Medical College Of Wisconsin Research Articles

Trileaflet Mitral Valve in the Setting of Hypertrophic Cardiomyopathy: A Curious Rarity With a Possible Association.

HomeCirculation: Cardiovascular ImagingVol. 15, No. 4Trileaflet Mitral Valve in the Setting of Hypertrophic Cardiomyopathy: A Curious Rarity With a Possible Association No AccessCase ReportRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialNo AccessCase ReportRequest AccessFull TextTrileaflet Mitral Valve in the Setting of Hypertrophic Cardiomyopathy: A Curious Rarity With a Possible Association Carson Castellani, MD, Aaron A. H. Smith, MD, Divyanshu Mohananey, MD and Noelle Garster, MD, MS Carson CastellaniCarson Castellani https://orcid.org/0000-0001-9164-9830 Department of Medicine (C.C.), Medical College of Wisconsin, Milwaukee. Search for more papers by this author , Aaron A. H. SmithAaron A. H. Smith Correspondence to: Aaron A.H. Smith, MD, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226. Email E-mail Address: [email protected] https://orcid.org/0000-0003-0559-3768 Division of Cardiovascular Medicine, Department of Medicine (A.A.H.S., D.M., N.G.), Medical College of Wisconsin, Milwaukee. Search for more papers by this author , Divyanshu MohananeyDivyanshu Mohananey Division of Cardiovascular Medicine, Department of Medicine (A.A.H.S., D.M., N.G.), Medical College of Wisconsin, Milwaukee. Search for more papers by this author and Noelle GarsterNoelle Garster Division of Cardiovascular Medicine, Department of Medicine (A.A.H.S., D.M., N.G.), Medical College of Wisconsin, Milwaukee. Search for more papers by this author Originally published29 Mar 2022https://doi.org/10.1161/CIRCIMAGING.121.013772Circulation: Cardiovascular Imaging. 2022;15FootnotesSupplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCIMAGING.121.013772.For Sources of Funding and Disclosures, see page 285.Correspondence to: Aaron A.H. Smith, MD, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226. Email aaron.ah.[email protected]com

Professional views on priorities for cervical cancer policy in Uganda: a qualitative study

BackgroundCervical cancer incidence in Uganda is three-times that of the global average, and is a leading cause of mortality for women. The main cause is human papillomavirus (HPV). Women living with HIV have a greater risk of acquiring HPV and need better cervical cancer care than their HIV-negative counterparts. Although funding and infrastructure exist for HIV control, they are not in place for cervical cancer. We aimed to assess Ugandan health professionals' knowledge of and perspectives regarding cervical cancer among women with HIV to identify perceived barriers and facilitators, and to guide potential interventions to reduce the burden of cervical cancer. MethodsWe used qualitative interviews to obtain primary data from professionals working in the HIV field in Uganda, identified through purposive and snowball sampling, and through consultation with colleagues at The AIDS Support Organisation (TASO) and Makerere University in Kampala. Inclusion criteria required the respondent to be a provider, researcher, community health worker, or other authority on cervical cancer and HPV and to be conversant in English. Exclusion criteria included being younger than 18 years. Written and verbal informed consent were obtained in accordance with the Medical College of Wisconsin and Makerere University human subjects protection protocols. Virtual, 1 h-long interviews were conducted and recorded. Interviews consisted of open-ended questions exploring perspectives on, knowledge about, and practices surrounding HPV and cervical cancer among women with HIV in Uganda. Institutional review board approval was obtained from TASO, the Uganda National Council for Science and Technology, and Medical College of Wisconsin. Transcripts were analysed and coded via MaxQDA software for common themes; emerging codes were generated from meaningful quotes as used in specific interviewee contexts of facilitators and barriers to HPV vaccination, cervical cancer screening, and treatment. FindingsTo date, we have conducted 50 interviews of health professionals with experience across Uganda. Common themes regarding barriers to cervical cancer control include misconceptions about treatment cost and effectiveness, scarce access to and distance to cervical cancer services, transient funding for cervical cancer screening and treatment supplies, and fears of social exclusion and death. Potential solutions offered by participants include decentralising care through integration with existing health programmes, and prioritising education that targets misconceptions surrounding cervical cancer. InterpretationProfessionals indicated numerous misconceptions and fears held by women with HIV and inaccessibility of care due to lack of funding and integration of services. Priorities should include increasing mass media campaigns that target misconceptions, decentralising care through integration with existing health-care infrastructure and HIV screening and treatment programmes, and training more professionals in rural areas. FundingMedical College of Wisconsin Cancer Center and Dr Elaine Kohler Global Health Research.

