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Background: The prognosis for patients (pts) with relapsed T-ALL and T-LL is dismal; the primary goal of T-ALL/T-LL treatment is to prevent relapse. AALL1231 was a COG phase 3 clinical trial that randomized children and young adults (age 1-30 years) to a modified augmented BFM (aBFM) backbone +/- the proteasome inhibitor bortezomib during induction and delayed intensification (DI) (1.3mg/m2 x 4 doses per block). Bortezomib was tested in frontline therapy based on strong preclinical data and data in relapse on COG AALL07P1. Pts were stratified as standard (SR), intermediate (IR), or very high risk (VHR), primarily based on disease response: morphologic and minimal residual disease (MRD) at end induction and end consolidation (T-ALL) and radiographic response (T-LL). To eliminate cranial radiation (CXRT) in all pts, (except VHR: Day 29 M3 marrow or EOC MRD >0.1% or pts with overt CNS leukemia at diagnosis, CNS3), the aBFM backbone was modified to use dexamethasone (dex) as the sole corticosteroid and an extra pegaspargase dose was added in both induction and DI, following the MRC strategy. IR pts received a second interim maintenance (IM) phase (one Capizzi MTX; one HD-MTX). Following consolidation, VHR pts received 3 BFM high-risk intensification blocks in lieu of IM. Results: AALL1231 accrued 847 patients (824 eligible and evaluable) of 1400 anticipated from 2014 until early closure in 2017 when COG AALL0434 established that nelarabine (NEL) improved DFS in T-ALL (AALL1231 did not include NEL). The 3-year EFS for Arm A (no bortezomib) vs Arm B (bortezomib) were 81.7±2.4% and 85.1±2.2 % (HR=0.782, p=0.074) (3/31/20 data cut-off; see Table 1 for additional outcomes). SR and IR pts, who account for 95% of pts, had significantly improved EFS on Arm B as compared with Arm A. Yet, VHR patients had improved EFS on Arm A. Patients with T-LL had improved EFS and OS with bortezomib: 3-year EFS (76.5±5.9% vs 88.3±4.5%; p = 0.01); 3-year OS (78.0±5.8% vs 89.5±4.2%, p = 0.007). A similar improvement in EFS and OS was not seen in T-ALL; however, with longer follow-up this may change. No excess toxicity was seen on Arm B. A dex-based Induction did result in lower MRD rates; more T-ALL pts on AALL1231 had Day 29 MRD <0.1% as compared with AALL0434 which used a prednisone-based Induction (AALL1231 Arm A: 69.6%; Arm B: 72.2%; AALL0434: 64.6%; p = 0.02). However, this did not translate into improved survival. Indeed OS, but not EFS was worse on AALL1231 than AALL0434. On-going analyses are investigating the increased mortality on AALL1231, but preliminary analyses suggest a combination of increased toxic deaths and overall poor outcome in the VHR group. On AALL0434, 90.8% of T-ALL pts received CXRT. On AALL1231, 9.5% of subjects were scheduled to receive CXRT (CNS3 T-ALL/T-LL: 5.7%; VHR T-ALL: 4.1%). A comparison of AALL0434 pts that received CXRT with similar AALL1231 pts not receiving CXRT on AALL1231 demonstrated similar EFS (p = 0.14) and OS (p = 0.42) (Table 2). CNS relapse rates were higher in these pts on AALL1231 (4.5%) as compared with AALL0434 (1.7%), but overall relapse rates were the same (6.5% vs 6.4%). Notably the benefit of NEL in AALL0434 was due to reduction of CNS relapses. 128 AALL1231 pts came off protocol therapy after the study was closed for physician or patient/parent choice. Data collection is underway to understand the reasons for removal, including if it was to receive NEL. Conclusions: Outcomes for SR and IR pts with T-ALL and T-LL treated with bortezomib were excellent despite the elimination of prophylactic CXRT. Bortezomib significantly improved 3-year EFS for these groups, comprising ~95% of pts. Outcomes for VHR pts were dismal and worse on the bortezomib arm. T-LL pts had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. This is the first trial to demonstrate an OS benefit for de novo pediatric T-LL with a new agent; however, longer follow-up is needed. Therapy intensification allowed elimination of CXRT in the majority of pts without excessive relapse. These results should be interpreted cautiously as the 3-yr OS on AALL1231 was inferior to AALL0434. Nevertheless, incorporating bortezomib into standard therapy for de novo T-LL appears advantageous. Future COG T-ALL/T-LLy trials will build on the positive findings from AALL0434 and AALL1231, balancing intensity while mitigating toxicity to maintain high cure rates without routine cranial radiation. (MLL, SPH, EAR contributed equally) Disclosures Teachey: Amgen: Consultancy; Janssen: Consultancy; La Roche: Consultancy; Sobi: Consultancy. Dunsmore:Dexcom: Current equity holder in publicly-traded company. Galardy:Abbott: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company. Harker-Murray:Regerenon Pharmaceuticals: Consultancy. Hermiston:Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Shimano:Novartis: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. McKay:Immunogen: Current Employment. Bollard:Mana Therapeutics: Other: IP. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. Hunger:Novartis: Consultancy; Amgen Inc.: Current equity holder in publicly-traded company, Honoraria. Raetz:Celgene/BMS: Other; Pfizer: Research Funding. OffLabel Disclosure: Bortezomib for the treatment of acute lymphoblastic leukemia under an IND

There is a lack of consensus on how we define heart failure with preserved ejection fraction (HFpEF), with wide variation in diagnostic criteria across society guidelines. This lack of uniformity in disease definition stems in part from an incomplete understanding of disease pathobiology, phenotypic heterogeneity, and natural history. We review current knowledge gaps and existing diagnostic tools and algorithms. We present a simple approach to implement these tools within the constraints of the current knowledge base, addressing separately (1) hospitalized individuals with rest congestion, where diagnosis is more straightforward; and (2) individuals with exercise intolerance, where diagnosis is more complex. Here, a potential role for advanced or provocative testing, including evaluation of hemodynamic responses to exercise is considered. More importantly, we propose focus areas for future studies to develop accurate and feasible diagnostic tools for HFpEF, including animal models that recapitulate human HFpEF, and human studies that both address a fundamental understanding of HFpEF pathobiology, and new diagnostic approaches and tools, as well. In sum, there is an urgent need to more accurately define the syndrome of HFpEF to inform diagnosis, patient selection for clinical trials, and, ultimately, future therapeutic approaches.

OBJECTIVE Among medical practices, surgical fields, including neurosurgery, are at a high risk for medical malpractice litigation. With meningiomas contributing to 10% of the total neurosurgery litigation cases, the aim of this study was to identify demographic characteristics, reasons for litigation, and surgical complications commonly reported in these cases. This analysis serves to increase neurosurgeons’ awareness of factors associated with medical malpractice litigation. METHODS The online legal database Westlaw was utilized to query public litigation cases related to the medical management of meningiomas between December 1985 and May 2020. Variables extracted included the following: plaintiff and defendant demographics, litigation category, plaintiff medical complaints, and trial outcomes. The authors compared these characteristics between cases with decisions in favor of the defendant and those with decisions in favor of the plaintiff. RESULTS A total of 47 cases met the inclusion criteria. Failure to diagnose (68.1%) was the most common type of malpractice claim, and surgical complications (19.1%), motor weakness (33%), and financial loss (33%) were cited as the most common postoperative complaints. Individual specialties that most often required defense due to malpractice claims were radiology (21.7%) and neurosurgery (19.6%). The jury verdict was in favor of the defense in 51.1% of cases and in favor of the plaintiff in 27.7% of cases. A settlement was reached in 19.1% of cases. The mean payout for a verdict in favor of the plaintiff was $3,409,650.22, while the mean payout for settlements was $867,555.56. The greatest average payout for specialties was in neurosurgery at $3,414,400, followed by radiology at $3,192,960. Cases with a verdict in favor of the plaintiff were more likely to involve an internal medicine physician as a defendant (p = 0.007). CONCLUSIONS Over one-half of the cases resulted in a defendant’s verdict with failure to diagnose cited as the most common reason for litigation. Radiology and neurosurgery were the most common specialties for legal cases and also had some of the largest average payouts based on specialty. Motor weakness and financial loss were the most common plaintiff postoperative complaints. These findings may inform surgeons on active measures to take, such as increasing focus on diagnostic accuracy and reducing specific postoperative complaints, such as motor weakness, through risk management and prophylactic measures, to reduce unfavorable legal outcomes.

