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INTRODUCTION: Esophageal epidermoid metaplasia (EEM) is a rare disease. METHODS: Patients with EEM diagnosed between 2014 and 2020 were reviewed. RESULTS: Forty EEM cases were identified. EEM occurred in 9 (23%) patients before, concordant, or after esophageal squamous cell carcinoma (ESCC). EEM was associated with previous esophageal lichen planus in 5 patients, Barrett's esophagus 7, and esophageal adenocarcinoma 1. EEM was focal in 28 (70%) or diffuse in 12 (30%) and not detected in 45% on recent previous endoscopy. DISCUSSION: EEM is a premalignant underrecognized condition associated with multiple conditions. Close follow-up or endoscopic treatment may be warranted because of its ESCC association.

INTRODUCTION: Studies have shown that dysplasia in Barrett's esophagus (BE) has a predilection for the right hemisphere. There is limited information on the longitudinal distribution. The aim was to determine both the longitudinal and circumferential distributions of dysplasia and early neoplasia from 3 prospective studies. METHODS: This is a pooled analysis from 3 prospective studies of patients with treatment-naive BE. Both circumferential and longitudinal locations (for BE segments greater than 1 cm) of dysplastic and early neoplastic lesions were recorded. RESULTS: A total of 177 dysplastic and early neoplastic lesions from 91 patients were included in the pooled analysis; of which 59.3% (n = 105) were seen on high-definition white light endoscopy, 29.4% (n = 52) on advanced imaging, and 11.2% (n = 20) with random biopsies. The average Prague score was C3M5. Of 157 lesions within BE segments greater than 1 cm, 49 (34.8%) lesions were in the proximal half, whereas 92 lesions (65.2%) were in the distal half ( P < 0.001). The right hemisphere of the esophagus contained 55% (86/157) of the total lesions compared with 45% (71/157) for the left hemisphere ( P = 0.02). This was because of the presence of high-grade dysplasia being concentrated in the right hemisphere compared with the left hemisphere (60% vs 40%, P = 0.002). DISCUSSION: In this pooled analysis of prospective studies, both low-grade dysplasia and high-grade dysplasia are more frequently found in the distal half of the Barrett's segment. This study confirms that the right hemisphere is a hot spot for high-grade dysplasia. Careful attention to these locations is important during surveillance endoscopy.

Abstract Introduction: Blastomycosis is an uncommon; potentially life threatening granulomatous fungal infection. The aim of this study is to report hospital and intensive care unit (ICU) outcomes of patients admitted with blastomycosis. Methods: All patients admitted for treatment of blastomycosis at the Mayo Clinic-Rochester, Minnesota between 01/01/2006 and 09/30/2019 were included. Demographics, comorbidities, clinical presentation, ICU admission, and outcomes were reviewed.Results: A total of 84 Patients were identified with 93 unique hospitalizations primarily for blastomycosis. The median age at diagnosis was 49 (IQR 28.1-65, range: 6-85) years and 56 (66.7%) were male. The most frequent comorbidities incl­uded hypertension (n=28, 33.3%); immunosuppressed state (n=25, 29.8%) and diabetes mellitus (n=21, 25%). The lungs were the only organ involved in 56 (66.7%) cases and the infection was disseminated in 19 (22.6%) cases. A total of 29 patients (34.5%) underwent ICU admission due to complications of blastomycosis. ICU related events included mechanical ventilation (n=21, 25%), acute respiratory distress syndrome (ARDS) (n=13, 15.5%), tracheostomy (n=9, 10.7%), renal replacement therapy (n=8, 9.5%), and extracorporeal membrane oxygenation (ECMO) (n=4, 4.8%). A total of 12 patients (14.3%) died in the hospital; all of whom had undergone ICU admission. In-hospital mortality was associated with renal replacement therapy (RRT) (P=0.0255).Conclusions: Blastomycosis is a serious, potentially life-threatening infection that results in significant morbidity and mortality with a 34.5% ICU admission rate. Renal replacement therapy was associated with in-hospital mortality.

