologic oncology (GO) patients. We sought to evaluate the prognostic performance of the surprise question in GO patients among physician and non-physician providers.

Methods: GO providers at two tertiary care centers were asked the surprise question about a cohort of their patients undergoing chemotherapy or radiation. Demographic and clinical information was chart abstracted. Mortality data were collected at one year; relative risk of death at one year based on response to the surprise question was then calculated.

Results: 32 providers (12 MDs, 7 APPs, 13 RNs) provided 942 surprise question assessments for 358 patients. Fifty-seven % had ovarian cancer and 54% had recurrent disease. Eighty-three (24%) patients died within a year. Patients whose physician answered "No" to the surprise question had a 43% one-year mortality (compared to 10% for "Yes"). Overall RR of 12-month mortality for "No" was 3.76 (95% CI 2.75-5.48); this association remained significant in all provider types. Among statistically significant predictors of 12-month mortality (including recurrent disease and >2 prior lines of chemotherapy), the surprise question had the highest RR.

Conclusions: The surprise question is a simple, one question tool that effectively identifies GO patients increased risk of 12-month mortality. The surprise question could be used to identify patients for early referral to palliative care and initiation advance care planning.
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http://dx.doi.org/10.1016/j.ygyno.2020.03.007DOI Listing
June 2020

Looking past PD-L1: expression of immune checkpoint TIM-3 and its ligand galectin-9 in cervical and vulvar squamous neoplasia.

Mod Pathol 2020 06 6;33(6):1182-1192. Epub 2020 Mar 6.

Department of Pathology, University of Virginia, Charlottesville, VA, USA.

Immunotherapies targeting the PD-1/PD-L1 pathway have shown some success in cervical and vulvar squamous cell carcinomas, but little is known about the potential vulnerability of these tumors to other checkpoint inhibitors. TIM-3 is a checkpoint molecule that exerts immunosuppressive function via its interaction with Gal-9. TIM-3 and Gal-9 have been identified on a variety of malignancies but have not been studied in cervical and vulvar cancers, nor has their relationship to PD-L1 been established. Sixty-three cervical and vulvar invasive (n = 34) and intraepithelial lesions (n = 29) were assessed for TIM-3, Gal-9, and PD-L1 in tumor/lesional cells and associated immune cells. Tumoral TIM-3 expression was identified in 85% of squamous cell carcinomas but only 21% of intraepithelial lesions (p < 0.0001). When immune cells were also accounted for, 97% of invasive and 41% of intraepithelial lesions had a TIM-3 combined positive score (CPS) ≥ 1 (p < 0.0001). Tumoral membranous expression of Gal-9 was seen in 82% of squamous cell carcinomas and 31% of intraepithelial lesions (p = 0.0001); nearly all cases had Gal-9-positive immune cells. Tumoral PD-L1 was seen in 71% of squamous cell carcinomas and 10% of intraepithelial lesions (p < 0.0001), while the PD-L1 CPS was ≥1 in 82 and 21%, respectively (p < 0.0001). There were no significant differences in TIM-3, GAL-9, or PD-L1 expression in cervical vs. vulvar neoplasms, nor was HPV status significantly associated with any of the three markers. Dual TIM-3/Gal-9 expression was present in the majority (86%) of PD-L1-positive cases including 100% of PD-L1-positive squamous cell carcinomas, suggesting a possible role for TIM-3 checkpoint inhibition in concert with anti-PD-1/PD-L1.
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http://dx.doi.org/10.1038/s41379-019-0433-3DOI Listing
June 2020

Chemotherapy alone may have equivalent survival as compared to suboptimal surgery in advanced endometrial cancer patients.

Gynecol Oncol Rep 2020 May 17;32:100535. Epub 2020 Jan 17.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia Medical Center, Charlottesville, VA 22908, United States.

Objective: To describe outcomes in patients with advanced endometrial cancer treated with chemotherapy only and compare them to patients treated with a combination of chemotherapy and surgery.

Methods: Retrospective chart review for all patients diagnosed with stage III and IV endometrial cancer from January 1, 2000 to December 31, 2015. We abstracted relevant demographic and clinical data. Kaplan-Meier analysis was used to create survival curves; Cox proportional hazards regression model was used to identify prognostic factors.

