Citations

696 Background: A number of treatments for metastatic renal cell carcinoma (RCC) have been FDA approved since December, 2005. Trials evaluating these agents excluded non-clear cell histologies and therefore the efficacy of these treatments remains unclear in patients (pts) with metastatic non-clear cell RCC (mncRCC). Methods: This is a single arm Phase II study designed to determine the efficacy of pazopanib in mncRCC. Treatment was pazopanib 800 mg by mouth daily until progression or intolerability of treatment. Dose reductions were allowed for toxicity with dose level -1 being 600 mg daily and dose level -2, 400 mg daily. Cycles were every 28 days. Main eligibility criteria included: (1) age ³ 18 years old; (2) histologic confirmation of ncRCC; (3) ECOG Performance Status (PS) 0, 1, or 2; (4) up to one prior treatment for mncRCC (5) measurable or non-measurable metastatic disease per RECIST criteria. The primary endpoint was overall survival rate at 12 months. Secondary endpoints were best tumor response rates after two cycles, PFS, OS and toxicity. Results: 38 pts were enrolled between May 16, 2013 and February 1, 2018. 35 pts were evaluable for primary endpoint. Median age 63 years old and 22/35 (62.9%) were male. Most common histology was papillary RCC, 14/35 (40%), and most common number of metastatic sites was 1. 29/35 (82.9%) had prior nephrectomy and 30/35 (85.7%) had no prior systemic therapy. Median number of cycles was 5. 12-month OS was 65.7% (90% CI, 50.5-78.9%). Best response in first 2 cycles: PR 11%, SD 60%, PD 9%, not evaluated 20%. Median PFS was 7.5 months (90% CI, 5.0-11.0); median OS 18.9 months (90% CI, 13.0-NE). Grade 3 / 4 AEs seen in 25 pts with hypertension, transaminitis and abdominal pain being most common (seen in >10%). Conclusions: There are limited data about the efficacy of available therapies for mncRCC. This study shows that pazopanib has similar efficacy compared to historical data in clinical trials using other TKIs in mncRCC. The safety profile of pazopanib in pts with mncRCC was found to be similar to that found in prior clinical trials studying pazopanib. Our findings warrant further investigation into the utility of pazopanib in metastatic ncRCC. Clinical trial information: NCT01767636.

176 Background: Multiple tumour tissue studies have demonstrated the prognostic utility of CNVs in mCRPC. However, accurate assessment of CNVs in plasma cfDNA remains challenging, and prognostic significance has not been well characterized. Using a large customized panel, we correlated plasma CNVs with clinical outcomes in a contemporary cohort of mCRPC patients. Methods: Deep targeted sequencing was performed using a 180-gene cfDNA panel (Predicine) in 56 patients commencing AR pathway inhibitors (enzalutamide or abiraterone; n = 34) or taxane chemotherapy (n = 22) at two Australian institutions. Kaplan-Meier estimates and Cox proportional-hazards models were used to correlate CNVs with progression-free survival (PFS) and overall survival (OS). Significant results were validated in an independent cohort (Mayo Clinic, n = 144). Results: Median follow-up was 19.4 months (mo; IQR 11.3-31.9). The most common CNVs in the Australian cohort are shown (Table). OS was significantly decreased in patients with PI3KCA gain (median 21.7 mo vs 6.6 mo, p < 0.0001), PTEN loss (24.8 mo vs 11.7 mo, p = 0.0019) and AR gain (21.7 mo vs 12.0 mo, p = 0.0083). Furthermore, all three alterations independently predicted for poor survival in multivariable analyses (MVA; Table). Findings in the independent cohort showed similar OS results in MVA: PIK3CA gain (HR 2.0, p = 0.07), PTEN loss (HR 1.7, p = 0.08) and AR gain (HR 1.7, p = 0.03). Conclusions: Sequencing of plasma cfDNA revealed that PTEN loss, and PIK3CA and AR gain are associated with inferior clinical outcomes in patients commencing contemporary systemic treatment. These data support therapeutic strategies co-targeting the PI3K and AR pathways in mCRPC.[Table: see text]

