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695 citation(s) found for "Tyler, A".

A Scoping Review of Mobile Apps in Plastic Surgery: Patient Care, Trainee Education, and Professional Development
Jarvis, Nicholas R. , Morris, Bryn E., Verhey, Erik M., Rebecca, Alanna M. , Howard, Michael A., Teven, Chad M. , Jarvis, Tyler

Plastic and Reconstructive Surgery - Global Open | April 13, 2023 | Volume: 11 | Issue: 4 | Pages: e4943

10.1097/gox.0000000000004943 | PMID 37063506 Get It

Background: Over the past 10 years, smartphones have become ubiquitous, and mobile apps serve a seemingly endless number of functions in our everyday lives. These functions have entered the realm of plastic surgery, impacting patient care, education, and delivery of services. This article reviews the current uses of plastic surgery mobile apps, app awareness within the plastic surgery community, and the ethical issues surrounding their use in patient care. Methods: A scoping review of electronically available literature within PubMed, Embase, and Scopus databases was conducted in two waves in November and May 2022. Publications discussing mobile application use in plastic surgery were screened for inclusion. Results: Of the 80 nonduplicate publications retrieved, 20 satisfied the inclusion criteria. Articles acquired from the references of these publications were reviewed and summarized when relevant. The average American Society of Plastic Surgeons evidence rating of the publications was 4.2. Applications could be categorized broadly into three categories: patient care and surgical applications, professional development and education, and marketing and practice development. Conclusions: Mobile apps related to plastic surgery have become an abundant resource for patients, attending surgeons, and trainees. Many help bridge gaps in patient care and surgeon-patient communication, and facilitate marketing and practice development. Others make educational content more accessible to trainees and performance assessment more efficient and equitable. The extent of their impact on patient decision-making and expectations has not been completely elucidated.
APOE and immunity: Research highlights
Kloske, Courtney M. , Barnum, Christopher J. , Batista, André F., Bradshaw, Elizabeth M. , Bu, Guojun , Dennison, Jessica , Gearon, Mary D, Goate, Alison , Haass, Christian , Hu, William T. , Huggins, Lenique , Jones, Nahdia S. , Liddelow, Shane A. , Marsh, Samuel E. , Petersen, Melissa, Piña‐Escudero, Stefanie Danielle , Reiman, Eric M. , Sexton, Claire E. , TCW, Julia , Wallings, Rebecca L. , Weninger, Stacie, Wharton, Whitney , Wishard, Tyler J. , Worley, Susan, Carrillo, María C. , Sexton, Claire , Bu, Guojun , Goate, Alison M , Hu, William T. , Brickman, Adam M. , Heneka, Michael T. , Koldamova, Radosveta P. , Lemere, Cynthia Ann , Marcora, Edoardo , Nielsen, Henrietta M. , Petersen, Kellen K. , Petersen, Melissa , Qiu, Wei Qiao , Quiroz, Yakeel T. , Tansey, Malú G. , Teunissen, Charlotte E. , Tijms, Betty M. , Kant, Rik van der , Wilcock, Donna M. , Zetterberg, Henrik

Alzheimer's & Dementia | March 28, 2023 | Volume: 19 | Issue: 6 | Pages: 2677-2696

10.1002/alz.13020 | PMID 36975090 Get It

AbstractINTRODUCTIONAt the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias.METHODSThe meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry.RESULTSDuring the 4‐day meeting, presenters illuminated aspects of the cross‐talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]).DISCUSSIONThis manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.
A phase 2 study of immunogenic cell death inducer PT-112 in patients with metastatic castration-resistant prostate cancer.
Karp, Daniel D. , Nordquist, Luke T., Dorff, Tanya B. , Baeck, Johan , O'Donnell, Joseph Francis, Ames, Tyler D. , Yim, Christina Y. , Price, Matthew R. , Scher, Howard I. , Bryce, Alan H. , Tagawa, Scott T. , Rathkopf, Dana E , Adra, Nabil

