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Abstract Background A decrease in antimicrobial stewardship activities has been observed in our hospital since the beginning of the pandemic. The study aim was to evaluate the impact of decrease in antimicrobial stewardship activities in Klebsiella pneumoniae and Escherichia coli acquired multidrug-resistance. Methods The quarterly percentage of broad-spectrum antibiotic prescriptions evaluated by antimicrobial stewardship team (AMST), the quarterly consumption of broad-spectrum antimicrobials and the quarterly proportion of multidrug-resistant K. pneumoniae and E. coli were assessed between October 2016 and December 2022, with 2 periods of time, before the pandemic (October 2016-March 2020) and after the pandemic (April 2020-December 2022).Time series analysis was performed with ARIMA models to evaluate the association between decrease in AMST activities with multidrug-resistance in K. pneumoniae or E. coli. Correlation between broad-spectrum antibiotic prescriptions reviewed by AMST with broad-spectrum antimicrobials consumption and proportion of multidrug-resistance in K. pneumoniae or E. coli in urine cultures was assessed using the Pearson correlation coefficient. Results Percentage of broad-spectrum antimicrobials evaluated by AMST was 77% in first period and 29% in second period. The mean of broad-spectrum antibiotics consumption in first period was 13.02 DDD/100 bed-days and 15.35 DDD/100 bed-days in second period. Decrease of AMST activities was associated with an 37% increase in multidrug-resistant K. pneumoniae in second period compared with first period (p=0.02). No differences were found in E. coli. Correlation between percentage of AMST-reviewed broad-spectrum antibiotics with consumption of these antibiotics was good (correlation coefficient -0,7; p< 0,01). Correlation between ASMT-reviewed broad-spectrum antibiotics and multidrug-resistant K. pneumoniae was moderate (correlation coefficient -0.44; p=0,02). No correlation between ASMT-reviewed broad-spectrum antibiotics and multidrug-resistant E. coli (correlation coefficient 0,09; p=0,6) was found. Conclusion Decrease in antimicrobial stewardship activities was associated with high isolation of multidrug-resistant K. pneumoniae in urine cultures. Disclosures All Authors: No reported disclosures

Key Points AKI survivors experience gaps in care that contribute to worse outcomes, experience, and cost. Challenges to optimal care include issues with information transfer, education, collaborative care, and use of digital health tools. Research is needed to study these challenges and inform optimal use of diagnostic and therapeutic interventions to promote recovery AKI affects one in five hospitalized patients and is associated with poor short-term and long-term clinical and patient-centered outcomes. Among those who survive to discharge, significant gaps in documentation, education, communication, and follow-up have been observed. The American Society of Nephrology established the AKINow taskforce to address these gaps and improve AKI care. The AKINow Recovery workgroup convened two focus groups, one each focused on dialysis-independent and dialysis-requiring AKI, to summarize the key considerations, challenges, and opportunities in the care of AKI survivors. This article highlights the discussion surrounding care of AKI survivors discharged without the need for dialysis. On May 3, 2022, 48 patients and multidisciplinary clinicians from diverse settings were gathered virtually. The agenda included a patient testimonial, plenary sessions, facilitated small group discussions, and debriefing. Core challenges and opportunities for AKI care identified were in the domains of transitions of care, education, collaborative care delivery, diagnostic and therapeutic interventions, and digital health applications. Integrated multispecialty care delivery was identified as one of the greatest challenges to AKI survivor care. Adequate templates for communication and documentation; education of patients, care partners, and clinicians about AKI; and a well-coordinated multidisciplinary posthospital follow-up plan form the basis for a successful care transition at hospital discharge. The AKINow Recovery workgroup concluded that advancements in evidence-based, patient-centered care of AKI survivors are needed to improve health outcomes, care quality, and patient and provider experience. Tools are being developed by the AKINow Recovery workgroup for use at the hospital discharge to facilitate care continuity.

Abstract High-grade glioma continues to have dismal survival owing in part to its intra- and inter-patient heterogeneity. Standard clinical protocol collects tumor samples with the aim of providing or confirming a diagnosis and determining the status of a few key genes (e.g. IDH1, MGMT). However, this protocol is unable to capture the diversity within tumor regions, immune expression or normal cell abundances that play key roles in the development of the disease. To overcome this, during surgery we collect image-localized multi-regional biopsies to characterize this disease heterogeneity. Data collection is ongoing, and we currently have 202 samples from 58 patients with available bulk RNA-Seq. With a single-cell reference dataset from Columbia University, we used CIBERSORTx, a deconvolution method, to predict relative abundances of 7 normal, 6 glioma, and 5 immune cell subpopulations for each sample. We used Cox proportional hazard models with first-order statistics (mean, minimum, maximum) of abundances within patients to determine whether these are prognostic, then used TCGA RNA-Seq data to validate these findings. We found that one glioma proneural subtype was significantly beneficial for patient survival relative to other glioma subtypes across all statistics (and showed significance in TCGA). Proliferative and mesenchymal glioma subtypes also showed significance for one or two of the calculated statistics. Oligodendrocyte progenitor cell abundances were consistently significantly beneficial for patient survival in our cohort, while an increased abundance of abnormal (reactive) astrocytes is associated with poor prognosis. We also ran these analyses within invasive margin and core tumor regions to determine location-specific population abundances associated with patient survival. In conclusion, understanding the in vivo diversity of cellular subpopulations within high grade glioma is important for treatment stratification and patient benefit.

