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Study Design: Retrospective, single institution, multisurgeon case control series. Objective: To determine whether there are differences in reoperation rates or outcomes for patients undergoing 2-level posterolateral fusion (PLF) augmented by a transforaminal lumbar interbody fusion (TLIF) at only one of the levels or at both. Methods: A total of 416 patients were identified who underwent 2-level PLF with a TLIF at either one of those levels (n = 183) or at both (n = 233) with greater than 1-year follow-up. Demographic, surgical, radiographic, and clinical data was reviewed for each patient. These included age, sex, race, body mass index, smoking status, Charleston Comorbidity Index, operative time, estimated blood loss, length of stay, and patient-reported outcome measures. Results: Each cohort underwent 24 reoperations. Although the number of overall reoperations was not significantly different ( P > .05), among the reoperation types, there were significantly more reoperations for adjacent segment disease in the 2-level group compared to the 1-level group (19 vs 12, P = .04). There was no difference in reoperation for pseudarthrosis between the groups ( P > .05). Although both groups experienced significant improvements in Oswestry Disability Index ( P < .001) and Short Form–12 health questionnaire ( P < .001), there were no differences between improvements for 1- versus 2-level cohorts. Conclusions: For patients undergoing 2-level PLF in the setting of a TLIF, using a TLIF at one versus both levels does not seem to influence reoperation rates or outcomes. However, reoperation rates for adjacent segment disease are increased in the setting of a 2-level PLF augmented by a 2-level TLIF.

Abstract Background: Adult acute myeloid leukemia (AML) patients with high-risk cytogenetics have a significantly worse survival compared to similarly treated intermediate- or favorable-risk patients. Although prior studies suggest better outcome in high-risk AML patients in first complete remission (CR1) who undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy, only 40% of patients proceed to HCT. The lack of a matched sibling donor (available in about 33%) should not be a barrier to HCT since alternative donors are available for the large majority of high-risk AMLpatients and recent data suggest outcomes after allogeneic HCT from fully matched unrelated donors are similar to those following matched related donor transplantation. We sought to determine if a prospective organized effort could rapidly identify alternative donors to improve the historical 40% allogeneic HCT rate in high-risk CR1 AML patients ≤ age 61. Secondly, we hypothesized that transplanting significantly more adults with high-risk AML in CR1 would lead to an improved outcome compared with the historical relapse-free survival (RFS) of 22%. Patients and Methods: Adult patients between ages 18 and 60 years with untreated AML were randomized to receive induction therapy with standard cytarabine plus daunorubicin (7+3; n=261), idarubicin with high-dose cytarabine (IA; n=261), or IA with vorinostat (IA+V; n=216). Conventional cytogenetics were obtained at time of enrollment and used to determine risk classification by standard criteria. All patients with high-risk cytogenetics underwent expedited HLA-typing. High-risk patientswere encouraged tobe referred for consultation with a transplant team with the goal of conducting an allogeneic HCT in CR1. Results: Of 738 eligible patients (median age, 49 years; range, 18-60), 159 (22%) had high-risk cytogenetics, of whom 60 (38%), 61 (38%), and 38 (24%) received induction with 7+3, IA, or IA+V, respectively. A total of 107 of the 159 high-risk patients achieved CR/CRi (67%). HCT was performed in 317 of all 738 patients (43%) and 68 (64%) of the high-risk patients received a transplant in CR1 (p<0.001 compared to historical rate of 40%). Twenty-five (37%) had a matched related donor, 31 (45%) had a matched unrelated donor, 3 (4%) had a mismatched related donor, 8 (12%) had a mismatched unrelated donor, and 1 (1%) received an umbilical cord blood transplant. Sixty-six high-risk patients transplanted in CR/CRi have detailed data. Median time to HCT from CR1 was 76 days (range, 20-365). Fifty-seven patients (86%) received a myeloablative regimen and 9 (14%) reduced-intensity conditioning. Reasons for 39 high-risk CR1 patients not receiving a transplant in CR1 were: co-morbidities (n=1), death (n=6), no insurance (n=1), no