Gynecologic oncology patient perspectives and knowledge on advance care planning: A quality improvement intervention.

Objectives: Assess and improve advance care planning (ACP) awareness and uptake among gynecologic oncology patients. Methods: Using a quality improvement Plan-Do-Check-Act framework, we completed a single institution needs assessment and intervention. The needs assessment was a 26-question survey assessing baseline ACP knowledge and preferences of gynecologic oncology patients. We used this survey to implement an outpatient intervention in which patients were offered ACP resources (pamphlet, discussion with their gynecologic oncologist, and/or social work referral). We conducted a post-intervention survey among patients who had and had not received ACP resource(s) to assess whether our intervention increased ACP knowledge, discussions, or uptake. Results: Among 106 patients surveyed in the needs assessment, 33 % had ACP documents, 26 % had discussed ACP with a physician, and 82 % thought discussing ACP was important. The majority preferred these conversations in the outpatient setting (52 %) with their gynecologic oncologist (80 %) instead of nurses or trainees. In the intervention, 526 patients were offered ACP resources. Compared to women who did not receive resources (n = 324), patients who received ACP resource(s) (n = 202) were more likely to have ACP discussions with their gynecologic oncologist (38 % vs 68 %, P = 0.001) and had greater proficiency regarding how to create ACP documents (median score 5/10 vs 8/10, P = 0.048), although they were no more likely to have ACP documented in their electronic medical record (27 % vs 9 %, p = 0.08). Conclusions: ACP uptake among gynecologic oncology patients is low, but ACP discussions with an oncologist during outpatient visits are important to patients and improve their knowledge regarding completing ACP documents.

Factors influencing residents' interest in gynecologic oncology fellowship.

OBJECTIVES: To identify the role of mentorship and other factors associated with obstetrics and gynecology (OB/GYN) resident interest in pursuing a fellowship in gynecologic oncology. METHODS: A survey link was emailed to U.S. OB/GYN residency program coordinators to disperse to current residents. The 80-item survey asked about plans to pursue fellowship and influencing factors. Participants were stratified based on decision to pursue a fellowship in gynecologic oncology. Student's t-test and Mann-Whitney tests were applied. RESULTS: Among 236 surveyed residents, 32 (13.6%) were planning to pursue a fellowship in gynecologic oncology. There were no demographic differences favoring the choice of gynecologic oncology; however, trainees at academic programs were more likely to aspire to the subspecialty (p = 0.01). Residents interested in gynecologic oncology had marginally more mentors than others (p = 0.06), were more likely to have a gynecologic oncology mentor (p < 0.01), and were more likely to have cited mentorship as a reason for their career aspirations (p = 0.01). These residents were also less likely to report obvious burnout among faculty and fellows in their department (p < 0.01 and p = 0.01, respectively). CONCLUSIONS: Strong mentor relationships and the display of job satisfaction and work-life balance influence OB/GYN residents' interest in gynecologic oncology fellowships. Programs should consider formal mentorship programs for residents, with priority on matching by subspecialty. The value of fellow and faculty efforts in mentorship should be recognized, and appropriate time should be protected for these relationships, along with efforts to support fellows and faculty at risk for burnout.

Wound Complication Rates After Vulvar Excisions for Premalignant Lesions.

OBJECTIVE: To assess the rate of wound complications and evaluate the effectiveness of antibiotic prophylaxis in vulvar wide local excision procedures. METHODS: We performed a single-institution, retrospective cohort study of women undergoing vulvar surgery for premalignant lesions between January 2007 and January 2017. The primary outcome was a composite wound complication rate that included breakdown or infection within 8 weeks postoperatively. Data were analyzed using Fisher exact or χ test, Student t-test, and Poisson regression. RESULTS: Wound complications occurred in 154 (28.7%) of the 537 patients. Mean age was 52 years; most patients were white (83.1%), cigarette smokers (65.2%), had no prior vulvar treatment (54.4%), and had a preoperative diagnosis of high-grade squamous intraepithelial lesion (vulvar HSIL) (70.0%). The presence of other predisposing factors was similar between groups. In multivariate analysis, smoking (odds ratio [OR] 1.64, 95% CI 1.14-2.38) and primary rather than repeat vulvar surgery (OR 1.99, 95% CI 1.31-3.01) were associated with increased risk for wound complications. There was no significant difference in wound complications between women who received preoperative antibiotics and those who did not (30.4% vs 27.4%, P=.45), although the mean length of wound separation in the antibiotic group was shorter (1 vs 2 cm, P=.03). CONCLUSION: Wound complications are common among women undergoing surgery for vulvar HSIL, and interventional trials are warranted to evaluate the role of smoking cessation and prophylactic antibiotics to reduce postoperative morbidity.

p5RHH nanoparticle-mediated delivery of AXL siRNA inhibits metastasis of ovarian and uterine cancer cells in mouse xenografts.