TPS358 Background: The anti–PD-L1 antibody ATEZO prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF BEV can increase dendritic cell maturation, enhance T cell infiltration, and reduce myeloid-derived suppressor cells and regulatory T-cells in tumors. This combination has been FDA approved for first-line treatment of advanced HCC based on the IMbrave 150 study. On the other hand, locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire. It is the standard of care for pts with intermediate-stage HCC (iHCC). Based on preclinical and clinical data, we hypothesize that the combination of Y90 TARE, BEV, and ATEZO induces synergistic tumor-killing. Methods: This is an open-label, multicenter, randomized phase II study of Y90 TARE and BEV plus ATEZO compared with Y90 TARE alone in pts with unresectable IHCC. The primary study objective is to assess and compare the progression-free survival (PFS) (per mRECIST 1.1) of pts in each arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of TARE combined with ATEZO and BEV in pts with HCC. Exploratory objectives are to assess the role of the immunoscore and PD-L1 expression levels in the prediction of improved clinical outcome in pts receiving Y-90 TARE and BEV plus ATEZO; the composition of tumor-infiltrating immune cell subtypes in predicting response to a chosen therapy; how Y90 therapy affects the proportion of antigen-presenting cells in the tumor; and symptoms experienced by pts receiving TARE and BEV plus ATEZO treatment, using patient-reported outcomes. Eligible pts have either HCC that is not amenable to surgical resection, confirmed by pathology review, or at least BCLC stage B HCC outside of downstaging criteria. Other standard eligibility criteria apply. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE followed by ATEZO and BEV (Arm B). Pts will have TARE mapping during week (wk) 1 and TARE treatment during wk 2. In Arm B, pts will start BEV plus ATEZO 4 wks (±1 wk) after TARE treatment. Pts will have abdominal MRI or CT scans every 12 weeks, CT scans of the chest every 24 wks, and a second tumor biopsy at 4 wks. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of TARE with BEV and ATEZO in the first 10 pts randomized to Arm B for two cycles. If there are no grade ≥ 3 unexpected toxicities possibly, probably or definitely related to combined TARE plus BEV plus ATEZO, the study will continue to accrue 128 pts in total. Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Enrollment began in September 2020. Clinical trial information: NCT04541173.

The importance of canonical versus noncanonical mechanisms for the generation of angiotensins remains a major challenge that, in part, is heavily swayed by the relative efficacy of therapies designed to inhibit renin, ACE (angiotensin-converting enzyme), or the Ang II (Angiotensin II) receptor. Ang (1–12) (angiotensin [1-12]) is an Ang II forming substrate serving as a source for Ang II–mediated tissue actions. This study identifies for the first time the presence of Ang (1–12) in the blood of 52 normal (22 women) and 19 (13 women) patients with hypertension not receiving antihypertensive medication at the time of the study. Normal subjects of comparable ages and body habitus had similar circulating plasma Ang (1–12) concentrations (women: 2.02±0.62 [SD] ng/mL; men 2.05±0.55 [SD] ng/mL, P >0.05). The higher values of plasma Ang (1–12) concentrations in hypertensive men (2.51±0.49 ng/mL, n=6) and women (2.33±0.63 [SD] ng/mL, n=13) were statistically significant ( P <0.02) and correlated with elevated plasma renin activity, systolic and pulse pressure, and plasma concentrations of NT-proBNP (N-terminal prohormone BNP). The increased plasma Ang (1–12) in patients with hypertension was not mirrored by similar changes in plasma angiotensinogen and Ang II concentrations. The first identification of an age-independent presence of Ang (1–12) in the blood of normotensive subjects and patients with hypertension, irrespective of sex, implicates this non-renin dependent substrate as a source for Ang II production in the blood and its potential contribution to the hypertensive process.