donor (n=1), physician decision (n=3), patient decision (n=3), relapse (n=6), other (n=10), or unknown (n=8). The 2-year RFS estimate in the entire high-risk cohort is 32%, significantly higher than the 22% historical rate (p=0.05). Median RFS in the high-risk CR1 cohort (n=107) was 10 months [range, 1-32* (censored) months]. RFS and OS were similar among HCT patients using matched related [1 year estimates: 40% (95% CI 27%, 74%) and 56% (37%, 74%), respectively] and matched unrelated [1 year estimates: 52% (37%, 75%) and 56% (37%, 74%), respectively] donors in CR1. The HR (reference = unrelated) for RFS was 0.67 (0.32, 1.37) and for OS was 0.88 (0.41, 1.90). Median overall survival (OS) among all patients in the high-risk cohort (n=159) was 12 months [range, 1-33* (censored) months] and was 18 months [range 3-33* (censored) months] for those transplanted in CR1 (Fig. 1). Conclusions: In newly diagnosed adults with AML age 18-60, early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donorled to a CR1 transplant rate of 64% in the high-risk group, which in turn led to a significant improvement in RFS over historical controls. Better outcomes in poor prognosis AML patients may be achieved simply by rapidly finding unrelated donors and performing allogeneic HCT in CR1 as soon as possible. Clinical Trials Registry: NCT #0180233; Support: NIH/NCI grants: CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI #021039 Figure 1 Overall Survival (OS) among all patients in the high-risk cohort, all high-risk patients achieving CR1, and in those high-risk patients transplanted in CR1. Figure 1. Overall Survival (OS) among all patients in the high-risk cohort, all high-risk patients achieving CR1, and in those high-risk patients transplanted in CR1. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Other: laboratory contract; ARIAD: Consultancy; Pfizer: Consultancy; TwinStrand: Consultancy; Bristol-MyersSquibb: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:AbbVie: Consultancy; Lundbeck: Consultancy; BMS: Consultancy, Honoraria; Velgene: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Jazz: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stone:Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Novartis: Consultancy; Celator: Consultancy; Karyopharm: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Research Funding.

Introduction: Waldenström macroglobulinemia (WM) is characterized by circulating monoclonal IgM and bone marrow infiltration with lymphoplasmacytic lymphoma (LPL) cells. Presently, there is limited data to guide prognosis or treatment options of WM based on the proportion of lymphocytes or plasma cells in the LPL population on the pathology. In this study, we aim to look at differing clinical features and outcomes of patients with WM based on the plasma cell (PC) percentage in the diagnostic bone marrow biopsy. Methods Patients with WM seen at Mayo Clinic, Rochester, MN between January 2001 and December 2017, with a bone marrow biopsy and a corresponding serum free light chain (FLC) examination at diagnosis of WM were included. The percentage of lymphocytes and PCs in the marrow biopsy was determined based on morphology ± immunohistochemistry. On immunohistochemistry, CD138 and/or MUM-1 positivity was used to quantify PCs, whereas CD20 and/or PAX5 were used to quantify lymphocytes. Patients with ≥10% PC component in the lymphoplasmacytic (LPL) cells on bone marrow biopsy were considered to have WM with excess plasma cells (WMEPC), while those with &lt;10% PCs were considered to have lymphocytic WM (LWM). Continuous variables were compared using Wilcoxon test and categorical variables were compared using Chi square test or Fisher's exact test. Time-to-next therapy (TTNT) was defined as the period from initiation of first line therapy to start of second line therapy or death due to any cause before second line therapy. Time-to-event analyses were conducted using Kaplan Meier method. Results: Of 228 evaluable patients, 147 (64%) had ≥ 10% PCs in the initial marrow biopsy. The median follow-up was 3.4 years (95% CI: 2.3-4.3 years) for LWM and 4.3 years (95% CI: 3.4-4.8 years) for WMEPC (p=0.33). The baseline characteristics of WMEPC versus LWM are depicted in Table 1. Patients with WMEPC had lower bone marrow involvement by LPL (30%) compared to LWM (60%; p&lt;0.001) at diagnosis, but the rate of symptomatic hyperviscosity was higher in WMEPC during the disease course (Table 1). The TTNT was shorter for WMEPC [2.6 years (95% CI: 1.8-4.5 