Presbyterian Hospital Research Articles

The potential role of EHR data in optimizing eligibility criteria definition for cardiovascular outcome trials

BackgroundCardiovascular outcome trials (CVOTs) include patients with high risks for cardiovascular events based on specific inclusion criteria. Little is known about the impact of such inclusion criteria on patient accrual and the incidence rate of cardiovascular events. Materials and methodsWe evaluated the impact of criteria on the accrual and the number of cardiovascular events in a cohort of 1544 diabetes patients identified from the clinical data warehouse of New York Presbyterian Hospital / Columbia University Irving Medical Center. ResultsThe highest incidence rate of the composite events (i.e., cardiovascular mortality, stroke, and myocardial infarction) was observed when the inclusion criteria seek patients with underlying cardiovascular diseases or age ≥ 60 with at least two of the risk factors including duration of diabetes, hypertension, dyslipidemia, smoking status, and albuminuria. ConclusionOur study shows that the electronic health records could be utilized to optimize the inclusion criteria while balancing study inclusiveness and number of events.

Stanley A. Klatsky, M.D., 1934 to 2020.

Stanley A. Klatsky, M.D., 1934 to 2020.

Understanding the Link Between Obesity and Severe COVID-19 Outcomes: Causal Mediation by Systemic Inflammatory Response.

BackgroundObesity is an established risk factor for severe COVID-19 outcomes. The mechanistic underpinnings of this association are not well-understood.ObjectiveTo evaluate the mediating role of systemic inflammation in obesity-associated COVID-19 outcomes.MethodsThis hospital-based, observational study included 3828 SARS-CoV-2-infected patients who were hospitalized February to May 2020 at Massachusetts General Hospital (MGH) or Columbia University Irving Medical Center/New York Presbyterian Hospital (CUIMC/NYP). We use mediation analysis to evaluate whether peak inflammatory biomarkers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], D-dimer, ferritin, white blood cell count and interleukin-6) are in the causal pathway between obesity (BMI ≥ 30) and mechanical ventilation or death within 28 days of presentation to care.ResultsIn the MGH cohort (n = 1202), obesity was associated with greater likelihood of ventilation or death (OR = 1.73; 95% CI = [1.25, 2.41]; P = 0.001) and higher peak CRP (P < 0.001) compared with nonobese patients. The estimated proportion of the association between obesity and ventilation or death mediated by CRP was 0.49 (P < 0.001). Evidence of mediation was more pronounced in patients < 65 years (proportion mediated = 0.52 [P < 0.001] vs 0.44 [P = 0.180]). Findings were more moderate but consistent for peak ESR. Mediation by other inflammatory markers was not supported. Results were replicated in CUIMC/NYP cohort (n = 2626).ConclusionFindings support systemic inflammatory pathways in obesity-associated severe COVID-19 disease, particularly in patients < 65 years, captured by CRP and ESR. Contextualized in clinical trial findings, these results reveal therapeutic opportunity to target systemic inflammatory pathways and monitor interventions in high-risk subgroups and particularly obese patients.

Generation and Application of T-Cell Lymphoma Patient Derived Tumor Xenograft Models

Introduction:Although pivotal “driver mutations” have been described in T-cell lymphomas (T-NHL), targetable dependences are lacking for many entities. As result, T-NHL patients experience dismal therapeutic responses and have a poor survival. Therapeutic improvements have been hindered by the lack of informative models. Patient-Derived-Tumor-Xenografts (PDTX), recapitulating many of the biological features of primary cancers, represent a novel and powerful platform. Here, we constructed a library of T-NHL PDTX to foster drug discovery programs and new patient-tailored approaches.Methods:Fresh and/or viable cryopreserved samples from primary T-NHL were obtained from Turin, WCM, and MSKCC hospitals. For the initial tumorgraft implants, lymphoma fragments, PBMC or bone marrow cells were implanted in NSG-B2m mice. Seeds from arising tumors were then serially transplanted. MRI was used to follow tumor growth and dissemination. The lymphoma phenotype was assessed by multi-channel flow cytometry and immunohistochemistry. We used TCR gene rearrangement analyses, whole exome sequencing (WES), total RNAseq, and CHIP-Seq (STAT3, methylation marks) to annotate primary and PDTX samples. For the in vitro studies, PDTX were digested and stromal cells were excluded by panning. Enriched Patient-Derived Tumor Cells (PDTC) were cultured in either RPMI/20% FBS or StemSpan/10% KSR media. High-throughput drug screening was performed using a library of 432 compounds (1 µM for 72hrs). Cell titer glo/blue, trypan blue cell count, and annexin-V/7AAD were used to assess cell viability, apoptosis, and proliferation.Results:We implanted 123 fresh T-NHL samples, resulting in the generation of 41 PDTX lines (Fig.1). In addition, 14 implants led to the growth of lymphoblastoid EBV+ populations. All PDTX lines were successfully propagated (5-26 serial passages) with the exception of angioimmunoblastic T-cell lymphoma (AITL) PDTX, which displayed a delay in engraftment over time, and eventually ceased growing (passage 3-7). Serially propagated PDTX showed distinct immunophenotypic profiles, which closely reflected their corresponding primary samples. TCR gene rearrangement studies confirmed the faithful correspondence between donor and PDTX over different generations. WES and total RNA-Seq on primary and serially propagated PDTX (at least T1-T5) yielded a rich landscape of mutations shared by primary tumors and PDTX derivatives. On going mutations were also defined along propagations. CHIP-Seq assay defined a STAT3 classifier in STAT+ PDTC.In vitro, all PDTC were shortly maintained (<7days), with some surviving for 6-8 weeks. To overcome their limited growth in vitro, we tested whether stromal cells (i.e. E4-Endothelial cells, E4-EC) could enhance their survival and/or growth. Indeed, co-culturing of PDTC with E4-ECs rescued cell death induced by ex vivo long-term propagation (peripheral T-cell lymphoma not otherwise specified and NK/T-Cell Lymphoma, PTCL-NOS and NK) or starvation (anaplastic large cell lymphoma, ALCL).PDTC were also used to perform a drug screening targeting major signaling pathways (>3x replicates of 8 ALCL, 1 NK, and 2 PTCL-NOS), demonstrating that each PDTX exhibited a unique drug sensitivity profile, mostly dictated by its genomic landscape. This was epitomized by two PDTC (IL-2 and IL-19) derived from the same PTCL-NOS patient bearing an activating V658F JAK1 somatic mutation. These two PDTC, once exposed to JAK inhibitors, displayed down-regulation of pSTAT3 (24hr) and massive cell death (T3-T6, >95% at 72hrs). Similar results were seen with ALK inhibitors in ALK+ ALCL PDTC (n=5). Moreover, specific drugs were identified to bypass refractory phenotypes in selective PDTC (i.e. proteasome and topoisomerase inhibitors).Conclusions:We built up a large and representative PDTX library from major T-NHL entities. Immunophenotyping, genomics and functional studies showed a close correspondence between primary samples and correspondent PDTX derivatives. Our in vitro models provide a starting point for elucidating stromal:tumor cell interactions that contribute to lymphoma growth and survival in vivo, and evidence that a drug screening can be successfully executed on PDTCs. We predict that this cohort may be a valuable tool for testing novel therapeutic compounds and fostering personalized therapeutic approaches in T-NHL patients. [Display omitted] DisclosuresThompson:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Founder; Merck: Membership on an entity's Board of Directors or advisory committees; Charles River Laboratories: Membership on an entity's Board of Directors or advisory committees. Aster:Eli Lilly and Company: Membership on an entity's Board of Directors or advisory committees. Ruan:Cell Medica: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dogan:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Peer Review Institute: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Pharmaceuticals: Consultancy. Cerchietti:Celgene: Research Funding; Lymphoma Research Foundation: Research Funding; Leukemia and Lymphoma Society: Research Funding; Weill Cornell Medicine - New York Presbyterian Hospital: Employment. Horwitz:Celgene: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy; HUYA: Consultancy; Aileron Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Millenium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Forty-Seven: Consultancy, Research Funding.