AbstractAnti‐CD19 chimeric antigen receptor T‐cell therapy (CART) has revolutionized the outcomes of relapsed and/or refractory B‐cell non‐Hodgkin lymphoma. However, CART is still limited by its availability, toxicity, and response durability. Not all patients make it to the CART infusion phase due to disease progression. Among those who receive CART, a significant number of patients experience life‐threatening cytokine release syndrome toxicity, and less than half maintain a durable response with the majority relapsing in pre‐existing sites of disease present pre‐CART. Radiation therapy stands as a promising peri‐CART and salvage treatment that can improve the outcomes of these patients. Evidence suggests that bridging radiotherapy prior to CART controls the disease during the manufacturing period, augments response rates and local control, cytoreduces/debulks the disease and decreases the severity of cytokine release syndrome, and may prolong disease‐free intervals and survival especially in patients with bulky disease. Consolidative radiotherapy for residual post‐CART disease alters the pattern of relapse and improves local recurrence‐free and progression‐free survivals. Salvage radiotherapy for relapsed post‐CART disease has favorable survival outcomes when delivered comprehensively for patients with limited relapsed disease and palliates symptoms for patients with diffuse relapsed disease. The biology of the disease during the peri‐CART period is poorly understood, and further studies investigating the optimal timing and dosing of radiation therapy (RT) are needed. In this review, we tackle the most significant challenges of CART, review and propose how RT can help mitigate these challenges, and provide The Mayo Clinic experts' approach on incorporating RT with CART.

Abstract Purpose: To identify potential predictors of response and resistance mechanisms in patients with hormone receptor–positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC) treated with the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib ± endocrine therapy (ET), baseline and acquired genomic alterations in circulating tumor DNA (ctDNA) were analyzed and associated with clinical outcomes. Experimental Design: MONARCH 3: postmenopausal women with HR+, HER2− ABC and no prior systemic therapy in the advanced setting were randomly assigned to abemaciclib or placebo plus nonsteroidal aromatase inhibitor (NSAI). nextMONARCH: women with HR+, HER2− metastatic breast cancer that progressed on/after prior ET and chemotherapy were randomly assigned to abemaciclib alone (two doses) or plus tamoxifen. Baseline and end-of-treatment plasma samples from patients in MONARCH 3 and nextMONARCH (monotherapy arms) were analyzed to identify somatic genomic alterations. Association between genomic alterations and median progression-free survival (mPFS) was assessed. Results: Most patients had ≥1 genomic alteration detected in baseline ctDNA. In MONARCH 3, abemaciclib+NSAI was associated with improved mPFS versus placebo+NSAI, regardless of baseline alterations. ESR1 alterations were less frequently acquired in the abemaciclib+NSAI arm than placebo+NSAI. Acquired alterations potentially associated with resistance to abemaciclib ± NSAI included RB1 and MYC. Conclusions: In MONARCH 3, certain baseline ctDNA genomic alterations were prognostic for ET but not predictive of abemaciclib response. Further studies are warranted to assess whether ctDNA alterations acquired during abemaciclib treatment differ from other CDK4/6 inhibitors. Findings are hypothesis generating; further exploration is warranted into mechanisms of resistance to abemaciclib and ET. See related commentary by Wander and Bardia, p. 2008