years)] compared to LWM [4.5 years (95% CI 3.2-8.2)], although it did not reach statistical significance (p=0.09, Figure 1). There was a trend towards shorter OS for WMEPC [Not reached (95% CI 7.2- NR)] compared to LWM [10.7 years (95% CI 7.3 -12.1 years); p=0.28], Figure 2. Of the 228 patients, 79% (n=182) had data available for systemic therapy. The rate of PR or better with frontline therapy was higher in rates in LWM compared to WMEPC (61 % vs 42% p=0.02, Table 1). Among WMEPC cohort, patients receiving either a proteasome inhibitor (PI)-based or an immunomodulatory (IMiD)-based combination as frontline therapy (n=16) had higher rates of partial response or better (68%) compared to non-PI/non-IMiD based therapy (n=114), p=0.04. Conclusion: WM with excess plasma cells at diagnosis is associated with a trend towards shorter TTNT and OS compared to WM with &lt;10% plasma cells in the lymphoplasmacytic population at diagnosis. Our preliminary data shows higher rates of partial response or better with the use of PI/IMiD based therapy, but the small cohort size limits the strength of this finding which needs to be validated externally. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy. Lacy:Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria.

Background: Less-fit patients with acute myeloid leukemia (AML) or high-risk myelodysplasia (MDS) age 60 years and older constitute the majority of patients with AML/MDS but are not well represented in clinical trials. DNA-methyltransferase inhibitor (HMA) monotherapy (e.g. azacitidine or decitabine) is usual. Overall response rates (ORR) are low; improvement in overall survival relative to supportive care alone is modest, highlighting the critical need for efficient identification of effective novel therapies. Blocking programed cell death protein-1 (PD-1) signaling with nivolumab may increase the sensitivity of AML cells to azacitidine and improve outcomes and is the focus of one arm of the S1612 trial. Signaling through PD-1 contributes to tumor immune evasion and growth in AML [Chen, Cancer Biol Ther 2008]. Increased expression of PD-1 (~40% of AML), is associated with poor HMA response [Ørskov, Oncotarget 2015]. A single center azacitidine/nivolumab non-randomized phase II study in relapsed/refractory AML reported ORR of 33% (23/70), including 22% complete remission/complete remission with incomplete hematologic recovery [Daver, Cancer Discovery 2018]. About 25% of the patients developed grade 2-4 immune toxicities; nivolumab immune-related adverse events led to treatment discontinuation in nearly 1 in 7 patients. Study Design and Methods:The S1612 trial [NCT03092674] is a platform randomized phase II/III clinical trial with a common azacitidine control arm (CA) and two currently active experimental arms (EA). Therapy is intended for community setting: azacitidine/nivolumab; and azacitidine/midostaurin. The innovative design utilizes a phase II go/no-go decision comparing each EA with the CA independently when there are 100 pts/arm and 104 deaths on the EA and CA combined. EAs will proceed to phase III if the null hypothesis (HR=1) is rejected in favor of the EA (15% one-sided alpha). When the two currently active EAs complete phase II accrual, a third EA (decitabine/cytarabine) will open. The CA stays open the entire length of the trial and only concurrently randomized patients will be compared across arms. If an EA proceeds to phase III, 200 additional patients (300 total patients) will be accrued. Phase III analysis occurs 1.5 years after accrual or at 414 deaths (in the respective EA and CA), whichever comes first. The phase III tests the null hypothesis with 4.5% two-sided alpha and 83% power for each EA to detect an improvement in median OS from 10.4 to 15.6 months. Eligible pts are age ≥60 years, newly diagnosed AML with ≥ 20% blasts or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2); deemed by the treating physician unfit for standard cytotoxic chemotherapy; and no prior HMA permitted. Trial in Progress Issues:Between December 2017 and October 2018, 113 patients were screened and 78 randomized to study treatment (median/range age: 75/61-86 years; median/range performance status 1/0-3). Two concerns challenged this trial: 1) required administration of 7-day azacitidine at the enrolling sites created a burden for this population and 2) an early excess grade 5 toxicity signal in the azacitidine/nivolumab arm compared with the control arm. Without a control comparison, this safety signal likely