Initial Treatment with Lenalidomide Plus Rituximab for Mantle Cell Lymphoma: 5-Year Follow-up and Correlative Analysis from a Multi-Center Phase II Study

Abstract BACKGROUND: We previously reported early results of a multicenter phase 2 study of lenalidomide plus rituximab as initial treatment for MCL (NEJM 2015:373:1835), which was highly effective (ORR 92%, CR 64%) and well tolerated. Here we present outcomes with 5-year follow-up, as well as exploratory analysis of immunologic biomarkers and minimal residual disease measurement. METHODS: The study includes both induction and maintenance. Lenalidomide was administered at 20 mg daily on days 1-21 of a 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during maintenance. Standard dose rituximab was administered weekly x 4 during cycle 1, then once every other cycle. Treatment was continuous until progression, with option to stop therapy after 3 years. Plasma samples were obtained at baseline, C2D1 and C4D1 to measure cytokines (IFN γ , IL10, IL12p70, IL12, IL1 β , IL2, IL4, IL6, IL8, TNF α) and chemokines (MCP1, MCP4, Eotaxin, IP10, MDC, Eotaxin3, TARC, MIP1 α , MIP1 β, IL8), using MesoScale Discovery V-plex assays. The cytokine/chemokine levels over time, and their associations with responses and treatment-emergent rash were analyzed with Wilcoxon signed-rank and rank-sum tests. MRD was assessed using ClonoSEQTM (Adaptive Biotechnologies, Seattle WA) on subjects with available paired pre-treatment tissue and post-induction PB samples. RESULTS: 38 subjects requiring therapy were enrolled at 4 centers from 7/2011 to 4/2014. The median age was 65 and MIPI scores evenly distributed between low-, intermediate-, and high-risk. Median follow-up was 58 months with range of 36-70 months. Two patients were inevaluable - one withdrew consent, other was intolerant of tumor flare. Twenty-two (61%) of the evaluable 36 patients remain in remission, including 13 (36%) beyond 5 years. Nineteen patients remain on treatment and 3 opted to stop therapy after 3 years. Eleven patients had progression - 3 with primary refractory disease and 8 following initial responses (4 CRs with PFS of 18, 38, 39 and 49 months, 4 PRs with PFS at 14, 25, 28 and 43 months). Six evaluable patients died, 3 from progression, 3 from unrelated comorbidities. Median PFS and DOR have not been reached. The 3-yr and 4-yr PFS rates were estimated at 80.3% (95% CI = 63.0%, 90.1%) and 69.7% (95% CI = 50.6%, 82.6%), with 3-yr and 4-yr OS rates at 91.9% (95% CI = 76.9%, 97.3%) and 82.6% (95% CI = 65.3%, 91.9%). TEAEs during maintenance included asymptomatic grade 3-4 cytopenias (42% neutropenia, 5% thrombocytopenia, 3% anemia), and grade 1-2 infections (45% URI, 16% UTI, 13% sinusitis and 8% cellulitis), all managed in outpatient settings. Five patients required brief hospitalization for IV antibiotics: 1 (3%) developed neutropenic fever in setting of cholecystitis, 3 (8%) had pneumonia and 1 (3%) had recurrent UTI. Secondary malignancies included squamous-cell carcinoma in 2 subjects, basal-cell carcinoma in 1 subject, and melanoma in situ in 2 subjects. Merkel-cell carcinoma developed in an 86-year-old subject after 18 months of therapy, and pancreatic cancer was diagnosed in a 68-year-old patient after 12 months of therapy. Compared to baseline, cytokine levels at C2D1 and C4D1 showed Th1/Th2 modulation, with significant increase in IFNγ (p=0.004 and p=0.007) and IL4 (p=0.004 and p=0.017), as well as significant decrease in IL2 (p=0.046 and p=0.032), IL10 (p=0.004 and p=0.007) and TNFα (p CONCLUSIONS: Lenalidomide and rituximab as initial treatment for MCL can achieve high rate of complete responses and MRD negativity with durable remissions beyond 4 years. The nature of toxicity was not significantly affected by continuous treatment, particularly in the context of close follow-up. Further evaluation of this active regimen in larger, randomized frontline trials is warranted (ClinicalTrials.gov - NCT01472562). Disclosures Ruan: Cell Medica: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Martin: Celgene: Consultancy; Janssen: Consultancy, Honoraria, Other: travel expenses; Teva: Research Funding; Novartis: Consultancy; Genentech: Consultancy; Gilead: Consultancy, Other: travel expenses. Cerchietti: Celgene: Research Funding; Lymphoma Research Foundation: Research Funding; Leukemia and Lymphoma Society: Research Funding; Weill Cornell Medicine - New York Presbyterian Hospital: Employment. Schuster: Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Merck: Research Funding. Svoboda: Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pharmacyclics: Research Funding; Kite: Consultancy; Merck: Research Funding; Celgene: Research Funding. Furman: Verastem: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Honoraria; TG Therapeutics: Consultancy; Abbvie: Consultancy, Honoraria; Gilead: Consultancy; Pharmacyclics: Consultancy, Honoraria; Sunesis: Consultancy. Leonard: Roche: Consultancy; Celgene: Consultancy, Research Funding.

