Prospective phase II trial of levonorgestrel intrauterine device: nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer.

BACKGROUND: The incidence of complex atypical hyperplasia and early-stage endometrioid endometrial cancer is increasing, in part owing to the epidemic of obesity, which is a risk factor tightly linked to the development of endometrial hyperplasia and cancer. The standard upfront treatment for complex atypical hyperplasia and early-stage endometrial cancer is hysterectomy. However, nonsurgical treatment of early-stage endometrial neoplasia may be necessary owing to medical comorbidities precluding surgery or desired future fertility. OBJECTIVE: This study aimed to evaluate the efficacy of the levonorgestrel intrauterine device to treat complex atypical hyperplasia and grade 1 endometrioid endometrial carcinoma. STUDY DESIGN: A single-institution, single-arm, phase II study of the levonorgestrel intrauterine device (52 mg levonorgestrel, Mirena) was conducted in patients with complex atypical hyperplasia or grade 1 endometrioid endometrial cancer. The primary endpoint was pathologic response rate at 12 months, including complete or partial response. Quality of life and toxicity were assessed. Molecular analyses for proliferation markers, hormone-regulated genes, and wingless-related integration site pathway activation were performed at baseline and 3 months. RESULTS: A total of 57 patients were treated (21 endometrial cancer, 36 complex atypical hyperplasia). The median age was 48.0 years, and the median body mass index was 45.5 kg/m2. Of the 47 evaluable patients, 12-month response rate was 83% (90% credible interval, 72.7-90.3)-37 were complete responders (8 endometrial cancer; 29 complex atypical hyperplasia), 2 were partial responders (2 endometrial cancer), 3 had stable disease (2 endometrial cancer; 1 complex atypical hyperplasia), and 5 had progressive disease (3 endometrial cancer; 2 complex atypical hyperplasia). After stratification for histology, the response rate was 90.6% for complex atypical hyperplasia and 66.7% for grade 1 endometrioid endometrial cancer. Notably, 4 patients (9.5%) experienced relapse after the initial response. Adverse events were mild, primarily irregular bleeding and cramping. Quality of life was not negatively affected. At 3 months, exogenous progesterone effect was present in 96.9% of responders (31 of 32) vs 25% of nonresponders (2 of 8) (P=.001). Nonresponders had higher baseline proliferation (Ki67) and lower dickkopf homolog 3 gene expression than responders (P=.023 and P=.030). Nonresponders had significantly different changes in secreted frizzled-related protein 1, frizzled class receptor 8, and retinaldehyde dehydrogenase 2 compared with responders. CONCLUSION: The levonorgestrel intrauterine device has a substantial activity in complex atypical hyperplasia and grade 1 endometrioid endometrial cancer, with a modest proportion demonstrating upfront progesterone resistance. Potential biomarkers were identified that may correlate with resistance to therapy; further exploration is warranted.

The DISINFECT Initiative: Decreasing the Incidence of Surgical INFECTions in Gynecologic Oncology.

BACKGROUND: Surgical site infections (SSIs) lead to increased patient morbidity and healthcare costs. Our objective was to decrease the SSI rate following gynecologic surgery. METHODS: Adult patients undergoing abdominal surgery for gynecologic malignancy or benign disease received the following: patient education; preoperative antibacterial soap; appropriate antibiotic prophylaxis; change of gloves and use of clean instruments at surgical closure; surgical dressing for 48 h; and a post-discharge phone call. The baseline SSI rate was determined retrospectively (1 April 2014-30 June 2014), while the post-intervention SSI rate was determined prospectively (16 February 2015-15 October 2015). The main outcome was the overall SSI rate with secondary outcomes, including the rate of superficial, deep, incisional and organ space infection, as well as the cost effectiveness of the bundle. RESULTS: A total of 232 baseline and 555 post-intervention patients were included in the study. No differences were observed between the baseline and post-intervention groups with regard to median body mass index (BMI), surgical approach, receipt of preoperative chemotherapy and/or radiation therapy, and cases including bowel surgery. Overall, the SSI rate decreased significantly from baseline [12.5 %] to post-intervention [7.4 %] (odds ratio [OR] 0.56, 90 % confidence interval [CI] 0.37-0.85; p = 0.01). A 40 % decrease was noted in the rate of superficial and deep infections (9.5 vs. 5.9 %; OR 0.60, 90 % CI 0.38-0.97; p = 0.04) and SSIs after open surgery (21.4 vs. 13.2 %; OR 0.56, 90 % CI 0.34-0.92; p = 0.03). The estimated cost of the intervention was $19.26/case and the net total amount saved during the post-intervention period was $65,625 month. CONCLUSIONS: This bundled intervention led to a significant decrease in the overall SSI rate and was cost effective. The largest decreases in SSIs were in incisional infections and following open surgery.

Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer.

OBJECTIVES: Small cell cervical cancer is a rare malignancy with limited treatment options for recurrent disease. We sought to determine if tumor specimens of small cell cervical cancer harbor common somatic mutations and if any of these are actionable. METHODS: Using a registry of patients with neuroendocrine cervical cancer, we identified 44 patients with pure or mixed small cell cervical cancer who had undergone mutational analysis. Mutations had been detected using next generation sequencing of mutational hotspots in 50 cancer-related genes. RESULTS: Thirty-five mutations were identified in 24 patients (55%). Fifteen of these 24 patients (63%) had 1 mutation, 7 patients (29%) had 2 mutations, and 2 patients (8%) had 3 mutations. In all 44 patients, the most commonly seen mutations were mutations in PIK3CA (8 patients; 18%), KRAS (6 patients; 14%), and TP53 (5 patients; 11%). No other mutation was found in >7% of specimens. Of the 24 patients who had a mutation, 21 (88%) had at least 1 alteration for which there currently exists a class of biological agents targeting that mutation. In the entire cohort of 44 patients, 48% had at least 1 actionable mutation. CONCLUSION: Although no single mutation was found in the majority of patients with small cell cervical cancer, almost half had at least 1 actionable mutation. As treatment options for patients with recurrent small cell cervical cancer are currently very limited, molecular testing for targetable mutations, which may suggest potential therapeutic strategies, may be useful for clinicians and patients.

Improvement in quality of life after robotic surgery results in patient satisfaction.

BACKGROUND: There are well-described benefits to minimally invasive surgery including decreased blood loss, shorter hospital-stay, and faster recovery. The role of robotic surgery in gynecologic oncology has become increasingly prominent; however limited data are available on quality of life (QOL) after robotic surgery. METHODS: In this prospective, IRB-approved study, women scheduled for robotic surgery for a gynecologic indication between May 2008 and February 2012 completed validated QOL measures at baseline, 6 weeks (6wk), and 4 months postoperative (4mo). Functional status (SF-12), symptom severity and interference (MDASI), sexual function (FSFI), and satisfaction with decision (SWD) were assessed at relevant time points. Differences between groups were evaluated using the Mann-Whitney test. RESULTS: Among 408 women who underwent robotic surgery 278 (68%) completed the QOL measures. Median age was 55.6 years (range 25.7-85.1). Median BMI was 31.3kg/m(2). The majority of patients were white (75%). The most common indication for surgery was endometrial cancer/hyperplasia (59.7%). While physical functioning declined from baseline to 6wk (51.4 to 41.6, p<0.001), it improved by 4mo (53.5). Mental functioning improved over time (baseline 48.6, 6wk 52.8, and 4mo 55.6, p<0.001). Symptom severity decreased over time (p<0.001) as did symptom interference (p<0.001). Sexual function improved significantly from baseline (8.6) to 4mo (20.2, p<0.001). Patients were satisfied with their decision making (SWD=30). CONCLUSION: In this prospective study, general health, symptom burden and sexual function returned to or improved beyond baseline levels within 6 weeks of surgery. Overall, women were satisfied with their decision to undergo robotic surgery.

Lymphovascular Space Invasion Portends Poor Prognosis in Low-Risk Endometrial Cancer.

