Citations

Produced by senescent cells, the senescence-associated secretory phenotype (SASP) is a potential driver of age-related dysfunction. We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20–90 years (retrospective cross-sectional) was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60–90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis (prospective longitudinal) or ovarian cancer (prospective case-control) were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes. We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), TNF receptor superfamily member 6 (FAS), osteopontin (OPN), TNF receptor 1 (TNFR1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.

e18097 Background: AB160 is a 160 nm nano-immunoconjugate consisting of nab-paclitaxel (NP) nanoparticles non-covalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of vascular-endothelial growth factor (VEGF). Both taxanes (GOG-0129C, GOG-0126R, GOG-0127V) and BEV (GOG-0229E, AURELIA, GOG-0227C) have demonstrated clinical activity in previously treated metastatic endometrial cancer (EC), ovarian cancer (OC), and cervical cancer (CC), respectively. Methods: A 3+3 phase I trial was conducted in patients with EC, platinum-resistant OC and CC who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose level (DL1) was NP at 125 mg/m2 with BEV at 50 mg/m2. There were 2 higher dose levels: DL2 (NP at 150 mg/m2 with BEV at 60 mg/m2) and DL3 (NP at 175 mg/m2 with BEV at 70 mg/m2). Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT < 25,000, serum creatinine ≥2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Disease evaluations were conducted after every 2 treatment cycles using RECIST criteria. Patients were treated until disease progression or intolerability. Samples were collected for pharmacokinetic (PK) studies. Results: Nine women 41 – 74 years of age (median 57) have enrolled (5 with EC and 4 with OC); data are available for the first 8. No DLTs have been observed among the 3 women enrolled on DL1, 3 women on DL2, and 2 women on DL3. All 3 patients on DL3 continue on treatment. The other 6 patients have discontinued due to adverse reactions (3), progression (2), and patient choice (1). The median number of cycles administered is 6 (4-14). The most common severe (G3/4) toxicities include neutropenia (37.5%) and leukopenia (25%). There have been 5 partial responses (62.5%): 1 on DL1 and 2 each on DL2 and DL3. PK evaluation is pending. Conclusions: AB160 therapy is safe and demonstrates promising clinical activity in patients with previously treated metastatic gynecologic malignancies. Further clinical testing is being pursued in this patient population. Clinical trial information: NCT02020707.

A detailed transabdominal and transvaginal ultrasound examination, performed by an expert examiner, could render a similar diagnostic performance to computed tomography for assessing pelvic/abdominal tumor spread disease in women with epithelial ovarian cancer (EOC). This study aimed to describe and assess the feasibility of lung and intercostal upper abdomen ultrasonography as pretreatment imaging of EOC metastases of supradiaphragmatic and subdiaphragmatic areas. A preoperative ultrasound examination of consecutive patients suspected of having EOC was prospectively performed using transvaginal, transabdominal, and intercostal lung and upper abdomen ultrasonography. A surgical-pathological examination was the reference standard to ultrasonography. Among 77 patients with histologically proven EOC, supradiaphragmatic disease was detected in 13 cases: pleural effusions on the right (n = 12) and left (n = 8) sides, nodular lesions on diaphragmatic pleura (n = 9), focal lesion in lung parenchyma (n = 1), and enlarged cardiophrenic lymph nodes (n = 1). Performance (described with area under the curve) of combined transabdominal and intercostal upper abdomen ultrasonography for subdiaphragmatic areas (n = 77) included the right and left diaphragm peritoneum (0.754 and 0.575 respectively), spleen hilum (0.924), hepatic hilum (0.701), and liver and spleen parenchyma (0.993 and 1.0 respectively). It was not possible to evaluate the performance of lung ultrasonography for supradiaphragmatic disease because only some patients had this region surgically explored. Preoperative lung and intercostal upper abdomen ultrasonography performed in patients with EOC can add valuable information for supradiaphragmatic and subdiaphragmatic regions. A reliable reference standard to test method performance is an area of future research. A multidisciplinary approach to ovarian cancer utilizing lung ultrasonography may assist in clinical decision-making.