Ovarian and uterine serous cancers are extremely lethal diseases that often present at an advanced stage. The late-stage diagnosis of these patients results in the metastasis of their cancers throughout the peritoneal cavity leading to death. Improving survival for these patients will require identifying therapeutic targets, strategies to target them, and means to deliver therapies to the tumors. One therapeutic target is the protein AXL, which has been shown to be involved in metastasis in both ovarian and uterine cancer. An effective way to target AXL is to silence its expression with small interfering RNA (siRNA). We investigate the ability of the novel siRNA delivery platform, p5RHH, to deliver anti-AXL siRNA (siAXL) to tumor cells both in vitro and in vivo as well as examine the phenotypic effects of this siRNA interference. First, we present in vitro assays showing p5RHH-siAXL treatment reduces invasion and migration ability of ovarian and uterine cancer cells. Second, we show p5RHH nanoparticles target to tumor cells in vivo. Finally, we demonstrate p5RHH-siAXL treatment reduces metastasis in a uterine cancer mouse xenograft model, without causing an obvious toxicity. Collectively, these findings suggest that this novel therapy shows promise in the treatment of ovarian and uterine cancer patients.

Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer.

Ovarian cancer, one of the deadliest malignancies in female cancer patients, is characterized by recurrence and poor response to cytotoxic chemotherapies. Fewer than 30% of patients with resistant disease will respond to additional chemotherapy treatments. This study aims to determine whether and how inhibition of the receptor tyrosine kinase AXL can restore sensitivity to first-line platinum and taxane therapy in ovarian cancer. AXL staining was quantified in a patient tissue microarray and correlated with chemoresponse of patients. We used small hairpin RNAs to knock down AXL expression and the small-molecule inhibitor BGB324 to inhibit AXL and assessed sensitivity of cell lines and primary patient-derived cells to chemotherapy. We quantified platinum accumulation by inductivity-coupled plasma phase mass spectrometry. Finally, we treated chemoresistant patient-derived xenografts with chemotherapy, BGB324, or chemotherapy plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant patient tumors and cell lines than in chemosensitive tumors and cell lines. AXL staining significantly predicted chemoresponse. Knockdown and inhibition of AXL dose-dependently improved response to paclitaxel and carboplatin in both cell lines and primary cells. AXL inhibition increased platinum accumulation by 2-fold (*, P < 0.05). In vivo studies indicated that AXL inhibition enhanced the ability of chemotherapy to prevent tumor growth (****, P < 0.0001). AXL contributes to platinum and taxane resistance in ovarian cancer, and inhibition of AXL improves chemoresponse and accumulation of chemotherapy drugs. This study supports continued investigation into AXL as a clinical target.

A rare case of endometrial cancer metastatic to the uveal choroid.

•Choroid metastases are extremely rare in endometrial cancer.•Choroid metastases can present as many different eye complaints.•Comprehensive eye exams are important in patients with visual complaints.

Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer.