160 Background: mCRPC is a heterogeneous disease state with variable survival and molecular markers that define survival continue to be determined. We applied a 120 gene panel based targeted next-gen sequencing (NGS) approach to probe plasma ctDNA based outcomes for survival. Methods: mCRPC chemo-naive patients (pts) were enrolled in a prospective study and plasma cell free DNA (cfDNA) extracted. ctDNA fractions estimated based on somatic variants. NGS of plasma cfDNA was performed using HiSeq X Ten on a panel of 120 genes (PredicineLDT). Clinical and molecular prognostic factors were determined for overall survival (OS). Cox proportional hazard regression was used to estimate hazard ratios (HR) at the univariate level and only significant associations included in multivariate analysis (significance at P<0.05). Results: 96 mCRPC pts were enrolled. 17/96 pts failed NGS QC. Median cfDNA, ctDNA yields for 79/96 pts are provided in Table. Median follow up for study cohort was 92.5 months (mon) (Range:62.3-109.6); median survival time was 25.9 mon (95% CI:19.9, 31.4) and 72/79 pts had died. TMPRSS2-ERG fusion was detected in 18/79 pts. Significant alterations associated with OS are listed in Table. 49/59 pts underwent subsequent docetaxel chemo. In chemo treated pts significant copy number alterations predictive of survival included AR amplification (p=0.01, HR=2.0, 95% CI[1.2, 3.5], RB1 loss (p=3.20E-06, HR=5.0, 95% CI[2.4, 10.6], PTEN(p=0.009, HR=2.6, 95% CI[1.2, 5.4]), CDH1(p=0.001, HR=4.3, 95% CI[1.6, 11.4]). Conclusions: ctDNA yield in mCRPC state was the most significant prognostic factor for survival, Several specific plasma genomic perturbations were observed topredict docetaxel efficacy and need further evaluation.[Table: see text]

Background: HIT has the potential to improve the health of individuals and the performance of providers, yielding improved quality, cost savings, and greater engagement by patients. Minorities face a variety of financial and nonfinancial barriers to obtaining appropriate and timely health care. Studying the behavior of minority patients will help understand the specific challenges to HIT adoption and engagement in patients and their caregivers. We undertook a patient-reported survey to explore these factors and understand any underlying disparities. Methods: A 21-question paper-based anonymous questionnaire addressing the responder's attitudes, understanding and needs of the electronic medical record (EMR) was used. This was administered to adult patients with lymphoid malignancies and their caregivers at two campuses of Mayo Clinic in Florida (San Pablo and inner-city; Riverside). Categorical and continuous variables between white and minority responders as well as minority responders from the two campuses were compared using the Chi-square test and U Mann Whitney with a significance level of 0.05. Results: The survey was completed by 1004 patients and caregivers. Average time taken to complete the survey was approximately 11 minutes. Of the responders, 716 (71%) were whites and 271 (27%) were minorities, with race-ethnicity not reported by 17 (2%). Among minorities, 30% (n=80) were seen at San Pablo and 64% (n=173) at the Riverside campus, with 6% at a multiple myeloma patient-caregiver symposium. Whites were older (median age 66 vs. 62 years, p&lt;0.001) and had higher education (undergraduate or higher 60% vs. 52%, p=0.023) as compared to minorities. Minority survey responders had lesser access to a computer (84% vs. 92%, p&lt;0.001) or a smartphone (85% vs. 89%, p=0.08). (Figure 1a) Exploring HIT awareness showed that only 51% of minorities were registered to use the EMR as compared to 72% whites (p&lt;0.001) and a lesser number of minorities even knew that they could access their medical records electronically (81% vs. 92%, p&lt;0.001). even among those registered to use the EMR, 13% minorities reported never using the EMR as compared to 4% whites (p&lt;0.001). Encouragingly, a higher willingness to learn about and use the EMR was noted among minorities who were more interested in knowing how to access the EMR (43% vs. 36%, p=0.04), would increase the use of EMR if someone explained how to use it (17% vs. 10%, p=0.002), and if someone explained about test results (14% vs. 6%, p&lt;0.001). (Figure 1b) Comparing minorities among the two campuses, those from the San Pablo campus were older (67.5 yrs. vs. 57 yrs., P&lt;0.001), had higher level of education (undergraduate or higher in 66% vs. 47%, p=0.005) and a higher number had access to a computer (94% vs. 78%, P=0.001) as compared to those from the inner-city Riverside. (Figure 2a) Minorities from the Riverside campus were less likely to be aware of the current HIT EMR (75% vs. 93%, p&lt;0.001), were significantly less likely to have registered for the patient EMR portal (38% vs. 76%, p&lt;0.001) and never used the EMR even if registered for it (22% vs. 7%, p=0.01) as against those from the San Pablo campus. Minorities at the Riverside campus had a higher interest in knowing how to access the EMR (47% vs. 33%, p=0.03). Linguistic barriers were more striking in the inner-city Riverside campus where a higher proportion of minority survey responders noted that it would help if the EMR was in their primary language (66% vs. 48%, p=0.006). (Figure 2b) Conclusions: Minorities continue to struggle with suboptimal utilization of healthcare system including that of HIT. There are barriers related to access, awareness, language and understanding of HIT that prevent the integration and participation of racial-ethnic minorities in the healthcare system to a full extent. It is important to qualify the minorities better, since there exist HIT utilization disparities even within the minorities from different areas representing socioeconomic and demographic differences. Efforts need to be made at several levels to help the minorities overcome educational, access and linguistic barriers so that they can benefit from advancements in the healthcare system. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Takeda: Consultancy. Manochakian:Novocure: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Guardant Health: Membership on an entity's Board of Directors or advisory committees. Chanan-Khan:AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding.