Journal of Clinical Oncology | March 14, 2023 | Volume: 41 | Issue: 6_suppl | Pages: TPS292-TPS292

10.1200/jco.2023.41.6_suppl.tps292 Get It

TPS292 Background: PT-112 is a novel small I-O molecule currently in development for several cancers. Preclinical studies have shown the robust induction of immunogenic cell death by PT-112, leading to an anti-cancer adaptive immune response. Biodistribution experiments in mice showed PT-112’s partial bone affinity. In two prior phase I studies, late-line metastatic castration-resistant prostate cancer patients (mCRPC pts) were treated with evidence of anti-cancer activity, including tumor volume reductions, improvements in PET and bone scans, PSA and alkaline phosphatase (ALP) reductions, and anecdotal cases of improvement in disease-related pain. This, taken together with the immunogenic and osteotropic properties observed in preclinical work, provided a strong rationale to further explore PT-112 in mCRPC, an immunologically “cold” disease with a high prevalence of bone metastases. Moreover, in an analysis of >6,000 mCRPC pts, circulating tumor cell (CTC) declines (CTC0 and CTC conversions) were correlated with improvements in survival to a greater extent than PSA declines (PSA50) (Heller et al., JCO, 36:6 2017), prompting incorporation of CTC changes as a secondary endpoint. Methods: The primary objective of the study is to define the dose regimen of PT-112 for pivotal study. Pts are randomized to one of three arms, receiving IV PT-112 on 28-day cycles via one hour infusions on (1) Days 1 and 15 at 250 mg/m2, (2) Days 1 and 15 at 360 mg/m2, or (3) Days 1 and 15 of cycle 1 at 360 mg/m2 followed by 250 mg/m2 on Day 15 of subsequent cycles. Key eligibility criteria include radiographically progressive disease at study entry; ≥3 life-prolonging therapies for metastatic disease including 1-2 taxanes, ≥1 new generation anti-androgen therapies, and other drugs FDA approved on the basis of survival; and allowing bone-only metastatic disease. Efficacy assessments comprise disease control rate at 4 months (DCR4) using RECIST and PCWG3 criteria, objective response rate, CTC0 and CTC conversion, PSA50 and ALP reductions. Additionally, T cell receptor sequencing is conducted to characterize treatment-induced changes in T cell fraction and clonal expansions, as a means of generating meaningful supportive data on the immune mechanism of PT-112 monotherapy. A Fleming two-stage design will be used to assess each arm, with a 20% DCR4 as the null hypotheses, requiring ≥6 of 25 pts responding in stage one and ≥14 of 45 in total to reject the null. In addition, other efficacy measures, such as CTC responses, as well as exposure/response and exposure/safety analyses will be applied to characterize the risk/benefit ratio and select the optimal dose regimen for PT-112. As of October 11th, 2022, 38 pts have been enrolled out of a planned maximum of 135. Clinical trial information: NCT02266745 .
NCCN Guidelines® Insights: Prostate Cancer Early Detection, Version 1.2023
Moses, Kelvin A. , Sprenkle, Preston C. , Box, Geoffrey N., Carlsson, Sigrid , Catàlona, William J. , Dahl, Douglas M. , Dall’Era, Marc , Davis, John W. , Epstein, Jonathan I. , Etzioni, Ruth B., Farrington, Thomas A., Garraway, Isla P. , Jarrard, David F. , Kauffman, Eric, Kaye, Deborah R. , Kibel, Adam S. , LaGrange, Chad A. , Maroni, Paul, Ponsky, Lee , Salami, Simpa S. , Shaneyfelt, Terrence, Smaldone, Marc C. , Sonn, Geoffrey A. , Tyson, Mark D. , Vapiwala, Neha , Wake, Robert, Washington, Samuel L. , Yu, Alice , Yuh, Bertram, Berardi, Ryan A., Freedman-Cass, Deborah A., Salami, Simpa S , Bahler, Clinton D. , Drake, Bettina F. , Etzioni, Ruth B., Reys, Brian D. , Sánchez, Alejandro , Seibert, Tyler M.