Development of a Novel Class of Microtubule Destabilizing Agents with Selectivity Against Diffuse Large B-Cell Lymphoma (DLBCL) with B-Cell Receptor (BCR) Activation

To identify drugs with preferential activity against phenotypically defined subtypes of DLBCL, we carried out a high throughput screening of 100,000 drug-like compounds in two cell lines with and without tonic BCR activation. After 3 rounds of progressive viability screening we identified a small molecule, named Li5, which decreased viability of BCR-DLBCLs. In an extended DLBCL panel including cell lines with tonic or chronic (OCI-Ly1, OCI-Ly7, Farage, OCI-Ly10), and no (Toledo, Karpas422, Pfeiffer) BCR activation, we confirmed that Li5 is over 40 times more selective against DLBCL with tonic or chronic BCR activity (P= 0.001). To determine whether this differential effect is maintained in animal models, we formulated Li5 and evaluated its toxicity in C57BL/6 mice. Li5 was administered up to 200 mg/kg without evidence of toxicity in biochemical and histological assays. To asses the selective anti-lymphoma effect, we xenografted two BCR-DLBCL cell lines (OCI-Ly1 and OCI-Ly7) and a non-BCR-DLBCL cell line (Toledo) into SCID mice. Once tumors developed, we administered 10 mg/kg/day of Li5 or vehicle. Li5 significantly decreased lymphoma size in OCI-Ly7 and OCI-Ly1 mice (P < 0.005 and P= 0.005, respectively, vs. vehicle) but not in Toledo mice (P= n.s., vs. vehicle), indicating the compound holds its selectivity in vivo.The mechanism of action (MOA) of Li5 was determined by comparing the transcriptomic changes (pre-post by RNA-seq in triplicates) induced by Li5 in a BCR-DLBCL cell line with those induced by drugs with known MOA using Connectivity-mapping. Surprisingly, we found a significant correlation with microtubule-destabilizing agents (MDAs), suggesting a common MOA. To validate the microtubules as targets of Li5, we first evaluated biochemically the formation of microtubules by spectroscopy and found that Li5 impairs their formation. Analytical ultracentrifugation experiments revealed that Li5 does not bind to unassembled tubulin unlike classic MDAs, while sedimentation/HPLC assays demonstrated that Li5 bounds to preformed microtubules. This represents a molecular MOA never reported before for a MDA. Studying the microtubule cytoskeleton of treated-cells by immunofluorescence, we observed a dose-dependent disruption of mitotic spindle microtubules but also interphase microtubules.We thus compared known cellular effects of MDAs in cells by treating BCR- and non-BCR DLBCL cell lines with Li5 and analyzing cell cycle and apoptosis. Li5 induced significant G2/M cell cycle arrest in both BCR and non-BCR cell lines however apoptosis was followed only in BCR cell lines. These effects remained after correcting by doubling time. Apoptosis was induced in non-BCR cells using chemotherapy agents indicating these cells do not have a defect in mechanisms inducing apoptosis. With all, these results suggest that Li5 inhibition of cell cycle is not the basis for its selectivity.To understand the basis of Li5 selectivity towards BCR-DLBCLs, we conducted a differential expression analysis (RNA-seq) comparing Li5 responsive (OCI-Ly1, OCI-Ly7, Farage, OCI-Ly10) and non-responsive (Toledo, Karpas422, Pfeiffer) DLBCLs. We found a significant (FRD<0.05) up-regulation of genes in the “P53/DNA damage response” (TP53, ZMAT3), “MAPK signaling” (DUSP16, PTPN7, GPER1) and “cytoskeleton signaling” (TUBB2A, SERP1, EVC, CCDC39 and APC2) pathways. Thus, our data suggests that Li5 selectivity could be explained due to a functional dependency of BCR signaling towards cytoskeletal components in BCR-DLBCL cells. In normal lymphocytes, BCR signaling drives remodeling of cytoskeletal elements to promote subsequent signaling events needed for full BCR activation and antigen internalization. The role of the cytoarchitecture in maintaining the activity of BCR in DLBCL is unknown. By using Li5, a novel MDA with a unique MOA, we identified the microtubules as critical determinants of survival of DLBCL with tonic and chronic BCR activation. DisclosuresRivera:Weill Cornell Medicine: Employment. Cerchietti:Lymphoma Research Foundation: Research Funding; Celgene: Research Funding; Leukemia and Lymphoma Society: Research Funding; Weill Cornell Medicine - New York Presbyterian Hospital: Employment.