AbstractGlycosylation is a critical post/peri‐translational modification required for the appropriate development and function of the immune system. As an example, abnormalities in glycosylation can cause antibody deficiency and reduced lymphocyte signaling, although the phenotype can be complex given the diverse roles of glycosylation. Human MGAT2 encodes N‐acetylglucosaminyltransferase II, which is a critical enzyme in the processing of oligomannose to complex N‐glycans. Complex N‐glycans are essential for immune system functionality, but only one individual with MGAT2‐CDG has been described to have an abnormal immunologic evaluation. MGAT2‐CDG (CDG‐IIa) is a congenital disorder of glycosylation (CDG) associated with profound global developmental disability, hypotonia, early onset epilepsy, and other multisystem manifestations. Here, we report a 4‐year old female with MGAT2‐CDG due to a novel homozygous pathogenic variant in MGAT2, a 4‐base pair deletion, c.1006_1009delGACA. In addition to clinical features previously described in MGAT2‐CDG, she experienced episodic asystole, persistent hypogammaglobulinemia, and defective ex vivo mitogen and antigen proliferative responses, but intact specific vaccine antibody titers. Her infection history has been mild despite the testing abnormalities. We compare this patient to the 15 previously reported patients in the literature, thus expanding both the genotypic and phenotypic spectrum for MGAT2‐CDG.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

Abstract Background: IMpower133 (NCT02763579), a global Phase I/III, randomized, double-blind, placebo (PBO)-controlled trial, showed that the addition of atezo (anti-PD-L1) to CE for 1L ES-SCLC led to statistically and clinically significant OS and PFS improvement vs CE alone. Here we report updated OS and exploratory analyses. Methods: Pts with untreated ES-SCLC were randomized 1:1 to receive four 21-day cycles of E (100 mg/m2 IV, days 1-3) + C (AUC 5 mg/mL/min IV, day 1) with atezo (1200 mg IV, day 1) or PBO, followed by maintenance therapy with atezo or PBO until intolerable toxicity, progression or loss of clinical benefit. PD-L1 testing was not required for enrollment. Coprimary endpoints were investigator-assessed PFS (RECIST 1.1) and OS. Interim and final OS analyses were planned for ≈240 and ≈306 events, respectively. OS was significant at the interim analysis. Updated OS, exploratory biomarkers and patterns of disease progression were analyzed. Results: 201 and 202 pts were randomized to receive atezo+CE and PBO+CE, respectively. The median follow-up was 22.9 mo and 302 deaths had occurred. Median OS for the atezo and PBO arms was 12.3 and 10.3 mo, respectively (HR, 0.76 [95% CI: 0.60, 0.95]; descriptive P = 0.0154). At the 18-mo landmark, the OS rate was 13% higher with atezo+CE than with PBO+CE (Table). Exploratory analyses showed treatment benefit with atezo+CE regardless of biomarker status. 