Journal of the National Comprehensive Cancer Network | March 10, 2023 | Volume: 21 | Issue: 3 | Pages: 236-246

10.6004/jnccn.2023.0014 | PMID 36898362 Get It

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.
International consensus statement on allergy and rhinology: Allergic rhinitis – 2023
Wise, Sarah K. , Damask, Cecelia, Ebert, Charles S. , Levy, Joshua M. , Lin, Sandra Y. , Luong, Amber , Rodriguez, Kenneth , Sedaghat, Ahmad R. , Toskala, Elina , Akdiş, Cezmi A. , Ansotegui, Ignacio J. , Azar, Antoine , Baroody, Fuad M. , Benninger, Michael S. , Casale, Thomas B. , Chaaban, Mohamad R. , Chew, Fook Tim , Chambliss, Jeffrey , Cianferoni, Antonella , Čustović, Adnan , Davis, Elizabeth Mahoney , DelGaudio, John M. , Flanagan, Carrie E. , Franzese, Christine B., Gill, Amarbir S. , Halderman, Ashleigh A. , Joe, Stephanie, Joshi, Shyam , Kuruvilla, Merin , Kim, Jean , Klein, Adam M. , Krouse, Helene J. , Lang, David M. , Laury, Adrienne M., Lee, Victoria S. , Loftus, Patricia A. , Marzouk, Haidy, Mims, James W., Oppenheimer, John , Orlandi, Richard R. , Phillips, Katie M. , Raymond, Mallory , Ryan, Matthew W., Sastre, J. , Schlosser, Rodney J. , Shaker, Marcus , Smith, Kristine A. , Soyka, Michael , Tang, Monica , Tantilipikorn, Pongsakorn , Taw, Malcolm B., Tversky, Jody , Tyler, Matthew A. , Veling, Maria C., Wallace, Dana , White, Andrew A. , Roland, Lauren T , Levy, Joshua M , Luong, Amber U , Sedaghat, Ahmad R , Villwock, Jennifer , Abdullah, Baharudin , Alt, Jeremiah A , Chaaban, Mohamad R , Gill, Amarbir , Kuruvilla, Merin Elizabeth , Kim, Jean , Kuan, Edward C , Lee, Victoria S , Marcus, Sonya , Mattos, Jose , McCoul, Edward D , Nayak, Jayakar V , Orlandi, Richard , Schuman, Theodore A , Smith, Kristine , Soyka, Michael B , Tantilipikorn, Pongsakorn , Tyler, Matthew A , Zhang, Luo , Schlosser, Rodney J , Chew, Fook Tim , Casale, Thomas , Alt, Jeremiah A. , Bernstein, Jonathan A. , Brook, Christopher D. , Campbell, Raewyn Gay , Ellis, Anne K. , Fokkens, Wytske Johanna , Greenhawt, Matthew , Hohlfeld, Jens Michael , Incorvaia, Cristoforo , Larenas‐Linnemann, Désirée E. , Lechner, Matt , Lee, Stella E. , Mattos, José L. , McCoul, Edward D. , Melén, Erik , Mullol, Joaquim , Nayak, Jayakar V. , Platt, Michael P. , Ramanathan, Murugappan , Raymond, Mallory J , Rhee, Chae‐Seo , Reitsma, Sietze , Sheikh, Aziz , Takashima, Masayoshi , Wang, De Yun , Zhang, Luo

International Forum of Allergy & Rhinology | March 6, 2023 | Volume: 13 | Issue: 4 | Pages: 293-859