OBJECTIVE: The prognostic significance of lymphovascular space invasion (LVSI) in patients with early-stage endometrial cancer is not established. We sought to determine if LVSI status in patients with early-stage low-risk endometrial cancer correlates with recurrence and survival. METHODS: The records of all women who underwent hysterectomy for primary treatment of endometrial cancer from January 2006 through January 2011 at 1 academic institution were reviewed. Patients with grade 1 or 2 endometrioid histology, myometrial invasion less than 50%, and disease confined to the uterus (clinical International Federation of Obstetrics and Gynecology stage IA) were analyzed. Fisher exact test and the Wilcoxon rank-sum test were applied to compare patients with and without LVSI. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: Two hundred forty patients met the inclusion criteria. Forty (16.7%) had LVSI. Ninety-one patients (37.9%) underwent lymphadenectomy. Median tumor size was 30 mm in patients with and 26 mm in patients without LVSI (P = 0.150). Thirty patients (12.5%) received adjuvant therapy. Site of recurrence did not differ between patients with and without LVSI. Patients with LVSI were more likely to have myometrial invasion (P < 0.001), postoperative pathologic grade 2 disease (P < 0.001), to undergo lymphadenectomy (P = 0.049) and receive adjuvant therapy (P < 0.001). The 5-year cumulative incidence of recurrence was 3.8% in the no-LVSI group and 14.2% in the LVSI group (P = 0.053). The presence of LVSI was significantly associated with worse RFS (P = 0.002) and OS (P = 0.013). CONCLUSIONS: Patients with low-risk endometrial cancer and LVSI have worse RFS and OS despite being more likely to undergo lymphadenectomy and adjuvant therapy.

Chemopreventive effects of metformin on obesity-associated endometrial proliferation.

OBJECTIVE: Obesity is a significant contributing factor to endometrial cancer risk. We previously demonstrated that estrogen-induced endometrial proliferation is enhanced in the context of hyperinsulinemia and insulin resistance. In this study, we investigate whether pharmacologic agents that modulate insulin sensitivity or normalize insulin levels will diminish the proliferative response to estrogen. STUDY DESIGN: Zucker fa/fa obese rats and lean controls were used as models of hyperinsulinemia and insulin resistance. Insulin levels were depleted in ovariectomized rats following treatment with streptozotocin, or modulated by metformin treatment. The number of BrdU-incorporated cells, estrogen-dependent proliferative and antiproliferative gene expression, and activation of mTOR and ERK1/2 MAPK signaling were studied. A rat normal endometrial cell line RENE1 was used to evaluate the direct effects of metformin on endometrial cell proliferation and gene expression in vitro. RESULTS: Streptozotocin lowered circulating insulin levels in obese rats and decreased the number of BrdU-labeled endometrial cells even in the presence of exogenous estrogen. Treatment with the insulin-sensitizing drug metformin attenuated estrogen-dependent proliferative expression of c-myc and c-fos in the obese rat endometrium compared to untreated controls and was accompanied by inhibition of phosphorylation of the insulin and IGF1 receptors (IRß/IGF1R) and ERK1/2. In vitro studies indicated metformin inhibited RENE1 proliferation in a dose-dependent manner. CONCLUSION: These findings suggest that drugs that modulate insulin sensitivity, such as metformin, hinder estrogen-mediated endometrial proliferation. Therefore, these drugs may be clinically useful for the prevention of endometrial cancer in obese women.

Uterine lavage identifies cancer mutations and increased TP53 somatic mutation burden in individuals with ovarian cancer.

Current screening methods for ovarian cancer (OC) have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with TP53 ultra-deep sequencing for the detection of disseminated OC cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood. Uterine lavage was collected preoperatively in 34 patients undergoing surgery for suspected ovarian malignancy including 14 patients with benign disease and 20 patients with OC (6 non-serous and 14 high grade serous-like (serous)). Ultra-deep duplex sequencing (~3000x) with a panel of common OC genes identified the tumor mutation in 33% of non-serous (all early stage) and in 79% of serous cancers (including four early stage). In addition, all lavages carried multiple somatic mutations (average of 25 mutations per lavage), more than half of which corresponded to common cancer driver mutations. Driver mutations in KRAS, PIK3CA, PTEN, PPP2R1A and ARID1A presented as larger clones than non-driver mutations and with similar frequency in lavages from patients with and without OC, indicating prevalent somatic evolution in all patients. Driver TP53 mutations, however, presented as significantly larger clones and with higher frequency in lavages from individuals with OC, suggesting that TP53-specific clonal expansions are linked to ovarian cancer development. Our results demonstrate that lavages capture cancer cells, even from early-stage cancers, as well as other clonal expansions and support further exploration of TP53 mutation burden as a potential OC risk factor.

