Varmus Research Articles

MP49-11 MEDICAL AND ECONOMIC JUSTIFICATION FOR MINIMALLY INVASIVE SURGERY SPECIFIC TO URINARY STONE DISEASE AT GEORGETOWN PUBLIC HOSPITAL CORPORATION IN GUYANA

You have accessJournal of UrologyCME1 Apr 2023MP49-11 MEDICAL AND ECONOMIC JUSTIFICATION FOR MINIMALLY INVASIVE SURGERY SPECIFIC TO URINARY STONE DISEASE AT GEORGETOWN PUBLIC HOSPITAL CORPORATION IN GUYANA Dominique Sherry, Budheshwar Ramsukh, Ava Yap, Chris Prashad, and David Bayne Dominique SherryDominique Sherry More articles by this author , Budheshwar RamsukhBudheshwar Ramsukh More articles by this author , Ava YapAva Yap More articles by this author , Chris PrashadChris Prashad More articles by this author , and David BayneDavid Bayne More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003297.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In high income countries, minimally invasive surgery (MIS) to treat urinary stone disease (USD) has demonstrated better health outcomes and lower costs. However, open surgery is still commonplace in low and middle income countries (LMICs) such as Guyana due to inequities in access to equipment, training and resources. We analyzed the current open surgeries for USD at Georgetown Public Hospital Corporation (GPHC) in Guyana and quantified the theoretical change in costs and health outcomes using MIS techniques. METHODS: Case logs of all urology patients at GPHC from January 2018 to July 2022 were retrospectively reviewed. A total of 211 patients with USD were identified and stratified based on procedure. A decision tree analysis was performed to ascertain the cost effectiveness of replacing open surgery with MIS. The analysis included surgical, hospital, complication, transfusion, and convalescence costs. GPHC data was used for hospital length of stay (LOS) and convalescence time. Data on outcome probabilities, hospital costs (scaled for Guyana), life expectancy, complications, transfusion rates and mortality were derived from publications conducted in LMICs similar to Guyana. Disability adjusted life years (DALYs) averted were calculated based on LMIC data and GPHC average patient age. RESULTS: 48% of USD procedures at GPHC were open surgery. Pyelolithotomy was the most common open procedure during the 5-year study period and 51 pyelolithotomy cases were identified that could be replaced by percutaneous nephrolithotomy (PCNL) (50.5% of open cases). A decision tree analysis showed that open surgery was 1.9 times more expensive ($2082 vs $1102) than the replaceable PCNL. A sensitivity analysis showed the higher cost of open surgery was predominantly a result of its longer hospital LOS. A cost effectiveness analysis showed the ICER was in the southeast quadrant of the cost effectiveness plane as PCNL costs $862 less than open surgery for every DALY averted. CONCLUSIONS: This study shows that PCNL is a cost-effective alternative to open surgery at GPHC and demonstrates an opportunity to improve standards of care for urological disease in LMICs. Source of Funding: UCSF School of Medicine Inquiry Funding Office & Harold Varmus Global Heath Scholars Fund © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e682 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Dominique Sherry More articles by this author Budheshwar Ramsukh More articles by this author Ava Yap More articles by this author Chris Prashad More articles by this author David Bayne More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract C037: Polyethnic-1000: A New York-based initiative to advance cancer genomics through recruitment of diverse racial & ethnic populations