Results: Ninety-six patients met inclusion criteria; the median age was 64.5. Seventy patients were treated with combination therapy and 26 with chemotherapy alone. For the entire group, median overall survival (OS) was significantly different between groups (22.3 months surgery versus 9.8 months chemotherapy only, p = 0.0002). After multivariable analysis, having carcinosarcoma (HR 3.84 95% CI 2.64-5.03, p = 0.03), having grade 3 disease (HR 4.95 95% CI 3.70-6.18, p = 0.01), and having chemotherapy only (HR 4.13 95% CI 3.23-5.02, p = 0.002) were associated with increased mortality. When analysis was restricted to just patients who had a suboptimal debulking or chemotherapy alone, median OS was equivalent similar at 9.4 and 9.8 months (p = 0.46).

Conclusion: For advanced endometrial cancer patients, surgery in addition to chemotherapy confers a survival advantage except when optimal debulking cannot be achieved.
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http://dx.doi.org/10.1016/j.gore.2020.100535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030985PMC
May 2020

A phase I study of intravenous or intraperitoneal platinum based chemotherapy in combination with veliparib and bevacizumab in newly diagnosed ovarian, primary peritoneal and fallopian tube cancer.

Gynecol Oncol 2020 01 7;156(1):13-22. Epub 2019 Nov 7.

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

Background: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC.

Methods: A phase I, 3 + 3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1-2. Once <2/6 patients experienced a DLT, that dose level expanded to evaluate feasibility over 4 cycles. This study opened 10/2009 and closed 8/2016. Eligible patients had untreated, stage II-IV EOC. Veliparib was added either continuous (day 1-21) or intermittent (day - 2 to 5) during 6 cycles of chemotherapy. Three chemotherapy backbones were evaluated (2 intravenous (q3week and weekly) and 1 intraperitoneal (IP)) all inclusive of bevacizumab with and as maintenance to 22 cycles.

Findings: Dose evaluations for 424 treated patients were available. Regimen 1 (q3 week), continuous (Reg1c) the maximum tolerated dose (MTD) was 250 mg veliparib BID and feasible dose was 150 mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250 mg BID. For Reg2c (weekly paclitaxel) the MTD and feasible dose were 150 mg BID. For Reg2i the MTD and feasible dose were 250 and 150 mg BID. For Reg3c (IP) the MTD and feasible dose were 150 mg BID and for Reg3i (IP), the MTD and feasible dose were 400 mg and 300 mg BID.

Interpretation: The feasible dose for Reg1c, 2c, 2i and 3c was 150 mg po BID. For Reg1i and 3i the dose was pushed to 250 and 300 mg po BID respectively. There is no apparent difference in efficacy between continuous and intermittent dosing indicating that the higher doses achieved in intermittent dosing may not be needed. (NCT00989651).

Funding: National Cancer Institute.
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http://dx.doi.org/10.1016/j.ygyno.2019.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048389PMC
January 2020

The role of pulmonary resection in the management of metastatic gestational trophoblastic neoplasia: Two cases of durable remission following surgery for chemo-resistant disease.

Gynecol Oncol Rep 2019 Nov 6;30:100496. Epub 2019 Sep 6.

Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA, United States of America.

•GTN is typically a chemo-responsive and highly curative gynecologic malignancy.•Surgery may be beneficial in as many as 2/3 of patients with high-risk GTN.•In select patients, resection of drug-resistant pulmonary metastases is effective.
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http://dx.doi.org/10.1016/j.gore.2019.100496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804952PMC
November 2019

The American Society of Clinical Oncology 2019 annual meeting: A review and summary of selected abstracts.

Gynecol Oncol 2019 09 12;154(3):454-460. Epub 2019 Jul 12.

Division of Gynecologic Oncology, Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Creighton University School of Medicine at St. Joseph's Hospital, Phoenix, AZ, USA.

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http://dx.doi.org/10.1016/j.ygyno.2019.06.019DOI Listing
September 2019

Quality Initiative to Improve Compliance With Perioperative Anticoagulation.

J Oncol Pract 2019 09 17;15(9):e835-e842. Epub 2019 Jun 17.

University of Virginia, Charlottesville, VA.

Purpose: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in gynecologic oncology surgical patients. Many centers use neuraxial analgesia (NA), which affects the timing of prophylactic anticoagulation. In 2012, we determined that the rate of VTE in patients undergoing laparotomy with NA was higher than in those who received alternative pain control. In addition, compliance with preoperative anticoagulation guidelines was only 40%. We undertook a quality initiative (QI) project to increase compliance to 80% in NA cases and maintain 90% in non-NA cases.

