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8034 Background: Phase 1 studies are evaluating IV and oral dosing of the reversible proteasome inhibitor MLN9708 in multiple tumor types. We report the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary responses with weekly oral MLN9708 in pts with relapsed/refractory MM (NCT00963820). Methods: Pts aged ≥18 yrs received MLN9708 on d 1, 8, and 15 of 28-d cycles. In the dose-escalation phase, pts required ≥2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). At the MTD, pts were to be enrolled to relapsed and refractory (RR), bortezomib-relapsed (VR), proteasome inhibitor (PI) naïve, and carfilzomib (CZ) expansion cohorts. Results: 36 pts have been enrolled to date (data cut-off: Dec 1, 2011), 32 in the dose-escalation phase (0.24–3.95 mg/m2) and 8 to expansion cohorts (2 RR, 5 VR, 1 PI naïve; RR and VR cohorts each include 2 pts from MTD dose-escalation cohort). Median age was 64.5 yrs (range 40–79), 53% were male, and median number of prior lines of therapy was 3.5 (range 1-13), including 92%, 92%, 56%, and 8% who had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively. Pts have received a median of 2 cycles (range 1–11); 5 pts remain on treatment. Among 24 DLT-evaluable pts, 3 DLTs were seen: 2 at 3.95 mg/m2 (1 grade 3 rash, 1 grade 3 GI AEs) and 1 at 2.97 mg/m2 (grade 3 GI AEs). The MTD was determined as 2.97 mg/m2. Overall, 69% of pts had drug-related AEs, and 28% had related grade ≥3 AEs, including thrombocytopenia (17%), diarrhea (11%), nausea, neutropenia, and fatigue (each 8%). Only 3 (8%) pts had drug-related peripheral neuropathy (PN; no grade ≥3). 2 pts discontinued due to AEs. In 18 response-evaluable pts, 1 had a VGPR at 3.95 mg/m2, 1 had a PR at 2.97 mg/m2, and 8 have achieved SD durable for up to 9.5 mos. PK analyses showed linear plasma PK (0.8–3.95 mg/m2), Tmax of 0.5-2 hr, and terminal half-life of 7 d for MLN2238 (biologically active hydrolysis product). There was a trend for a dose-dependent increase in whole blood 20S proteasome inhibition. Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows early signs of antitumor activity.

Abstract Importance: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections outbreak in China is now a global issue. There is only a limited understanding of the clinical characteristics of patients with SARS-CoV-2 infections is available.Objective:To describe the characteristics, management strategies, and outcomes of critically ill patients with SARS-CoV-2 infection.Design, Setting, and Patients: This is aretrospective, multi-center case series of 50 critically ill patients with confirmed SARS-CoV-2 infection who were admitted at Zhongnan Hospital of Wuhan University and Wuhan Pulmonary Hospital in Wuhan, China, from January 8 to February 9, 2020.Exposures:Documented Corona Virus Disease, 2019 (COVID-19).Main Outcome Measures: Demographic, clinical, laboratory, imaging data were collected along with management strategies, complications and outcomes of enrolled individuals. Results Fifty critically ill patients with SARS-CoV-2 infections were enrolled. Their median age was 62 (range, 29-92) [IQR,49.5-69.0] years, 68% were male, and 28 (56%) patients had comorbidities, the most common being hypertension. In this cohort, 20(40%) patients survived ,16(32%) patients died, and the rest remained hospitalized. The invasive mechanical ventilator was used in 36(72%) patients with 15(30%) of them requiring prone positioning, and 17(34%) switched to ECMO. The compliance scores of lungs (Cstat)on the day of ICU admission among survivors were higher than those in non-survivors [42.0(18.0-47.0), vs. 19.5(14.0-24.2), p=0.038].The blood IL-6 levels and neutrophils counts at the first day of ICU admission were significantly higher in non-survivors compared to survivors [123.7(85.3-228.8), vs. 20.2(6.8-67.2) ng/ml, p=0.025 for IL-6, and 20.2(6.8-67.2) vs. 4.01(1.99-7.05) × 10⁹/L, p=0.02 for neutrophils counts].The heart rates, PaCO2, lung injury scale (LIS), and positive end-expiratory pressure levels were constantly higher for 10 days in non-survivors than those who survived (p<0.05). The frequency of vasopressor uses and neuromuscular blockers was higher in non-survivors from day 1 to day 10 compared to survivors (p<0.05). In the whole cohort, the most common complications were ARDS (97%), shock (44%), arrhythmia (38%), acute cardiac injury (26%), and acute kidney injury (22%). A secondary bacterial infection was noted in 17(34%) patients. Univariate analysis indicated that lower lung complianceand higher neutrophil counts at the day of ICU admission were related to higher mortality (p-0.03, and 0.04, respectively)ConclusionWe demonstrated that SARS-CoV-2 infection-related critical illness predominantly affected old individuals with comorbidities and characterized by severe hypoxemic respiratory failure, often requiring prolonged mechanical ventilation and rescue therapies. Low lung compliance and persistently elevated PaCO2 indicated poor outcomes.