Uterine serous cancer (USC) is aggressive, and the majority of recurrent cases are chemoresistant. Because the receptor tyrosine kinase AXL promotes invasion and metastasis of USC and is implicated in chemoresistance in other cancers, we assessed the role of AXL in paclitaxel resistance in USC, determined the mechanism of action, and sought to restore chemosensitivity by inhibiting AXL in vitro and in vivo We used short hairpin RNAs and BGB324 to knock down and inhibit AXL. We assessed sensitivity of USC cell lines to paclitaxel and measured paclitaxel intracellular accumulation in vitro in the presence or absence of AXL. We also examined the role of the epithelial-mesenchymal transition (EMT) in AXL-mediated paclitaxel resistance. Finally, we treated USC xenografts with paclitaxel, BGB324, or paclitaxel plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant USC patient tumors and cell lines than in chemosensitive tumors and cell lines. Knockdown or inhibition of AXL increased sensitivity of USC cell lines to paclitaxel in vitro and increased cellular accumulation of paclitaxel. AXL promoted chemoresistance even in cells that underwent the EMT in vitro Finally, in vivo studies of combination treatment with BGB324 and paclitaxel showed a greater than 51% decrease in tumor volume after 2 weeks of treatment when compared with no treatment or single-agent treatments (P < 0.001). Our results show that AXL expression mediates chemoresistance independent of EMT and prevents accumulation of paclitaxel. This study supports the continued investigation of AXL as a clinical target, particularly in chemoresistant USC. Mol Cancer Ther; 16(12); 2881-91. ©2017 AACR.

Identification of molecular targets in vulvar cancers.

OBJECTIVES: To identify molecular alterations that contribute to vulvar cancer pathogenesis with the intent of identifying molecular targets for treatment. METHODS: After retrospective analysis of a database of molecularly-profiled gynecologic cancer patients, 149 vulvar cancer patients were included and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and gene amplification (C/FISH). A Fisher's exact test was used when indicated with a p-value≤0.05 indicating significance. RESULTS: Median age was 65. 85% had squamous cell carcinoma (SCC) and 15% adenocarcinoma (ADC) histologies. 46% had metastatic (Stage IV) disease. Targeted hot-spot sequencing identified variants in the following genes: TP53 (33%), PIK3CA/BRCA2 (8%, 10%, respectively), HRAS/FBXW7 (5%, 4%, respectively) and ERBB4/GNAS (3%, 3% respectively). Mutations in AKT1, ATM, FGFR2, KRAS, NRAS (n=1, respectively) and BRAF (n=2) also occurred. Specific protein changes for targetable genes included clinically pathogenic mutations commonly found in other cancers (e.g. PIK3CA: exon 9 [E545K], RAS: G13D, Q61L, BRCA2: S1667X, BRAF: R443T, FBXW7: E471fs, etc.). Drug targets identified by IHC and ISH methodologies include cMET (32% IHC, 2% ISH), PDL1 (18%), PTEN loss (56%), HER2 (4% IHC, 2% ISH) and hormone receptors (AR, 4%; ER, 11%; PR, 4%). Comparisons between SCC and ADC identified differential rates for AR, ER, HER2 and GNAS with an increased presence in ADC (p-values all <0.05). CONCLUSIONS: Molecularly-guided precision medicine could provide vulvar cancer patients alternative, targeted treatment options.

The clinical management of inoperable endometrial carcinoma.

Unresectable endometrial cancer, while rare, has a very poor prognosis, with a survival rate of 2 to 8 months. Although endometrial cancer is generally regarded as a survivable disease, the less common advanced and aggressive forms account for a large portion of endometrial cancer related deaths. Given the paucity of inoperable disease, randomized clinical data is lacking in this specific patient population. Management decisions regarding radiation therapy or systemic therapy are largely guided by the existing data in the setting of recurrence or second-line treatment, adjuvant therapy following optimal debulking, or in patients who are considered inoperable due to medical comorbidities rather than the extent of their disease.

Physician Specialty Influences Care of Pelvic Inflammatory Disease.

BACKGROUND: CDC guidelines recommend Neisseria gonorrhoeae, Chlamydia trachomatis, and HIV testing, as well as specific antibiotic regimens in the diagnosis and treatment of pelvic inflammatory disease (PID), although latitude in adhering to these guidelines is common. We hypothesized that adherence to CDC guidelines for antibiotic regimens and laboratory testing, coverage for anaerobic organisms, and the use of diagnostic imaging techniques do not differ significantly between practitioners with emergency medicine (EM) versus obstetrics and gynecology (OB-GYN) training. MATERIALS AND METHODS: We conducted a retrospective medical chart review on patients (N = 351) discharged with a diagnosis of PID over a 20-month period at two neighboring emergency care facilities-one with EM-trained providers and the other with OB-GYN-trained providers. RESULTS: Adjusted for demographic predictors and chief complaint, there was no significant difference in adherence to N. gonorrhoeae and C. trachomatis antibiotic coverage guidelines between the two facilities (adjusted odds ratio [AOR] 1.34; 95% CI 0.66-2.74), using the OB-GYN facility in the numerator of the AOR. Anaerobic coverage was significantly more common at the OB-GYN facility (AOR 9.11; 95% CI 5.36-15.48). Both sites had very low rates of adherence to CDC laboratory testing guidelines with overall rates of adherence at 4.0% (95% CI 1.9%-5.9%). Utilization of diagnostic tests differed greatly between facilities: ultrasound utilization was 66.7% (95% CI 58.2%-75.2%) at the OB-GYN facility and 39.7% (95% CI 33.4%-45.9%) at the EM facility. CONCLUSIONS: The diagnostic pathway for PID and adherence to guidelines differ significantly depending on physician specialty and practice environment, suggesting the need for further standardization, perhaps with cross-disciplinary training.

