Citations

As rhinologists return to practice amid SARS‐CoV‐2, special considerations are warranted given the unique features of their subspecialty. Rhinologist manipulation of nasal tissue, proximity, and frequent aerosol‐generating procedures (AGPs) create high risk for infection transmission. There are 4 areas of special consideration to mitigate risk: (1) previsit planning for risk stratification/mitigation, (2) appropriate personal protective equipment, (3) preprocedural testing, and (4) environmental controls. During previsit planning, risk factors of the patient and procedures are considered. High‐risk AGPs are identified by duration, proximity, manipulation of high–viral load tissue, and use of powered instrumentation. Appropriate personal protective equipment includes selection of respiratory and eye protection. COVID‐19 testing can screen for asymptomatic carriers prior to high‐risk procedures; however, alternative testing methods are required in rhinologic patients not eligible for nasopharyngeal testing due to nasal obstruction or skull base defects. Last, AGPs in rhinologic practices require considerations of room air handling and environmental controls.

Abstract Introduction Sleepiness has been associated with functional and cognitive decline, and may present with excessive daytime sleepiness (EDS) and/or increased sleep duration. We investigated whether sleepiness and changes in sleep patterns are associated with FDG-PET levels in wake-promoting regions. Methods From the Mayo Clinic Study of Aging cohort, we identified 373 cognitively-unimpaired middle-aged and older adults (mean +/- s.d. 66.1 +/- 13.2 yo) who underwent FDG-PET. EDS was defined as ESS score >=10. Changes in sleep patterns (sleeping more, less, or no change) were assessed using question #16 of the Beck Depression Inventory-2. We used probabilistic maps to create regions of interest (ROIs): the locus coeruleus (LC), posterior lateral hypothalamus (PLH), and the basal forebrain divided in 1) medial septum/diagonal band of Broca (MS/DB) and 2) nucleus basalis of Meynert (nbM). FDG-PET levels were referenced to the pons (SUVR). In this cross-sectional analysis, we fit linear models to assess the association between EDS and changes in sleeping patterns with FDG SUVR in in each ROI, while controlling for age, sex, education, BMI, witnessed apneas, and cardiovascular risk factors. Results 10.5% had EDS, 15% reported sleeping more and 21% reported sleeping less than usual. 30.7% of participants with EDS reported sleeping more, 25.6% less, and 43.5% the same. EDS was associated with an elevation in FDG-PET SUVR in the MS/DB region (.035 [95% CI .008; .063], p=.012), while sleeping more was associated with a decrease in FDG-PET SUVR in the same region (-.027 [95%CI -.052; -.002], p=.036). Sleeping less was associated with an increase in FDG-PET SUVR in the PLH (.021 [95% CI .005; .03], p=.019). No associations were found in other ROIs. Conclusion Our results suggest that sleepiness and changes in sleep patterns in cognitively-unimpaired middle-aged and older adults were associated with measurable metabolic changes in areas of the brain involved in sleep and wakefulness. Further research should clarify whether these findings could represent different phenotypes of sleepiness with potential diagnostic and prognostic implications. Support NIA/NIH

e23544 Background: Rare diseases are defined as conditions that affect less than 200,000 people annually in the United States. Around 17000 cases of sarcoma will be diagnosed in 2020. Collaboration among institutions is needed to best understand rare diseases such as sarcoma. One measure of collaboration is publications with multiple institutions as authors. We sought to determine if collaboration in sarcoma has increased since 2011 and compared that to another rare disease, CNS tumors based on multi-institution-authored abstracts presented at ASCO. Methods: All sarcoma and CNS oral abstracts, clinical science symposia, poster presentations, poster discussions, and published-only ASCO Annual Meetings from 2011 to 2019 were reviewed. Collaboration was determined if the abstract authors were from more than one institution. Results: 2,134 abstracts were reviewed. Collaboration for sarcoma ranged from 0.603 to 0.720 and 0.582 to 0.755 for CNS. From 2011-2019 a positive linear trend in collaboration was found in CNS (P < 0.05), but not in sarcoma (P = NS). There was no significant trend in the incidence of collaboration in Sarcoma based on the type of presentation at ASCO. There was no difference in collaboration between bone or soft tissue sarcoma abstracts or median number of institutions collaborating between sarcoma and CNS. There were more international collaborations and absolute number of institutions in sarcoma vs CNS. Conclusions: Sarcoma collaboration has remained constant from 2011-2019 with greater number of institutions and more international collaborations as compared to CNS. CNS collaboration has increased from 2011-2019. Sarcoma collaboration at ASCO is robust and reflects the need for multi-institutional partnership.