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Abstract Disclosure: K.M. Dahir: Consulting Fee; Self; Alexion Pharmaceuticals, Inc., Ultragenyx, Inozyme, AM Pharma. Grant Recipient; Self; Regeneron Pharmaceuticals, Alexion Pharmaceuticals, Inc., AstraZeneca, Ultragenyx. J. McGinniss: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E. Forleo-Neto: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Mellis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R.J. Sanchez: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. M. Di Rocco: Research Investigator; Self; Regeneron Pharmaceuticals, Ipsen. R. Keen: Advisory Board Member; Self; International Clinical Council on FOP and IFOPA Registry. Research Investigator; Self; Ipsen, Regeneron Pharmaceuticals, Clementia. P. Orcel: Research Investigator; Self; Regeneron Pharmaceuticals. C. Roux: Consulting Fee; Self; Alexion Pharmaceuticals, Inc., Amgen Inc. Grant Recipient; Self; Regeneron Pharmaceuticals, Kyowa, Kirin Brewery, Alexion Pharmaceuticals, Inc. J. Tabarkiewicz: Speaker; Self; Merck, Novartis Pharmaceuticals. Other; Self; SoftSystem. J. Bachiller-Corral: Research Investigator; Self; Regeneron Pharmaceuticals. A.M. Cheung: Consulting Fee; Self; Ipsen. Grant Recipient; Self; Ipsen, Incyte, Regeneron Pharmaceuticals. M. Al Mukaddam: Grant Recipient; Self; Ipsen, Clementia, Incyte, Regeneron Pharmaceuticals. K. Mohammadi: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. D. Srinivasan: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A. Rankin: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A.N. Economides: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. D. Gonzalez Trotter: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. F.S. Kaplan: Research Investigator; Self; Regeneron Pharmaceuticals, Clementia, Ipsen. M.W. Eekhoff: Grant Recipient; Self; Regeneron Pharmaceuticals, Ipsen, AstraZeneca, IMI, IFOPA. R.J. Pignolo: Grant Recipient; Self; Regeneron Pharmaceuticals, Clementia, Ipsen, Incyte. Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare autosomal dominant disorder driven by missense mutations in ACVR1. This results in inappropriate activation by activin-A. FOP is characterized by progressive heterotopic ossification and painful soft tissue inflammatory events known as flare-ups. Garetosmab, an investigational, fully human monoclonal antibody against activin-A, prevents formation of new heterotopic ossification lesions in FOP. Here we describe the impact of garetosmab on flare-up events in the LUMINA-1 study (NCT03188666). Methods: This was a post hoc analysis of phase 2 LUMINA-1, a randomized double-blind placebo-controlled study that evaluated the safety and efficacy of garetosmab 10 mg/kg/every 4 weeks intravenous vs placebo in adult patients with FOP over 28 weeks (Period 1), followed by a 28-week open-label treatment period (Period 2) and subsequent open-label extension (Period 3). Patient-reported flare-ups were collected via a patient diary and severity of symptoms was reported as mild, moderate, or severe. Clinician-reported flare-ups were collected as adverse events. Results: In Period 1, there was a significant reduction in the proportion of patients reporting one or more flare-ups (35% vs 71%, p=0.032) and clinician-reported flare-ups (10% vs 42%, p=0.039) with garetosmab vs placebo, respectively. The overall number of patient-reported flare-ups (13 vs 34) and mean days experiencing new flare-ups (42.6 days vs 65.4 days) were also reduced with garetosmab vs placebo, respectively. Most flare-ups occurred in the back in garetosmab-treated patients, and most flare-ups occurred in the lower extremities and back for those on placebo. Pain was the most frequent symptom among both cohorts. Flare-up associated joint stiffness and severity of flare-up associated symptoms were nominally reduced at both patient and flare-up level of assessment in those treated with garetosmab. No patients reported severe swelling or severe decrease in movement. One patient reported severe pain and joint stiffness in the garetosmab cohort. In Period 2, there were significant reductions in the proportion of patients experiencing flare-ups (68% vs 14%, p=0.0002) and number of patient-reported flares (31 vs 11) among those who crossed over from placebo in Period 1 to garetosmab. Patients who continued on garetosmab through Period 2 maintained a sustained reduction in number of flare-ups (12 vs 6) and proportion of patients experiencing flare-ups (33.3% vs 22.2%). Reductions were maintained through the open-label extension. Conclusions: Patients treated with garetosmab experienced significant and sustained reductions in the frequency, duration, and severity of flare-ups. The ability of garetosmab to reduce flare-up events may provide a clinically meaningful benefit for patients with FOP. Presentation: Sunday, June 18, 2023

ABSTRACT Histiocytic sarcoma (HS) is a rare hematologic malignancy that has historically been treated with lymphoma-based regimens with a median survival of 6 months. We describe a case of a 51-year-old woman who presented with acute back pain and cord compression. She was diagnosed with HS with diffuse skeletal lesions and high expression of programmed death ligand 1 (PD-L1). She was subsequently treated with chemotherapy plus off-label use of pembrolizumab followed by allogeneic stem cell transplantation. Ultimately, the patient died in the setting of progression of disease 17 months after her stem cell transplantation and 26 months after her diagnosis. This article also presents a literature review of cases of HS treated with programmed death ligand inhibition.