Methods for the Comprehensive in vivo Analysis of Energy Flux, Fluid Homeostasis, Blood Pressure, and Ventilatory Function in Rodents.

Cardiovascular disease represents the leading cause of death in the United States, and metabolic diseases such as obesity represent the primary impediment to improving cardiovascular health. Rodent (mouse and rat) models are widely used to model cardiometabolic disease, and as a result, there is increasing interest in the development of accurate and precise methodologies with sufficiently high resolution to dissect mechanisms controlling cardiometabolic physiology in these small organisms. Further, there is great utility in the development of centralized core facilities furnished with high-throughput equipment configurations and staffed with professional content experts to guide investigators and ensure the rigor and reproducibility of experimental endeavors. Here, we outline the array of specialized equipment and approaches that are employed within the Comprehensive Rodent Metabolic Phenotyping Core (CRMPC) and our collaborating laboratories within the Departments of Physiology, Pediatrics, Microbiology & Immunology, and Biomedical Engineering at the Medical College of Wisconsin (MCW), for the detailed mechanistic dissection of cardiometabolic function in mice and rats. We highlight selected methods for the analysis of body composition and fluid compartmentalization, electrolyte accumulation and flux, energy accumulation and flux, physical activity, ingestive behaviors, ventilatory function, blood pressure, heart rate, autonomic function, and assessment and manipulation of the gut microbiota. Further, we include discussion of the advantages and disadvantages of these approaches for their use with rodent models, and considerations for experimental designs using these methods.

Reconstructing the tumor microenvironment to unlock therapeutic options in pancreatic cancer.

589 Background: Spatiotemporal heterogeneity, paucity of actionable targets, and complexity of the tumor microenvironment (TME) are major barriers to therapeutic advances in pancreatic ductal adenocarcinoma (PDAC). We reconstructed the transcriptomic data from a heterogeneous cohort of PDAC patients (pts) to examine the TME and identify putative therapeutic strategies. Methods: Transcriptomic profiling and targeted gene sequencing data (Tempus) on primary or metastatic specimens from PDAC pts treated at the Medical College of Wisconsin (MCW) between 2015-2020 were analyzed. Mutation calling, expression analysis, cell type deconvolution from the transcriptome, and TME reconstruction were performed using BostonGene’s automated pipelines. Mann-Whitney U test and Fisher's exact test were used to assess statistical significance. Results: The cohort (N = 79) comprised of resectable (19%), borderline resectable (37%), locally advanced (24%) and metastatic (20%) PDAC pts. The most frequently used tumor sites for transcriptomic profiling were pancreas primary (59%), liver (16%), lung (10%) and peritoneum (10%). Four distinct subtypes were identified based on the BostonGene classification of the transcriptomic TME– Immune Enriched (IE; 14%), Fibrotic (F; 28%), Immune Enriched & Fibrotic (IEF; 36%), and Immune Depleted (ID; 22%). Analyses of the cellular composition of the TME subtypes with RNA-seq-based deconvolution showed that T-cell fractions (CD4, CD8) were higher in the IE/IEF subtypes compared to the F/ID subtypes (CD8 means: 6.4% vs 2.9%, p < 0.001; CD4 means: 15.1% vs. 7.6%, p < 0.001), while fibroblast content was higher in the F/IEF subtypes compared to the IE/ID subtypes (37.4% vs 18.4%; p < 0.001). KRAS wild-type (WT) tumors were enriched in the IEF subtype (58%), while KRAS mutated tumors comprised all four transcriptomic subtypes. Primary PDACs that underwent radiotherapy were significantly more enriched in fibroblasts compared to samples from the TCGA cohort that did not undergo radiotherapy (means: 30%(MCW) vs. 20% (TCGA), p < 0.001). Primary PDACs were enriched in the IEF subtype (46%), while liver and lung metastases were enriched in the ID (74%) and IE subtypes (70%), respectively. When pts were dichotomized to short (< 400 days) versus long (> 800 days) survivors, tumors from pts with longer survival demonstrated a trend towards enrichment in CD4/CD8 T cells and IE subtype that did not meet statistical significance. Conclusions: Lung metastases and KRAS WT PDACs harbor an immunogenic TME while liver metastases harbor an immune-cold TME, highlighting the biologic heterogeneity of PDAC. The efficacy of immunotherapeutic strategies in PDAC pts who demonstrate an IE/IEF transcriptomic subtype merits prospective evaluation. The four distinct subtypes identified by TME transcriptomic classification highlight the possibility of personalized immunotherapeutic strategies in PDAC.