Prospective evaluation of insulin resistance among endometrial cancer patients.

OBJECTIVE: Obesity and estrogen are strong risk factors for endometrial cancer (EC). Whereas diabetes also increases the risk, little is known about related insulin resistance (IR). The purpose of this study was to determine the prevalence of IR in newly diagnosed EC patients. STUDY DESIGN: EC patients from a large, metropolitan county were prospectively enrolled from 2005 to 2008. Fasting serum was analyzed for glucose and insulin. IR was defined as a history of diabetes or a quantitative insulin sensitivity check index (QUICKI) (1/[log fasting insulin + log fasting glucose]) value of less than 0.357. RESULTS: Among 99 patients, diabetes was present in 30, and an abnormal QUICKI was found in 36 additional patients. Increased risk of IR was significantly associated with higher body mass index (P < .001), lower socioeconomic status (P = .007), and nulliparity (P = .029). CONCLUSION: IR was highly prevalent in endometrial cancer patients, including nonobese women. Better characterization of metabolic risks in addition to obesity may provide avenues for targeted cancer prevention in the future.

Endometrial Cancer Associated Symptoms: A Case-Control Study.

BACKGROUND: The majority of women with endometrial cancer (EC) present at an early stage with an associated 5-year survival rate of >90%. High rates of early detection are attributed to warning symptoms; however, the prevalence of such symptoms has not been well defined. METHODS: A case-control study was conducted assessing the prevalence of symptoms in EC patients at a large cancer center compared with healthy controls. Controls included patients seen for an annual gynecologic care visit (AV) or for a gynecological problem-based visit (PV). A self-administered questionnaire was given to all participants addressing EC-associated symptoms, at the time of initial clinic visit. Odds ratios (ORs) were used to compare prevalence of symptoms between EC cases and controls. Logistic regression was used to determine the impact of menopausal status and obesity on symptom prevalence. RESULTS: The cases (n = 75) were significantly older than the AV (n = 203) and PV (n = 151) controls (59.7 vs. 49.8 vs. 51.0 years, p < 0.01), had a higher body mass index (35.5 vs. 29.4 vs. 30.9 kg/m2, p < 0.01), and were more likely to be postmenopausal (76% vs. 53.7% vs. 52.0%, p < 0.01). The cases were more likely to report postmenopausal bleeding (OR = 32.99 and 5.83, p < 0.01) and abnormal vaginal discharge (OR = 8.8 and 3.3, p < 0.01) compared with the AV and PV groups. Overall, 55.4% of cases reported abnormal vaginal discharge. CONCLUSIONS: Symptoms of both postmenopausal bleeding and abnormal vaginal discharge were significantly higher in EC compared with controls. The presence of such symptoms should raise concern for malignant disease and prompt immediate gynecological evaluation.

What Is the Real Rate of Surgical Site Infection?

PURPOSE: Surgical site infections (SSIs) are associated with patient morbidity and increased health care costs. Although several national organizations including the University HealthSystem Consortium (UHC), the National Surgical Quality Improvement Program (NSQIP), and the National Healthcare Safety Network (NHSN) monitor SSI, there is no standard reporting methodology. METHODS: We queried the UHC, NSQIP, and NHSN databases from July 2012 to June 2014 for SSI after gynecologic surgery at our institution. Each organization uses different definitions and inclusion and exclusion criteria for SSI. The rate of SSI was also obtained from chart review from April 1 to June 30, 2014. SSI was classified as superficial, deep, or organ space infection. The rates reported by the agencies were compared with the rates obtained by chart review using Fisher's exact test. RESULTS: Overall SSI rates for the databases were as follows: UHC, 1.5%; NSQIP, 8.8%; and NHSN, 2.8% (P < .001). The individual databases had wide variation in the rate of deep infection (UHC, 0.7%; NSQIP, 4.7%; NHSN, 1.3%; P < .001) and organ space infection (UHC, 0.4%; NSQIP, 4.4%; NHSN, 1.4%; P < .001). In agreement with the variation in reporting methodology, only 19 cases (24.4%) were included in more than one database and only one case was included in all three databases (1.3%). CONCLUSION: There is discordance among national reporting agencies tracking SSI. Adopting standardized metrics across agencies could improve consistency and accuracy in assessing SSI rates.