181 (90.0%) And 194 (96.0%) pts in the atezo+CE and PBO+CE arms, respectively, had RECIST-defined disease progression. Progression at existing, new or existing and new lesions was numerically lower with atezo+CE than with PBO+CE. Common sites of new lesions included the CNS, lung, lymph node and liver, with similar incidences between arms. Conclusion: Adding atezo to CE continued to provide OS improvement for 1L ES-SCLC in an all-comer population. The updated results of IMpower133 further support this regimen for untreated ES-SCLC. Landmark OSAtezo + CE, n = 201PBO + CE, n = 20212 Mo, n (%)93 (51.9)74 (39.0)18 Mo, n (%)61 (34.0)39(21.0)Median OS in biomarker subgroupsAtezo + CEPBO + CEITT (N = 403), mo12.310.3HR (95% CI)0.76 (0.61, 0.96)aITT-BEP (n = 137), mo9.98.9HR (95% CI)0.70 (0.48, 1.02)Non-BEP (n = 266), mo14.611.2HR (95% CI)0.81 (0.61, 1.08)PD-L1 expression, 1% TC or IC< 1% (n = 65), mo10.28.3HR (95% CI)0.51 (0.30, 0.89)≥ 1% (n = 72), mo9.710.6HR (95% CI)0.87 (0.51, 1.49)PD-L1 expression, 5% TC or IC< 5% (n = 108), mo9.28.9HR (95% CI)0.77 (0.51, 1.17)≥ 5% (n = 29), mo21.69.2HR (95% CI)0.60 (0.25, 1.46)Disease progression at sites, n (%)Atezo + CEPBO + CEExisting116 (57.7)131 (64.9)New86 (42.8)99 (49.0)Existing and new42 (20.9)57 (28.2)BEP, biomarker-evaluable population; ITT, intention-to-treat population.a Stratified HR. BEP included pts evaluable by PD-L1 IHC using the VENTANA SP263 assay. Citation Format: Leora Horn, Stephen V. Liu, Aaron S. Mansfield, Tony Mok, Arnaud Scherpereel, Niels Reinmuth, Marina Chiara Garassino, Javier De Castro Carpeno, Raffaele Califano, Makoto Nishio, Francisco Orlandi, Jorge Arturo Alatorre Alexander, Ticiana Leal, Ying Cheng, Jong-Seok Lee, Sivuonthanh Lam, Mark McCleland, Yu Deng, See Phan, Martin Reck. IMpower133: Updated OS and exploratory analyses of first-line (1L) atezolizumab (atezo) + carboplatin (C) + etoposide (E) in extensive-stage SCLC (ES-SCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT220.

Abstract Daratumumab in combination with lenalidomide‐dexamethasone (D‐Rd) recently received FDA approval for the treatment of transplant‐ineligible patients with newly diagnosed multiple myeloma (NDMM). The present PEGASUS study compared progression‐free survival (PFS) in patients treated with D‐Rd in the MAIA trial and patients treated with common standard‐of‐care regimens from the Flatiron Health electronic health record‐derived deidentified database, which has data from patients treated primarily at community‐based oncology practices in the United States. Individual‐level patient data from both data sources were used to perform an anchored indirect treatment comparison (ITC) of D‐Rd to bortezomib‐lenalidomide‐dexamethasone (VRd) and bortezomib‐dexamethasone (Vd); lenalidomide‐dexamethasone (Rd) was the common anchor for the ITC. Hazard ratios (HRs) reflecting direct comparisons of PFS within MAIA (D‐Rd vs Rd) and Flatiron Health (VRd vs Rd; Vd vs Rd) were used to make ITCs for D‐Rd vs VRd and Vd, respectively. After application of MAIA inclusion/exclusion criteria and propensity‐score weighting, the Flatiron Health patients resembled the MAIA trial population on measured baseline characteristics. Based on the direct comparison within MAIA, treatment with D‐Rd was associated with a significantly lower risk of progression or death compared to Rd (HR 0.54; 95% CI 0.42, 0.71). Based on the ITCs, D‐Rd was associated with a significantly lower risk of progression or death compared to VRd (HR 0.68; 95% CI 0.48, 0.98) and Vd (HR 0.48; 95% CI 0.33, 0.69). In the absence of head‐to‐head trials comparing D‐Rd to VRd or Vd, the present ITC may help inform treatment selection in transplant‐ineligible patients with NDMM.