Methods: A multidisciplinary working group designed and deployed a QI intervention bundle. Compliance was defined as the receipt of a prophylactic dose of anticoagulant within 1 hour after NA or before skin incision regardless of anesthesia type. Data were abstracted from the medical record after the study period. Cases from the year before QI were used for comparison. Primary outcome was compliance and secondary outcome was the rate of VTE.

Results: One hundred women were treated under the QI project and 182 historical cases (HCs) were used for comparison. Overall compliance improved (96% QI 73% HC; < .001). This difference was marked in cases with NA (95% QI 40% HC; < .001) and remained stable in non-NA cases (97% QI 91% HC; = .29). The overall rate of VTE, independent of anesthesia type, remained unchanged (2.1% HC 0% QI; = .3).

Conclusion: Relatively simple and inexpensive initiatives to improve routine processes within the surgical pathway are feasible and attract staff participation. Such efforts are likely to translate into greater levels of patient safety.
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http://dx.doi.org/10.1200/JOP.18.00748DOI Listing
September 2019

Interpreting Randomized Clinical Trials in Gynecologic Oncology Surgery: Does One Size Fit All?

Am Soc Clin Oncol Educ Book 2019 Jan 17;39:342-350. Epub 2019 May 17.

1 University of Virginia, Charlottesville, VA.

Randomized clinical trials (RCTs) are considered the gold standard of clinical research. They are designed to eliminate bias and to produce objective and generalizable results about new treatment paradigms. Although RCTs have recognized limitations, including long completion time and high cost, they also have transformed clinical research and improved the quality of health care by rigorously evaluating countless new treatment options. Surgical RCTs present their own unique set of limitations including an inability to standardize surgical technique and expertise; an inability to overcome enrollment bias by enrolling surgeons; and a lack of generalizability with respect to institutional resources and abilities. Here, we discuss surgical RCTs in two domains: upfront management of advanced ovarian cancer and surgical management of early-stage cervical cancer. Familiarity with the abundant retrospective data available for both of these clinical scenarios as well as recognition of the strengths and limitations of surgical RCTs are critical to determine the best treatment for an individual patient.
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http://dx.doi.org/10.1200/EDBK_237945DOI Listing
January 2019

Phase II trial of nintedanib in patients with bevacizumab-resistant recurrent epithelial ovarian, tubal, and peritoneal cancer.

Gynecol Oncol 2019 06 28;153(3):555-561. Epub 2019 Mar 28.

Division of Gynecologic Oncology, University of Virginia, United States of America.

Background: Bevacizumab provides benefit in epithelial ovarian cancer (EOC), yet resistance to bevacizumab often occurs. We determined if nintedanib, a tyrosine kinase inhibitor of VEGF, FGF, and PDGF receptors has antitumor activity in bevacizumab-resistant recurrent EOC, tubal, and peritoneal cancer.

Methods: This phase II study evaluated nintedanib 200 mg/day until disease progression or unacceptable toxicity. The primary objective was 6-month progression free survival (PFS6m). Secondary objectives were response rate and toxicity. Simon two-stage optimal design was used. Baseline angiogenic plasma biomarkers were measured.

Results: 27 patients were enrolled evaluable for PFS; 26 were evaluable for PFS6m. The median age was 65 years (range 44-73); 89.9% had high-grade serous EOC; 70% received at least >2 prior chemotherapies; and 81% (22/27) had chemoresistant disease. With median follow up of 15.6 months (range 2-38) the PFS6m rate was 11.5% (3/26). Three participants had long duration of disease control (8-16 months). Median PFS and overall survival were 1.8 and 16 months, respectively. Response rate was 7.4% (2/27 PR). Thirty-seven percent (10/27) had stable disease, while 56% (15/27) had progressive disease. Adverse events included Grade 3 liver enzyme elevation (15%), Grade 3 diarrhea (7%), Grade 2 fatigue (7%), and Grade 2 nausea/vomiting (15%). PD patients exhibited higher levels of CD73, IL6, and VEGFD (p < 0.05) compared to PR/SD patients. IL6 was associated with worse PFS (p = 0.03).

