Citations

Abstract Noninvasive wearable devices have great potential to aid the management of epilepsy, but these devices must have robust signal quality, and patients must be willing to wear them for long periods of time. Automated machine learning classification of wearable biosensor signals requires quantitative measures of signal quality to automatically reject poor‐quality or corrupt data segments. In this study, commercially available wearable sensors were placed on patients with epilepsy undergoing in‐hospital or in‐home electroencephalographic (EEG) monitoring, and healthy volunteers. Empatica E4 and Biovotion Everion were used to record accelerometry (ACC), photoplethysmography (PPG), and electrodermal activity (EDA). Byteflies Sensor Dots were used to record ACC and PPG, the Activinsights GENEActiv watch to record ACC, and Epitel Epilog to record EEG data. PPG and EDA signals were recorded for multiple days, then epochs of high‐quality, marginal‐quality, or poor‐quality data were visually identified by reviewers, and reviewer annotations were compared to automated signal quality measures. For ACC, the ratio of spectral power from 0.8 to 5 Hz to broadband power was used to separate good‐quality signals from noise. For EDA, the rate of amplitude change and prevalence of sharp peaks significantly differentiated between good‐quality data and noise. Spectral entropy was used to assess PPG and showed significant differences between good‐, marginal‐, and poor‐quality signals. EEG data were evaluated using methods to identify a spectral noise cutoff frequency. Patients were asked to rate the usability and comfort of each device in several categories. Patients showed a significant preference for the wrist‐worn devices, and the Empatica E4 device was preferred most often. Current wearable devices can provide high‐quality data and are acceptable for routine use, but continued development is needed to improve data quality, consistency, and management, as well as acceptability to patients.

Abstract Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multicenter trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with the standardized brain tumor imaging protocol (BTIP) for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this paper provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40–50 ms at 1.5 T, 20–35 ms at 3 T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time.

OBJECTIVE Cushing’s disease arises from functioning adrenocorticotropic hormone (ACTH)–secreting pituitary adenomas. These tumors can be very small and evade detection by MRI. Empty sella syndrome is a phenomenon by which an arachnoid outpouching of CSF into the sella leads to compression of the pituitary, likely due to intracranial hypertension (a common issue in Cushing’s disease), further leading to difficulty in visualizing the pituitary gland that may contribute to difficulty in finding a tumor on MRI, so-called MRI-negative Cushing’s disease. The authors sought to examine the association between empty sella syndrome and MRI-negative Cushing’s disease. METHODS A single-institution database of Cushing’s disease cases from 2000 to 2017 was reviewed, and 197 cases were included in the analysis. One hundred eighty patients had a tissue diagnosis of Cushing’s disease and 17 had remission with surgery, but no definitive tissue diagnosis was obtained. Macroadenomas (tumors > 1 cm) were excluded. The degree of empty sella syndrome was graded on the degree of CSF visualized in the sella on midline sagittal T1-weighted MRI. RESULTS Of the 197 cases identified, 40 (20%) presented with MRI-negative disease, and empty sella syndrome was present in 49 cases (25%). MRI-negative disease was found in 18 (37%) of 49 empty sella cases versus 22 (15%) of 148 cases without empty sella syndrome present. Empty sella syndrome was significantly associated with MRI-negative disease (OR 3.32, 95% CI 1.61–6.74, p = 0.0018). Decreased thickness of the pituitary gland was also associated with MRI-negative disease (mean thickness 5.6 vs 6.8 mm, p = 0.0002). CONCLUSIONS Empty sella syndrome is associated with an increased rate of MRI-negative Cushing’s disease. Pituitary compression causing a relative reduction in the volume of the pituitary for imaging is a plausible cause for not detecting the tumor mass with MRI.