Gemcitabine and Docetaxel Compared With Observation, Radiation, or Other Chemotherapy Regimens as Adjuvant Treatment for Stage I-to-IV Uterine Leiomyosarcoma.

OBJECTIVES: We aimed to compare progression-free survival (PFS) and overall survival (OS) among patients with stage I-to-IV uterine leiomyosarcoma (uLMS) who received adjuvant gemcitabine-docetaxel, were observed, received radiation only, or were treated with a chemotherapy regimen other than gemcitabine-docetaxel. METHODS/MATERIALS: This is a retrospective cohort study of 128 women with uLMS. Data included age, body mass index, race, stage, mitotic count, residual disease, adjuvant treatment, PFS, and OS. Variables were compared by Fisher exact or Wilcoxon rank-sum tests. Time to progression or death was plotted using Kaplan-Meier curves. Cox proportional hazards regression was used to estimate hazard ratios for progression or death by patient and tumor characteristics. RESULTS: Fifty-six (44%) women received adjuvant chemotherapy, 41 (32%) received adjuvant radiation, and 31 (24%) were observed. Of those receiving chemotherapy, 30 received gemcitabine-docetaxel, and 26 received other chemotherapy. Disease stage for the chemotherapy groups was evenly distributed. In the radiation group, 80% of patients had early-stage disease. Age, body mass index, and residual disease were similar between the groups. Mitotic count was uniformly 10 or greater only in the gemcitabine-docetaxel group. Age, stage, and residual disease were associated with worst PFS and OS. After adjusting for these variables, there was no difference in PFS or OS between gemcitabine-docetaxel and the other treatment groups. CONCLUSIONS: There was no difference in PFS or OS in women with uLMS treated with adjuvant gemcitabine-docetaxel versus those who were observed or received radiation only or a chemotherapy regimen other than gemcitabine-docetaxel. There is a need to identify novel therapies to treat this aggressive disease.

Assessing the risk of ovarian malignancy algorithm for the conservative management of women with a pelvic mass.

OBJECTIVE: To evaluate the use of as an aid in the identification of women who can safely undergo conservative, non-surgical management. METHODS: All patients referred to the Program in Women's Oncology for surgery with a pelvic mass are evaluated at a prospective multidisciplinary tumor board (TB) where ROMA and imaging are used for management recommendations. This study evaluated women presented to TB with a pelvic mass between 2009 and 2013 who had either surgical or conservative management. RESULTS: Of the 498 patients assessed, 392 (79%) had benign disease, 22 (4%) had LMP tumors, 28 (6%) had stage I-II epithelial ovarian cancer (EOC), 36 (7%) had stage III-IV EOC and 20 (4%) had non-EOC. Using clinical assessment in conjunction with ROMA, the TB recommended observation in 188 (37.8%) women. All patients diagnosed with an invasive malignancy were recommended for surgery by the TB. In the 315 patients managed surgically, 212 were found to have benign disease and 84 women were diagnosed with an invasive malignancy. The sensitivity for the initial TB recommendations using ROMA in conjunction with clinical judgment for detecting malignancy was 100% with a specificity of 47.7% and a NPV of 100%. When including low malignant potential tumors the sensitivity was 99.1%. For stage I-IV EOC ROMA alone had a sensitivity of 95.3%. CONCLUSIONS: ROMA in conjunction with clinical assessment can safely identify women for conservative management.