The patients engaged in education and research (PEER) health care-associated infection prevention project: A Veteran perspective

My involvement in Veteran research began about 10-15 years ago through researchers at the Medical College of Wisconsin (MCW) and the Milwaukee VA. They were interested in Dryhootch of America, where I served as Cofounder and Director of Community Programs and Peer Coordinator. We partnered in the Dryhootch Partners for Veteran Health – Veteran Centered Research and Action project to support mental health initiatives. I am an Army Veteran in recovery, and my passion for the past 15 years has been working on Veterans’ issues and helping Veterans in their journey of transition to living a productive life, especially at points when they may not think they can. I'm also involved in some other peer support programs supporting suicide prevention (Captain John D. Mason Peer Support Program, the Growing Rural Outreach through Veteran Engagement 'GROVE' project and Assessing Social and Community Environments with National Data 'ASCEND').

The evolution of the general surgery resident operative case experience in the era of robotic surgery.

Robotic-assisted general surgery proceduresare becoming commonplace, requiring more residency programs to establish training curricula for residents. Concerns exist regarding the impact this will have on surgical residents' operative case distribution in laparoscopic and open surgery. This study aimed to analyzetheimpact of a growing robotic operative case volume and established robotic surgery training curriculum on the general surgery resident operative experience. The robotic surgery training curriculum at the Medical College of Wisconsin was established in 2017. ACGME operative case logs of residents from 2014 to 2020 were analyzed to determine resident participation in open, laparoscopic, and robotic cases. Case categories included alimentary tract, abdomen, endocrine, thoracic, pediatric, and trauma. A one-way analysis of variance (ANOVA) was used to analyze overall cases, as well as participation by case type, post-graduate year (PGY) level, resident role, and institution type. Statistical significance was defined as a p value < 0.05. Operative case logs from 77 residents were analyzed with a total of 34,757 cases: 59.3% open, 39.6% laparoscopic, and 1.1% robotic. There was no significant change in open or laparoscopic case volumes. However, there was a 3.4% increase in robotic cases, from 2014 to 2020 (p = 0.01), specifically in foregut (4.0%, p = 0.01), intestinal (1.6%, p = 0.03), and hernia (8.3%, p = 0.003) procedures. Academic (2.8%, p = 0.01) and veterans' hospital (2.0%, p = 0.01) institutions saw a significant increase in their residents' robotic cases. The only resident role with a significant increase in robotic cases was first assistant (8.0%, p = 0.004). There was no significant difference across PGY levels by surgical approach. This study highlights that the growth of robotic cases has not had a detrimental effect on the resident experience with open and laparoscopic cases. As robotic cases continually increase, the impact on laparoscopic and open case volumes must be monitored to ensure a well-balanced training experience.

Intra-aortic balloon pump counterpulsation: technical function, management, and clinical indications.

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin Address Correspondence to: Laura S. González, MD, Department of Anesthesiology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226. E-mail: [email protected]

Abstract PO-071: A curriculum to bridge the divide between basic science researchers and community members to address cancer disparities

Abstract Medical mistrust and misunderstanding remain significant challenges that impede collaboration between community members and researchers. In African American, Hispanic, and Native American communities, medical mistrust limits participation in biomedical studies which constrains the development of new and relevant research questions minimizing our understanding of biomedical and social factors affecting certain groups. Mistrust, misunderstanding and a lack of connection between researchers and community members contribute to the persistence of disparities, including cancer. To bridge this divide, we partnered with a senior basic scientist and a community leader with significant adult education experience to co-lead and create a pilot “Research and Community Scholars” curriculum for community members and researchers to develop a shared understanding and vocabulary regarding research, address health issues and concerns, and build positive collaboration experiences. Through a year-long process, the team met regularly to intentionally explore the role of equity around potential topics and approaches, develop a shared lexicon, survey researchers and community members on concepts and curriculum design, foster a collaborative relationship and nourish equitable co-leadership. The co-leaders concluded that s participants in the curriculum need focused time, effort, and guidance to learn about and from each other, grow their capacity to collaborate, and build trust through collaboration. The pilot curriculum will invite early-career biomedical researchers (“Research Scholars”) from the Medical College of Wisconsin (MCW) and Milwaukee community members affiliated with local community based organizations (“Community Scholars”). Scholars will meet together bi-weekly for 9-months. Course lectures and exercises, facilitated by community and academic leaders, will cover cancer, disparities, implicit bias, institutional racism, research violations and protections, and communication across audiences. A Community Scholar and a Research Scholar will be paired at the beginning of the course to develop a project. This approach mirrors the equitable and trusting partnership the co-leaders they developed while creating the curriculum. Dyad projects could include a presentation on how laboratory science is enhanced by a community-based orientation, or development of a podcast on ways community and researchers can bridge communication differences. The projects will be presented at the end of the course to other program scholars, leaders in the community and MCW. To sustain the relationships built during the course, scholars will be invited to become part of an alumni network. The design of this curriculum will result in new research mechanisms and ways to center community in the development of biomedical research. Positioning community as an equitable partner in scientific discovery addresses issues of mistrust and misunderstanding and contributes to the reduction of cancer disparities. Citation Format: Tobi A, Cawthra, Laura Pinsoneault, Jessica Olson, Deborah Thomas, Carol Williams, Melinda Stolley. A curriculum to bridge the divide between basic science researchers and community members to address cancer disparities [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-071.