10.1002/alr.23090 | PMID 36878860 Get It

Abstract Background In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR‐Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR‐Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence‐based findings and recommendation from the full document. Methods ICAR‐Allergic Rhinitis 2023 employed established evidence‐based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work. Results ICAR‐Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost. Conclusion The ICAR‐Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment.
The Resident Learning Journey in the Medical Intensive Care Unit
Herzog, Tyler L. , Sawatsky, Adam P. , Kelm, Diana J. , Nelson, Darlene R. , Park, John G. , Niven, Alexander S. , Niven, Alexander S

ATS Scholar | February 28, 2023 | Volume: 4 | Issue: 2 | Pages: 177-190

10.34197/ats-scholar.2022-0103oc | PMID 37533538 Get It

Abstract Background The medical intensive care unit (MICU) offers rich resident learning opportunities, but traditional teaching strategies can be difficult to employ in this fast-paced, high-acuity environment. Resident perspectives of learning within this environment may improve our understanding of the common challenges residents face and inform novel approaches to transform the MICU educational experience. Objective We conducted a qualitative study of internal medicine residents to better understand their approach to learning the critical care activities that they are entrusted to perform in the MICU. Methods Using a thematic analysis approach, we conducted six focus group interviews with 15 internal medicine residents, separated by postgraduate year. A trained investigator led each interview, which was audio-recorded and transcribed verbatim for analysis. Our diverse research team, representing different career stages across the continuum of learning to minimize interpretive bias, identified codes and subsequent themes inductively. We refined these themes through group discussion and sensitizing social learning theory concepts using Wenger’s community of practice and organized them to create learner archetypes and a conceptual framework of resident learning in the MICU. Results We identified three thematic resident learning categories: learning goals and motivation, clinical engagement, and interprofessional collaboration. We distinguished three learner archetypes, the novice, experiential learner, and practicing member, to describe progressive resident development within the interprofessional MICU team, the challenges they frequently encounter, and potential teaching strategies to facilitate learning. Conclusion We developed a conceptual framework that describes the resident’s journey to becoming a trusted, collaborating member of the interprofessional MICU team. We identified common developmental challenges residents face and offer educational strategies that may support their progress. These findings should inform future efforts to develop novel teaching strategies to promote resident learning in the MICU.
Clinical Administration Characteristics of Subcutaneous and Intravenous Administration of Daratumumab in Patients With Multiple Myeloma at Mayo Clinic Infusion Centers
Soefje, Scott A. , Carpenter, Corinne , Carlson, Katherine , Awasthi, Samir , Lin, Thomas S., Kaila, Shuchita, Tarjan, Daniel R., Kayal, Nikhil , Kirkup, Christian , Wagner, Tyler E. , Gray, Kathleen, Kumar, Shaji , Soefje, Scott A , Tarjan, Daniel, Wagner, Tyler E

JCO Oncology Practice | February 9, 2023 | Volume: 19 | Issue: 4 | Pages: e542-e549