Exportin-1 Connects Dynamic Transcription and Translation of Genotoxic Stress Genes in Diffuse Large B-Cell Lymphoma Patients

Exportin-1 (XPO1), that exports a subset of proteins from the nucleus to the cytoplasm, is amplified in 30% of DLBCL. Regardless of XPO1 gene status, DLBCLs require XPO1 to proliferate and survive as demonstrated in pre-clinical (Marullo et al. AACR 2015) and clinical (Kuruvilla at al. Blood 2017) studies with the covalent XPO1 inhibitor selinexor. However, the mechanism underlying such dependency remains unknown.We analyzed the expression of XPO1 protein in a cohort of 57 DLBCL patients by IHC and correlated with XPO1 gene status and clinical outcome. XPO1 increased copy number is associated with elevated protein expression (p = 0.03) and, importantly, patients with elevated XPO1 levels (XPO1 high) are less likely to respond to RCHOP as refractory/early relapse diseases (p = 0.005). This suggests that XPO1 high DLBCL could be biologically fitter to tolerate genotoxic stress. To explore this hypothesis, we compared gene expression profiles (RNA-sequencing) of XPO1 high (n = 15) vs. XPO1 low (n = 16) DLBCLs by DESeq2. XPO1 high DLBCLs were enriched (q<0.005) for genes regulating “cell proliferation”, “DNA damage response and repair”, “mRNA processing” and “RNA export”; whereas depleted (q<0.05) for genes regulating “immune response”. Gene Set Enrichment Analysis also revealed that XPO1 high were enriched for transcripts up-regulated in highly aneuploid tumors (FDR = 0, NES = 2.19). All these findings were validated in an independent cohort of 72 DLBCL patients.To gain insight into the mechanism by which XPO1 enhances genotoxic stress tolerance, we exposed a panel of 5 DLBCL cell lines to DNA damaging agents (etoposide, doxorubicin, mechloretamine) with or without XPO1 inhibition (selinexor). Comet assay experiments revealed that selinexor did not affect the amount of DNA damage induced by chemotherapy, but delayed cell's ability to repair the DNA damage (P>0.005). This translated into a significant increase of sensitivity toward otherwise sub-lethal effect of chemotherapy, as all the combinations tested showed synergistic effect on growth inhibition. To determine the existence of a therapeutic window to capitalize on this effect, we evaluated the combination of CHOP +/- selinexor in an XPO1 high DLBCL patient-derived xenograft mice model (n = 40). Combination treatment achieved higher anti-lymphoma effect compared to either selinexor or CHOP alone (p>0.005 and p= 0.0015, respectively). Importantly, no increase in toxicity was observed by biochemistry or pathological examination. Thus, proliferating DLBCL cells but not normal cells rely on XPO1 to survive exogenous genotoxic stress.To characterize the molecular consequences of XPO1 inhibition, we quantified the expression of proteins involved in DNA damage response and repair (immunoblotting). Exposure to selinexor decreased the expression of a subset of these proteins including CHEK1, BRCA1, BCL6 and RAD51. This reduction was neither due to decreased gene transcription (qRT-PCR) nor to increased protein degradation (cycloheximide chase). Instead, analysis of nascent proteins by L-azido-homo-alanine labeling revealed that XPO1 inhibition decreases the synthesis of specific DNA damage repair proteins whose increased turnover is required to survive genotoxic stress. Since XPO1 inhibition affected only a subset of proteins, the mechanism may involve selective decrease in nuclear export of mRNA templates. Thus, we quantified the nuclear/cytoplasmic ratio of mRNAs encoding for DNA damage repair proteins in DLBCL cells treated with selinexor. XPO1 inhibition resulted in nuclear retention of BRCA1, RAD51, BCL6 and CHEK1 mRNAs but not of β-actin. Since XPO1 is unable to directly bind mRNAs, we reasoned that its inhibition may impair the export of proteins carrying mRNA (ribonucleoproteins). Indeed, we identified eIF4E as one of these cargoes. Immunofluorescence experiments revealed that eIF4E is retained in the nucleus of DLBCL cells upon XPO1 inhibition and its nuclear retention is enhanced in etoposide-treated cells. Moreover, RIP-qPCR experiments revealed that eIF4E binds several DNA damage repair mRNAs such as CHEK1, BCL6 and BRCA1 in the nucleus of DLBCL cells and this binding increases significantly in response to DNA damage.Overall, our data demonstrate that XPO1, by regulating the selective export of mRNA-binding proteins, promotes genotoxic stress tolerance thus conferring a survival advantage to XPO1high DLBCLs. DisclosuresYang:Regeneron Pharmaceuticals: Employment. Cerchietti:Leukemia and Lymphoma Society: Research Funding; Lymphoma Research Foundation: Research Funding; Celgene: Research Funding; Weill Cornell Medicine - New York Presbyterian Hospital: Employment.