Establishing an interdisciplinary research team for cardio-oncology artificial intelligence informatics precision and health equity

Study objectiveA multi-institutional interdisciplinary team was created to develop a research group focused on leveraging artificial intelligence and informatics for cardio-oncology patients. Cardio-oncology is an emerging medical field dedicated to prevention, screening, and management of adverse cardiovascular effects of cancer/cancer therapies. Cardiovascular disease is a leading cause of death in cancer survivors. Cardiovascular risk in these patients is higher than in the general population. However, prediction and prevention of adverse cardiovascular events in individuals with a history of cancer/cancer treatment is challenging. Thus, establishing an interdisciplinary team to create cardiovascular risk stratification clinical decision aids for integration into electronic health records for oncology patients was considered crucial. Design/setting/participantsCore team members from the Medical College of Wisconsin (MCW), University of Wisconsin-Milwaukee (UWM), and Milwaukee School of Engineering (MSOE), and additional members from Cleveland Clinic, Mayo Clinic, and other institutions have joined forces to apply high-performance computing in cardio-oncology. ResultsThe team is comprised of clinicians and researchers from relevant complementary and synergistic fields relevant to this work. The team has built an epidemiological cohort of ~5000 cancer survivors that will serve as a database for interdisciplinary multi-institutional artificial intelligence projects. ConclusionLessons learned from establishing this team, as well as initial findings from the epidemiology cohort, are presented. Barriers have been broken down to form a multi-institutional interdisciplinary team for health informatics research in cardio-oncology. A database of cancer survivors has been created collaboratively by the team and provides initial insight into cardiovascular outcomes and comorbidities in this population.

Abstract PO-235: Changes in low-dose CT lung cancer screening patterns post-COVID-19

Abstract Purpose: Nationally, only 23% of lung cancer cases are diagnosed at an early stage and on top of that Black Americans with lung cancer are 16% less likely to be diagnosed early. If everyone currently eligible were screened, close to 48,000 lives could be saved. Interestingly, pre-COVID-19 17% of the individuals getting screened for lung cancer were Black, and post-COVID-19 36% are Black. This study aims to explore potential reasons for this sudden increase in low-dose CT lung cancer screenings in Black patients by examining variables in the electronic health record and by interviewing pundits in clinical oncology practice. Methods: 416 deidentified electronic health records were collected from a data repository at the Medical College of Wisconsin. We analyzed low-dose CT screening for lung cancer among Black and white patients pre- and post-COVID-19 (4 cohorts). The post-COVID-19 cohorts looked at screening from 1/1/2020 – 7/8/2021, compared to a proportionate time frame pre-COVID-19 (1/1/2018 – 7/8/2019). Because of low numbers of other racial/ethnic backgrounds (Asian, Hispanic, Pacific Islander, etc.), only Black and white patients were examined in this study. Variables examined include insurance status, marital status, age, COVID-19 testing or diagnosis, gender, employment status, comorbidities (cardiovascular disease, chronic obstructive pulmonary disease, diabetes and hypertension), and lung cancer diagnosis. Results: Employment status, lung cancer diagnosis, and gender were all significantly different between Black and white cohorts pre-COVID-19. Post-COVID-19, similar differences are seen in employment status, while patterns in lung cancer diagnosis, gender, and insurance status are contradictory. Black patients pre-COVID-19 had a higher incidence of being men and a lower incidence of lung cancer diagnosis. On the contrary, post-COVID-19 Black patients have a higher incidence of being women and lung cancer diagnosis, and additionally a higher incidence of Medicare use. Despite the drastic differences in healthcare before and after COVID-19, COVID-19 testing and diagnosis did not appear to be linked to increased lung cancer screenings for Black patients. However, in conversations with thoracic surgeons and community health workers, we learned of significant screening efforts within Black populations due to grants funded during the COVID-19 pandemic. Conclusions: In this study, insurance status was the strongest difference between the pre- and post-COVID-19 Black cohorts. In a conversation with thoracic surgeons, we learned that a major initiative was launched post-COVID-19 that increased insurance access for Black populations. Increasing access to healthcare appears to be a promising first step in eradicating lung cancer disparities in Black populations. So, this research could serve as a guidepost to provide policymakers, researchers and healthcare providers, as well as patients and families, with data that pinpoints where future resources should be aimed in the effort to end lung cancer and its corresponding health disparities. Citation Format: Katherine Hullin, Jessica Olson. Changes in low-dose CT lung cancer screening patterns post-COVID-19 [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-235.

