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The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms “nonalcoholic” and “fatty” were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction–associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction–associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction–associated steatotic liver disease, who consume greater amounts of alcohol per week (140–350 g/wk and 210–420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

Introduction: Acrocyanosis and erythema pernio are 2 dermatologic manifestations of vasospastic changes. Primary care providers should consider that these conditions can occur as primary or idiopathic conditions and as secondary conditions related to another disease or medication. Herein we describe a case of acrocyanosis and erythema pernio attributed to vincristine therapy. Case Description: A 22-year-old man was evaluated for discomfort and red lesions involving the toes of both feet for several weeks. He had completed chemotherapy 1 month earlier for Ewing sarcoma in the right femur. Local control for the primary tumor included wide local excision and reconstruction with a vascularized fibular allograft from the right fibula. On examination, his right foot was dark blue and cool. Toes on both feet had nonpainful erythematous papules. After the case was discussed with the patient’s oncology team, the diagnosis was medication-induced acrocyanosis of the right foot and bilateral erythema pernio. Treatment consisted of supportive care to keep the feet warm and promote circulation to the feet. At 2-week follow-up, the patient’s symptoms and the appearance of his feet had markedly improved. Discussion: Primary care clinicians should be able to recognize dermatologic manifestations of vasospastic changes, including acrocyanosis and erythema pernio, and rule out possible secondary causes, such as pharmacologic agents. This patient’s history of therapy for Ewing sarcoma prompted consideration of medication-induced vasospastic changes most likely related to the adverse vasospastic effects of vincristine. Symptoms should improve with cessation of the offending medication.

Introduction: Relatively little is known about outcomes following return of secondary findings detected in large scale sequencing projects. We assessed 1-year outcomes following return of pathogenic/likely pathogenic (P/LP) variants associated with familial hypercholesterolemia (FH) in phase III of the eMERGE network (2015-2019). Methods: Adult participants (n=18,544) at 7 sites were enrolled in a prospective cohort study to study the clinical impact of returning results from targeted sequencing of 68 actionable genes, including LDLR , APOB , and PCSK9 . Process, intermediate, and/or clinical outcomes within 1-year after return of results (RoR) were ascertained by electronic health record (EHR) review. A process outcome was defined as referral to a specialist or ordering new tests, including lipid profile and screening tests for coronary heart disease. An intermediate outcome was defined as new diagnosis of FH or atherosclerotic cardiovascular disease. A clinical outcome was defined as initiation or change in lipid-lowering medication. The primary outcomes were a new diagnosis of FH and modification of lipid lowering therapy. Results: Results were returned to 134 individuals, and data for 119 participants were available for the outcomes analysis. Process (86%), intermediate (49%), and/or clinical (26%) outcomes occurred in 92% of participants. Process outcomes included 72% with new tests ordered and 61% referred to a specialist. Before RoR, 86.5% of individuals with FH associated P/LP variants had a diagnosis of hypercholesterolemia but only 17.6% had a diagnosis of FH; 89% were on a statin but only 58% were on a high intensity statin. Following RoR, 44% (52/119) received a new diagnosis of FH. Lipid lowering treatment was modified in 26% (31/119), including initiation of a statin in 5%, increasing statin dose in 13%, and adding ezetimibe or a PCSK9 inhibitor in 12.6%. Conclusions: In a multisite cohort of EHR-linked biobanks, monogenic FH was underdiagnosed (only 17.6% had a specific diagnosis) and undertreated (only 58% were on a high intensity statin); 44% of participants received a new diagnosis of FH and 26% had lipid lowering treatment modified after RoR. These results highlight the clinical utility of returning FH variants in EHR-linked biobanks.