Cellular Proliferation By Multiplex Immunohistochemistry Identifies Aggressive Disease Behavior in Relapsed Multiple Myeloma

Background: As treatment options in relapsed and refractory multiple myeloma (MM) increase, prognostic biomarkers are needed to aid clinical decision making. The plasma cell labeling index (PCLI) has been a validated prognostic tool in MM but utilization remains limited due to technical burden. A novel multiplex immunohistochemical (mIHC) co-staining technique for CD138 and Ki67 expression was developed to quantify plasma cells in active cycling: the Plasma Cell Proliferation Index (PCPI). Previously presented results from newly diagnosed patients (pts) demonstrated an elevated PCPI is associated with shorter progression-free (PFS) and overall survival (OS) in pts undergoing first line MM treatment. Here we assess MM pts with PCPI both at diagnosis and relapse to assess the impact of cell cycling ratio at relapse on outcomes with subsequent therapy and overall clinical course.Methods: A retrospective cohort study of pts with MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital (WCMC/NYPH). For inclusion in the analysis, pts required bone marrow (BM) available for evaluation for PCPI. Pts must have completed their first line and relapse treatments at WCMC/NYPH. The PCPI was calculated as the percentage of plasma cells expressing CD138 that were also found to express Ki67 after a total of 200 CD138+ cells were scored. Treatment outcomes were stratified and evaluated based on the PCPI at relapse, the change in the PCPI between diagnostic and relapse samples(∆PCPI), and the presence or acquisition of new high risk cytogenetic abnormalities in diagnostic and relapse samples.Response comparison was made using a 2-sided t test with a Satterthwaite adjustment for variance. Survival analyses were performed using a univariate cox proportional hazard model.Results: We identified 48 pts with BM PCPI both at diagnosis and relapse. These pts received a median of 2 lines of therapy prior to relapse BM (range 1-7). The overall response rate (ORR) to post biopsy therapy with 56% (27/48 pts). There was no difference in response rate between pts with (n=35, ORR 57%) and without (n=12, ORR 58%) high risk cytogenetic abnormalities on relapse biopsy. Nor was there a difference in pts who acquired a new high risk cytogenetic abnormality at relapse (n=26, ORR 57%) and those who did not (n=21, ORR 57%). PCPI at relapse was strongly associated with ORR with the median PCPI in pts who achieved response of 7.9% vs 26.6% in non-responders (p=0.003). Additionally, a rising PCPI was associated with a decreased likelihood of response. The median ∆PCPI in patients with a response to relapse therapy was 2.4% vs 19.2% in patients who failed to respond (p=0.007). PCPI was strongly associated with risk of progression and death with each 1% increase in PCPI correlating with a 4% increase in risk of progression (HR 1.038 95% CI 1.019,1.058; p<0.001) and death (HR 1.037 95% CI 1.019, 1.056; P<0.001). The ∆PCPI showed similar results with each 1% increase correlating with a 3% increase in risk of progression (HR 1.034 95% CI 1.013, 1.055; p<0.001) and death (HR 1.035 95% CI 1.016, 1.054; p<0.001). The presence of high risk cytogenetic abnormality on relapse biopsy was not associated with increased risk of progression, HR 0.882 (95% 0.418, 1.859; p0.741), but did approach significance for OS, HR 3.31 (95% CI 0.98, 11.1; p=0.053), while acquisition of a new high risk cytogenetic abnormality was not associated with either risk of progression, HR 0.75 (95% CI 0.418, 1.859; p=0.741) or death, HR 0.76 (95% CI 0.342, 1.71; p=0.513).Discussion: In this retrospective analysis PCPI identified aggressive disease behavior in relapsed MM with significant associations with treatment responsiveness and risk for both progression and death. Alternatively, the acquisition of new high risk cytogenetic factors at relapse was much less prognostically impactful, with no clear association with treatment responsiveness, risk for progression or death identified. DisclosuresRossi:Thrassos: Consultancy; Celgene: Consultancy. Niesvizky:BMS: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Ely:Weill Cornell Medical College: Patents & Royalties: Dr. Ely is one of the holders of US Patent RE46379 for PCPI.

A Phase I, Open Label, Multicenter Trial of Oral Azacitidine (CC-486) Plus R-CHOP in Patients with High-Risk, Previously Untreated Diffuse Large B-Cell Lymphoma, Grade 3B Follicular Lymphoma, or Transformed Lymphoma

A Phase I, Open Label, Multicenter Trial of Oral Azacitidine (CC-486) Plus R-CHOP in Patients with High-Risk, Previously Untreated Diffuse Large B-Cell Lymphoma, Grade 3B Follicular Lymphoma, or Transformed Lymphoma

Universal COVID-19 testing and a three-space triage protocol is associated with a nine-fold decrease in possible nosocomial infections in an inpatient psychiatric facility

In May of 2020, the Substance Abuse and Mental Health Service Administration (SAMSA) issued guidelines for state psychiatric hospitals, recommending that these facilities adopt universal testing for COVID-19 and “three-space” triage protocols for dedicated COVID-19 positive, negative, and quarantine spaces to mitigate the risk of nosocomial infection. The Westchester Behavioral Health Center of New York Presbyterian Hospital (WBHC-NYP) adopted a comprehensive infection control protocol consistent with these recommendations in April, 2020.We reviewed the records of 1,139 patients treated on the inpatient service at WBHC-NYP between March 14th and June 10th, 2020, dates corresponding to the first COVID-19 surge in the New York City metropolitan region. The incidence of detected nosocomial or possible nosocomial infections before and during the implementation of the protocol was 0.096 (16/167), or 0.96 infections per 10 at-risk patients. The incidence of nosocomial or possible nosocomial infections after complete implementation was 0.0110 (2/182), or 1.1 infections per 100 at-risk patients. The difference in incidence between the two time points was statistically significant (p<.0003) and represents a 9-fold decrease. Our findings support the institutional use of a combined testing and space allocation protocol to mitigate risk of outbreaks in confined settings.

COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital.

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38–97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20–30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.

Simulation Based Educational Intervention for Enhancing Irrigation Skills of Nurses Caring for Patients With Cutaneous Continent Urinary Diversions and Orthotopic Neobladders.