An 18-year Experience with an Innovative Geriatrics Training Model: Implications for the Workforce

Despite the growing population of older adults, the geriatrics workforce has not similarly expanded. The number of geriatrics fellows has declined by 14.3% from 2012-2017. Implementation of innovative training programs may improve this reality. In 2002, the Medical College of Wisconsin (MCW) created the first four-year combined medicine residency and geriatrics fellowship (Med-Ger). Similar programs are currently being developed. The aim of this study is to describe the outcomes of the MCW Med-Ger program. Primary endpoints: American Board of Internal Medicine (ABIM) pass rates, ABIM Geriatric Medicine Certification pass rates, fellowship completion rates, and geriatric-focused practice. Results: There was a Med-Ger program fill rate of 73.7% (n=38). There was equivalent ABIM pass rate of 100% between Med-Ger graduates (n=18) and traditional graduates (n=25). Med-Ger trainees were more likely to complete their geriatrics fellowship (94.4% vs. 88%) and practice in geriatric-focused careers (82.4% vs. 68.2%). These outcomes suggest the benefit of a combined program for training future geriatricians. The MCW Med-Ger fill rate exceeds the national geriatrics fellowship fill rate of under 50%. Additionally, graduates may be more likely to practice geriatric medicine. This may help address population needs for an increased geriatrics workforce. In 2020, the ACGME approved an Advancing Innovation in Residency Education (AIRE) Medicine-Geriatrics Integrated Residency and Fellowship national pilot program. Further investigation of why trainees choose Med-Ger training and are more likely to continue with careers in geriatrics is needed in order to replicate the success of the MCW Med-Ger program.

Underdiagnosis of primary hyperparathyroidism in patients with osteoarthritis undergoing arthroplasty

BackgroundPrimary hyperparathyroidism (HPT) is commonly underdiagnosed and undertreated. Joint pain is a nonspecific symptom associated with osteoarthritis or primary HPT. We hypothesize that patients treated for osteoarthritis are underdiagnosed with primary HPT. MethodsAdult patients diagnosed with hip/knee osteoarthritis at the Medical College of Wisconsin from January 2000 to October 2020 were queried. Patients with a calcium level drawn within 1 year of diagnosis of osteoarthritis were included. Patients who had undergone prior parathyroidectomy were excluded. Patients were stratified by serum calcium level, HPT diagnosis, and PTH level. Arthroplasty rates were compared between groups. ResultsOf 54,788 patients, 9,967 patients (18.2%) had a high serum calcium level, of whom 1,089 (10.9%) had a diagnosis of HPT. Only 76 (7.0%) patients with HPT underwent parathyroidectomy, 208 (19.1%) underwent knee/hip arthroplasty, and 14 (1.3%) underwent both. Arthroplasty was performed in 1,793 patients without evaluation and/or definitive treatment for HPT. There were higher rates of arthroplasty performed in patients with a high serum calcium level compared with those without (21.2% vs 17.4%, P < .001). ConclusionPatients with high serum calcium levels were more likely to undergo arthroplasty than those with normocalcemia. Hypercalcemia in the setting of hip or knee osteoarthritis should prompt a full evaluation for primary HPT.