PURPOSE Radiation-associated cardiac disease is a major cause of morbidity/mortality among childhood cancer survivors. Radiation dose-response relationships for cardiac substructures and cardiac diseases remain unestablished. METHODS Using the 25,481 5-year survivors of childhood cancer treated from 1970 to 1999 in the Childhood Cancer Survivor Study, we evaluated coronary artery disease (CAD), heart failure (HF), valvular disease (VD), and arrhythmia. We reconstructed radiation doses for each survivor to the coronary arteries, chambers, valves, and whole heart. Excess relative rate (ERR) models and piecewise exponential models evaluated dose-response relationships. RESULTS The cumulative incidence 35 years from diagnosis was 3.9% (95% CI, 3.4 to 4.3) for CAD, 3.8% (95% CI, 3.4 to 4.2) for HF, 1.2% (95% CI, 1.0 to 1.5) for VD, and 1.4% (95% CI, 1.1 to 1.6) for arrhythmia. A total of 12,288 survivors (48.2%) were exposed to radiotherapy. Quadratic ERR models improved fit compared with linear ERR models for the dose-response relationship between mean whole heart and CAD, HF, and arrhythmia, suggesting a potential threshold dose; however, such departure from linearity was not observed for most cardiac substructure end point dose-response relationships. Mean doses of 5-9.9 Gy to the whole heart did not increase the risk of any cardiac diseases. Mean doses of 5-9.9 Gy to the right coronary artery (rate ratio [RR], 2.6 [95% CI, 1.6 to 4.1]) and left ventricle (RR, 2.2 [95% CI, 1.3 to 3.7]) increased risk of CAD, and to the tricuspid valve (RR, 5.5 [95% CI, 2.0 to 15.1]) and right ventricle (RR, 8.4 [95% CI, 3.7 to 19.0]) increased risk of VD. CONCLUSION Among children with cancer, there may be no threshold dose below which radiation to the cardiac substructures does not increase the risk of cardiac diseases. This emphasizes their importance in modern treatment planning.

TPS4204 Background: The role of neoadjuvant chemotherapy in resectable pancreatic cancer has yet to be defined. Recent phase II trial results demonstrate a median overall survival time (mOS) of only 22.4 months after treatment with perioperative modified FOLFIRINOX (mFOLFIRINOX) with 36% not reaching surgery due to disease progression during neoadjuvant therapy. While potential benefits and shortcomings of neoadjuvant chemotherapy have been well documented, to date, no phase III trial has directly compared a perioperative versus an adjuvant chemotherapy strategy in resectable pancreatic cancer. Alliance for Clinical Trials in Oncology A021806 is an actively accruing randomized controlled phase III trial evaluating the efficacy of perioperative chemotherapy with mFOLFIRINOX in patients with resectable pancreatic cancer. Methods: To qualify for enrollment, patients must have biopsy-proven localized resectable pancreatic adenocarcinoma as defined by the National Comprehensive Cancer Network. Patients must have good performance status (ECOG 0 or 1) and be candidates to receive mFOLFIRINOX treatment. All patients enrolled undergo central radiologic eligibility review for quality control and are then randomized to either Arm 1 which consists of 8 cycles of neoadjuvant mFOLFIRINOX followed by 4 cycles of adjuvant mFOLFIRINOX or Arm 2 which includes upfront surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary endpoint of the trial is overall survival with secondary endpoints evaluating disease-free survival, margin-negative resection rate, surgical complications, and chemotherapeutic adverse events. Additional correlative endpoints include quality of life and radiomic imaging assessments. A total enrollment of 352 patients is planned from the US and Canada; current enrollment for this trial is at 145 patients. An OS interim analysis will be performed when 50% of the events (124) are observed combining the two arms. If the trial continues after interim analysis, the final OS analysis will be performed with a total of 248 events (combined arms). If the Cox model (stratified by tumor location and ECOG PS) comparing OS between arms produces a one-sided p-value < 0.05, then we will conclude that the OS of the perioperative therapy arm is superior to adjuvant therapy. The Alliance A021806 phase III trial aims to define a new standard of care for patients with resectable pancreatic cancer. Clinical trial information: NCT04340141 .