Abstract Senescent cells drive age-related tissue dysfunction through their potent secretome, termed the senescence associated secretory phenotype (SASP). Circulating concentrations of SASP factors may reflect biological age and serve as clinically useful biomarkers of surgical risk and ultimately, surrogate endpoints in clinical trials. However, they remain largely uncharacterized. We tested associations between circulating concentrations of SASP proteins and biological age, as determined by the accumulation of age-related health deficits, and/or postoperative outcomes in a sample of residents in Olmstead County, MN, age 60-90 years (n = 115) and cohorts of older adults undergoing surgery for severe aortic stenosis (prospective; n = 97) or ovarian cancer (case-control; n = 36). Circulating concentrations of SASP factors were associated with biological age and adverse postoperative outcomes, including risk of any adverse event or rehospitalization within the year following surgery (aortic stenosis group) or admission to an intensive care unit within 30 days of hospital discharge (ovarian cancer group). Gradient boosting machine modeling revealed a panel of SASP factors that predicted adverse outcomes across both surgical groups better than biological age or chronological age and sex. This suggests that the circulating SASP is a robust indicator of age-related health status and may help guide clinical decision making. Furthermore, circulating SASP factors may be harnessed as a readily quantifiable biomarkers in senescence-targeting interventional human studies.

INTRODUCTION: Obesity is associated with endometrial cancer (EC); however, most patients are unaware of this association and the long-term consequences of their elevated body mass index (BMI). Our objectives were to increase both patient awareness of this association and referral rates to our weight loss clinic using quality improvement (QI) methodology. METHODS: A multidisciplinary team used QI methods to create a multi-pronged toolkit to improve obesity education in patients < 80 years old with a BMI ≥30 mg/kg2 and diagnosis of grade 1-2, stage I EC. Gynecologic oncology and bariatric surgery providers, endocrinologists, nutritionists, and psychologists collaboratively implemented the toolkit comprised of provider communication workshops, patient education resources, and dictation templates. A historic cohort from (July through December 2015) was compared to a post-intervention cohort (July through December 2017). Clinical characteristics, documented conversations, and referrals to the weight loss clinic were abstracted. Data for the two cohorts were compared using Chi-squared test, Fisher exact test, and Student t-test. RESULTS: The historic cohort had 54 patients and the post-intervention cohort had 53 patients. Clinical characteristics were balanced between groups. Conversations about obesity increased from 11.1% (6/54) to 79.2% (42/53) after toolkit implementation (P<.001). Referral rates to the weight loss clinic also increased from 3.7% (2/54) to 25.9% (14/53) (P<.005). No clinical characteristics, including age, BMI, or pre-operative diagnosis, were associated with documented conversations or referrals (P=1.0). CONCLUSION: A multidisciplinary quality improvement project can be used to increase discussion about obesity and referral to a weight loss clinic in patients with low-risk EC.

INTRODUCTION: To compare two published risk stratification criteria (Milwaukee Model vs. Mayo Criteria) to predict lymphatic dissemination (LD) in endometrioid endometrial cancer (EC). METHODS: Patients who underwent surgery for EC between 1/1/2004-9/30/2013 and had endometrioid histology without stage IV disease were included and classified as either low-risk or at-risk for LD using two independent risk stratification systems. LD was defined as positive nodes at time of surgery or lymph node recurrence within 2 years of surgery after negative lymph node assessment (LNA) or when LNA was not performed. False positive (FP) and false negative (FN) rates for each risk model were calculated. RESULTS: Among 1103 patients, 81 (7.3%) had LD (72 positive LN and 9 LN recurrences). Most patients (90.2%) had stage I disease. Integration of the Milwaukee Model was associated with a low at-risk rate for LD (38.1%) but a relatively high FN rate (13.6%, 95% CI 7.0-23.0). Conversely, the traditional Mayo Criteria using a tumor diameter (TD) cutoff of ≤2 cm (vs >2 cm) had a higher at-risk rate for LD (69.5%) but a FN rate of 0.0% (95% CI, 0-4.5). Modifying Mayo Criteria using a TD cutoff of ≤3 cm (vs >3 cm) identified fewer women at-risk than using ≤2 cm cutoff (56.8% vs. 69.5%), but had a higher FN rate of 3.7% (95% CI, 0.8-10.4). CONCLUSIONS: The Milwaukee Model had the lowest at-risk rate of LD but an unacceptable FN rate. Modifying the Mayo Criteria by increasing the TD cutoff from the traditional ≤2 cm to ≤3 cm would spare an estimated 12.7% of patients LNA, but the accompanying FN rate is unacceptably high. The traditional Mayo Criteria for low-risk EC remains the most accurate in determining which patients LNA can be omitted.

