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ImportanceSystematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.ObjectiveTo assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.ExposureTreatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.Main Outcomes and MeasuresMain outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.ResultsOf 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).Conclusions and RelevanceIn this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19–related thromboembolism in patients with cancer.

With more than 6000 attendees between in-person and virtual offerings, the American Epilepsy Society Meeting 2022 in Nashville, felt as busy as in prepandemic times. An ever-growing number of physicians, scientists, and allied health professionals gathered to learn a variety of topics about epilepsy. The program was carefully tailored to meet the needs of professionals with different interests and career stages. This article summarizes the different symposia presented at the meeting. Basic science lectures addressed the primary elements of seizure generation and pathophysiology of epilepsy in different disease states. Scientists congregated to learn about anti-seizure medications, mechanisms of action, and new tools to treat epilepsy including surgery and neurostimulation. Some symposia were also dedicated to discuss epilepsy comorbidities and practical issues regarding epilepsy care. An increasing number of patient advocates discussing their stories were intertwined within scientific activities. Many smaller group sessions targeted more specific topics to encourage member participation, including Special Interest Groups, Investigator, and Skills Workshops. Special lectures included the renown Hoyer and Lombroso, an ILAE/IBE joint session, a spotlight on the impact of Dobbs v. Jackson on reproductive health in epilepsy, and a joint session with the NAEC on coding and reimbursement policies. The hot topics symposium was focused on traumatic brain injury and post-traumatic epilepsy. A balanced collaboration with the industry allowed presentations of the latest pharmaceutical and engineering advances in satellite symposia.

136 Background: Studies using International Classification of Diseases (ICD) codes have aimed to characterize the safety profile of cancer therapies in the Real-World Data setting, but this approach has limitations including an inability to illustrate patient journey and offer insights into drug-Adverse Event (AE) causality. Using data from a cohort of ~9000 patients treated with immune checkpoint inhibitors (ICI) at Mayo Clinic, we recently demonstrated the feasibility of applying Augmented Curation (AC), a natural language processing (NLP)-based innovation, on unstructured electronic health record (EHR) data to detect and characterize immune related AEs (irAEs). While the ability to identify and extract clinical details from EHRs has been previously demonstrated, our approach focuses on applying these techniques to identify implied textual causality of drug-event pairs. This study aims to build upon our prior findings and compare the accuracy, speed, and resource savings enabled by AC analysis versus manual review of patient notes. Methods: We compared the prevalence of adrenal insufficiency, colitis, and hypophysitis (A.C.H) among ICI patients at Mayo Clinic using ICD codes and AC which leverages SciBERT to perform scientific NLP tasks. AC models trained to identify drug-adverse event relationships were used to assess irAEs and subsequent treatments and demonstrated strong performance with F1 scores of 0.85. Manual curation of relevant clinical data, i.e. medications and adverse events, was employed to create a “gold standard” A.C.H. cohort. Time required for manual review compared to AC was documented for overall comparison. Corticosteroid/immunosuppressant use and ICI discontinuations were used as proxies of severity. Results: In our cohort, 540 unique patients experienced at least one of the A.C.H. irAEs. A.C.H patients were found to receive corticosteroids for their respective irAE 79% of the time and discontinued the ICI due to the irAE 7.7% of the time. 6.1% of Colitis patients were treated with a 2L immunosuppressant. Similar to the previous study, AC showed higher sensitivity, PPV and NPV compared to ICD codes alone within the A.C.H. cohort. Sentence extraction and entity classification using AC models on all 9,000-patients took ~10 minutes, whereas manual review of this cohort would take roughly 9 weeks (~10 minutes per patient). Conclusions: The results from this study reinforce that AC models are a valuable tool to comprehensively extract information and to impute relationships between entities, such as therapies and AEs. The AC models demonstrated better accuracy at a much greater speed compared to manual review of patient EHRs. Leveraging AC models provides the ability to manipulate unstructured clinical text married to structured EHR data at scale while minimizing need for manual curation.