LBA3 Background: Bortezomib (btz) combined with lenalidomide (len) and dexamethasone (dex) (VRd) is a standard initial therapy for NDMM. Carfilzomib (cfz), a next-generation proteasome inhibitor, in combination with len-dex (KRd) has shown higher efficacy in phase II trials. This randomized phase III trial was designed to examine if KRd improves progression free survival (PFS) compared to VRd in NDMM (current results), and whether indefinite maintenance with len improves OS compared with two-year maintenance (to be analyzed once data matures). Methods: Patients (Pts) with NDMM, were randomized to receive VRd or KRd in a 1:1 fashion for 36 weeks followed by a second randomization (1:1) to indefinite versus two years of len maintenance. Pts without del17p, t (14;16), t(14;20), plasma cell leukemia or high-risk GEP70 profile, were enrolled. VRd arm included btz 1.3 mg/m2 on days(d) 1, 4, 8, and 11 (d 1, 8 for cycles 9-12), len 25 mg d 1-14, and dex 40 mg d 1, 2, 4, 5, 8, 9, 11, 12 of a 3-week (wk) cycle for 12 cycles, while pts in the KRd arm received cfz 36 mg/m2 d 1, 2, 8, 9, 15, 16 with len 25 mg daily on d 1-21 and dex 40 mg wkly, in 4 wk cycles for 9 cycles. Maintenance included len 15mg d 1-21 every 4 wks. The study was designed to detect a hazard ratio (HR)=0.75 with 80% power at 1-sided 2.5% alpha and 399 PFS events (progression or death regardless of intervening therapy). Results: The study accrued 1087 pts (VRd=542, KRd=545). The median age was 65y. Treatment, efficacy, and toxicity data are in the table. At the second of 3 planned interim analyses, with PFS HR=1.04 (95% CI, 0.8 to 1.3, p=0.74), futility was met. Median PFS was VRd=34.4m and KRd=34.6m; no differences were seen based on age (<65 or ≥65), presence or absence of t(4;14) or ISS stage. The three-year OS (95% CI) was similar: VRd 84% (80 to 88) and KRd 86% (82 to 89). Conclusions: In this randomized phase 3 trial, KRd did not improve PFS compared with VRd in NDMM. A significantly higher rate of cardio-pulmonary and renal toxicity was observed with KRd, while neuropathy rates were higher with VRd. VRd remains the standard triplet induction regimen in standard and intermediate risk NDMM, and a suitable backbone for 4 drug combinations. Clinical trial information: NCT01863550 . [Table: see text]

Abstract Background Lips are considered a key element of facial attractiveness due to their central position in the face and their elemental role in verbal and nonverbal communication. Objectives The authors sought to provide clinically relevant information on the 3-dimensional pathway of the superior and inferior labial arteries within the lips to increase safety during labial soft tissue filler injections. Methods The study enrolled 41 healthy volunteers with a mean age of 26.17 ± 9.6 years and a mean body mass index of 23.09 ± 2.3 kg/m2. Ultrasound imaging was performed at 6 different locations. The position of the labial arteries within the lips, depth of the arteries, cranio-caudal location of each artery in relation to the vermilion border, and diameter of the superior/inferior labial arteries were recorded. Results The most frequent location of both the superior and inferior labial arteries was the submucosal plane (58.5%) followed by intramuscular (36.2%) and subcutaneous (5.3%) planes. The depth of the superior labial artery in the upper lip was 5.6 ± 0.13 mm, whereas the depth of the inferior labial artery in the lower lip was 5.2 ± 0.14 mm. Both arteries were more frequently located within the red lip: upper lip (83% vs 18.7%) and lower lip (86.2% vs 13.8%). In the midline, the artery coursed within the red lip in all investigated volunteers. Conclusions Clinically, results of this study favor a superficial injection plane for lip volumization procedures. A perpendicular approach to the lip (coming from the cutaneous lip) might increase safety because the artery is located most frequently within the red lip.