Conclusions: Single-agent nintedanib has minimal activity in an unselected bevacizumab-resistant EOC population. Nintedanib was tolerable and toxicities were manageable. Plasma CD73, IL6, and VEGFD were identified as prognostic markers for progressive disease, and IL6 was associated with worse PFS confirming similar observations made in patients treated with other anti-angiogenic agents.
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http://dx.doi.org/10.1016/j.ygyno.2019.03.246DOI Listing
June 2019

Emerging biomarkers in ovarian granulosa cell tumors.

Int J Gynecol Cancer 2019 03 4;29(3):560-565. Epub 2019 Jan 4.

Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia, USA.

Objective: Although the majority of ovarian granulosa cell tumors can be successfully managed with surgery, a subset require chemotherapy for residual and recurrent disease. The benefit of chemotherapy in this population, however, remains controversial. There is therefore interest in the development of more tolerable and effective treatment options for advanced ovarian granulosa cell tumors. We report the use of immunohistochemistry to investigate how biomarkers could inform clinical trials in granulosa cell tumors with an emphasis on emerging androgen antagonistic, immunotherapeutic, and anti-angiogenic approaches.

Methods: Immunohistochemistry for androgen receptor, the immune markers programmed cell death ligand 1, indoleamine-2,3 dioxygenase, and cluster of differentiation 8, and the vascular marker cluster of differentiation 31 were evaluated on formalin-fixed paraffin-embedded whole tissue sections from 29 cases of adult-type granulosa cell tumors. Results were evaluated with clinicopathologic variables including recurrence.

Results: 59% of granulosa cell tumors were androgen receptor-positive, suggesting a potential role for anti-androgen therapy in this tumor type. In contrast, the targetable immune modulatory molecules programmed cell death ligand 1 and indoleamine-2,3 dioxygenase were scarcely expressed, with no cases showing tumorous programmed cell death ligand 1 and a single case demonstrating very focal tumorous indoleamine-2,3 dioxygenase staining. A minority of cases expressed programmed cell death ligand 1 in occasional tumor-associated macrophages and indoleamine-2,3 dioxygenase in peritumoral vessels. Tumor-infiltrating cytotoxic T cells were also scarce in granulosa cell tumors, arguing against a significant role for immunotherapy in the absence of additional immunostimulation. Cluster of differentiation 31 immunostaining revealed a range of vascular densities across granulosa cell tumors, and future studies evaluating the role of vascular density as a predictor of response to angiogenesis inhibition are warranted. None of the biomarkers investigated were significantly correlated with recurrence, and the only clinicopathologic feature significantly correlated with outcome was stage at presentation.

Conclusions: Biomarker data suggest that many ovarian granulosa cell tumors could be candidates for anti-androgen therapy, while the potential role for immunotherapy appears more limited. Vascular density could be useful for identifying optimal candidates for angiogenesis inhibition. Incorporation of these biomarkers into clinical trials could help optimize patient selection.
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http://dx.doi.org/10.1136/ijgc-2018-000065DOI Listing
March 2019

Cancer Screening and Prevention Highlights in Gynecologic Cancer.

Obstet Gynecol Clin North Am 2019 Mar;46(1):19-36

Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Virginia, University of Virginia Medical Center, PO Box 800712, Charlottesville, VA 22908, USA.

This article provides an up-to-date summary of screening approaches and key strategies in prevention of gynecologic malignancies. The Pap smear is the only proven screening intervention in the field of gynecologic oncology. Women should receive treatment for precancerous conditions of the cervix, vulva, vagina, and endometrial lining. Women with inherited conditions should consider having a risk-reducing surgery once they have finished childbearing. The human papilloma virus vaccination should be offered to all girls and boys aged 11 to 12 years, and can also be given as early as age 9 and through 26 years of age.
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http://dx.doi.org/10.1016/j.ogc.2018.09.002DOI Listing
March 2019

The association between progesterone receptor expression and survival in women with adult granulosa cell tumors.

Gynecol Oncol 2019 04 18;153(1):74-79. Epub 2019 Jan 18.

Division of Gynecologic Oncology, Duke Cancer Institute, Durham, NC, United States of America.

Background: Granulosa cell tumors (GCT) variably express estrogen receptors (ER) and progesterone receptors (PR). The goal of this study is to evaluate the relationship between ER and PR expression patterns and clinical outcomes in women with GCT.