Background The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate (TL). The tumor lysate, particle only (TLPO) vaccine uses autologous TL-loaded YCWPs coated with silicate for in vivo DC loading. Here we report the 36-month prespecified analyses of this prospective, randomized, double-blind trial investigating the ability of the TLPO and TLPLDC (±granulocyte-colony stimulating factor (G-CSF)) vaccines to prevent melanoma recurrence in high-risk patients. Methods Patients with clinically disease-free stage III/IV melanoma were randomized 2:1 initially to TLPLDC versus placebo (n=124) and subsequently TLPO versus TLPLDC (n=63). All patients were randomized and blinded; however, the placebo control arm was replaced in the second randomization scheme with another novel vaccine; some analyses in this paper therefore reflect a combination of the two randomization schemes. Patients receiving the TLPLDC vaccine were further divided by their method of DC harvest (with or without G-CSF pretreatment); this was not randomized. The use of standard of care checkpoint inhibitors was not stratified between groups. Safety was assessed and Kaplan-Meier and log-rank analyses compared disease-free (DFS) and overall survival (OS). Results After combining the two randomization processes, a total of 187 patients were allocated between treatment arms: placebo (n=41), TLPLDC (n=103), or TLPO (n=43). The allocation among arms created by the addition of patients from the two separate randomization schemes does not reflect concurrent randomization among all treatment arms. TLPLDC was further divided by use of G-CSF in DC harvest: no G-CSF (TLPLDC) (n=47) and with G-CSF (TLPLDC+G) (n=56). Median follow-up was 35.8 months. Only two patients experienced a related adverse event ≥grade 3, one each in the TLPLDC+G and placebo arms. DFS was 27.2% (placebo), 55.4% (TLPLDC), 22.9% (TLPLDC+G), and 60.9% (TLPO) (p<0.001). OS was 62.5% (placebo), 93.6% (TLPLDC), 57.7% (TLPLDC+G), and 94.6% (TLPO) (p=0.002). Conclusions The TLPO and TLPLDC (without G-CSF) vaccines were associated with improved DFS and OS in this clinical trial. Given production and manufacturing advantages, the efficacy of the TLPO vaccine will be confirmed in a phase 3 trial. Trial registration number NCT02301611 .

Background: Corticosteroid therapy is often employed in thyroid eye disease (TED), but its efficacy is variable. Teprotumumab and tocilizumab have been considered as effective alternatives. This study aims to evaluate their clinical outcomes and safety in patients with steroid-resistant TED. Methods: A retrospective case–control study was conducted between 2018 and 2022 within a national multicenter health system. Thirty-seven patients with moderate to severe steroid-resistant TED treated with teprotumumab or tocilizumab (cases) were compared with steroid-naïve patients treated with similar therapy (controls). Due to lack of steroid-naïve patients treated with tocilizumab, a control subgroup for tocilizumab was not included in the analysis. Demographic and clinical characteristics were described. Proptosis, diplopia, clinical activity score (CAS), and disease severity (European Group on Graves' orbitopathy classification) were evaluated at weeks 0, 12, 24, and 52 after therapy initiation. Results: Thirty-one patients received teprotumumab (13 cases and 18 controls) and 6 received tocilizumab (cases). The mean age was 57 years (standard deviation ±14.3), median duration of TED was 11.5 months (interquartile range [IQR]: 7.2–17.7), and median excess proptosis was 4 mm (IQR: 2–8) above the upper limit of normal for sex and race. At week 24, in the teprotumumab cases, 81% had proptosis response (reduction of ≥2 mm), 45.5% resolution of diplopia, 85.7% disease inactivation (CAS <3), and 58.3% reverted to mild disease severity. There were comparable results in teprotumumab controls, with no significant differences between subgroups. In the tocilizumab cases, 50% had a proptosis response, 16.7% resolution of diplopia, 100% disease inactivation, and 75% returned to mild disease. In the teprotumumab cases, there was a trend toward worsening proptosis and diplopia between weeks 24 and 52. In the same time frame, the tocilizumab cases had a trend toward worsening diplopia, disease activity, and severity. In the teprotumumab subgroup, 46.2% experienced otic changes and 23.1% hyperglycemia. In the tocilizumab subgroup, there were no reported adverse events. Conclusions: Teprotumumab and tocilizumab improved inflammation in patients with moderate to severe TED who had failed previous steroid therapy. Additionally, the teprotumumab cases demonstrated similar improvement in proptosis and diplopia to the teprotumumab controls. Further evaluation, particularly regarding the long-term response and side effect profile, of these medications in steroid-resistant TED is needed.