Eight-Color Flow Cytometry Phenotypic Markers and Disease Progression in Monoclonal Gammopathy of Unknown Significance

Introduction: Flow cytometric immunophenotyping is considered an indispensable tool for the diagnosis, classification, and monitoring of plasma cell disorders. Herein, we seek to study the clinical significance of expression of phenotype markers in monoclonal gammopathy of unknown significance (MGUS).Methods: We identified a cohort of patients with a diagnosis of MGUS from the institutional myeloma database. Bone marrow (BM) aspirate assessment was performed using 8-color immunophenotypic next-generation flow cytometric (NGF) analysis with a minimum sensitivity of 10 -5 cells at the time of diagnosis or first visit to our institution. BM aspirate samples were immunophenotyped on a FACSCanto II flow cytometer using antibodies (BD) to delineate normal and abnormal plasma cells [CD138 (V-500), CD38 (FITC), CD19 (PE-Cy7), CD45 (V-450), CD27 (PercpCy5.5), CD81 (APC-H-7), CD56 (APC) and CD20 (PE)]. The sensitivity or the Limit of Detection (LOD) for this assay was validated to 20 cells in 2 ×10 6 events (0.001%), and the reproducibility or Lower Limit of Quantitation (LLOQ) is 50 cells in 2 ×10 6 events. Clinical and laboratory variables were also collected. Based on previously published data, expression (CD19, CD45, CD81), and lack of expression (CD56, CD27, CD20) of the above-mentioned surface antigens were analyzed. Additional variables such as IgA isotype, size of M-protein (≥15 g/L), and abnormal free light chain ratio(abnFLR) (defined as <0.1 or >10) were included in regression fitting models.Results: A total of 157 patients with MGUS were included in this analysis. The median age at diagnosis was 60 years (range 24- 84), 84 (53 %) patients were female and 25 (16%) were African American. Overall, IgG Kappa (75/148, 50%) was the most common isotype. Fluorescent-in-situ hybridization (FISH) data were available in 35 patients with t (4:14) and t (14;16) seen in 3 patients each. At a median follow-up of 18.15 years (quantiles 11.35, 33.62), 28 patients experienced disease progression (25 to MM, 2 to Waldenstrom macroglobulinemia, and 1 Smoldering myeloma). The median progression-free survival of this cohort was 17.3 years. Among these, occurrences of the bone lesion (8/28; 28.6%) were the most common pattern of disease progression to MM. This analysis showed lower odds of progression with the expression of CD27 (OR-0.39, 95% CI 0.15-0.99) (figure 1A). Disease progression was more common in patients with an abnormal plasma cell clone size ≥ of 3.1% at diagnosis (60% vs. 12.5%, p=0.0005). An abnormal plasma cell clone of ≥3.1% at diagnosis, was associated with increased odds of progression (OR-10.79, 95% CI 4.02-28.98) and a shorter PFS (12.5 years versus NR, p=0.01) (figure 1B). Serum M-spike ≥1.5 g/dL (OR-3.54;95% 1.30-9.62) and abnFLR (OR-2.30, 95% CI 1.00-5.32) were also associated with a higher odds of progression. However, in this population, the presence of IgA isotype did not increase the odds of MGUS progression. In a stepwise regression model, serum M-spike≥1.5 g/dL, abnFLR, and the lack of expression of CD27 were associated with the risk of disease progression.Conclusion: In addition to previously published risk factors, our cohort shows that the expression of CD27 antigen by eight-color flow cytometry confers a lower risk of disease progression of MGUS. This is consistent with our previous report that CD27 is progressively down-regulated in the transition from normal plasma cells (NPC) to MGUS to MM (Zhan et al, Blood 2006). Furthermore, we show that size of the myeloma clone (≥ 3.1% ) is a possible surrogate marker for disease progression in MGUS.Figure 1: 1A shows forest plot of odds ratios for flow cytometry markers, IgA isotype, size of M protein, abnFLR and plasma cell clone size. 1B shows the Kaplan Meier estimates of PFS for patients stratifies by plasma cell clone size. [Display omitted] DisclosuresMohan: Medical College of Wisconsin: Current Employment. Atrash: GSK: Research Funding; AMGEN: Research Funding; Jansen: Research Funding, Speakers Bureau.

Phase 1b/2 Study of the First-in-Class SUMO-Activating Enzyme Inhibitor TAK-981 in Combination with Monoclonal Antibodies in Patients with Triple-Class Refractory Multiple Myeloma

Phase 1b/2 Study of the First-in-Class SUMO-Activating Enzyme Inhibitor TAK-981 in Combination with Monoclonal Antibodies in Patients with Triple-Class Refractory Multiple Myeloma

Risk of Infections with BCMA-Directed Immunotherapy in Multiple Myeloma

Risk of Infections with BCMA-Directed Immunotherapy in Multiple Myeloma

Concomitant Deletion of Short Arm (del 1p) and Amplification or Gain (1q21) of Chromosome 1 By Fluorescence in Situ Hybridization (FISH) Is Associated with Poor Clinical Outcome