would have been missed. Strategies to address these concerns were developed by the study team. Discussion with the sponsor and US Food and Drug Administration (FDA) focused on allowance of standard-of-care protocol-directed azacitidine administration in the patient's primary care doctor's office rather than at the oncology center. Because of the toxicity concern, the trial was placed on partial clinical hold for further evaluation and possible nivolumab-arm eligibility changes, along with new surveillance and pre-emptive action including prompt steroid initiation for suspected immune-related toxicities. The S1612 trial highlights special concerns when enrolling vulnerable populations onto leukemia clinical trials, and the importance of collaborative strategies including with the FDA to preserve clinical trial integrity for patient benefit. It also demonstrates the efficiency this novel platform design has for therapeutic investigation and, importantly, very early identification of serious toxicity. Updates on accrual and resolution and of these issues will be presented. Disclosures Hay: Kite: Research Funding; Gilead: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Roche: Research Funding; Novartis: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria. Walter:Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; New Link Genetics: Consultancy; Agios: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Seattle Genetics: Research Funding; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy. Foran:Agios: Honoraria, Research Funding. Radich:TwinStrand Biosciences: Research Funding; Novartis: Other: RNA Sequencing. Othus:Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Erba:Astellas Pharma: Consultancy; Amgen: Consultancy; Amgen: Consultancy; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Pfizer: Consultancy; Pfizer: Consultancy; ImmunoGen: Consultancy, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Astellas Pharma: Consultancy; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Michaelis:Pfizer: Equity Ownership, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; BMS: Research Funding; Bioline: Research Funding; ASTEX: Research Funding; Janssen: Research Funding; Millenium: Research Funding; Macrogeneics: Research Funding. OffLabel Disclosure: Off label experimental combination therapies in newly diagnosed AML/MDS will be discussed, including nivolumab and azacitidine.

Abstract Systemic immunosuppression following neurological insults including stroke, traumatic brain injury, and glioblastoma (GBM) causes mortality and leads to failure of immune-modulating therapies. Exact immunological nature and the underlying mechanisms of this immunosuppression are unknown. Our goal was to define effects of neurological insults given exclusively to the brain on the thymus. The thymus is the primary immune organ responsible for T-cell development and maintenance both in children and in adults. We evaluated the brain-thymus communication using the following neurological insults: physical injury, CNS viral infection, sterile injury, tumor implantation, and seizures. All insults resulted in significant thymic involution that was reversible upon clearance of the insult. Thymic involution did not occur following similar peripheral insults. We next demonstrated that the GL261 model of GBM recapitulates hallmark features of peripheral immunosuppression observed in GBM patients including low CD4 T-cell counts. Thus, we aimed to further study the immunosuppression affecting the thymus in this clinically relevant model. Principle component analysis following RNA-sequencing of thymi from naïve and glioma-bearing mice revealed unbiased separation of the groups suggesting that the thymus is directly affected by a brain tumor. To determine the extent to which thymic involution was caused by a soluble factor we employed parabiosis. We demonstrated that thymic involution was transferable from glioma-bearing to non-tumor-bearing parabionts. Similarly, serum taken from GL261 glioma-bearing mice potently inhibited proliferation of T-cells in vitro. Together our data demonstrate that CNS-specific insults, regardless of nature, cause immunosuppression by prompting thymic involution through circulating factors. This accounts at least partially for immune deficiencies observed following neurological injuries. Identification of this suppressive factor is crucial in designing future therapeutics for GBM patients, and patients with other acute and chronic neurological trauma.