AbstractBackground:Esophageal adenocarcinoma is a lethal cancer with rising incidence. There are limited data in younger (&lt;50 years) patients with esophageal adenocarcinoma. We aimed to assess time trends in the incidence and outcomes of “young-onset” esophageal adenocarcinoma using a population-based database.Methods:We queried the Surveillance, Epidemiology, and End Results 9 database to identify patients with esophageal adenocarcinoma between 1975 and 2015. Patients were stratified into three age strata: &lt;50, 50 to 69, and ≥70 years. Staging was stratified as localized, regional, and distant. Trends in incidence, disease stage, and survival were assessed in three periods (1975–89, 1990–99, and 2000–2015). Univariate and multivariate models were created to identify predictors of mortality.Results:Esophageal adenocarcinoma incidence has increased in patients &lt;50 years of age, with an annual percentage change of 2.9% (95% confidence interval, 1.4%–4.4%) from 1975 to 2015. Young-onset esophageal adenocarcinoma presented at more advanced stages (regional + distant) compared with older patients (84.9% vs. 67.3%; P &lt; 0.01), with increasing proportion of advanced stages over the study period. These patients also experienced poorer 5-year esophageal adenocarcinoma–free survival compared with older patients (22.9%% vs. 29.6%; P &lt; 0.01), although this finding was attenuated on stage-stratified analysis.Conclusions:Young-onset esophageal adenocarcinoma, while uncommon, is rising in incidence. Concerningly, the proportion of advanced disease continues to increase. Young-onset esophageal adenocarcinoma also presents at more advanced stages, resulting in poorer esophageal adenocarcinoma–free survival.Impact:Patients with esophageal adenocarcinoma younger than 50 years present at more advanced stages with higher esophageal adenocarcinoma–specific mortality compared with older peers. Current diagnostic and management strategies for young-onset esophageal adenocarcinoma may need to be reevaluated.

Abstract Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q &lt; 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Atrial and B-type natriuretic peptides (ANP and BNP) are cardiac hormones secreted as compensatory measures to preserve cardiorenal homeostasis. Treating heart failure (HF) with sacubitril/valsartan increased ANP and not BNP, suggesting the ANP system may confer therapeutic benefit. Thus, the presence of an ANP deficient subgroup of HF patients possibly posing higher risk for HF severity, underscores a need to characterize both, the biologically active and inactive (NT-proANP and NT-proBNP) natriuretic peptides (NPs)(latter resistant to degradation), to highlight the extent of NP production in HF. Characterizing neprilysin (NEP) activity may also provide insights into the degree of NP degradation in HF. This study aims to both highlight the cardiac NP response in acute decompensated HF(ADHF) by measuring molecular forms of ANP and BNP together with defining circulating soluble NEP activity as to assess mechanisms impairing the NP response in HF. We recruited 47 healthy individuals with neither cardiovascular nor metabolic disease and compared ANP, BNP, NT-proANP, NT-proBNP, and NEP activity levels with 107 recruited ADHF patients. In ADHF, compared to a healthy setting, median ANP, BNP, NT-proANP, and NT-proBNP were all elevated (15.7 vs. 118.1 pg/mL , p<0.0001; 23 vs. 515 pg/ml, p<0.0001; 60.1 vs. 651.6 pg/mL, p<0.0001; 46 vs. 3330 pg/mL, p<0.0001, respectively). However, circulating NEP activity was significantly lower in ADHF than in healthy circulation (32 vs. 12.3 nM/mL/min, p<0.0001). NPs did not correlate with NEP activity in healthy circulation. However, only ANP (r = 0.4788, p<0.0001) and NT-proANP (r = 0.6819, p<0.0001) correlated with NEP activity in ADHF. The presence of an impaired ANP response in ADHF, underscored by insufficient increases in NT-proANP than NT-proBNP, suggests decreased ANP production may induce not only an ANP deficient ADHF state, but be characteristic of ADHF. The presence of NEP activity in ADHF circulation, despite lower NEP activity compared to healthy individuals, suggests ANP degradation may second impaired production, further lowering ADHF ANP levels. Our studies support augmenting the ANP system in ADHF through either endogenous stimulation or exogenous supplementation as optimal therapeutic strategies.