Methods: A multicenter, retrospective analysis was performed of all cases of GCT diagnosed between 1989 and 2012. Immunohistochemical staining for ER and PR was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue and interpreted using a semiquantitative scoring system that incorporated tumor cell staining proportion and intensity. Demographics, disease status, and survival information were collected. Associations between ER and PR staining scores and recurrence-free and overall survival were assessed using univariate Cox proportional hazards models.

Results: FFPE tumor blocks were available for 149/186 GCT patients. The majority of the women had clinical stage I disease (76%). ER and PR expression was present in 52% and 98% of subjects, respectively. The median composite scores of ER and PR staining were 1 (range 0-8) and 9 (range 0-15), respectively. In univariate analysis, PR composite score >9 was strongly associated with decreased recurrence-free survival (HR = 2.9, 95% CI = 1.5-5.5) and decreased overall survival (HR = 3.7, CI 1.3-10.2). ER composite score was not a significant predictor of recurrence-free survival or overall survival (p = 0.7, HR = 1.1, 95% CI 0.6-2.0 and p = 0.06, HR = 1.1, 95% CI 0.4-2.9, respectively).

Conclusions: Our results reveal that high PR composite score (≥9) was associated with both decreased recurrence-free and overall survival in patients with GCT while ER expression was not associated with survival outcomes.
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http://dx.doi.org/10.1016/j.ygyno.2019.01.016DOI Listing
April 2019

Endocrine therapy in endometrial cancer: An old dog with new tricks.

Gynecol Oncol 2019 04 5;153(1):175-183. Epub 2019 Jan 5.

Division of Medical Oncology and Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. Electronic address:

One of the most prevalent potential therapeutic targets for women with endometrioid endometrial cancer (EC) is the estrogen receptor (ER)/progesterone receptor (PR) pathway. Despite a high proportion of endometrioid ECs being ER and/or PR positive, endocrine therapy is only effective in a minority of women with EC and ultimately patients progress with resistance developing to treatment. A variety of treatment approaches with progestins, selective ER modulators (SERMs) and aromatase inhibitors (AIs) are available. Exploration of these agents is desirable given their favorable toxicity profile. Greater understanding of ER and PR biology may help identify patient populations who will derive benefit and strategies for new therapeutic options. Here we review the clinical efficacy of endocrine therapy in EC, discuss the role of ER and/or PR as prognostic biomarkers, describe disease-specific mechanisms of resistance to endocrine therapy and explore potential strategies to enhance response for the "next generation" of endocrine therapy clinical trials. We also describe the use of endocrine therapy in younger women seeking to pursue fertility sparing options for management of EC.
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http://dx.doi.org/10.1016/j.ygyno.2018.12.018DOI Listing
April 2019

Clinical and Genomic Implications of Luminal and Basal Subtypes Across Carcinomas.

Clin Cancer Res 2019 04 20;25(8):2450-2457. Epub 2018 Dec 20.

Department of Radiation Oncology, University of California San Francisco, San Francisco, California.

Purpose: Carcinomas originate from epithelial tissues, which have apical (luminal) and basal orientations. The degree of luminal versus basal differentiation in cancer has been shown to be biologically important in some carcinomas and impacts treatment response.

Experimental Design: Although prior studies have focused on individual cancer types, we used a modified clinical-grade classifier (PAM50) to subtype 8,764 tumors across 22 different carcinomas into luminal A, luminal B, and basal-like tumors.

Results: We found that all epithelial tumors demonstrated similar gene expression-based luminal/basal subtypes. As expected, basal-like tumors were associated with increased expression of the basal markers KRT5/6 and KRT14, and luminal-like tumors were associated with increased expression of the luminal markers KRT20. Luminal A tumors consistently had improved outcomes compared with basal across many tumor types, with luminal B tumors falling between the two. Basal tumors had the highest rates of TP53 and RB1 mutations and copy number loss. Luminal breast, cervical, ovarian, and endometrial tumors had increased ESR1 expression, and luminal prostate, breast, cervical, and bladder tumors had increased androgen receptor (AR) expression. Furthermore, luminal B tumors had the highest rates of AR and ESR1 mutations and had increased sensitivity to bicalutamide and tamoxifen. Luminal B tumors were more sensitive to gemcitabine, and basal tumors were more sensitive to docetaxel.