Abstract Recent advances in DNA sequencing technologies have revolutionized approaches to the prevention, early detection, diagnosis, and treatment of cancers. However, our current knowledge about tumor biology, cancer risk, and response to treatment is limited due to significant underrepresentation of non-European populations in genomic cancer research, including clinical trials. The vast majority of samples in publicly available genomic databases have been derived from patients of European descent. These inequities limit our understanding of cancer and the impact of ancestry on the various manifestations of this disease. Moreover, exclusion of minoritized populations may exacerbate health disparities and stymie their ability to equally benefit from participation in trials or the innovations that result from such studies. Through the Polyethnic-1000 (P1000) initiative, we sought to leverage the racial and ethnic diversity within New York City to conduct initial investigations that address the existing disparities in cancer genomics studies. We recruited healthcare facilities to join the P1000 Consortium with a particular focus on hospitals outside Manhattan that served a diverse racial and ethnic population. In Phase 1, clinical and scientific protocols were implemented to collect and process 176 archival tumor samples representing 39 cancer types from individuals who self-identified as “non-white.” This pilot study confirmed our ability to procure and analyze tissues using whole-exome and RNA sequencing. Importantly, we estimated each participant’s percentage of ancestry at the continental and subregional levels by applying ADMIXTURE software to our tumor samples using the reference populations from the 1000 Genomes Project. We observed that genetic information nearly always correlates at least partially with self-identified origins, but genetic classifications are more specific and allow the identification of mixed ancestry. We entered Phase 2 of the P1000 Initiative by launching a research program. The awards allowed investigators in the Consortium to compete for support of new or recently initiated projects designed to identify ancestry-associated genomic determinants in specific cancer types. We funded seven of the competing groups; the projects span eight primary cancers. All but one of the studies are focused on individuals of African ancestry; one addresses lung cancer in East Asian patients. With support from Illumina, we plan to perform tumor/normal whole genome sequencing and tumor RNASeq on 1000 cases. The resulting data set would be among the largest and most diverse collection of full-genome pairs available in oncology. It will be housed at the NYGC with initial access for all members of the P-1000 Consortium then for the entire research community after an embargo period. P1000 has established a framework to enhance interactions among our region’s academic and health centers to advance cancer genomics. These efforts should improve and widen the use of genomics for all, especially currently underserved racial and ethnic populations. Citation Format: Onyinye Balogun, Melissa Davis, Michelle Mehallow, Nicolas Robine, Lara Winterkorn, Dayna Oschwald, Michael Zody, Samuel Aparicio, Tom Maniatis, Harold Varmus, Charles Sawyers, David Tuveson. Polyethnic-1000: A New York-based initiative to advance cancer genomics through recruitment of diverse racial & ethnic populations [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C037.

SRC Signaling in Cancer and Tumor Microenvironment.

Pioneering experiments performed by Harold Varmus and Mike Bishop in 1976 led to one of the most influential discoveries in cancer research and identified the first cancer-causing oncogene called Src. Later experimental and clinical evidence suggested that Src kinase plays a significant role in promoting tumor growth and progression and its activity is associated with poor patient survival. Thus, several Src inhibitors were developed and approved by FDA for treatment of cancer patients. Tumor microenvironment (TME) is a highly complex and dynamic milieu where significant cross-talk occurs between cancer cells and TME components, which consist of tumor-associated macrophages, fibroblasts, and other immune and vascular cells. Growth factors and chemokines activate multiple signaling cascades in TME and induce multiple kinases and pathways, including Src, leading to tumor growth, invasion/metastasis, angiogenesis, drug resistance, and progression. Here, we will systemically evaluate recent findings regarding regulation of Src and significance of targeting Src in cancer therapy.

Raymond L. Erikson, PhD: In Memoriam (1936–2020)

![][1] > I hoed and trenched and weeded, And took the flowers to fair. > > The Shropshire Lad by A. E. Houseman In 2016, Ray started a personal reflection on his career in science titled “Four Decades of Protein Phosphorylation and Cancer Research.” Nothing more aptly fit his

Abstract A072: Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York

Abstract Background and aims Advances in sequencing technologies have revolutionized our approaches in medicine. However, our current knowledge about the molecular attributes of cancer has primarily been derived from patients of European descent. The overall aim of Polyethnic-1000 is to bring genomic innovation to under-represented ethnic groups in the diverse patient population of New York City. Methods and results A dynamic research platform is being created, involving the New York Genome Center and academic centers and partnering hospitals in the New York City region. In a first, retrospective stage, the infra-structure, sample workflow, analysis and data sharing within the consortium has been developed and whole exome and RNA sequencing has been performed on 100 samples from self-identified non-white cancer patients treated at 14 different centers. Data from over 24 tumor types were shared with our collaborators and the somatic variants were made available through our in-house instance of cBioPortal. The knowledge gained during this stage is used to design a prospective study with formation of cohorts of interest for particular cancer types and particular ethnicities, with uniform consent allowing germline and somatic sequencing with broad data sharing of the somatic variants identified. Conclusion By establishing a collaborative network, Polyethnic-1000 will deepen our understanding of the contributions that ethnicities make to the incidence and biology of cancers, potentially improving outcomes for patients who currently lack access to the most recent advances in medical science. Citation Format: Benjamin Hubert, Fieke Froeling, Kanika Arora, Tim Chu, Nicolas Robine, Michael Zody, Dayna Oschwald, Harold Varmus, Charles Sawyers, David Tuveson. Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A072.