The purpose of this study was to investigate the effect of a nurse practitioner-led simulation-based education program on nursing knowledge and confidence in the care of patients with a cutaneous continent urinary diversion (Indiana pouch) or orthotopic neobladder. Single-group, before-after study. The sample comprised 11 RNs practicing at New York Presbyterian Hospital in New York City. Subjects were predominantly female, ethnically diverse, and held a bachelor's degree. About half of the subjects had less than 3 years of experience, and more than half reported prior experience caring for patients with a urinary diversion. Participants completed a demographic survey, and a continent urinary diversion confidence survey and pretest measuring knowledge of nursing care of patients with a urinary diversion. Following baseline data collection, an educational session focused on the irrigation of a continent urinary diversion was made available for participants to review. An onsite simulation experience was scheduled several weeks later. Investigators provided education on proper irrigation of a continent urinary diversion and observed participants' skills when irrigating a continent urinary diversion on a high-fidelity simulated patient mannequin. The simulation intervention was followed by video replay and debrief providing feedback on each participant's performance. At the conclusion of the onsite simulation intervention, participants completed a postintervention confidence survey and a knowledge posttest related to the care of a continent urinary diversion. The Wilcoxon signed rank test was used to analyze baseline and postintervention changes in nursing knowledge and confidence. Participants achieved significant improvements in knowledge (P = .005) and confidence (P = .009) following the simulation-based educational intervention. A nurse practitioner-led simulation-based educational program for RNs caring for patients with continent urinary diversions demonstrates enhanced nursing knowledge and confidence caring for patients with continent urinary diversions. We anticipate this experience will enhance care we provided to patients undergoing cystectomy and continent cutaneous urinary diversion or orthotopic neobladder construction.

Factors Predicting Chronic Opioid Use after Orthopedic Surgical Procedures

Opioid abuse has been an increasing problem since the 1990s. With over 47,000 opioid related deaths recorded in 2017 alone, concerns have been raised regarding the dangers of introducing opioids perioperatively to patients undergoing major surgeries. The present study proposes to examine the frequency, amount, and trends in post-operative opioid consumption in patients undergoing orthopedic surgical procedures. This was a randomized, retrospective questionnaire-based study. Patients who underwent any type of orthopedic surgery at the University of Pennsylvania Presbyterian Hospital from 1/1/2018 to 3/12/2019 were randomly selected and called during the summer of 2019. In this retrospective questionnaire-based study, 828 patients were called by telephone in the summer of 2019. These patients were asked a variety of questions involving opioid consumption behavior post-surgery. The study ended after receiving responses from 200 patients. Nineteen (9.5%) patients reported positively for experiencing euphoria while taking opioids post-surgery. Of the 200 patients contacted, 6 patients (3%) reported switching to marijuana instead of opioids. Thirty-eight (19%) patients preferred to take no opioids at all post-surgery, and one patient was found to have given their prescription to a family member or friend. Twenty-one patients (10.5%) were found to have been taking opioids for non-severe pain. Blacks and whites were the most common racial demographics, making up 84 and 109 of the totals, respectively. The odds ratios for all of the predictors showed that the relative risk for opioid misuse was higher for black patients than white patients (OR = 3.034). There was no relationship between the intra- and post-operative opioid administration and long-term opioid misuse. Patients are self-selected and had the option to opt out of the study when contacted. Some patients may not have been available to answer the phone when our study was being conducted. This study was only conducted for orthopedic patients and for patients who received surgery at the University of Pennsylvania Presbyterian Hospital, thus affecting the demographics for our research. Prescription opioid misuse is more common among the black population. The total opioid consumption is frequently lower than the quantity prescribed. Patients frequently use opioids even though they feel that pain is insufficient to deserve such an intervention. Euphoria is experienced by a significant number of patients taking prescription opioids Often patients do not take any opioids, although they had prescriptions.

Relationship between NIH stroke symptoms and post-traumatic stress disorder in patients evaluated for transient ischemic attack/stroke

ObjectivePost-traumatic stress disorder (PTSD) can develop after a life-threatening medical event. According to the enduring somatic treat (EST) model, internal somatic cues (e.g., rapid heart rate) may contribute to symptoms of stroke/TIA-induced PTSD. To address this possibility, the present study tested the association of stroke-induced disability with PTSD symptoms in patients treated for stroke or transient ischemic attack (TIA). MethodParticipants (n = 300) were drawn from an observational cohort study examining PTSD symptoms in patients admitted to the NewYork Presbyterian Hospital between 2015 and 2017 for a stroke/TIA. Patients self-reported acute stress symptoms in-person approximately 3 days post-stroke/TIA and PTSD symptoms via telephone one month later. Severity of stroke symptoms (i.e., stroke disability) was evaluated using the NIH Stroke Scale prior to hospital discharge. ResultsStroke disability had a significant, positive association with acute stress symptoms early post-stroke/TIA, B = 0.46, se = 0.15, p = .002, and with PTSD symptoms one month later, B = 0.56, se = 0.19, p = .003. ConclusionsStroke disability is positively associated with both acute distress and PTSD symptoms one month later following a stroke/TIA, supporting the hypothesis that internal somatic symptoms contribute to the development stroke/TIA-induced PTSD symptoms.

Abstract P843: Stroke Patient Monitoring Used in Adult Emergency Department During Covid-19 Acting Both Rapidly and Safely