A clinical perspective on genetic counseling and testing during end of life care for women with recurrent progressive ovarian cancer: opportunities and challenges.

10-15% of invasive epithelial ovarian cancer is attributable to hereditary breast and ovarian cancer. The identification of BRCA1/BRCA2 mutations in women with ovarian cancer allows for accurate predictive genetic testing of their at-risk relatives, who can then avail themselves of early detection and risk reduction strategies. In the case of women with recurrent progressive ovarian cancer, the window of opportunity for genetic testing can be particularly limited. Here we describe our perspective on providing genetic counseling during these patients' end of life care, incorporating two illustrative examples from our clinical practice. While these situations pose unique challenges, they also present a significant opportunity to benefit the patient and her family. Further attention and research should be directed towards provision of genetic counseling and testing during end of life care.

Risk of thromboembolic disease in patients undergoing laparoscopic gynecologic surgery.

OBJECTIVE: To estimate the incidence of venous thromboembolism among patients undergoing gynecologic laparoscopy and characterize the risk of venous thromboembolism among patients with gynecologic malignancy. METHODS: Data were collected for patients who underwent laparoscopic gynecologic surgery from January 2000 to January 2009. Incidence of deep vein thrombosis (DVT) or pulmonary embolism diagnosed within 6 weeks of surgery was estimated. Fisher's exact test was used to estimate the association between the presence of perioperative venous thromboembolism and categorical variables. RESULTS: Six (of 849) patients developed symptomatic venous thromboembolism (0.7%, 95% confidence interval: 0.024-1.44%). The median time to diagnosis of venous thromboembolism was postoperative day 15.5 (range, 1-41 days), median body mass index was 25.4 kg/m (range, 18.4-50 kg/m), median operative time was 176 minutes (range, 53-358 minutes), and median estimated blood loss was 125 mL (range, 10-250 mL). Five of 430 (1.2%) patients with a history of gynecologic malignancy developed postoperative thromboembolic events. Venous thromboembolism was diagnosed in three of 662 (0.5%) patients undergoing intermediate complexity procedures and three of 106 (2.8%) patients undergoing high-complexity procedures. Three patients with venous thromboembolism (50%) had a history of at least one previous modality of cancer treatment before laparoscopy. One patient (17%) had DVT only, four (67%) had pulmonary emboli without an identified DVT, and one (17%) had both. There were no associated mortalities. CONCLUSION: The incidence of thromboembolism in patients undergoing low- and intermediate-complexity, minimally invasive surgery was low, even among patients with a gynecologic malignancy. Patients undergoing high-complexity, minimally invasive procedures may benefit from postoperative anticoagulation. LEVEL OF EVIDENCE: II.

Relaxin signaling in uterine fibroids.

Uterine fibroid is the most common tumor of female reproductive organs. The role of relaxin signaling in leiomyoma development was analyzed. We used 23 matched pairs of leiomyoma and normal myometrium samples to compare the expression of relaxin family peptide receptors RXFP1 and RXFP2, caveolin 1, desmin, and steroid receptors and their cofactors, NCOR1 and NCOR2. The expression of RXFP1, evaluated by quantitative reverse transcription-PCR, was downregulated in fibroid tissues. Relaxin or insulin-like peptide 3 treatment suppressed transforming growth factor beta-induced phosphorylation of SMAD2 in rat leiomyoma ELT-3 cells in vitro, suggesting a possible involvement of relaxins in the etiology of leiomyoma.