Conclusions: This first pan-carcinoma luminal/basal subtyping across epithelial tumors reveals global similarities across carcinomas in the transcriptome, genome, clinical outcomes, and drug sensitivity, emphasizing the biological and translational importance of these luminal versus basal subtypes.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3121DOI Listing
April 2019

A window-of-opportunity clinical trial of dasatinib in women with newly diagnosed endometrial cancer.

Cancer Chemother Pharmacol 2019 03 8;83(3):473-482. Epub 2018 Dec 8.

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Objective: To determine the extent of dasatinib uptake and effect on Src kinase activity in tumor, normal adjacent tissue, and blood in newly diagnosed endometrial cancer patients.

Methods: Dasatinib was dosed at 100 or 200 mg PO BID at 32 and 8 h preoperatively. Blood and tissue were collected pre-treatment and at surgery to assess active (pY419) and total Src protein (pharmacodynamics [PD]) and pharmacokinetics (PK). Plasma PK and PD were also analyzed at 2, 4 and 8 h following the second dose.

Results: Ten patients completed the study, 5 at each dose level (DL). Average (median, standard deviation, range) 2 h plasma concentration of drug was 119 (121, 80, 226) and 236 (162, 248, 633) ng/mL, for the 100 and 200 mg DL, respectively. Average ratio of 8 h normal and tumor tissue to plasma concentration overall was 3.6 (2.3, 3.4, 9.6) and 8.3 (3.2, 11.9, 38.7), respectively. Dasatinib concentration in tumor was higher than in plasma for both DL. Four patients displayed significant reductions in pTyr419Src at ≥ 1 time points in blood, and four patients satisfied the PD activity criteria in tissue, with reductions in pTyr419Src of ≥ 60%.

Conclusions: This is the first study to show PK and PD effects of dasatinib in tumor tissue, allowing evaluation of tissue PD markers as a function of tumor dasatinib concentration. Dasatinib tissue concentrations at 8 h after dosing were associated with modulation of pTyr419Src, total Src protein, and pTyr419Src/Src ratio. All patients had reduction in at least one Src parameter in either tissue or blood.
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http://dx.doi.org/10.1007/s00280-018-3749-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628688PMC
March 2019

International Gynecologic Cancer Society (IGCS) 2018: Meeting report.

Gynecol Oncol 2019 01 28;152(1):7-10. Epub 2018 Oct 28.

Department of Obstetrics and Gynecology, University of Chicago, Chicago IL USA.

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http://dx.doi.org/10.1016/j.ygyno.2018.10.020DOI Listing
January 2019

Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial.

JAMA Oncol 2019 01 10;5(1):e183773. Epub 2019 Jan 10.

Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival.

Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2).

Design, Setting, And Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study.

Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles.

Main Outcomes And Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug).

Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug.

Conclusions And Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted.

Trial Registration: ClinicalTrials.gov identifier: NCT01091428.
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http://dx.doi.org/10.1001/jamaoncol.2018.3773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439781PMC
January 2019

Cervical cancer care in rural Virginia: The impact of distance from an academic medical center on outcomes & the role of non-specialized radiation centers.

Gynecol Oncol 2018 08 21;150(2):338-342. Epub 2018 Jun 21.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA, United States of America.

Objective: To determine whether distance to a tertiary care facility affects outcomes for locally advanced cervical cancer and to evaluate the impact of receiving care at non-specialized centers in rural communities.

Methods: Retrospective, single institution study of patients with locally advanced cervical cancer managed with chemo-radiation from January 1, 2000 to June 1, 2014. Kaplan-Meier survival curves and Cox proportional hazard models were used to compare progression free and overall survival for patients by median distance to the tertiary care facility (<72 miles or >72 miles) and facility where treatment was received.

Results: 180 patients met inclusion criteria. There was no difference in PFS or OS between the travel distance cohorts. When compared by location of external beam radiation, patients treated at outside facilities were older (p = 0.02) and significantly more likely to be insured (95.6% versus 71.7%, p < 0.0002). There were more recurrences among patients treated at outside facilities (31.1% versus 15.8%) but this was non-significant (p = 0.24). On multivariable analysis, FIGO stage and insurance status were associated with overall survival. Uninsured patients had a significantly increased hazard risk of death as compared to privately insured patients (HR 3.85 95% CI 3.07-4.64, p = 0.0008).