7006 Background: Older adult patients (pts) with Philadelphia-chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) have poor survival with chemotherapy. The α-CD22 Ab-drug conjugate inotuzumab ozogamicin (InO) and α-CD19/CD3 T-cell engager blinatumomab (blina) were each superior to chemotherapy in Phase III studies in relapsed/refractory B-ALL. Because InO induces high CR rates and blina can induce durable remissions in low burden disease, we conducted a Phase II trial of induction InO then blina for older adults with newly-diagnosed (ND), Ph-, B-ALL. Methods: Eligible were pts ≥60 years old with ND, Ph-, CD22+ (≥20% of blasts) B-ALL without plan for allogeneic HCT (alloHCT). Pts with CNS leukemia or liver disease were excluded. Induction IA was InO 0.8 mg/m 2 day (d) 1, 0.5 mg/m 2 d8, d15 IV on a 21d cycle. Pts with adequate cytoreduction (marrow blasts by ≥50% or cellularity ≤20%) after IA went to IB if in CR/CRi (InO 0.5 mg/m 2 d1, d8, d15 IV; 28d cycle) or IC if no CR/CRi (InO 0.8 mg/m 2 on d1 and 0.5 mg/m 2 on d8 and d15 IV; 28d cycle). Those without cytoreduction to IA started course II blina. Pts without events in IA/B/C received course II blina CIV (9 mcg/d x 7d then 28 mcg/d x 21d; 14d break; 28 mcg/d x28d). Pts with CR/CRi to InO received 2 more 28d cycles of blina, others received 3 more. CNS prophylaxis was methotrexate 15 mg intrathecal x 8. The primary endpoint was 1-yr event-free survival (EFS) with a lower limit of a 90% CI for 1-yr EFS >10% defined as success. EFS was the time from therapy start to failure to achieve CR/CRh/CRi by end Course II, progression, relapse, or death, whichever occurred first. Results: Thirty-three eligible pts were treated (1 ineligible, 2 nd malignancy). The median age was 71 years (range 60-84). Median WBC count was 3,200/mcl (range 6-38,000). Median CD22 expression was 92% (range 21-100%). Eight pts had therapy-related ALL. The cumulative CR rates through Course IA/B/C and Course II were 85% and 97%, respectively (Table). With median follow up of 22 mo, the 1-yr EFS was 75% (95% CI 61-92%). The 2-sided 90% CI was 63-89% for 1-yr EFS with lower bound above 10% indicating regimen success. Twelve pts had events: 9 relapses, 2 deaths in remission (1 after alloHCT), and 1 death without remission from respiratory failure with sinusoidal occlusion syndrome of liver. The 1-yr OS was 84% (95% CI 72-98%). Nine pts have died, 6 after relapse. Conclusions: InO induction then blina consolidation is highly active for ND, Ph-, CD22+ B-ALL. The regimen is an option for older adults and a comparator regimen for future studies. Support: U10CA180821, U10CA180882, U10CA180820 https://acknowledgments.alliancefound.org . Clinical trial information: NCT03739814 . N=33 I A/B/C II Composite CR* 28 ( 85%) 32 ( 97%) CR 15 (45%) 19 (58%) CRh 11 (33%) 12 (36%) CRi 2 (6%) 1 (3%) Refractory 3 (9%) † - 1-yr EFS 75% (95% CI 61-92%) 1-yr OS 84% (95% CI 72-92%) *CR+CRh+CRi † 1 completed IA only

ObjectiveWe aimed to develop readily measurable digital quality measure statements for clinical care in systemic lupus erythematosus (SLE) using a multistep process guided by consensus methods.MethodsUsing a modified Delphi process, an American College of Rheumatology (ACR) workgroup of SLE experts reviewed all North American and European guidelines from 2000 to 2020 on treatment, monitoring, and phenotyping of patients with lupus. Workgroup members extracted quality constructs from guidelines, rated these by importance and feasibility, and generated evidence‐based quality measure statements. The ACR Rheumatology Informatics System for Effectiveness (RISE) Registry was queried for measurement data availability. In 3 consecutive Delphi sessions, a multidisciplinary Delphi panel voted on the importance and feasibility of each statement. Proposed measures with consensus on feasibility and importance were ranked to identify the top 3 measures.ResultsReview of guidelines and distillation of 57 quality constructs resulted in 15 quality measure statements. Among these, 5 met high consensus for importance and feasibility, including 2 on treatment and 3 on laboratory monitoring measures. The 3 highest‐ranked statements were recommended for further measure specification as SLE digital quality measures: 1) hydroxychloroquine use, 2) limiting glucocorticoid use >7.5 mg/day to <6 months, and 3) end‐organ monitoring of kidney function and urine protein excretion at least every 6 months.ConclusionThe Delphi process selected 3 quality measures for SLE care on hydroxychloroquine, glucocorticoid reduction, and kidney monitoring. Next, measures will undergo specification and validity testing in RISE and US rheumatology practices as the foundation for national implementation and use in quality improvement programs.image

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3−, MCP-2−, and IL20-dependent pathways.

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor. Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 10 6 plaque-forming units (PFU)/mL in week 1, followed by 10 8 PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported. At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number: NCT01740297 .