11561 Background: Angiosarcoma has a particularly poor prognosis with 5-year overall survival rates of approximately 30-40%. Treatment of locally advanced and metastatic angiosarcoma is inadequate. Data strongly suggest concurrent, potent inhibition of VEGFR and Tie2 represents an attractive therapeutic strategy in angiosarcoma. Regorafenib displays potent VEGFR and Tie2 receptor inhibition and also possesses activity against additional potential targets in angiosarcoma including PDGFRs, RAF, KIT and FGFR, amongst others. Methods: A multicenter phase II study of regorafenib in patients with locally advanced or metastatic angiosarcoma was conducted through the Midwest Sarcoma Trials Partnership. Adequate performance status, organ function, measurable disease (RECIST 1.1) and 1-4 prior therapies were required. Regorafenib 160 mg PO daily was given in 28-day cycles (21 days on, 7 days off) until disease progression (PD) or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), assessed at 16 weeks. Secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), OS, and safety and tolerability. A Simon 2-stage design was used. Results: After final enrollment of the second stage, a total of 31 pts were enrolled at 6 sites, 23 are evaluable for response. Median age was 65 (range 30-91); 50% were female, 67.7% had metastatic disease. PFS at 4 months is 52.2% with a median PFS and OS of 3.55 and 11.4 months. 1 confirmed CR and 2 PR, 12 SD and 8 PD were observed. ORR and CBR are 14.29 and 65.2%, respectively. No uncommon grade 3-4 adverse events were observed. 6 pts were non-evaluable due to refusal of further therapy and 2 patients progressed prior to first evaluation. Conclusions: Regorafenib was well tolerated in this study of pretreated patients with angiosarcomas and met its primary endpoint with a median PFS > 45% at 4 months. Treatment was feasible and did not reveal any previously unreported toxicities. Efficacy outcomes were complicated by early withdrawals of patients. RECIST responses were encouraging and regorafenib has a clinically meaningful 4-month PFS. Clinical trial information: NCT02048722 .

Background: Recurrent pericarditis (RP) episodes and conventional treatments result in morbidity, but the impact on patient health-related quality of life (HRQoL) has not been quantified. The Phase 2 trial NCT03980522 of rilonacept (IL-1α/IL-1β inhibitor) evaluated HRQoL. Methods: Patients with active RP who were symptomatic at Baseline (A-RP, n=16) and RP patients who were not currently experiencing a recurrence but were corticosteroid-dependent at Baseline (CSD-RP, n=9) were enrolled. All received rilonacept weekly for 6 weeks to end of base treatment period (TP) plus an optional 18-week extension treatment period (EP). Corticosteroid tapering occurred in the EP. Physical and mental HRQoL (PROMIS Global Health v1.2 Physical and Mental Component Scores [PCS/MCS]) were assessed at baseline and follow-up. Results: Figure 1 presents the PROMIS PCS/MCS and pain scale scores (both patient-reported) as well as C-reactive protein levels over time. Mean PCS/MCS scores at baseline were 39.9/44.5 and 43.3/46.5 for A-RP and CSD-RP groups respectively (versus the norm mean of 50). In A-RP, PCS/MCS scores improved by 11.4/5.6 points by end of base TP, and this improvement was sustained throughout the EP (increase of 11.4/6.0 points from baseline at end of EP). In CSD-RP, PCS/MCS scores increased by 1.8/1.4 points by end of TP and improved by 3.5/4.2 points at end of study, after tapering or discontinuation of corticosteroid without disease recurrence. Conclusion: Impaired baseline HRQoL suggests negative impact of RP. For A-RP, rilonacept rapidly improved pericarditis signs and symptoms which was associated with HRQoL improvements. For CSD-RP, rilonacept supported tapering/withdrawal of corticosteroids without recurrence, with maintained/improved HRQoL. These results suggest rilonacept can improve RP patient HRQoL while providing an alternative to corticosteroids.