Abstract B063: Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York

Abstract Recent advances in DNA sequencing technologies have revolutionized approaches to the prevention, risk assessment, early detection, diagnosis, and treatment of cancers. However, many ethnic groups, especially nonEuropean populations, have been significantly underrepresented in cancer research, including clinical trials, and have not received equal benefits in clinical practice. As a result, our current knowledge about tumor biology, cancer risk, and response to treatment has primarily been derived from patients of European descent. These inequities limit our understanding of the many types of cancer and may exacerbate health disparities in the United States. In this proposal, we address both the scientific and social issues by creating a dynamic research platform within the greater New York area that promises to enhance the ways in which cancer is prevented, diagnosed, and treated. This initiative, named Polyethnic-1000, will involve patients and staff at several academic health centers and partner hospitals in the New York City region. It will use the genomics and informatics capabilities of the New York Genome Center to determine how inherited and somatically acquired genetic variations affect the behavior of cancers occurring in ethnically diverse populations. In a first, retrospective phase, we will establish the workflow from sample acquisition to whole-exome and RNA sequencing, data analysis, and data sharing within the consortium. Then we will start a prospective study enabling the formation of cohorts of interest for particular cancer types and particular ethnicities, with uniform consent allowing broad data sharing of the somatic variants identified. Polyethnic-1000 will establish a framework to enhance interactions among our region's academic and health centers to advance cancer genomics. These efforts should improve and widen the use of genomics for all, especially currently underserved ethnic minority populations. Citation Format: Nicolas Robine, Fieke Froeling, Benjamin Hubert, Michael C. Zody, Dayna Oschwald, Harold Varmus, Charles Sawyers, David Tuveson. Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B063.

Herceptin: A First Assault on Oncogenes that Launched a Revolution

This year's Lasker Clinical Research Award honors H. Michael Shepard, Dennis J. Slamon, and Axel Ullrich for their invention of Herceptin, the first monoclonal antibody that blocks a cancer-causing protein, and for its development as a life-saving therapy for women with breast cancer.

MSphere of Influence: a Sphere of Influence beyond the Bench Can Help Shape the Future of U.S. Research.

Megan E. Spurgeon works in the field of viral oncology. In this mSphere of Influence article, she reflects on how the paper "Rescuing US biomedical research from its systemic flaws" by Bruce Alberts, Marc W. Kirschner, Shirley Tilghman, and Harold Varmus (Proc Natl Acad Sci U S A 111:5773-5777, 2014, https://doi.org/10.1073/pnas.1404402111) made an impact on her by influencing her research and career outlook. The way researchers think about their science is shaped by a variety of factors, and these often include research articles that influence their technical or experimental approaches and interpretations. However, it is rare that an article influences the broader career and research perspectives of scientists by compelling them to look beyond the bench. The article highlighted in this commentary prompted the realization that a sphere of influence beyond our routine scientific focus can create a scientific community that is better equipped to address the systemic threats facing the larger research ecosystem to which we all belong.

Of oncogenes and open science: an interview with Harold Varmus.

Harold Varmus has made pioneering contributions to our understanding of cancer as a genetic disease. The discovery of the cellular origin of retroviral oncogenes earned him and his long-term collaborator, Michael Bishop, the Lasker Prize for Basic Medical Sciences in 1982 and the Nobel Prize in Physiology and Medicine in 1989. Throughout his career, Varmus has held several leadership roles that shaped science policy in the US and worldwide, and he has been an outspoken advocate for open science. In this interview, he talks (among other things) about the factors that shaped his early career choices, the thrill of scientific discovery, and the importance of including diverse populations in genomic studies of cancer and other diseases.

From academics to access, Harold Varmus reflects on the achievements and challenges in cancer research

From academics to access, Harold Varmus reflects on the achievements and challenges in cancer research

Preprint Déjà Vu.

Twenty‐five years ago, in August 1991, I spent a couple of afternoons at Los Alamos National Laboratory writing some simple software that enabled a small group of physicists to share drafts of their articles via automated email transactions with a central repository. Within a few years, the site migrated to the nascent WorldWideWeb as arXiv.org, and experienced both expansion in coverage and heavy growth in usage that continues to this day. In 1998, I gave a talk to a group of biologists—including David Lipman, Pat Brown, and Michael Eisen—at a meeting at Cold Spring Harbor Laboratory (CSHL) to describe the sharing of articles “pre‐publication” by physicists. The talk was met with some enthusiasm and prompted the “e‐biomed” proposal in the following spring by then NIH director Harold Varmus. He encouraged the creation of an NIH‐run electronic archive for all biomedical research articles, including both a preprint server and an archive of published peer‐reviewed articles, which generated significant discussion.