TPS9082 Background: Limited stage small cell lung cancer (LS-SCLC) is treated with standard of care platinum/etoposide (EP) and thoracic radiation therapy (TRT) with curative intent, however the majority of patients are not cured and median overall survival is approximately 30 months. Addition of atezolizumab to chemotherapy in extensive stage SCLC has improved progression free and overall survival in a non-curative setting leading to hope that addition of an immune checkpoint inhibitor to standard chemoradiotherapy could benefit LS-SCLC patients. LU005 is a randomized phase II/III trial of standard concurrent chemoradiation with or without atezolizumab for patients with LS-SCLC. Methods: Patients are randomly assigned in a 1:1 ratio to standard EP chemotherapy with concurrent TRT (45 Gy BID or 66 Gy QD) with or without atezolizumab beginning concurrently with TRT, and continued every 3 weeks for up to 12 months. Eligible patients have LS-SCLC, PS 0-2, adequate organ function, no concerning comorbidities (including no active autoimmune disease) and are eligible for TRT. Patients are randomized prior to their second cycle of EP and thoracic radiation begins with the second overall cycle of chemotherapy (first cycle of study therapy) in both treatment arms. Prophylactic cranial radiation (PCI) is recommended for patients who respond to treatment. The phase II/III primary endpoints are progression free (PFS) and overall survival (OS) respectively. Secondary endpoints include objective response rates, local and distant disease control, and quality of life/patient reported outcomes assessment. Translational science component includes blood and tissue based immune related assays. This study activated in May 2019. 50 of 506 planned patients have been accrued as of 2/1/2020. Supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U23CA180803 (IROC) from the National Cancer Institute (NCI) and Genentech. *Authors Ross and Higgins are co-first authors and contributed equally to this work. Clinical trial information: NCT03811002.

e17587 Background: Radium (Ra)-223 has become the cornerstone treatment in patients with metastatic castrate-resistant prostate cancer (mCRPC) with bone metastases. Ra-223 has been shown to suppress abnormal bone formation by inducing DNA double-strand breaks in tumor cells. This can reduce skeletal-related events, as well as improve survival and quality of life. Studies have indicated mutations that regulate DNA damage response in prostate cancer as susceptible to PARP inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. Methods: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics, genetic mutations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. Results: 239 mCRPC patients treated with Ra-223 were identified. Germline and/or somatic genetic sequencing was available in 50 patients, who had a median age of 61 years at time of diagnosis and 68 years at time of Ra-223 treatment. Median Gleason score at time of diagnosis was 8.0. 100% of patients received prior androgen deprivation therapy. 72% received prior docetaxel, and 18% received prior cabazitaxel. Notable mutations included TP53 (45.2%), TMPRSS2-ERG (28.6%), PTEN (26.2%), BRCA1/2 (14.3%), ATM (9.3%), CDK12 (7.1%), and Rb (4.9%). TMPRSS2-ERG was the second most commonly found mutation, with median OS 12.7 mo versus 15.4 mo in patients without TMPRSS2-ERG mutations (p = 0.099). In patients with CDK12 mutations (2 of 28 tested positive), PFS was 10.4 mo versus 5.6 mo in patients without CDK12 mutations (p = 0.157). The assessment of ALP and PSA response to radium treatment stratified by genetic mutation did not reach statistical significance. Conclusions: Among mCRPC patients treated with Ra-223 at Mayo Clinic, TMPRSS2-ERG was the second most commonly found genetic mutation and had observed worse survival outcomes that approached statistical significance. Prospective studies and increased sample sizes are needed to determine the impact of genetic mutations in response to Ra-223.