Conclusions: Median distance to a tertiary care facility had no significant impact on PFS or OS, however treating facility for radiation may influence recurrence rates. Having non-private insurance or being uninsured is significantly associated with increased risk of death and speaks to the many barriers these patients face.
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http://dx.doi.org/10.1016/j.ygyno.2018.06.019DOI Listing
August 2018

Salpingectomy Compared With Tubal Ligation at Cesarean Delivery: A Randomized Controlled Trial.

Obstet Gynecol 2018 07;132(1):29-34

Departments of Obstetrics and Gynecology and Public Health Sciences, University of Virginia, and the Clinical Trials Office, University of Virginia School of Medicine, Charlottesville, Virginia.

Objective: To estimate whether performance of salpingectomy compared with standard tubal ligation for sterilization at the time of cesarean delivery increases operating time or complication rates.

Methods: A randomized controlled noninferiority trial was performed at a single academic institution. Women undergoing planned cesarean delivery who desired sterilization were randomized to salpingectomy or standard tubal ligation. The primary outcome was length of time of the sterilization procedure, with the noninferiority margin set at 5 minutes. With a one-sided independent sample t test, to achieve a power of 90% with an α of 0.05, 18 women needed to complete each intervention.

Results: Forty-four women were enrolled, with 19 successfully undergoing salpingectomy and 18 undergoing standard tubal ligation. Salpingectomy could not be completed in 1 of 20 patients (as a result of adhesions). Baseline demographics were equivalent between groups. Salpingectomy procedure time was noninferior to standard tubal ligation, with a mean difference of 0.5 minutes, with a mean sterilization procedure time of 5.6 minutes in the salpingectomy group and 6.1 minutes in the standard tubal ligation group (P <.05, one-sided 95% CI upper bound 1.8 minutes). There was no difference between cesarean delivery with salpingectomy compared with cesarean delivery with standard tubal ligation in median total operating time (60 vs 68 minutes, P=.34) or estimated blood loss (600 vs 700 mL, P=.09). No patients in either group required reoperation or readmission.

Conclusion: Salpingectomy procedure time was not longer than standard tubal ligation during cesarean delivery, with a mean difference of 30 seconds. There was a high completion rate for salpingectomy (95%) and no apparent increase in complications.

Clinical Trial Registration: Clinicaltrials.gov, NCT03028623.
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http://dx.doi.org/10.1097/AOG.0000000000002674DOI Listing
July 2018

Access to quality gynecologic oncology care: A work in progress.

Authors:
Linda R Duska

Cancer 2018 07 16;124(13):2680-2683. Epub 2018 May 16.

Division of Gynecologic Oncology, University of Virginia School of Medicine, Charlottesville, Virginia.

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http://dx.doi.org/10.1002/cncr.31391DOI Listing
July 2018

Opioid use in gynecologic oncology in the age of the opioid epidemic: Part II - Balancing safety & accessibility.

Gynecol Oncol 2018 05 12;149(2):401-409. Epub 2018 Mar 12.

Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University of Colorado Denver, Aurora, CO, United States; Department of Internal Medicine, Palliative Care, University of Colorado Denver, Aurora, CO, United States. Electronic address:

As the only oncologists that provide both medical and surgical care, gynecologic oncologists encounter an exceptionally broad range of indications for prescribing opioids in clinical situations ranging from management of acute post-operative pain to chronic cancer-related pain to end-of-life care. While opioids are essential to the practice of gynecologic oncology, they can also have significant side effects and can be misused. Due to the explosive growth of opioid prescriptions and opioid-related overdoses and deaths during the first decade of the 21st century, there has been a recent concerted public health effort to prevent and treat opioid misuse through both legislation and education [1]. The first article in this two part series focused on appropriate use of opioids across clinical settings. This article addresses both the clinical and regulatory aspects of balancing opioid safety and accessibility for patients with gynecologic cancer.
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http://dx.doi.org/10.1016/j.ygyno.2018.02.008DOI Listing
May 2018

Targeted Therapies and Immunotherapy for Gynecologic Malignancies: Living Longer, Living Better With Noncytotoxic Options in Recurrent Disease.

Clin Ther 2018 03 7;40(3):358-360. Epub 2018 Mar 7.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia School of Medicine, USA.

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http://dx.doi.org/10.1016/j.clinthera.2018.02.007DOI Listing
March 2018