Abstract 4163: Molecular and physiological effects of splicing factor mutant U2AF1 in human lung cell lines and in mice

Abstract The splicing factor gene, U2AF1, is commonly mutated in myeloid neoplasms and occasionally in solid tumors such as lung adenocarcinomas (LUADs), yet the molecular and physiological consequences of U2AF1 mutations are not well understood. Through genome editing of the endogenous locus, we created a common U2AF1 mutant allele (U2AF1-S34F) in an immortalized human bronchial epithelial cell line, and we inactivated the U2AF1-S34F allele in two LUAD cell lines that naturally harbor this mutation. Cells expressing U2AF1-S34F deployed altered splicing of many transcripts, and they displayed a S34F-characteristic sequence pattern at the proximal 3’ splice site, as previously reported. Remarkably, S34F-associated alternative splicing patterns remained unaffected by changes in the amount of mutant U2AF1 protein, as long as the ratio of mutant and wild-type U2AF1 remained constant, as evidenced by RNA interference-mediated knockdown of the expression of both mutant and wild-type alleles. On the other hand, perturbing the ratio of mutant and wild-type U2AF1, either through overexpression or allelic-specific inactivation of wild-type U2AF1, greatly affected S34F-associated splicing. These results suggest that the ratio of mutant and wild-type U2AF1, rather than the absolute amount of either protein, is critical in controlling splicing outcome. Expression of U2AF1-S34F does not cause cell transformation and LUAD cells with endogenous U2AF1-S34F expression are not dependent on the U2AF1-S34F allele. Instead, wild-type U2AF1 is absolutely required for cell survival in the presence of the mutant allele. To study the effect of U2AF1-S34F in vivo, we created transgenic mice carrying a conditional mutant allele, MG-S34F, at the endogenous U2af1 locus. By crossing the MG-S34F mice with mice carrying a Mx1-Cre transgene and treating the progeny with poly IC, we activated MG-S34F by Cre-mediated recombination to express U2af1-S34F in bone marrow cells. This resulted in cytopenia in multiple blood cell lineages. Similar results were observed in recipient mice following non-competitive transplant. Bone marrow cells expressing U2af1-S34F were competitively disadvantaged in repopulating the hematopoietic system in irradiated mice, suggesting defective hematopoietic stem cell function, and we are currently assessing the long-term impact of U2af1-S34F expression on the incidence of myeloid neoplasms. Citation Format: Dennis Fei, Hayley Motowski, Sameer Prasad, Jovian Yu, Robert Bradley, Harold Varmus. Molecular and physiological effects of splicing factor mutant U2AF1 in human lung cell lines and in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4163.

A Conversation with Harold Varmus.

A Conversation with Harold Varmus.

Mistletoe - From mythology to evidence-based medicine

This is the time of the precision medicine, as President Barak Obama addressed the Nation on January 20, 2015 in a State of the Union Address: Tonight, I'm launching a new Precision Medicine Initiative to bring us closer to curing diseases like cancer and diabetes — and to give all of us access to the personalized information we need to keep ourselves and our families healthier (Francis S. Collins and Harold Varmus, A New Initiative on Precision Medicine; N Engl J Med 2015;372:793-795). This new field already show several actors, not only the NIH but also private company like APPLE, MICROSOFT and others, investing a lot of many: all together already several billions, dollars or euro doesn’t matter, a fact that testify how hot is becoming this new biomedical perspective....

Abstract A39: Initial characterization of genetically engineered mice carrying a conditional allele of a splicing factor gene (U2AF1) commonly mutated in myeloid disorders.

Abstract Putative “driver” mutations in genes encoding splicing factors---including recurrent mutations in U2AF1, which encodes a component of the U2 auxiliary factor to regulate pre-mRNA splicing---have been identified in myeloid dysplasias, related neoplasms, and lung adenocarcinomas. To study the functional impact of U2AF1 mutations, we have created transgenic mice carrying a conditional mutant allele, MG-S34F, at the endogenous U2AF1 locus. We have crossed the MG-S34F mice with mice carrying a Mx1-Cre transgene, and demonstrated efficient Cre-mediated recombination and expression of U2AF1-S34F in bone marrow cells two weeks after treatment with poly IC. Bone marrow cells from compound transgenic mice had a modest but statistically significant reduction in their ability to form monocyte and granulocyte colonies in culture. A small cohort of mice is also being followed for long-term hematologic defects after exposing these mice to low doses of N-ethyl-N-nitrosourea (ENU). While U2AF1-S34F expression coupled with ENU treatment has not produced myeloid leukemia after 3 months, a low ratio of U2AF1-S34F to wild-type U2AF1 RNA in blood cells implies that expression of U2AF1-S34F affects normal hematopoiesis or survival of blood cells in mice. We are now expanding our mouse cohort to study the hematologic defects apparently induced by U2AF1-S34F in greater detail. Citation Format: Dennis Liang Fei, Harold Varmus. Initial characterization of genetically engineered mice carrying a conditional allele of a splicing factor gene (U2AF1) commonly mutated in myeloid disorders. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A39.