Introduction- Chromosome 1 abnormalities in multiple myeloma (MM) are increasingly recognized as high risk defined features. While there is robust data on 1q21 gain and amplification (amp), the clinical characteristics and outcome of patients with del 1p is less defined. Novel agents are incorporated into a backbone of multi-agent chemotherapy and tandem autologous stem cell transplantation (ASCT) in successive Total Therapy (TT) protocols for MM patients. We hereby report the prognostic value of del 1p by FISH at enrollment in subjects treated on TT protocols.Methods: (FISH was performed on bone marrow obtained at the time of first visit to our institution or initial diagnosis. FISH probes were generated from specific BAC DNA clones for AHCYL1 gene locus (1p13.3) and CKS1B locus (1q21). MM cells were identified post-hybridization using isotype specific antibody conjugated with 7-amino-4-methylcoumarin-3-acetic acid (AMCA) to stain Ig-Kappa or Ig-Lambda light chain in cytoplasm (cIg) of myeloma tumor cells. The FISH signals in 100 myeloma cells were recorded. For this analysis, 3 copies of 1q21 are considered as 1q21 gain and ≥ 4 copies as 1q21 amp. A 20% cutoff point was used for detection of significant abnormalities, i.e. del 1p and 1q21 gain and amp. A multivariable logistic regression model was used to examine the combined effects of clinical variables on progression free (PFS) and overall survival (OS).Results- A total of 1133 patients were included in this analysis. The median age was 60 (range 30.2-75), 434 (38.3%) patients were female and 106 (9.4%) were African Americans. ISS stage III disease accounted for 287 (25.3%). GEP70 high-risk was noted in 160/1133 (14.1%) of all patients. Of all patients, 1084 (95.7%) had at least one ASCT and 812 (71.7%) had tandem upfront ASCT. Metaphase cytogenetic abnormalities were noted in 548 (48.4%). While del 1p was detected in 220 (19.4%) patients, 1q21 gain or amplification were observed in 300 (26.5%) and 150 (13.2%) patients, respectively. Isolated 1q21 gain and amplification without del 1p were seen in 235 (20.7%) and 121 (10.7%) patients. Overall, there was enrichment of high-risk features such as ISS stage III disease (5.7% vs 10.9% p=0.049), GEP70 high-risk (8.4% vs 36.8%), GEP 70 subtypes such as MF (4.6% vs 8.2%), MS (10.5% vs 13.6%) and PR (11.3% vs 22.7%) and abnormal cytogenetic abnormalities (45.7% vs 59.5% p=<0.01) in the group with del 1p . The median progression free survival (57 vs 39m; p= <0.0004) and overall survival (131 vs 89 m; p=<0.0013) were inferior in the subgroup with del 1p. On multivariate analysis, presence of ISS stage III disease, GEP high-risk, 1q21 gain and amplification were significant while presence of del 1p did not emerge as independent predictors of PFS or OS. Next, we looked at concomitant 1q21 gain and amp in the context of del 1p. del 1p with 1q21 gain or amp was observed in 65 (5.7%) and 29 (2.5%) patients, respectively. The PFS of the group with combined del 1p/1q21 gain and del 1p/1q21 amp were 25m and 35m respectively compared to 44 m with 1q21 gain and 37m with 1q21 amp alone. The OS of the group with both 1 del 1p/1q21 gain and del 1p/1q21 amp were dismal at 59m and 84 m respectively compared to 108 m with 1q21 gain and 76 m with 1q21 amp alone (Fig 1).Conclusion: Deletion of short arm of chromosome 1p was observed in 19% of MM patients. Concomitant del 1p with 1q21 gain and /or amp was present in 8% of patients. The PFS and OS of patients with combined del1p/1q21gain abnormalities was significantly worse compared to del 1p alone and 1q21 gain alone and thus identifies a subset of patients with poor clinical outcome. [Display omitted] DisclosuresMohan: Medical College of Wisconsin: Current Employment.