Despite recent developments in the therapy of chronic lymphocytic leukemia (CLL), Richter's transformation (RT), an aggressive lymphoma, remains a clinical challenge. Immune checkpoint inhibitor (ICI) therapy has shown promise in selective lymphoma types, however, only 30-40% RT patients respond to anti-PD1 pembrolizumab; while the underlying CLL failed to respond and 10% CLL patients progress rapidly within 2 months of treatment. Studies indicate pre-existing T cells in tumor biopsies are associated with a greater anti-PD1 response, hence we hypothesized that pre-existing T cell subset characteristics and regulation in anti-PD1 responders differed from those who progressed in CLL. We used mass cytometry (CyTOF) to analyze T cell subsets isolated from peripheral blood mononuclear cells (PBMCs) from 19 patients with who received pembrolizumab as a single agent. PBMCs were obtained baseline(pre-therapy) and within 3 months of therapy initiation. Among this cohort, 3 patients had complete or partial response (responders), 2 patients had rapid disease progression (progressors) (Fig. A), and 14 had stable disease (non-responders) within the first 3 months of therapy. CyTOF analysis revealed that Treg subsets in responders as compared with progressors or non-responders (MFI -55 vs.30, p=0.001) at both baseline and post-therapy were increased (Fig. B). This quantitative analysis indicated an existing difference in Tregs and distinct molecular dynamic changes in response to pembrolizumab between responders and progressors. To delineate the T cell characteristics in progressors and responders, we performed single-cell RNA-seq (SC-RNA-seq; 10X Genomics platform) using T (CD3+) cells enriched from PBMCs derived from three patients (1 responder: RS2; 2 progressors: CLL14, CLL17) before and after treatment. A total of ~10000 cells were captured and an average of 1215 genes was detected per cell. Using a clustering approach (Seurat V3.1.5), we identified 7 T cell clusters based on transcriptional signature (Fig.C). Responders had a larger fraction of Tregs (Cluster 5) as compared with progressors (p=0.03, Fig. D), and these Tregs showed an IFN-related gene signature (Fig. E). To determine any changes in the cellular circuitry in Tregs between responders and progressors, we used FOXP3, CD25, and CD127 as markers for Tregs in our SC-RNA-seq data. We saw a greater expression of FOXP3, CD25, CD127, in RS2 in comparison to CLL17 and CLL14. Gene set enrichment analysis (GSEA) revealed the upregulation of genes involved in lymphocyte activation and FOXP3-regulated Treg development-related pathways in the responder's Tregs (Fig.F). Together, the greater expression of genes involved in Treg activation may reduce the suppressive functions of Tregs, which led to the response to anti-PD1 treatment seen in RS2 consistent with Tregs in melanoma. To delineate any state changes in T cells between progressors and responder, we performed trajectory analysis using Monocle (R package tool) and identified enrichment of MYC/TNF/IFNG gene signature in state 1 and an effector T signature in state 3 For RS2 after treatment (p=0.003), indicating pembrolizumab induced proliferative and functional T cell signatures in the responder only. Further, our single-cell results were supported by the T cell receptor (TCR beta) repertoire analysis (Adaptive Biotechnology). As an inverse measure of TCR diversity, productive TCR clonality in CLL14 and CLL17 samples was 0.638 and 0.408 at baseline, respectively. Fifty percent of all peripheral blood T cells were represented by one large TCR clone in CLL14(progressor) suggesting tumor related T-cell clone expansion. In contrast, RS2(responder) contained a profile of diverse T cell clones with a clonality of 0.027 (Fig. H). Pembrolizumab therapy did not change the clonality of the three patients during the treatment course (data not shown). In summary, we identified enriched Treg signatures delineating responders from progressors on pembrolizumab treatment, paradoxical to the current understanding of T cell subsets in solid tumors. However, these data are consistent with the recent observation that the presence of Tregs suggests a better prognosis in Hodgkin lymphoma, Follicular lymphoma, and other hematological malignancies. Figure 1 Disclosures Kay: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Sunesis: Research Funding; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; MEI Pharma: Research Funding. Ansell:AI Therapeutics: Research Funding; Takeda: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol Myers Squibb: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding. Ding:Astra Zeneca: Research Funding; Abbvie: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; DTRM: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: pembrolizumab