10.1200/op.22.00421 | PMID 36758192 Get It

PURPOSE: Median duration of daratumumab (DARA) administration for treatment of multiple myeloma is 3-7 hours for the intravenous formulation (DARA IV) and 3-5 minutes for the subcutaneous formulation (DARA SC). Here, we describe clinical administration characteristics of DARA using a novel method for data extraction from electronic health records. METHODS: Time-based measurements were extracted using a scheduling/pharmacy software program that tracked patient movement through appointments for patients initiating DARA in Mayo Clinic infusion centers from April 5, 2017, to October 14, 2021. Cohorts included patients who received DARA IV or DARA SC, or converted from DARA IV to DARA SC. The DARA SC cohort was further analyzed before (DARA SC initial) and after (DARA SC shortened) a reduction in the postadministration observation time mandated by the treatment plan. Events associated with administration-related reactions (ARRs) were also identified. RESULTS: Median total clinic times were 2.7-3.0 hours shorter for DARA SC versus DARA IV. Median clinic times were highest at dose 1 and decreased with subsequent doses. Median total chair times were 2.7-2.8 hours shorter for DARA SC versus DARA IV. Incidences of ARR-related events with DARA SC were low across doses. CONCLUSION: Reduced clinic times were observed with DARA SC, indicating that use of DARA SC as a treatment option results in time savings that may free clinic resources. Furthermore, novel methods of electronic health record data extraction can provide insights that may help inform clinic resource optimization.
Benefits and challenges in implementation of artificial intelligence in colonoscopy: World Endoscopy Organization position statement
Hassan, Cesare , Halvorsen, Natalie , Berzin, Tyler M. , Renteln, Daniel von , Hewett, David G. , Repici, Alessandro , Ramchandani, Mohan , Khatry, Maryam Al , Yu, Honggang , Saito, Yutaka , Misawa, Masashi , Parasa, Sravanthi , Matsubayashi, Carolina Ogawa , Ogata, Haruhiko , Tajiri, Hisao, Ahmad, Omer F. , Rex, Douglas K. , Berzin, Tyler M , Hewett, David G , Wang, Pu , Saito, Yutaka , Misawa, Masashi , Matsubayashi, Carolina Ogawa , Hassan, Cesare , Mori, Yuichi , East, James E. , Byrne, Michael F. , Kudo, Shin‐ei , Wang, Pu , Pausawasdi, Nonthalee , Dekker, Evelien , Sharma, Prateek

Digestive Endoscopy | February 7, 2023 | Volume: 35 | Issue: 4 | Pages: 422-429

10.1111/den.14531 | PMID 36749036 Get It

The number of artificial intelligence (AI) tools for colonoscopy on the market is increasing with supporting clinical evidence. Nevertheless, their implementation is not going smoothly for a variety of reasons, including lack of data on clinical benefits and cost‐effectiveness, lack of trustworthy guidelines, uncertain indications, and cost for implementation. To address this issue and better guide practitioners, the World Endoscopy Organization (WEO) has provided its perspective about the status of AI in colonoscopy as the position statement. WEO Position Statement: Statement 1.1: Computer‐aided detection (CADe) for colorectal polyps is likely to improve colonoscopy effectiveness by reducing adenoma miss rates and thus increase adenoma detection; Statement 1.2: In the short term, use of CADe is likely to increase health‐care costs by detecting more adenomas; Statement 1.3: In the long term, the increased cost by CADe could be balanced by savings in costs related to cancer treatment (surgery, chemotherapy, palliative care) due to CADe‐related cancer prevention; Statement 1.4: Health‐care delivery systems and authorities should evaluate the cost‐effectiveness of CADe to support its use in clinical practice; Statement 2.1: Computer‐aided diagnosis (CADx) for diminutive polyps (≤5 mm), when it has sufficient accuracy, is expected to reduce health‐care costs by reducing polypectomies, pathological examinations, or both; Statement 2.2: Health‐care delivery systems and authorities should evaluate the cost‐effectiveness of CADx to support its use in clinical practice; Statement 3: We recommend that a broad range of high‐quality cost‐effectiveness research should be undertaken to understand whether AI implementation benefits populations and societies in different health‐care systems.
A Bibliometric and Visual Analysis of the Most Cited Articles on Disc Arthroplasty
Stefano, Frank A. De , Warner, Tyler , Reardon, Taylor , Jarrah, Ryan , Mayo, Timothy , Ezeudu, Chibueze S., Fiani, Brian , Stefano, Frank De , Ezeudu, Chibueze

Global Spine Journal | February 3, 2023 | Volume: 13 | Issue: 8 | Pages: 2516-2525