Abstract Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation, including epigenetic decoration of chromatin structure and functional modulation of bioactive components. Here we report that expression of the histone H3-specific demethylase KDM4 is upregulated in human stromal cells upon cellular senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation are correlated with adverse survival of cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq and expression profiling through RNA-seq reveal extensive reorganization of chromosomes and spatiotemporal reprogramming of the transcriptomic landscape, events responsible for development of the senescence-associated secretory phenotype (SASP). Selectively targeting KDM4 dampens the SASP of senescent stromal cells and enhances the apoptotic index of cancer cells in the treatment-damaged tumor microenvironment (TME), together prolonging overall survival of experimental animals. Our study supports the dynamic change of H3K9/H3K36 methylation marks during cellular senescence, identifies an unusually permissive chromatin state, unmasks KDM4 as a key modulator of the SASP, and presents a novel therapeutic avenue to manipulate cellular senescence and curtail age-related pathologies.

Abstract Aims Catheter ablation is an effective treatment for post-infarction ventricular tachycardia (VT). However, some patients may experience a worsened arrhythmia phenotype after ablation. We aimed to determine the prevalence and prognostic impact of arrhythmia exacerbation (AE) after post-infarction VT ablation. Methods and results A total of 1187 consecutive patients (93% men, median age 68 years, median ejection fraction 30%) who underwent post-infarction VT ablation at six centres were included. Arrhythmia exacerbation was defined as post-ablation VT storm or incessant VT in patients without prior similar events. During follow-up (median 717 days), 426 (36%) patients experienced VT recurrence. Events qualifying as AE occurred in 67 patients (6%). Median times to VT recurrence with and without AE were 238 [interquartile range (IQR) 35–640] days and 135 (IQR 22–521) days, respectively (P = 0.25). Almost half of the patients (46%) who experienced AE experienced it within 6 months of the index procedure. Patients with AE had had longer ablation times during the ablation procedures compared to the rest of the patients (median 42 vs. 34 min, P = 0.02). Among patients with VT recurrence, the risk of death or heart transplantation was significantly higher in patients with than without AE (hazard ratio 1.99, 95% CI 1.28–3.10; P = 0.002) after adjusting for age, gender, ejection fraction, cardiac resynchronization therapy, post-ablation non-inducibility, and post-ablation amiodarone use. Conclusion Arrhythmia exacerbation after ablation of infarct-related VT is infrequent but is independently associated with an adverse long-term outcome among patients who experience a VT recurrence. The mechanisms and mitigation strategies of AE after catheter ablation require further investigation.

Abstract BackgroundOur study aims to fill the vacancy of litigation studies related to trigeminal neuralgia management, and to give healthcare providers the necessary information needed to better understand the potential litigious outcomes that often follow certain treatment methods.MethodsWe queried the Westlaw Edge legal database to identify litigation cases related to the management of trigeminal neuralgia for the years 1985-2019 using the following search criteria: (trigeminal & neuralgia), (tic & douloureux) and (microvascular & decompression). Key variables extracted included the following: plaintiff medical complaints, trial outcome, payout, and demographic characteristics. Continuous variables were compared between cases in favor of defendant and cases in favor of plaintiff using t-test or Wilcoxon rank sum test. Categorical variables were compared using chi-square or Fischer’s exact test.Results49 cases met the inclusion criteria – for those cases surgical complication (42.9%) and failure to diagnose (32.7%) were cited as the most common alleged reasons for filing a malpractice claim. Cranial nerve deficits (34.7%) and loss of consortium (12.2%) were the most frequent post-operative complaints. Verdicts ruled in favor of the defendant in 61.2% of cases, and for the plaintiff in 26.5% of cases with a mean payout of $1,982,428.46. Dental specialists were included in the most cases, 63.3%, and the average payout was $415,908, while Neurosurgical specialists were involved in 20.4% of cases with an average payout of $618,775. Cases where the verdict was in favor of the plaintiff were more likely to be older than cases with a verdict in favor of the defendant (p=0.03). ConclusionsOver one-half of the cases resulted in a defendant’s verdict with surgical complications cited as the most common reason for litigation. Dentistry and neurosurgery were listed as the most common individual physician specialties for defendants, also contributing to the largest average payouts based on specialty (for specialties > 1 occurrence). Cranial nerve deficits and loss of consortium were the most common plaintiff post-operative complaints. A key implication of this study is the need for more extensive discussions between physician and patient regarding informed consent, especially when neurosurgical interventions are required.