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ImportanceMultisystem inflammatory syndrome in adults (MIS-A) is a poorly understood complication of SARS-CoV-2 infection with significant morbidity and mortality.ObjectiveIdentify clinical, immunological, and histopathologic features of MIS-A to improve understanding of the pathophysiology and approach to treatment.DesignThree cases of MIS-A following SARS-CoV-2 infection were clinically identified between October 2021 – March 2022 using the U.S. Centers for Disease Control and Prevention diagnostic criteria. Clinical, laboratory, imaging, and tissue data were assessed.FindingsAll three patients developed acute onset cardiogenic shock and demonstrated elevated inflammatory biomarkers at the time of hospital admission that resolved over time. One case co-occurred with new onset Type 1 diabetes and sepsis. Retrospective analysis of myocardial tissue from one case identified SARS-CoV-2 RNA. All three patients fully recovered with standard of care interventions plus immunomodulatory therapy that included intravenous immunoglobulin, corticosteroids, and in two cases, anakinra.ConclusionMIS-A is a severe post-acute sequela of COVID-19 characterized by systemic elevation of inflammatory biomarkers. In this series of three cases, we find that although clinical courses and co-existent diseases vary, even severe presentations have potential for full recovery with prompt recognition and treatment. In addition to cardiogenic shock, glucose intolerance, unmasking of autoimmune disease, and sepsis can be features of MIS-A, and SARS-CoV-2 myocarditis can lead to a similar clinical syndrome.

While the genomic landscape of CNS lymphomas at diagnosis has largely been defined, there remains a significant gap in our understanding of the molecular pathways that mediate therapeutic resistance and disease progression. CNS lymphomas generally exhibit multifocal dissemination as an end-stage manifestation. To elucidate key genetic and pathophysiologic pathways of CNS lymphoma that mediate resistance, we have conducted what may be the first study to apply next generation sequencing to compare the genetic features of PCNSL and SCNSL at the time of diagnosis with multifocal lesions isolated from relapsed, treatment-refractory disease from matched patient specimens at final lymphoma progression, isolated from whole brain autopsy specimens. Whole-exome sequencing from diagnostic specimens (4 brain and 1 retinal biopsy) were compared with matched whole brain autopsy specimens in 5 patients: 4 with PCNSL and 1 with SCNSL. A median of 6 distinct anatomical CNS lymphoma-containing brain regions were analyzed/whole brain autopsy specimen. Median age was 57 (range 51-81 yrs). Two patients died after primary refractory disease to methotrexate-based induction and three died after median of four progressions; each of these later patients progressed after lenalidomide, and one also received pomalidomide followed by ibrutinib before final disease progression. Four cases were from UCSF and 1 from Stanford. Tumor tissue and uninvolved normal brain was microdissected from formalin-fixed, paraffin-embedded blocks of initial biopsy prior to therapy and multiple distinct tumor regions at time of autopsy. Multiplex library preparation was performed from extracted genomic DNA and hybridization-capture of pooled libraries performed using NimbleGen SeqCap EZ Human Exome Probes Bait Library. Captured libraries were sequenced as paired-end 100 base pair reads and sequence reads mapped to the reference human genome build GRCh37 (hg19) using Sentieon DNAseq. Somatic variant detection including single nucleotide variants and insertions/deletions was performed. Single nucleotide variants and insertions/deletions were verified using Integrated Genome Viewer. Copy number analysis was performed using CNVkit and visualized using Nexus. High-confidence somatic nonsynonymous mutations were identified and pathway analysis applied using gene sets for canonical pathways and Gene Ontology (GO) terms downloaded from Molecular Signatures Database) at http://www.broad.mit.edu/gsea/msigdb. Lymphoid-specific signatures were curated by Staudt lab (http://lymphochip.nih.gov/signaturedb/) or previous publications. Fisher's Exact test was used to calculate enrichment p values for each of those gene sets and the BH method used for False Discovery Rate (FDR) control. A mean of 214 lymphoma-specific mutations per specimen was identified (range 56-1,764). Notably, of the 283 distinct molecular pathways analyzed, only 1 pathway was significantly enriched for mutations in tumors from each of the 5 CNS lymphoma whole brain autopsy specimens compared to pre-treatment diagnostic biopsies: the Ikaros 1(IKZF1) in centroblast pathway (p<0.05). The 2 cases of CNS lymphoma that had been exposed to an IMiD most proximate to brain autopsy (< 6 weeks) exhibited the strongest enrichment for mutations in IKZF1 pathway (p<0.005). Genes recurrently mutated in the IKZF1 pathway in relapsed CNS lymphomas included CD79A/B, IGLL5, BTG2, and TMEM30A. Mutations in the BCL6 and BACH2 transcriptional repressor pathway were significantly enriched in CNS lymphomas at autopsy compared to diagnostic specimens in 3 out of 5 cases. We also detected marked regional heterogeneity in DNA copy number aberrations in lymphoma from whole brain autopsy specimens. High level focal amplification of 9p24.1 targeting PD-L1 was enriched in only one case: a highly refractory PCNSL that had been exposed to pomalidomide followed by ibrutinib within two months of autopsy; amplification of PD-L1 was not detected in the diagnostic specimen. While multiple genetic aberrations are associated with disease progression in CNS lymphoma, our study suggests that mutational activation of the IKZF1 pathway may be a unique canonical mechanism in the evolution of resistance to multiple interventions, including first-line methotrexate. This observation may have significant therapeutic implications. Supported by NCI and Leukemia Lymphoma Society. Disclosures Rubenstein: Genentech: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding.