OBJECTIVES: Alcohol-associated liver disease is increasing, especially hospitalizations with acute on chronic liver failure and need for liver transplant. We examined trends in prevalence, inhospital mortality, and resource utilization associated with AALD and ACLF in the young. METHODS: The National Inpatient Sample (2006–2014) was queried for hospitalizations with a discharge diagnosis of cirrhosis using the International Classification of Diseases, Ninth Edition, codes. ACLF hospitalization was defined as ≥2 organ failures and stratified by age: young (≤35 years) and older (>35 years). RESULTS: Of 447,090 AALD admissions (16,126 in young) between 2006 and 2014, ACLF occurred in 29,599 (6.6%), of which 1,143 (7.1%) were in young. Compared with older, admissions in young had more women (35% vs 29%), were obese (11% vs 7.6%), were Hispanics (29% vs 18%), have alcoholic hepatitis (AH) (41% vs 17%), and have ACLF grades 2 or 3 (34% vs 25%), P < 0.001 for all. Between 2006 and 2014, ACLF in AALD among young increased from 2.8% to 5.2%, with an AH proportion from 24% to 42%, P < 0.0001 for both. Young had more complications requiring ventilation (79% vs 76%) and dialysis (32% vs 28%), P < 0.001 for both. Compared with older, ACLF admission in young had longer hospitalization (12 vs 10 days) with higher hospital charges ($127,915 vs $97,511), P < 0.0001 for both, with 20% reduced inhospital mortality (54%–45%), P < 0.001. DISCUSSION: AALD-related hospitalizations are increasing in young in the United States, mainly because of the increasing frequency of AH. Furthermore, this disease burden in young is increasing with a higher frequency of admissions with more severe ACLF and consumption of hospital resources. Studies are needed to develop preventive strategies to reduce burden related to AALD and ACLF in young.

With the launch of the National Cancer Institute’s Precision Medicine Initiative in 2015, there has been a shift to trial designs that tailor health care solutions to individual patients by using a screening platform and by moving away from the one-trial/one-biomarker-at-a-time approach. To make precision medicine a reality, it is critical to identify and validate potential biomarkers to help select patients who will truly benefit from a targeted therapy. In this article, we discuss five trial designs: enrichment, umbrella, basket, subgroup, and window of opportunity. For each trial design, we describe the design characteristics, use ongoing or completed trials as case studies, provide any recent advances to the trial design, and discuss advantages and disadvantages of each design.