Introduction: The healthcare system was facing two challenges: acute patients presenting to the adult emergency department diagnosed with Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)/ COVID-19 and how to treat life-threating emergencies. Emergency, neurovascular and multidisciplinary teams, therefore, had to be ready to treat these emergencies rapidly and safely. The goals were to balance substantial needs and preserve resources during this extraordinary time for incoming acutely ill patients. Background: The World Health Organization (WHO) defined COVID-19 as a pandemic. New York City was the epicenter for the 2019-2020 COVID -19 pandemic. There were 30,000 confirmed cases resulting in over 2,500 hospitalizations as of March 30, 2020. Hence, it was vital to develop new monitoring protocols, based upon the expert opinion of the stroke and multidisciplinary leadership at New York Presbyterian Hospital that required minimum monitoring and criteria for admission necessary to safely care for complex stroke patients. Purpose: This quality improvement project evaluated patient outcomes after the implementation of the modified stroke protocol. Methods: Retrospective data review was conducted for patients who presented via the Emergency Department with stroke symptoms, and were treated with intravenous thrombolysis (IVT) between 3/30 and 6/30/2020, with a focus on whether patients required a higher level of care or developed hemorrhagic transformation post IVT. Results: The sample consisted of 10 patients (60% female), median age 54 (range 37-73). Length of stay ranged from 2 to 12 days. Two patients (20%) were SARS-CoV-2 positive. None (0%) of the patients developed hemorrhagic transformation. None (0%) of the patients admitted to non-ICU units required critical care transfer or interventions within 24 hours of receiving IVT. Six (60%) patients were discharged to home. Conclusions: Using the modified patient monitoring protocol post IVT none of the patients developed symptomatic hemorrhagic transformation and did not require transfer to higher level of care within 24 hours. If there is another wave of the COVID-19 pandemic, this protocol could be adopted and its effectiveness and safety can continue to be evaluated.

CORR Synthesis: When Should the Orthopaedic Surgeon Use Artificial Intelligence, Machine Learning, and Deep Learning?

CORR Synthesis: When Should the Orthopaedic Surgeon Use Artificial Intelligence, Machine Learning, and Deep Learning?

Abstract PS5-21: Use of a novel convolutional neural network (CNN)-based mammographic evaluation to assess response to adjuvant endocrine therapy

Abstract Background: The standard of care for early-stage hormone receptor (HR)-positive breast cancer is 5-10 years of adjuvant endocrine therapy (ET), which is associated with a 50-60% relative risk reduction in breast cancer recurrence. However, patients remain at risk of recurrence up to 20 years after diagnosis, and there is a need for biomarkers of response to ET. While decrease in mammographic density (MD) is associated with improved disease-free survival (DFS), measurement is subject to variability in radiologists’ interpretations. We developed a novel, fully-automated convolutional neural network (CNN)-based mammographic evaluation that is a more accurate, independent predictor of breast cancer risk than MD. We evaluated the role of the CNN model as a pharmacodynamic biomarker of response to adjuvant ET among women with early-stage HR-positive breast cancer. Methods: We conducted a retrospective cohort study among women with HR-positive, stage I-III unilateral breast cancer diagnosed at Columbia University Irving Medical Center (CUIMC) in New York, NY, from 2007-2017, who received adjuvant ET and had at least two contralateral mammograms (baseline and on ET) in our electronic health record (EHR). Demographics, clinical characteristics, breast cancer treatment (surgery, radiation, systemic therapy), type of ET (aromatase inhibitor [AI], tamoxifen, or both), and breast cancer relapse (distant, local, new breast primary) were extracted from the EHR and New York Presbyterian Hospital (NYPH) Tumor Registry. We performed CNN analysis of contralateral mammograms at baseline (within 1 year of diagnosis and prior to ET) and at 1- and 2-year (y) follow-up on ET. The primary endpoint was change in CNN risk score, expressed as a continuous variable (range, 0-1.00). Paired t-tests were used to assess for differences in CNN scores between baseline and 1y and 2y follow-up. Logistic regression was used to evaluate if CNN scores at baseline and change from baseline were associated with relapse, with adjustment for known prognostic factors. Results: Of 2,559 women diagnosed with stage I-III HR-positive breast cancer at CUIMC from 2007-2017, 465 had serial mammograms available for CNN analysis. Mean age at diagnosis was 61.2y (SD, 12.2y), and 38.1% of women were non-Hispanic white, 12.5% non-Hispanic black, 39.8% Hispanic, and 9.7% other/unknown. At initial diagnosis, 62.2% had stage I tumors, 74.4% received lumpectomy, and 41.7% received chemotherapy. There were 28 (6.0%) breast cancer relapses (15 distant, 10 local, 3 new primary). Women who had relapsed were more likely to be obese (p=0.009), have higher tumor stage (p&amp;lt;0.001) and grade (p=0.022), higher Ki67% (p=0.003), and have received chemotherapy (p=0.036). While baseline CNN risk scores were higher among women who had relapsed compared to those who did not (0.295 vs 0.269), this difference was not statistically significant (p=0.197). Among all women, mean CNN scores were 0.271 (SD, 0.101) at baseline, 0.216 (SD, 0.073) at 1y, and 0.208 (SD, 0.072) at 2y; changes in scores from baseline to 1y and 2y were significant (p&amp;lt;0.001), consistent across subgroups. However, in multivariable logistic regression, there was no significant association between change in CNN score from baseline to 1y and 2y and breast cancer relapse. Conclusions: We demonstrated a significant change in CNN risk scores from baseline to short-term follow-up among women with early-stage breast cancer who received adjuvant ET. Women who relapsed had higher baseline CNN risk scores, but this was not significant. Due to the small number of relapses, change in CNN risk scores was not associated with breast cancer recurrence. The CNN risk model will be evaluated prospectively in adjuvant clinical trials, to further evaluate its role as a predictor of breast cancer relapse and response to adjuvant ET. Citation Format: Julia E McGuinness, Jana Lee, Aishwarya Anuraj, Simukayi Mutasa, Richard S Ha, MD, Katherine D Crew, MDMS. Use of a novel convolutional neural network (CNN)-based mammographic evaluation to assess response to adjuvant endocrine therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-21.