10.1177/21925682231154857 | PMID 36734604 Get It

Study Design Bibliometric literature review. Objective Total disc arthroplasty (TDA) is an evolving technique used by surgeons to preserve neural elements and range of motion in patients with degenerative disc disease, spondylosis and more. In comparison to discectomy, disc arthroplasty has been shown to decrease morbidity, reduce adjacent-level disease, and preserve pre-operative range of motion. The objective of this manuscript is to provide a bibliometric analysis of the use of disc arthroplasty in scientific literature and highlight the main contributing authors and their publication characteristics. Methods The Scopus database was used to perform a title-specific, keyword-based search for all publications until June 2022. The keyword “total disc arthroplasty” was used. The most-cited 100 articles were selected for analysis. Parameters included the following: title, citation count, citations per year, authors, specialty first author, institution, country of origin, publishing journal, Source Normalized, Impact Per Paper (SNIP), and Hirsch index. Results Our search on disc arthroplasty yielded 580 articles that were published, with the first publication on the topic found in 1966. The most cited 100 articles received a total of 8694 citations, with an average of 86.94 citations per article. After assessing countries with the greatest contributions, United States, China, and Germany were top 3 with 54, 14, and 7 articles, respectively. Conclusion The bibliometric analysis provides an overview of how medical research is analyzed in academic medicine. In the present study, we evaluated the global trends in disc arthroplasty for the treatment of degenerative disc disease.
Multisite institutional study of efficacy and safety of cabozantinib following immunotherapy in patients with advanced hepatocellular carcinoma.
Palmer, Mathias Earl, Storandt, Michael H. , Gile, Jennifer , Zemla, Tyler , Bekaii‐Saab, Tanios , Jin, Zhaohui , Tran, Nguyen H. , Mahipal, Amit

Journal of Clinical Oncology | January 24, 2023 | Volume: 41 | Issue: 4_suppl | Pages: 559-559

10.1200/jco.2023.41.4_suppl.559 Get It

559 Background: Cabozantinib, a multikanase inhibitor, is approved by the Food and Drug Administration (FDA) for treatment of advanced stage hepatocellular carcinoma (HCC) following progression on sorafenib. The CELESTIAL study which demonstrated benefit from cabozantinib following sorafenib included only patients with Child Pugh class A liver function. Recently, bevacizumab plus atezolizumab has replaced sorafenib as the first line treatment for HCC. It is unclear whether there is benefit from using Cabozantinib following progression on immunotherapy as CELESTIAL trial included very few patients who received prior immunotherapy. We describe the outcomes of individuals with advanced stage HCC treated with Cabozantinib following progression on immunotherapy. Methods: This was a multicenter, retrospective analysis of patients with advanced HCC diagnosed between 2010-2021 at Mayo Clinic Arizona, Florida, and Minnesota. Progression free survival (PFS) and median overall survival analysis were performed using Kaplan-Meier method. Results: We identified a total of 26 patients with advanced stage HCC who received cabozantinib following progression on immunotherapy. The median age of patients was 61 years (range, 39 – 81) and the majority were male (85%). Eighteen (72%) patients had Child Pugh A at initiation of cabozantinib therapy. Four (15%) patients received cabozantinib as second line therapy, the rest received it as third line or later. PFS on cabozantinib was 2.1 months (95% CI: 1.3 – 3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3 – 14.9). PFS was shorter with Child Pugh Class B, 1.3 months (95% CI: 0.9 – NE) compared to those with Child Pugh Class A, 2.1 months (95% CI: 1.5 – 4); although this difference was not significant (p=0.55). Common adverse events included fatigue (50%), anorexia (35%), aspartate aminotransferase (AST) elevation (35%), and diarrhea (31%); 7 (26%) patients experienced Grade 3 or greater adverse events including hypertension, diarrhea, anorexia, and bowel obstruction. Two patients discontinued cabozantinib due to side effects including one for uncontrolled blood pressure elevations and the other due to fatigue. Conclusions: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy is unknown. Treatment with cabozantinib may improve clinical outcomes following progression on immunotherapy with similar adverse event profile. This study included patients with Child Pugh class B liver disease (28%) and heavily pretreated population and demonstrated mPFS and mOS similar to other work examining outcomes of cabozantinib in real world setting after progression on sorafenib. Further studies to determine optimal treatment sequencing for this patient population are needed.