5564 Background: Cabozantinib (C) may enhance response to immune checkpoint inhibitors (ICIs) by promoting an immune-permissive microenvironment and has shown encouraging activity in combination with ICIs in tumor types including RCC and HCC. C and atezolizumab (A) have shown low objective response rates as monotherapy in metastatic castration-resistant prostate cancer (mCRPC) (Smith JCO 2012; Kim JCO 2018). COSMIC-021 (NCT03170960), a multinational phase 1b study, is evaluating the combination of C + A in various solid tumors. We report results for Cohort 6 in mCRPC. Methods: Eligible patients (pts) were required to have radiographic progression in soft tissue after enzalutamide and/or abiraterone, measurable disease, and an ECOG PS of 0 or 1. Prior chemotherapy for mCSPC was permitted. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for the first year and Q12W thereafter. The primary endpoint is ORR per RECIST 1.1. Other endpoints include safety, ORR per irRECIST, duration of response (DOR), PFS, and OS. Results are presented for the first 44 pts enrolled. Results: Median follow-up as of Dec 20, 2019 was 12.6 mo (range 5, 20) for the 44 mCRPC pts. Median age was 70 y (range 49, 90), 50% had ECOG PS 1, 34% had visceral metastases, and 61% had extrapelvic lymph node metastases. 27% had prior docetaxel and 52% had 2 prior novel hormonal therapies. The most common any grade treatment-related adverse events (TRAEs) were fatigue (50%), nausea (43%), decreased appetite (39%), diarrhea (39%), dysgeusia (34%), and PPE (32%). One grade 5 TRAE of dehydration was reported in a 90 y/o. Median duration of treatment was 6.3 mo. ORR per RECIST 1.1 among all 44 pts was 32% (2 CRs [4.5%] and 12 PRs [27%]); 21 (48%) pts had SD resulting in a disease control rate of 80% in all pts. One pt with PD per RECIST 1.1 had an irPR per irRECIST. ORR per RECIST 1.1 was 33% in 36 pts with high-risk disease (visceral and/or extrapelvic lymph node metastases). Median DOR for all pts with response per RECIST 1.1 was 8.3 mo (range 2.8, 9.8+). 17 (50%) of 34 pts with post-baseline PSA evaluation had a decrease in PSA. In 12 responders with post-baseline PSA evaluation, 8 (67%) had a PSA decrease ≥50%. Tumor PD-L1 expression will also be reported. Conclusions: The combination of C + A had a tolerable safety profile and demonstrated clinically meaningful activity with durable responses in men with mCRPC. Given the encouraging activity in these pts, especially in those with high-risk disease, further evaluation of C + A in men with mCRPC is being pursued. Clinical trial information: NCT03170960 .

e16771 Background: AbGn-107 is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric (G), colorectal (CRC), pancreatic (PDA), and biliary (BIL) cancers. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a Phase Ia trial in patients with the aforementioned GI malignancies. Methods: Standard 3+3 dose escalation was used. Key eligibility included locally advanced or metastatic G, CRC, PDA, or BIL cancer, previously treated, ECOG PS 0-1; positive AG-7 expression was not required. Two dosing intervals were tested: AbGn-107 administered i.v. Q4 weeks (at doses ranging from 0.1-1.2 mg/kg) and Q2 weeks (at doses from 0.8-1.0 mg/kg). Dose limiting toxicities (DLT) were based on grade 3/4 hematologic and non-heme AEs occurring during the initial 4-week rx window. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments Q8 weeks. 1o objectives: safety and MTD; 2o objectives: PK, immunogenicity, and efficacy defined by ORR (RECIST 1.1). Results: 35 patients were enrolled across 6 dose levels (median age 61.5 yo (range 40 – 81); G (0)/CRC (12)/PDA (20)/BIL (3); median # lines of prior rx = 3 (range 1-7). Safety: 5 patients experienced Grade 3 or 4 neutropenia, all at higher dose levels, inc. 1 episode of febrile neutropenia. Other frequent drug-related AEs, mostly grade 1/2, inc. fatigue (29%), nausea (20%), and diarrhea (14%). DLTs included grade 4 CK elevation (n = 1) at 0.8 mg/kg Q4W and grade 3 arthralgias (n = 1) at 1.2 mg/kg Q4W. Based on safety profile and PK data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase. Efficacy: Median duration of treatment = 56 days (range, 8 – 225 days). Six pts have demonstrated a minor response by RECIST (range, -1.3 to -21.1%); 4 pts (all PDA) have had durable dz control > 180 days. Conclusions: Overall, AbGn-107 appears well-tolerated with encouraging prelim signs of efficacy in unselected pts with heavily pre-treated advanced GI cancers. Updated safety and efficacy data will be provided at the time of the meeting for the cohort expansion phase of this study (currently open across multiple sites in U.S. and Taiwan), in which subjects with G, CRC, PDA, and BIL cancers are pre-screened for high levels of AG-7 tumor expression. Clinical trial information: NCT02908451 .