High Plasma Apolipoprotein(a) Concentration and Low Plasmin Tpa Enzymatic Activity in Hospitalized Patients with COVID-19

Thrombotic and thromboembolic complications in patients diagnosed with coronavirus disease 2019 (COVID-19) are emerging as important sequelae that contribute to mortality, including disseminated intravascular coagulation, pulmonary embolism, deep vein thrombosis, ischemic stroke, and myocardial infraction. Reported incidence of thrombotic and thromboembolic complications in moderate/severe COVID-19 patients is from 21% to 49%, while even higher incidence in non-surviving COVID-19 patients. However, the underlying mechanism between thrombosis and COVID-19 is still unclear.Tissue-type plasminogen activator (tPA) plays an important role on initiating fibrinolysis by converting zymogen plasminogen to plasmin, a serine protease that degrades the fibrin clot, and therefore preventing excessive pathological blood clots. A homologous protein to plasminogen is apolipoprotein(a) [apo(a)], a major component of lipoprotein(a). The apo(a) inhibits fibrinolysis and exacerbates thrombosis through blocking the conversion from Glu-plasminogen to Lys-plasminogen, which has a higher binding affinity to fibrin and is a better substrate to tPA. The population distribution of plasma apo(a) level is positively skewed (most values are clustered around the left tail of the distribution close to zero), and the plasma apo(a) level in most people is less than 300 μg/mL. High plasma concentration of apo(a) (> 300 μg/mL), or genetic variants of LPA, the gene that encodes for apo(a), correlates with thrombotic cardiovascular risk and thromboembolic risk in many population-based clinical or genetic studies. To investigate the potential correlation between infection of SARS-COV-2 and thrombosis, we tested de-identified plasma samples collected from hospitalized patients with or without positivity of SARS-CoV-2 testing results and COVID-19 diagnosis (ICD10CM:U07.1) through the COVD-19 Tissue Bank at the Medical College of Wisconsin. The tPA enzymatic activity was measured by the release of p-nitroaniline chromophore from a plasmin-specific synthetic substrate with exogenous human plasminogen, with the intensity of color proportional to tPA activity. The apo(a) concentration is measured by ELISA capturing total apo(a) antigen.Our results show that the SARS-CoV-2-positive inpatients have higher plasma tPA concentration than the SARS-CoV-2 negative inpatients (6.0 versus 3.0 ng/mL, p<0.05), while plasma tPA enzymatic activity is lower in SARS-CoV-2-positive inpatients than the SARS-CoV-2 negative inpatients (15.2 versus 25.5 ΔA/min/mL/10 4, p<0.0001) (Figure A). The plasma apo(a) concentration is significantly higher in SARS-CoV-2-positive inpatients than in the plasma from SARS-CoV-2-negative inpatients (the median of the two groups are 114.8 versus 34.4 μg/mL, p<0.05) (Figure B). Among the 20 hospitalized patients with COVID-19, 13 survived. The 13 survived patients have one additional plasma sample collected after recovering from COVID-19 (date range between the two blood collections of onset and after recovery is from 19 to 87 days, the mean duration is 42 days). After recovery, 11 out of 13 surviving patients have increased plasma tPA enzymatic activity (the mean value at onset versus recovery is 5.2 versus 7.1 ΔA/min/mL/10 4, p<0.05) (Figure C). Consistently, 11 out of 13 surviving patients have decreased plasma apo(a) concentration compared to the plasma collected during the onset of COVID-19 from the same individuals (the median values of the onset and recovery are 141.1 versus 106.5 μg/mL, p<0.001) (Figure D).In summary, our study shows lower tPA enzymatic activity and higher apo(a) concentration in SARS-CoV-2-positive hospitalized patients compared to SARS-CoV-2-negative hospitalized patients. Among the survived patients, the reduction of apo(a) concentration after recovering from COVID-19 is accordance with the increase of tPA enzymatic activity. Considering the role of apo(a) in inhibiting fibrinolysis through limiting tPA-mediated plasminogen to plasmin conversion, the alteration in apo(a) concentration provide a possible explanation of change of tPA activity in patients with severe COVID-19. [Display omitted] DisclosuresBaumann Kreuziger: CSL Behring: Consultancy; Quercegen Pharmaceuticals: Consultancy; Vaccine Injury Compensation Program: Consultancy.

Characteristics Associated with Disparities in Survival between Hispanic and Non-Hispanic White Patients with Multiple Myeloma: A Matched Cohort Study

Characteristics Associated with Disparities in Survival between Hispanic and Non-Hispanic White Patients with Multiple Myeloma: A Matched Cohort Study

Hawks et al. Respond

AffiliationsLaura Hawks is with the Medical College of Wisconsin, Milwaukee. Emily A. Wang and Benjamin Howell are with the Yale School of Medicine, New Haven, CT. Steffie Woolhandler and David U. Himmelstein are with Hunter College, City University of New York, New York, NY, and Harvard Medical School, Boston, MA. David Bor and Danny McCormick are with the Cambridge Health Alliance, Cambridge, MA, and Harvard Medical School.

Healing After Moderate to Severe TBI Takes Time

Healing After Moderate to Severe TBI Takes Time