10500 Background: ACGME survey results consistently show that 40% of University of California, San Francisco (UCSF) internal medicine (IM) residents are dissatisfied with their oncology education—higher than the oncology national average and highest among UCSF IM subspecialties. A needs assessment revealed that UCSF residents desire online oncology resources for asynchronous learning. To address this need, we sought online oncology videos targeted to residents but found none. We thus used cognitive theory of multimedia learning principles to develop an oncology video curriculum and evaluated three feasibility components: demand (frequency of use), efficacy, and acceptability. Methods: We chose common cancers from the ABIM blueprint and filmed five 10-minute videos of UCSF oncologists discussing content they chose for residents. We created modules with pre/post tests derived from video content. After a pilot, we sent links to all IM residents on required oncology clinic rotations over four months (n = 25) and offered protected clinic time for optional completion. We compared pre/post test scores with a paired t test and surveyed residents. Results: Demand: 72% (18 of 25) completed ≥1 module; 32% completed all 5. Efficacy: The mean pre- vs. post-test score improved (50% vs. 87%, p = 0.002). Acceptability: 64% completed the survey. Of those who completed ≥1 module, 93% (13 of 14) felt strongly that the videos contributed to their knowledge. 93% recommended the videos to others. Residents praised the length, key points, and pre/post tests. Finding time for the modules was difficult; most did them at home. Suggestions included focusing on fundamentals and creating videos for all common cancers. Conclusions: We present demand, efficacy, and acceptability evidence supporting the feasibility of a resident oncology video curriculum. Formal protected time for module use is critical. We will focus on fundamentals for generalists as we make more videos. We will track ACGME survey results, examination scores, and clinical performance to study impact. We aim to publish the modules online for broader use and as a model solution to address similar needs across specialties and institutions, as complex resident schedules increasingly require asynchronous learning.

Background: The etiologic basis for neurocognitive and neuropsychological deficits in cancer patients and cancer survivors is poorly understood. Because of ongoing improvements in therapy and advances in survival, the problem of cancer-associated cognitive dysfunction is increasingly significant. While there is agreement that T2-weighted imaging abnormalities on MRI correlate with neurocognitive deficits, there has been limited insight into the neurochemical abnormalities associated with cognitive dysfunction in brain tumor patients. We are testing the hypothesis that tumor metabolism directly impairs neurotransmitter pathways and cognitive function, independent of anatomic extent of the cancer. Methods: Our approach has been to focus on a type of brain tumor, CNS lymphoma, in which we are able to simultaneously monitor cognitive function, as assayed by repeat Mini-Mental Status Examinations (MMSE), tumor volume, as assessed by MRI, and dynamic changes in the tumor metabolic microenvironment, as characterized by quantitative measurement of tumor-associated metabolites in correlation with neurotransmitters that we hypothesize to be linked to normal cognitive function. Our initial study was to evaluate 14 subjects with CNS lymphoma that were treated on a phase I trial of the immunomodulatory agent lenalidomide. Volumetric analysis of CNS lymphomas was performed using Smartbrush Software (Brainlab) on pre-and post-therapy MRI's conducted at baseline and at monthly restaging. Metabolomic analysis of cerebrospinal fluid (CSF), using GC/MS, was conducted at baseline and at timepoints within 1 week of corresponding MRI. MMSE tests were conducted in all subjects at baseline and at corresponding monthly restaging examinations. Results: Of 20 CSF metabolites analyzed, including 12 neurotransmitters, elevated CSF lactate correlated most strongly with impaired neurocognitive function as measured by MMSE score. (P=2.5e-6; rho= -0.66). Patients with high lactate had lower relative CSF concentration of the inhibitory neurotransmitter GABA, and higher concentrations of the excitotoxic glutamate. Notably, we determined that CSF lactate concentration more significantly correlated with lower MMSE score than size of the brain tumor, as quantified by volumetric analysis of tumor T2 hyperintensity and lesional contrast-enhancing volume. Conclusions: To our knowledge, this is the first data linking cancer metabolism, neurotransmitter dysregulation, and neurocognitive deficits in a brain tumor patient population. We anticipate that elucidation of the mechanistic basis between tumor lactate metabolism, neurotransmitter imbalance, and neurocognitive deficits will provide potential opportunities for pharmacologic intervention to preserve neurologic function and potentially minimize cognitive and neuropsychological deficits in cancer patients. Citation Format: Lakshmi Subbaraj, Huimin Geng, Jigyasa Sharma, Marisa LaFontaine, James L. Rubenstein. Tumor metabolism and cognitive dysfunction in CNS lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4975.