Abstract Combination of carfilzomib with dexamethasone (Kd) is approved for use in relapsed and/or refractory multiple myeloma (RRMM), with carfilzomib administered twice weekly at 56 mg/m 2 (Kd56 BIW) or once weekly at 70 mg/m 2 (Kd70 QW). Post hoc cross‐trial comparisons were performed to compare efficacy and safety profiles of Kd70 QW vs Kd56 BIW dosing schedules using data from three trials of patients with RRMM: A.R.R.O.W., CHAMPION‐1, and ENDEAVOR. To select for comparable patient populations, side‐by‐side efficacy and safety comparisons were performed in subgroups of patients with 2‐3 prior lines of therapy who were not refractory to bortezomib. The overall response rate (ORR) was 69.9% (95% confidence interval [CI], 61.7‐77.2) for Kd70 QW and 72.4% (95% CI, 65.9‐78.2) for Kd56 BIW. Median progression‐free survival (PFS) was 12.1 months (95% CI, 8.4‐14.3) for Kd70 QW and 14.5 months (95% CI, 10.2—not evaluable) for Kd56 BIW. Frequency of grade ≥ 3 adverse events (AEs) was 67.6% for Kd70 QW and 85.3% for Kd56 BIW. Regression analyses (adjusting for prognostic factors) of all patients in the trials who received Kd70 QW vs Kd56 BIW estimated a PFS hazard ratio of 0.91 (95% CI, 0.69‐1.19; P = .47) and an ORR odds ratio of 1.12 (95% CI, 0.74‐1.69; P = .61). These results suggest that Kd70 QW has a comparable efficacy profile compared with Kd56 BIW and represents a convenient and well‐tolerated treatment for patients with RRMM.

149 Background: Patients with metastatic hormone-sensitive prostate cancer (mHSPC) have a variable response to ADT and some benefit from the addition of docetaxel or an androgen signaling pathway inhibitor. We found that loss of the epigenetic regulator KDM5D is associated with more aggressive prostate cancer (PC). We sought to determine whether MYBL2 which is regulated by KDM5D mediates this effect. MYBL2 is a transcription factor which controls key genes (e.g. FOXM1) and increases cell cycle progression and survival. Methods: AR expressing hormone-sensitive cell lines, LNCaP and LAPC4 were used. Motif analysis and CHiPseq of LNCaP with and without siKDM5D was performed and impact of modulation of KDM5D and MYBL2 in both cells on cell survival was assessed. Gene expression profiling (GEP) data assessed MYBL2’s association with KDM5D levels in localized disease (publicly available data) and mHSPC (Decipher whole Affymetrix platform on CHAARTED samples). Results: Silencing KDM5D increased H3K4me3 and increased MYBL2 expression. GEP showed a strong negative correlation between KDM5D and MYBL2 in patients with localized PC (-0.66; TCGA) but not from primary prostate cancer tissue with mHSPC (-0.03; CHAARTED). Cells with low KDM5D and high MYBL2 were androgen independent and more resistant to docetaxel. In TCGA, patients with high MYBL2 had a higher rate of relapse from localized disease. In patients with metastatic disease (CHAARTED) low MYBL2 was associated with a better overall survival (OS) on multivariable analysis when treated with ADT or ADT + docetaxel. Conclusions: Low MYBL2 is associated with a longer OS with ADT alone and ADT and docetaxel independent of clinical variables. Patients with high MYBL2 expression had better OS with ADT plus docetaxel compared with patients with high MYBL2 treated with ADT alone.[Table: see text]