Abstract Background: The Ehlers-Danlos Syndromes (EDS) are a set of connective tissue disorders that are hereditary in nature and characterized by joint hypermobility and tissue fragility. The complex nature of this unique patient population requires multidisciplinary care, but appropriate centers for such care do not exist in large portions of the country. Need for more integrated services has been identified in the Chicagoland region. In order to explore and begin to address barriers to seeking out appropriate care facing EDS patients in this region, we developed an online survey which we circulated through EDS social media groups for Chicagoland patients. Results: Three hundred and nine unique respondents participated. We found that there exists a strong medical need for and interest in the development of a center in the region, and participants reported that, if made available to them, that they would make extensive and regular use of such a facility. Conclusions: We conclude that the establishment of a collaborative medical center specializing in the diagnosis and treatment of EDS, HSD, and related disorders in the Chicagoland area would greatly benefit patients by providing comprehensive care, alleviate the burden on overworked healthcare providers, and generate revenue for medical facilities.

Histone‐lysine N‐methyltransferase SETD2 (SETD2), the sole histone methyltransferase that catalyzes trimethylation of lysine 36 on histone H3 (H3K36me3), is often mutated in clear cell renal cell carcinoma (ccRCC). SETD2 mutation and/or loss of H3K36me3 is linked to metastasis and poor outcome in ccRCC patients. Epithelial‐to‐mesenchymal transition (EMT) is a major pathway that drives invasion and metastasis in various cancer types. Here, using novel kidney epithelial cell lines isogenic for SETD2, we discovered that SETD2 inactivation drives EMT and promotes migration, invasion, and stemness in a transforming growth factor‐beta‐independent manner. This newly identified EMT program is triggered in part through secreted factors, including cytokines and growth factors, and through transcriptional reprogramming. RNA‐seq and assay for transposase‐accessible chromatin sequencing uncovered key transcription factors upregulated upon SETD2 loss, including SOX2, POU2F2 (OCT2), and PRRX1, that could individually drive EMT and stemness phenotypes in SETD2 wild‐type (WT) cells. Public expression data from SETD2 WT/mutant ccRCC support the EMT transcriptional signatures derived from cell line models. In summary, our studies reveal that SETD2 is a key regulator of EMT phenotypes through cell‐intrinsic and cell‐extrinsic mechanisms that help explain the association between SETD2 loss and ccRCC metastasis.

Abstract Background: While cigarette smoking has declined among the U.S. general population, sale and use of non-cigarette alternative tobacco products (ATP; e.g., e-cigarettes, cigars) and dual use of cigarettes/ATPs are rising. Little is known about ATP use patterns in cancer survivors enrolled in clinical trials. We investigated prevalence of tobacco product use, and factors associated with past 30-day use, among patients with cancer in national trials. Methods: Cancer survivors (N = 756) enrolled in 9 ECOG-ACRIN clinical trials (2017–2021) completed a modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) which assessed baseline cigarette and ATP use since cancer diagnosis and in the past 30 days. Results: Patients were on average 59 years old, 70% male, and the mean time since cancer diagnosis was 26 months. Since diagnosis, cigarettes (21%) were the most common tobacco product used, followed by smokeless tobacco use (5%), cigars (4%), and e-cigarettes (2%). In the past 30 days, 12% of patients reported smoking cigarettes, 4% cigars, 4% using smokeless tobacco, and 2% e-cigarettes. Since cancer diagnosis, 5.5% of the sample reported multiple tobacco product use, and 3.0% reported multiple product use in the past 30 days. Males (vs. females; OR 4.33; P = 0 &lt; 0.01) and individuals not living with another person who smokes (vs. living with; OR, 8.07; P = 0 &lt; 0.01) were more likely to use ATPs only versus cigarettes only in the past 30 days. Conclusions: Among patients with cancer, cigarettes were the most prevalent tobacco product reported. Impact: Regardless, ATPs and multiple tobacco product use should be routinely assessed in cancer care settings.

Abstract Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.