Bloodstream infection with Acinetobacter baumanii in a Plasmodium falciparum positive infant: a case report

BackgroundThe increasing incidence of multi-antibiotic-resistant bacterial infections, coupled with the risk of co-infections in malaria-endemic regions, complicates accurate diagnosis and prolongs hospitalization, thereby increasing the total cost of illness. Further, there are challenges in making the correct choice of antibiotic treatment and duration, precipitated by a lack of access to microbial culture facilities in many hospitals in Ghana. The aim of this case report is to highlight the need for blood cultures or alternative rapid tests to be performed routinely in malaria patients, to diagnose co-infections with bacteria, especially when symptoms persist after antimalarial treatment.Case presentationA 6-month old black female child presented to the Agogo Presbyterian Hospital with fever, diarrhea, and a 3-day history of cough. A rapid diagnostic test for malaria and Malaria microscopy was positive for P. falciparum with a parasitemia of 224 parasites/μl. The patient was treated with Intravenous Artesunate, parental antibiotics (cefuroxime and gentamicin) and oral dispersible zinc tablets in addition to intravenous fluids. Blood culture yielded Acinetobacter baumanii, which was resistant to all of the third-generation antibiotics included in the susceptibility test conducted, but sensitive to ciprofloxacin and gentamicin. After augmenting treatment with intravenous ciprofloxacin, all symptoms resolved.ConclusionEven though this study cannot confirm whether the bacterial infection was nosocomial or otherwise, the case highlights the necessity to test malaria patients for possible co-infections, especially when fever persists after parasites have been cleared from the bloodstream. Bacterial blood cultures and antimicrobial susceptibility testing should be routinely performed to guide treatment options for febril illnesses in Ghana in order to reduce inappropriate use of broad-spectrum antibiotics and limit the development of antimicrobial resistance.

Analysis of the Plasma Metabolome after Trauma, Novel Circulating Sphingolipid Signatures, and In-Hospital Outcomes

Trauma is the leading cause of death and disability for individuals under age 55. Many severely injured trauma patients experience complicated clinical courses despite appropriate initial therapy. We sought to identify novel circulating metabolomic signatures associated with clinical outcomes following trauma. Untargeted metabolomics and circulating plasma immune mediator analysis was performedon plasma collected during 3 post-injury time periods (<6 hours [h], 6 h-24h, day 2-day 5) in critically ill trauma patients enrolled between April 2004 and May 2013 at UPMC Presbyterian Hospital in Pittsburgh, PA. Inclusion criteria were age ≥ 18 years, blunt mechanism, ICU admission, and expected survival ≥ 24 h. Exclusion criteria were isolated head injury, spinal cord injury, and pregnancy. Exploratory endpoints included length of stay (overall and ICU), ventilator requirements, nosocomial infection, and Marshall organ dysfunction (MOD) score. The top 50 metabolites were isolated usingrepeated measures ANOVA and multivariate empirical Bayesian analysis for further study. Eighty-six patients were included for analysis. Sphingolipids were enriched significantly (chi-square, p < 10-6) among the top 50 metabolites. Clustering of sphingolipid patterns identified 3 patient subclasses: nonresponders (no time-dependent change in sphingolipids, n= 41), sphingosine/sphinganine-enhanced (n= 24), and glycosphingolipid-enhanced (n=21). Compared with the sphingolipid-enhanced subclasses, nonresponders had longer mean length of stay, more ventilator days, higher MOD scores, and higher circulating levels of proinflammatory immune mediators IL-6, IL-8, IL-10, MCP1/CCL2, IP10/CXCL10, and MIG/CXCL9 (all p < 0.05), despite similar Injury Severity Scores (p=0.12). Metabolomic analysis identified broad alterations in circulating plasma sphingolipids after blunt trauma. Circulating sphingolipid signatures and their association with both clinical outcomes and circulating inflammatory mediators suggest a possible link between sphingolipid metabolism and the immune response to trauma.

Detrimental Impact of Social Determinants of Health on Hospitalized Patients with COVID-19

Background: Sars-COV-2, the virus responsible for COVID-19, has a diverse clinical presentation and course that is amplified across different populations. It intensifies existing health outcome disparities that minorities and individuals in lower socioeconomic groups face when compared to the general population. However, the particular elements among these groups that contribute to health disparities with COVID-19 infections are unclear. Objective: To examine the relationship between various Social Determinants of Health (SDH) such as ethnicity, financial class, primary language, age and zip code have on the course and progression of COVID-19 infections. Design: A retrospective cohort analysis of data from patients who tested positive for the coronavirus admitted to the Emanate Health hospital system across all three campuses at Queen of the Valley Hospital, Inter-Community Hospital and Foothill Presbyterian Hospital. We extracted data from the hospital electronic medical records (EMR) and analyzed the following aspects of SDH including zip code, financial class, ethnicity, primary language and age as related to length of stay and mortality rate at Emanate Health. Participants: Patients (18 years of age or older) admitted to the Emanate Health hospital system in the San Gabriel Valley, California between 3/17/2020-6/30/2020 (n=400) who tested positive for the novel coronavirus via nasopharyngeal, oropharyngeal and/or serologic testing based on availability. Results: Statistical significance was noted for the SDH parameters of insurance status, primary language and ethnicity with respect to insurance. Medicare patients had the longest average length of stay in contrast to self pay patients with the lowest average days (P <0.0001). Hospital length of stay increased with increasing age when grouped by ages 19-29, ages 30-49, ages 50-69 or ages 70+ (p value <0.0001). English was the primary language of 75.25% of patients but mortality rate was higher for patients whose primary language was Spanish. The average length of stay for Hispanics when classified by financial class was statistically significant (p =0.0002) as well as the average hospital length of stay for Non-Hispanics when classified by financial class (p <0.0001). Conclusions: The environment in which people are born, live and age is long known to govern a wide degree of health outcomes. Our data specifically highlights the differences in the course of COVID-19 infections amongst people with different social determinants of health and how COVID-19 further unveiled these existing social disparities. We should be cognizant of the large Hispanic/Latino population that’s makes up the San Gabriel Valley and take heed of these particular socioeconomic factors that drive poorer health outcomes.