A Commentary on "A New Initiative on Precision Medicine".

U.S. President Barack Obama recently announced a new Precision Medicine Initiative, and Drs. Francis Collins and Harold Varmus have begun to provide a vision for how some of this initiative might be implemented by the U.S. National Institutes of Health (NIH) (1). Precision medicine may be defined as “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person” (2). A vision of the NIH portion of the Precision Medicine Initiative is to launch a large-scale national cohort study of a Million or more Americans to advance understanding of how to optimize treatments customized to individual variability in genomic and environmental health-determinants (2). A precision-medicine approach, using shared-decision making with patients and their providers as partners in patient-centered care, offers an important opportunity to improve substance-use disorders (SUDs) prevention and treatment outcomes (3, 4). Pertinent to precision medicine, the Collaborative Research on Addictions at NIH, comprising the National Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism, and the National Cancer Institute, in partnership with other NIH Institutes, Centers and Offices, is currently planning to launch a longitudinal cohort study of Adolescent Brain and Cognitive Development (ABCD). This study will follow 10,000 youth over up to a 10-year period, approximately ages 9–10 at baseline when largely naive to use of alcohol, marijuana, nicotine, and other drugs. This national cohort study presents a key opportunity to answer fundamentally important questions to informing a precisionmedicine approach regarding prevention of SUDs in youth (5). Several relevant questions are: (1) how does repeated exposure to abused substances, such as nicotine, alcohol, and cannabis, impact normative brain development essential for memory and cognitive functioning? (2) How do drug-altered brain-maturation pathways inform precision-medicine-tailored SUDs prevention approaches targeting high-risk youth? (3) Which brain-development events altered following adolescent drug use heighten likelihood of transformation of unhealthy drug use into full-blown SUDs in subpopulations with, or without, co-occurring mental health disorders? (4) How do druginduced alterations in brain-development and memory impairments interact with genomic and epigenetic risk factors in these different subpopulations to increase vulnerability to SUDs? (5) In what manner does use of specific substances impact use of other substances? Thus, the objective of the ABCD study is timely to precision medicine: to better understand how exposure to abused substances modifies brain-development trajectories and how this relates to emotional and mental health, social development, memory and other cognitive function, as well as academic and other outcomes (5).

News from the NIH: potential contributions of the behavioral and social sciences to the precision medicine initiative.

At this year’s State of the Union address, the President announced a new $215 million Precision Medicine Initiative in the 2016 budget that will pioneer a new model of patient-empowered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients [1, 2]. Concurrently, Directors of the National Institutes of Health and the National Cancer Institute, Drs. Francis Collins and Harold Varmus, respectively, published an article in the New England Journal of Medicine that describes two main components of this initiative, a near-term focus on cancer therapy and a longer-term effort to generate knowledge applicable to a wide range of health and disease [3]. This longer-term initiative seeks to generate a cohort of one million or more Americans to “enable better assessment of disease risk, understanding of disease mechanisms, and the prediction of optimal therapy for many more diseases, with the goal of expanding the benefits of precision medicine into myriad aspects of health and healthcare” [3]. Matching treatment to the unique biological, behavioral, or environmental characteristics of the individual is nothing new. Matching blood type for transfusions has been common practice for nearly a century [4]. The guidelines for the management of cholesterol have been based on individual patient factors for over a decade [5]. Tailored behavioral interventions have been evaluated for over two decades. Although early treatment matching studies were disappointing [6], tailored behavioral interventions, especially computerized tailored interventions, have generally been found more efficacious than untailored interventions [7, 8]. The concept of precision medicine is not new, but recent advances in genome sequencing, cohort study designs, health informatics, and mobile/wireless technologies make now an opportune time for a large precision medicine cohort initiative.

Harold Varmus on Stepping Down as NCI Director, and His New Position at Weill Cornell

Harold Varmus on Stepping Down as NCI Director, and His New Position at Weill Cornell

Harold Varmus stepping down as director of U.S. cancer institute

Harold Varmus stepping down as director of U.S. cancer institute

Harold Varmus to resign as head of US cancer institute

Harold Varmus to resign as head of US cancer institute