763 Background: Non-invasive biomarkers with high sensitivity and specificity would be of great value for patients with Pancreatic Ductal Adenocarcinoma (PDAC). This would aid in early detection and serve other purposes that 'liquid biopsies' are being explored in. Besides circulating tumor DNA (ctDNA) and methylation markers, glycosylation markers hold great potential promise. We developed a novel workflow using high-resolution quantification of site-specific protein glycosylation by liquid chromatography and tandem mass spectrometry to evaluate the clinical utility of glycoprotemics signature for patients with PDAC. Methods: Serum samples from newly diagnosed PDAC patients and controls were obtained from a commercial biobank (Indivumed, Hamburg, Germany), and a panel of 504 glycan motifs, representing 73 previously reported proteomic markers, was determined. Age-adjusted generalized linear regression models were used to evaluate the differential abundance of each marker, and stepwise variable selection was used for model construction. Results: We analyzed 45 PDAC and 136 control samples. PDAC patients (60% male) had a mean age of 67 (±11) years. with 4.4%, 71.1%, 4.4%, and 20% at stage 1, 2, 3,4, respectively. Controls were women with benign histology after pelvic mass surgery; with a mean age of 61 (±11) years. Twenty-six glycoproteomic markers showed statistically highly significant differential abundance among cases and controls (p<1e-4 each) and were highly reproducible(Pearson’s r > 0.85), which were glycoforms in proteins that have previously been found to be associated with PDAC. Fourteen of these markers displayed >0.8 area under the curve of the receiver operating characteristic (AUC). Multivariate logistic regression modeling with backward selection yielded a classification model with an AUC of 0.94 (95% CI: 0.89-0.99), sensitivity of 91% (95% CI: 75-97%) and specificity of 86% (95% CI: 81-92%). Conclusions: Circulating glycoproteomic biomarkers may be useful in the early detection and clinical management of PDAC patients; offering a new platform to explore and validate.

Objective Activin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, may become a new target for the treatment of diabetic kidney disease (DKD) and chronic kidney diseases. We tested the hypothesis that human DKD-related injury leads to upregulation of activin A in blood and urine and in a human kidney cell model. We further hypothesized that circulating activin A parallels kidney injury markers in DKD. Research design and methods In two adult diabetes cohorts and controls (Minnesota, USA; Galway, Ireland), the relationships between plasma (or urine) activin A, estimated glomerular filtration rate (eGFR) and DKD injury biomarkers were tested with logistic regression and correlation coefficients. Activin A, inflammatory, epithelial-mesenchymal-transition (EMT) and senescence markers were assayed in human kidney (HK-2) cells incubated in high glucose plus transforming growth factor-β1 or albumin. Results Plasma activin A levels were elevated in diabetes (n=206) compared with controls (n=76; 418.1 vs 259.3 pg/mL; p<0.001) and correlated inversely with eGFR (r s =−0.61; p<0.001; diabetes). After eGFR adjustment, only albuminuria (OR 1.56, 95% CI 1.16 to 2.09) and tumor necrosis factor receptor-1 (OR 6.40, 95% CI 1.08 to 38.00) associated with the highest activin tertile. Albuminuria also related to urinary activin (r s =0.65; p<0.001). Following in vitro HK-2 injury, activin, inflammatory, EMT genes and supernatant activin levels were increased. Conclusions Circulating activin A is increased in human DKD and correlates with reduced kidney function and kidney injury markers. DKD-injured human renal tubule cells develop a profibrotic and inflammatory phenotype with activin A upregulation. These findings underscore the role of inflammation and provide a basis for further exploration of activin A as a diagnostic marker and therapeutic target in DKD.