The correct selection and utilization of respiratory personal protective equipment is of the utmost importance in the current COVID‐19 pandemic. This is especially true for health care workers exposed to high‐risk aerosol‐generating procedures, including otolaryngologists, ophthalmologists, neurosurgeons, maxillofacial surgeons, and laparoscopic surgeons. This communication provides a review of approved forms of respiratory protection and compares their characteristics, including surgical masks, N95 respirator, elastomeric respirators, powered air‐purifying respirators, and controlled air‐purifying respirators. For standard airborne precautions, N95 respirator are appropriate for respiratory protection. However, high‐risk aerosol‐generating procedures may create aerosolization of high viral loads that represent increased risk to health care workers. In these situations, enhanced respiratory protection with filters certified as 99, 100, or HEPA (high‐efficiency particulate air) may be appropriate.

The worldwide prevalence of type 2 diabetes (T2D) is increasing. Despite normal to higher bone density, patients with T2D paradoxically have elevated fracture risk resulting, in part, from poor bone quality. Advanced glycation endproducts (AGEs) and inflammation as a consequence of enhanced receptor for AGE (RAGE) signaling are hypothesized culprits, although the exact mechanisms underlying skeletal dysfunction in T2D are unclear. Lack of inducible models that permit environmental (in obesity) and temporal (after skeletal maturity) control of T2D onset has hampered progress. Here, we show in C57BL/6 mice that a onetime pharmacological intervention (streptozotocin, STZ) initiated in adulthood combined with high-fat diet–induced (HFD-induced) obesity caused hallmark features of human adult-onset T2D, including prolonged hyperglycemia, insulin resistance, and pancreatic β cell dysfunction, but not complete destruction. In addition, HFD/STZ (i.e., T2D) resulted in several changes in bone quality that closely mirror those observed in humans, including compromised bone microarchitecture, reduced biomechanical strength, impaired bone material properties, altered bone turnover, and elevated levels of the AGE CML in bone and blood. Furthermore, T2D led to the premature accumulation of senescent osteocytes with a unique proinflammatory signature. These findings highlight the RAGE pathway and senescent cells as potential targets to treat diabetic skeletal fragility.

PURPOSE To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes. METHODS The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process. RESULTS Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria. RECOMMENDATIONS Patients with newly diagnosed BC and BRCA1/ 2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1/ 2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1/ 2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/ 2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines .

Abstract Background: We have previously identified Glycogen Synthase Kinase-3 beta (GSK-3β) nuclear accumulation as a hallmark of pancreatic ductal adenocarcinoma (PDAC) and demonstrated the antitumor effects of GSK-3β tool compound inhibitors in vivo (Ougolkov, Clin Cancer Res 2006). 9-ING-41 (Actuate Therapeutics Inc), a first-in-class, small-molecule potent selective GSK-3β inhibitor, has significant preclinical antitumor activity in PDAC. 9-ING-41 is synergistic with gemcitabine (GEM) in significantly reducing PDAC cell proliferation via impairment of ATR/Chk1 DNA damage response (Ding, Clin Cancer Res 2019). These data provided the rationale for inclusion of patients with PDAC in the 1801 phase 1/2 study evaluating 9-ING-41 alone and in combination with chemotherapy, including GEM and GEM plus nab-paclitaxel. Methods: Parts 1 and 2 of the 1801 phase 1/2 study evaluate the safety and tolerability of 9-ING-41 in patients with refractory malignancies. Part 1 establishes the recommended phase 2 study dose (RP2D) for 9-ING-41 monotherapy, while Part 2 assesses 9-ING-41 in combination with chemotherapies. For Part 1, patients received twice-weekly IV infusions of 9-ING-41 (21-day cycle). Based on prior treatment, Part 2 for those with PDAC consists of 9-ING-41 plus GEM (1000 to 1250 mg/m2 days 1 and 8; 21-day cycle) or 9-ING-41 plus GEM and nab-paclitaxel (125 mg/m2). Part 3 (Simon 2-stage phase 2 at the RP2D) will assess clinical benefit in patients with refractory PDAC treated with 9-ING-41-based combinations at the RP2D established in Part 2. Response is defined by response evaluation criteria in solid tumors (RECIST) criteria in evaluable lesions. The study is opening in 25 sites globally and will accrue approximately 300 patients. Results: To date, the study has accrued 34 patients with advanced solid tumors (n=33) or hematologic malignancies (n=1). Four dose levels (1, 2, 3.3, and 5 mg/kg) have been completed without dose-limiting toxicities (DLT). Part 2 of the study evaluating combination of 9-ING-41 with chemotherapy agents has been activated. Six patients with advanced PDAC have enrolled. One patient has completed 5 cycles of treatment with 9-ING-41 (1mg/kg) with stable disease (SD) as the best response. Another patient with SD as the best response has completed 6 cycles and now is joining the arm combining 9-ING-41 with GEM after disease progression. Four additional patients are awaiting first response assessment with enrollment ongoing. 9-ING-41-attributable AE to date are Grade 1 transient visual changes (color perception). Conclusions: 9-ING-41 is well tolerated. Preclinical data support the inclusion of patients with advanced PDAC on clinical studies of 9-ING-41. Citation Format: Benedito A. Carneiro, Malika Dhawan, Brittany Borden, Ludimila Cavalcante, Howard Safran, Andrey Ugolkov, Andrew P. Mazar, Daniel D. Billadeau, Francis J. Giles, Pamela Munster. GSK-3β blockade with 9-ING-41 in pancreas cancer: The 1801 phase 1/2 study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B09.

10588 Background: Accurate tumor classification is increasingly critical to individualized care as patient outcomes improve with use of targeted cancer therapies and predictive biomarkers. In metastatic cancers of uncertain or unknown origin, identification of a primary site remains equivocal in a significant number of cases. Gene expression signatures may improve accuracy and specificity of tumor classification, however, large-scale, blinded validation studies that demonstrate stable performance in metastatic and poorly differentiated cases are currently lacking. Methods: Seven hundred and ninety cases (51% female, 44% metastatic, 63% grade 2 and 3, 14% limited tissue specimens) representing 28 tumor types and 50 subtypes were processed and adjudicated between Mayo Clinic, UCLA and Massachusetts General Hospital. Blinded FFPE tumor sections were submitted and tested using a 92-gene RT-PCR assay (CancerTYPE ID, bioTheranostics Inc.). Molecular predictions were evaluated for concordance with the reference diagnosis; diagnostic accuracy between clinical subsets was compared. Results: The 92-gene assay demonstrated overall sensitivities of 87% for tumor classification and 82% for subtyping. Forty-seven (5.9%) cases were considered unclassifiable. Comparative analysis of performance between metastatic (n=329) and primary (n=414) tumors showed no statistically significant difference in accuracy (85% vs 88%, p=0.16). Similarly, no significant decreases in performance were observed across histological grades (p=0.58) and when comparing limited tissue to excisional biopsy specimens (p=0.16). Strong precision was demonstrated for accurate identification of a primary tumor in tissues biopsied from common metastatic sites, reported as positive predictive values of 100% for lung, brain and peritoneum, 92% for ovary and 80% for liver. Conclusions: Results from this multisite, blinded study validate the diagnostic accuracy of the 92-gene assay for classifying a diverse set of tumors, and support its clinical utility in the diagnosis of metastatic tumors to determine tissue of origin, and in the differential diagnosis of metastatic vs new primary disease.