Abstract Context Glucagon-like peptide-1 (GLP-1) potently reduces food intake and augments glucose-stimulated insulin secretion. Recent animal data suggest that GLP-1 may also influence reproduction. As GLP-1 receptor agonists are currently widely used in clinical practice to treat obesity/type 2 diabetes, it is necessary to determine the effects of GLP-1 on the reproductive system in humans. Objective To investigate the effects of GLP-1 administration on the reproductive axis in humans. Design Single-blind, randomized, placebo-controlled crossover study. Setting Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy men (mean age 24.7 ± 0.1years, mean BMI 22.1 ± 0.4kg/m2). Intervention Eight-hour intravenous infusion of 0.8 pmol/kg/min GLP-1 or rate-matched vehicle infusion. Main Outcome Measures Number of luteinizing hormone (LH) pulses, LH, follicle-stimulating hormone (FSH), and testosterone levels. Results The number of LH pulses (number of LH pulses/500 min: vehicle 4.2 ± 0.4, GLP-1 4.5 ± 0.3, P = 0.46), LH area under the curve (AUC) (vehicle 1518 ± 88min.IU/L, GLP-1 1524 ± 101min.IU/L, P = 0.95), follicle-stimulating hormone AUC (vehicle 1210 ± 112 min IU/L, GLP-1 1216 ± 112 min IU/L, P = 0.86), and testosterone AUC (vehicle 10893 ± 615 min nmol/L, GLP-1 11088 ± 792 min nmol/L, P = 0.77) did not significantly differ during vehicle and GLP-1 administration. Glucagon-like peptide-1 significantly reduced food intake (vehicle 15.7 ± 1.3 kcal/kg, GLP-1 13.4 ± 1.3 kcal/kg, P = 0.01). Conclusions In contrast to the animal literature, our data demonstrate that acute GLP-1 administration does not affect reproductive hormone secretion in healthy men.

Abstract Purpose Preclinical and clinical data have shown promise in using antiangiogenic agents to treat malignant pleural mesothelioma (MPM). We conducted this phase II study to evaluate the efficacy and toxicity of single-agent pazopanib in patients with MPM. Materials and Methods Patients with MPM who had received 0–1 prior chemotherapy regimens were eligible to receive pazopanib at a dose of 800 mg daily. The primary endpoint was progression-free survival rate at 6 months (PFS6), with a preplanned interim analysis for futility. Secondary endpoints included overall survival (OS), PFS, adverse events assessment and clinical benefit (complete response, partial response [PR], and stable disease [SD]). Results Thirty-four evaluable patients were enrolled, with a median age of 73 years (49–84). The trial was closed early because of lack of efficacy at the preplanned interim analysis. Only 8 patients (28.6%; 95% confidence interval [CI], 13.2–48.7%) in the first 28 evaluable were progression-free at 6 months. PFS6 was 32.4% (95% CI, 17.4–50.5). There were 2 PR (5.9%) and 16 SD (47.1%). The overall median PFS and OS were 4.2 months (95% CI, 2.0–6.0) and 11.5 months (95% CI: 5.3–18.2), respectively. The median PFS and OS for the previously untreated patients was 5.4 months (95% CI, 2.7–8.5) and 16.6 months (95% CI, 6.6–30.6), respectively; and 2.0 months (95% CI, 1.3–4.2) and 5.0 months (95% CI: 3.0–11.9), respectively, for the previously treated patients. Grade 3 or higher adverse events were observed in 23 patients (67.6%). Conclusion Single-agent pazopanib was poorly tolerated in patients with MPM. The primary endpoint of PFS6 was not achieved in the current study. ClinicalTrials.gov identification number. NCT00459862. Implications for Practice Single-agent pazopanib did not meet its endpoint in this phase II trial in malignant mesothelioma. Pazopanib is well tolerated in mesothelioma patients with a manageable toxicity profile. There is a need to better identify signals of angiogenesis that can be targeted in mesothelioma. Encouraging findings in frontline treatment warrant further investigations in combination with chemotherapy or immunotherapy.