Purpose Hyperpolarized 129 Xe MRI characterizes regional lung ventilation in a variety of disease populations, with high sensitivity to airway obstruction in early disease. However, ventilation images are usually limited to a single breath‐hold and most‐often acquired using gradient‐recalled echo sequences with thick slices (~10‐15 mm), which increases partial‐volume effects, limits ability to observe small defects, and suffers from imperfect slice selection. We demonstrate higher‐resolution ventilation images, in shorter breath‐holds, using FLORET (Fermat Looped ORthogonally Encoded Trajectories), a center‐out 3D‐spiral UTE sequence. Methods In vivo human adult ( N = 4; 2 healthy, 2 with cystic fibrosis) 129 Xe images were acquired using 2D gradient‐recalled echo, 3D radial, and FLORET. Each sequence was acquired at its highest possible resolution within a 16‐second breath‐hold with a minimum voxel dimension of 3 mm. Images were compared using 129 Xe ventilation defect percentage, SNR, similarity coefficients, and vasculature cross‐sections. Results The FLORET sequence obtained relative normalized SNR, 40% greater than 2D gradient‐recalled echo ( P = .012) and 26% greater than 3D radial ( P = .067). Moreover, the FLORET images were acquired with 3‐fold‐higher nominal resolution in a 15% shorter breath‐hold. Finally, vasculature was less prominent in FLORET, likely due to diminished susceptibility‐induced dephasing at shorter TEs afforded by UTE sequences. Conclusion The FLORET sequence yields higher SNR for a given resolution with a shorter breath‐hold than traditional ventilation imaging techniques. This sequence more accurately measures ventilation abnormalities and enables reduced scan times in patients with poor compliance and severe lung disease.

Purpose: To test the association between participant King-Devick Test (KDT) times and obstructive sleep apnea (OSA) severity and evaluate for improvement after continuous positive airway pressure (CPAP) treatment. Methods: Study dates January 30 to July 31, 2018. Patients were referred for initial evaluation of sleep disordered breathing concerns. OSA severities were defined by Apnea Hypopnea Index (AHI) results, with ≥15 considered at least moderate OSA. The KDT is an objective physical measure of brain function. We estimated correlation between KDT time and AHI and compared mean KDT time between patients with and without moderate OSA. For the OSA subgroup, we evaluated for potential improvement in KDT after CPAP. Results: We enrolled 60 participants, of whom 35 (58.3%) had OSA with an AHI ≥15. Initial analyses noted no significant KDT time differences between patients based on OSA severity. However, after excluding 3 participants who had baseline neurologic illness, adjusted analyses demonstrated that mean KDT time was significantly prolonged for patients with moderate or greater OSA (AHI ≥15) as compared to those with mild or no sleep apnea (AHI <15); 63.4 seconds (95% CI 58.9-67.8) versus 55.7 seconds (95% CI 50.2-61.1), P = .03. CPAP-treated subjects demonstrated significantly improved KDT test times; 63.5 seconds mean pretreatment versus 55.6 posttreatment; −6.6 seconds mean difference, 95%CI (−12.0, −1.13), P = .02. Conclusion: Neurologic abnormalities in patients with OSA are potentially demonstrable utilizing this objective physical measure. Significant improvement is achieved in patients after CPAP treatment.