Abstract Background In a phase 2 PIONEER-HCM study, pts with symptomatic, obstructive hypertrophic cardiomyopathy (oHCM) showed improvement in left ventricular outflow tract (LVOT) obstruction, exercise capacity, and symptoms after 12 wk of treatment with the novel myosin modulator, mavacamten (Mava). Purpose To examine the long-term safety and effectiveness of Mava in PIONEER-OLE study Methods PIONEER-OLE (NCT03496168) is an ongoing 2-y multicenter study for adults with symptomatic oHCM who completed PIONEER-HCM (NCT02842242). The starting dose of Mava is 5 mg/d with titration at wk 6 to an individualized therapeutic dose (5, 10, or 15 mg). Evaluations are at wk 4, 6, 8, 12 and every 12 wk thereafter to monitor LV ejection fraction (LVEF), LVOT gradient, New York Heart Association (NYHA) class, NT-proBNP, drug concentration, and safety. Results 13 pts (mean age, 57.8 y; 9 male; 12 on beta-blockers) were enrolled. Mean baseline LVOT obstruction and LVEF, and wk 12 changes from baseline, were similar to those in PIONEER-HCM (Table). Mava significantly reduced resting and provoked LVOT gradients and NT-proBNP at wk 12 and 24 compared with baseline (P<0.004). Of 10 pts who reached wk 24, 8 reported improvement in NYHA class (1 improved Class III to II; 7 improved Class II to I), and 2 pts remained Class II. Mava has been well tolerated up to 40 wk; 31 adverse events (AEs; 22 mild, 5 moderate) were reported in 8 pts; 1 pt had 3 severe and 1 serious AE (cholangiocarcinoma); all AEs were unrelated to study drug. Results from PIONEER-OLE Parameter PIONEER-HCMa PIONEER-OLE Baseline Wk 12 Baselineb Wk 12 Change at Wk 12 Wilcoxon Signed Wk 24 Change at Wk 24 Wilcoxon Signed Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Rank Mean ± SD Mean ± SD Rank (n=13) (n=13) (n=13)c (n=12)c (n=12)c P value (n=10)c (n=10)c P value LVOT Rest gradient, mmHg 69.7±53.9 27.8±31.3 67.3±42.8 12.0±5.4 −57.9±43.2 0.0005 10.5±4.8 −66.6±42.4 0.0020 LVOT Valsalva gradient, mmHg 93.7±55.6 36.8±37.5 89.9±30.7 (n=12) 23.6±20.0 −66.4±35.3 (n=11) 0.0020 21.1±11.5 −67.3±33.5 (n=9) 0.0039 LVEF, % 73.0±5.6 64.6±10.5 72.0±4.9 67.6±7.2 −4.4±5.5 0.0269 68.2±6.5 −3.2±3.3 0.0195 NT-proBNP, pg/mL 1601.3±2782 (n=12) 684±980 1836±2886 181±211 −1759±2789 0.0005 170±225 −2128±3104 0.0039 Data extraction date January 24, 2019. aCombined results shown for pts from PIONEER-HCM originally in cohort A (n=5) and cohort B (n=8). bBaseline in PIONEER-OLE occurred 6–18 months after completion of PIONEER-HCM. cNumber of pts with data available for analysis, unless otherwise specified. Conclusion Despite management with current therapies, pts enrolled in PIONEER-OLE with similar levels of obstruction and hypercontractility as in PIONEER-HCM. In this longest observation period, Mava significantly reduced obstruction (LVOT gradient) in pts with oHCM beyond standard HCM therapy, while maintaining normal LVEF and improving symptoms. Acknowledgement/Funding MyoKardia

Abstract Background Diabetes is a prognostic factor for some malignancies, but its association with outcome in patients with advanced or metastatic colorectal cancer (CRC) is less clear. Methods This cohort study was nested within a randomized trial of first-line chemotherapy and bevacizumab and/or cetuximab for advanced or metastatic CRC. Patients were enrolled at 508 community and academic centers throughout the National Clinical Trials Network. The primary exposure was physician-documented diabetes at the time of enrollment. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS) and adverse events. Tests of statistical significance were two-sided. Results Among 2326 patients, 378 (16.3%) had diabetes. The median follow-up time was 6.0 years. We observed 1973 OS events and 2173 PFS events. The median time to an OS event was 22.7 months among those with diabetes and 27.1 months among those without diabetes (HR = 1.27, 95% CI = 1.13 to 1.44; P &lt; .001). The median time to a PFS event was 9.7 months among those with diabetes and 10.8 months among those without diabetes (HR = 1.16, 95% CI = 1.03 to 1.30; P = .02). Patients with diabetes were more likely to experience no less than grade 3 hypertension (8.1% vs 4.4%; P = .054) but were not more likely to experience other adverse events, including neuropathy. Conclusions Diabetes is associated with an increased risk of mortality and tumor progression in patients with advanced or metastatic CRC. Patients with diabetes tolerate first-line treatment with chemotherapy and monoclonal antibodies similarly to patients without diabetes.