131 Background: Gynecologic oncologists report a lack of knowledge and comfort with palliative care topics including opioid management, despite their clinical importance. The objective of this study is to evaluate the impact of an online opioid educational module among gynecologic oncologists. Methods: A 25-minute video module was developed to provide an overview and example cases for opioid initiation, titration, and conversion. Fellows and early career gynecologic oncologists were invited to participate in a 24-question online survey addressing demographics, palliative care education in training, and preparedness and opioid-related knowledge. After viewing the module, participants completed a post-intervention survey, which was comprised of the same six knowledge-based questions and an assessment of the module. Responses were anonymous. A 3 month follow up survey will be sent to assess knowledge retention. Results: A total of 38 participants completed the initial and post-module survey, including 14 residents, 12 fellows, and 12 candidate members. Nineteen (50%) respondents had been previously taught to calculate a 24-hour oral morphine equivalent (OME) and to titrate opioids, but only 7 (18%) had received formal teaching on opioid rotation. Twenty four (63%) participants rated the quality of teaching overall in their fellowship as good, very good, or excellent, but only 15 (39%) rated palliative care education as at least good. Eleven (30%) respondents had a palliative care rotation in fellowship. Knowledge scores improved from pre-module to post-module, 49.5% correct answers compared to 74.6% (p<0.001). Thirty five (92%) of respondents were satisfied or very satisfied with this module and are interested in additional palliative care modules. Conclusions: A single online palliative care education module was associated with significantly improved participant knowledge on opioid management. Over 90% of respondents were satisfied with the module demonstrating an opportunity for improvement in palliative care education in gynecologic oncology via online education.

ObjectiveTo evaluate the effect of body mass index on the surgical outcomes in ovarian cancer patients. In addition, we performed a systematic review to compare our outcomes with the current literature.DesignRetrospective cohort study and a systematic review of the literature.SettingGynaecology department at the Royal Cornwall Hospital Trust.PopulationSurgically managed stage I‐IV ovarian cancer patients between September 2006 and September 2014.MethodsPrimary and secondary outcome measures were evaluated across BMI categories; BMI <25 kg/m², BMI 25–29.9 kg/m², BMI ≥30 kg/m² and BMI ≥40 kg/m². A systematic review was performed according to Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) guidelines.Main outcome measuresThe primary outcome measure was surgical complications. Secondary outcome measures were other intra‐ and postoperative outcomes.ResultsTwo hundred twenty‐eight women were included in the study, of which 84 had a BMI <25 kg/m², 84 women had a BMI 25–29.9 kg/m², and 60 women were obese (BMI ≥30 kg/m²), 13 of whom were morbidly obese. Morbid obesity was associated with increased rates of wound complications. However, BMI did not show an association with other outcomes. In the review, an increasing BMI was associated with increased rates of wound complications and prolonged hospital stay, but did not impact other surgical outcomes.ConclusionObesity is associated with increased rates of wound complications and a prolonged hospital stay, but does not appear to affect other operative outcomes including cytoreduction status and 30‐day mortality. Therefore, operative management and postoperative care require a multifactorial approach to minimise adverse outcomes.Tweetable abstractObesity is associated with more wound complications and prolonged hospital stay in ovarian cancer surgery.