PurposeWe investigate the importance of high gradient‐amplitude and high slew‐rate on oscillating gradient spin echo (OGSE) diffusion imaging for human brain imaging and evaluate human brain imaging with OGSE on the MAGNUS head‐gradient insert (200 mT/m amplitude and 500 T/m/s slew rate).MethodsSimulations with cosine‐modulated and trapezoidal‐cosine OGSE at various gradient amplitudes and slew rates were performed. Six healthy subjects were imaged with the MAGNUS gradient at 3T with OGSE at frequencies up to 100 Hz and b = 450 s/mm2. Comparisons were made against standard pulsed gradient spin echo (PGSE) diffusion in vivo and in an isotropic diffusion phantom.ResultsSimulations show that to achieve high frequency and b‐value simultaneously for OGSE, high gradient amplitude, high slew rates, and high peripheral nerve stimulation limits are required. A strong linear trend for increased diffusivity (mean: 8–19%, radial: 9–27%, parallel: 8–15%) was observed in normal white matter with OGSE (20 Hz to 100 Hz) as compared to PGSE. Linear fitting to frequency provided excellent correlation, and using a short‐range disorder model provided radial long‐term diffusivities of D∞,MD = 911 ± 72 µm2/s, D∞,PD = 1519 ± 164 µm2/s, and D∞,RD = 640 ± 111 µm2/s and correlation lengths of lc,MD = 0.802 ± 0.156 µm, lc,PD = 0.837 ± 0.172 µm, and lc,RD = 0.780 ± 0.174 µm. Diffusivity changes with OGSE frequency were negligible in the phantom, as expected.ConclusionThe high gradient amplitude, high slew rate, and high peripheral nerve stimulation thresholds of the MAGNUS head‐gradient enables OGSE acquisition for in vivo human brain imaging.

Background The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm—the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. Results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.

Background The Global Burden of Disease Study (GBD) has historically produced estimates of causes of injury such as falls but not the resulting types of injuries that occur. The objective of this study was to estimate the global incidence, prevalence and years lived with disability (YLDs) due to facial fractures and to estimate the leading injurious causes of facial fracture. Methods We obtained results from GBD 2017. First, the study estimated the incidence from each injury cause (eg, falls), and then the proportion of each cause that would result in facial fracture being the most disabling injury. Incidence, prevalence and YLDs of facial fractures are then calculated across causes. Results Globally, in 2017, there were 7 538 663 (95% uncertainty interval 6 116 489 to 9 493 113) new cases, 1 819 732 (1 609 419 to 2 091 618) prevalent cases, and 117 402 (73 266 to 169 689) YLDs due to facial fractures. In terms of age-standardised incidence, prevalence and YLDs, the global rates were 98 (80 to 123) per 100 000, 23 (20 to 27) per 100 000, and 2 (1 to 2) per 100 000, respectively. Facial fractures were most concentrated in Central Europe. Falls were the predominant cause in most regions. Conclusions Facial fractures are predominantly caused by falls and occur worldwide. Healthcare systems and public health agencies should investigate methods of all injury prevention. It is important for healthcare systems in every part of the world to ensure access to treatment resources.

Study Design: Literature review. Objectives: Surgical site infection (SSI) following spine surgery leads to significant patient morbidity, mortality, and increased health care costs. The purpose of this article is to identify risk factors and strategies to prevent SSIs following spine surgery, with particular focus on avoiding infections in posterior cervical surgery. Methods: We performed a literature review and synthesis to identify methods that can be used to prevent the development of SSI following spine surgery. Specific pearls for preventing infection in posterior cervical spine surgery are also presented. Results: SSI prevention can be divided into patient and surgeon factors. Preoperative patient factors include smoking cessation, tight glycemic control, weight loss, and nutrition optimization. Surgeon factors include screening and treatment for pathologic microorganisms, skin preparation using chlorhexidine and alcohol, antimicrobial prophylaxis, hand hygiene, meticulous surgical technique, frequent irrigation, intrawound vancomycin powder, meticulous multilayered closure, and use of closed suction drains. Conclusion: Prevention of SSI following spine surgery is multifactorial and begins with careful patient selection, preoperative optimization, and meticulous attention to numerous surgical factors. With careful attention to various patient and surgeon factors, it is possible to significantly reduce SSI rates following spine surgery.