Citations

Background and Objective: The published cardiology literature is critical for scientific communication, and we sought to determine if the published clinical cardiology evidence base has evolved over time. Methods: We evaluated the cardiology related publications in the medical journals (M) JAMA (J) and the New England Journal of Medicine (N) and all publications by the specialty journals (CA) Circulation (Ci) and the European Heart Journal (E) in 2000, 2010, and 2020 and added 2001, 2011, and 2021 for JAMA to account for potential annual variability. Results: Publication information is shown in the graph. For the M journals there has been an increase in the percentage of randomized controlled trials (RCT). For the CA journals there has been a significant decrease in single center studies (Si) and a proportionate increase in reanalysis (Re) of data whether from subanalysis of an RCT, registry, or meta-analysis. For CA journals there has been an increase in the size of clinical studies mainly due to the use of larger datasets from registries or claims (Ci: 2000: 4,500/study; 2010: 9,298/study; 2020: 258,725/study and E: 2000: 2,282/study; 2010: 12,652/study; 2020: 249,388/study). CA journals have an increased of studies with patients from multiple continents (Ci: 2000: 5.5%; 2010: 13%; 2020: 35% and E: 2000: 7%; 2010: 14.8%; 2020: 18.8%). There has been an increase in the percentage of clinical studies with documentation of different populations by region or color (In 2020, 58% for all Ci articles and 52% for US and multicontinental EHJ articles), although the number of nonwhites remains small in most studies unless the study was specifically addressing disparities in care. Conclusions: Over the last two decades, the published evidence base has changed with more RCT in the Med journals and more studies that reanalyze large datasets in CA journals. Published studies are now larger, more likely to involve multiple continents, and document population details.

8056 Background: Multiple myeloma (MM) is preceded by monoclonal gammopathy of undetermined significance (MGUS). A transitional stage of smoldering multiple myeloma (SMM) can be identified between MGUS and MM. While MGUS carries a steady risk of progression of 1% per year, SMM is more heterogenous with nearly 40% of patients progressing in the first 5 years, 15% in the next 5 years, reaching the same low risk as MGUS after 10 years. SMM with its high risk of progression in the initial years after diagnosis presents a viable opportunity for early intervention. For implementing early intervention, the ability to identify SMM patients at the highest risk of progression is critical. This has led to the development of several risk stratification systems. Using these systems high risk SMM patients studied in phase 3 trials demonstrated delayed progression to MM and improved overall survival with early initiation of therapy. However, these approaches showed limited specificity exposing patients at lower risk of progression to therapy. To date, identifying high risk SMM patients and confirming disease stability in low risk SMM patients remain an important clinical need. Genomic instability has been shown to be a sensitive indicator of disease progression in cancer. Telomere dysfunction is an early event in genomic instability. The 3-dimensional spatial profiling of telomeres using TeloView technology allows for quantification of telomere dysfunction, and was shown to be instrumental in risk stratification of cancer patients generally, but particularly in selected hematological malignancies. Importantly, in a previous SMM proof-of-concept study telomeric parameters measured by TeloView technology was found to be significantly different between SMM patients who progressed to active MM within 2 years and those who remained stable for over 5 years. Methods: We analyzed a total of 162 SMM patients using TeloView technology. 88 patients were employed as training dataset in Receiver Operating Curve (ROC) modeling to develop a scoring model that stratifies individual SMM patients based on risk of progression to full stage MM. An additional cohort of 74 SMM patients was used for blind validation of the developed scoring model. Results: We report area-under-the-curve (AUC) in the ROC analysis of 0.8 (accuracy 80%) achieved by the scoring model developed using the training dataset. Furthermore, the independent blind validation achieved positive predictive value of 83% and negative predictive value of 71%, with sensitivity and specificity of 80% and 76% respectively. Conclusions: The result of this study supports presenting TeloView as an accurate prognostic biomarker which appears able to stratify SMM patients into their respective risk groups with high sensitivity and specificity. This will potentially allow for evidence-based treatment decisions for high risk SMM patients and confident monitoring of stable patients.

Background Hereditary and acquired thrombophilia are risk factors for venous thromboembolism (VTE). Whether testing helps guide management decisions is controversial. Objective These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about thrombophilia testing. Methods ASH formed a multidisciplinary guideline panel covering clinical and methodological expertise and minimizing bias from conflicts of interest. The McMaster University GRADE Centre provided logistical support, performed systematic reviews, and created evidence profiles and evidence-to-decision tables. The Grading of Recommendations Assessment, Development, and Evaluation approach (GRADE) was used. Recommendations were subject to public comment. Results The panel agreed on 23 recommendations regarding thrombophilia testing and associated management. Nearly all recommendations are based on very low certainty in the evidence due to modeling assumptions. Conclusions The panel issued a strong recommendation against testing the general population before starting combined oral contraceptives (COCs) and conditional recommendations for thrombophilia testing in the following scenarios: (a) patients with VTE associated with nonsurgical major transient or hormonal risk factors; (b) patients with cerebral or splanchnic venous thrombosis, in settings where anticoagulation would otherwise be discontinued; (c) individuals with a family history of antithrombin, protein C, or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors and for guidance to avoid COCs/hormone replacement therapy; (d) pregnant women with a family history of high-risk thrombophilia types; and (e) patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE. For all other questions, the panel provided conditional recommendations against testing for thrombophilia.

A wireless, wearable Doppler ultrasound offers a new paradigm for linking physiology to resuscitation medicine. To this end, the image analysis of simultaneously-acquired venous and arterial Doppler spectrograms attained by wearable ultrasound represents a new source of hemodynamic data. Previous investigators have reported a direct relationship between the central venous pressure (CVP) and the ratio of the internal jugular-to-common carotid artery diameters. Because Doppler power is directly related to the number of red cell scatterers within a vessel, we hypothesized that (1) the ratio of internal jugular-to-carotid artery Doppler power (V/APOWER) would be a surrogate for the ratio of the vascular areas of these two vessels and (2) the V/APOWER would track the anticipated CVP change during simulated hemorrhage and resuscitation. To illustrate this proof-of-principle, we compared the change in V/APOWER obtained via a wireless, wearable Doppler ultrasound to B-mode ultrasound images during a head-down tilt. Additionally, we elucidated the change in the V/APOWER during simulated hemorrhage and transfusion via lower body negative pressure (LBNP) and release. With these Interesting Images, we show that the Doppler V/APOWER ratio qualitatively tracks anticipated changes in CVP (e.g., cardiac preload) which is promising for both diagnosis and management of hemodynamic unrest.

AbstractBackgroundThe aim of this study was to correlate peripheral blood gene expression profile (GEP) results during the first post‐transplant year with outcomes after kidney transplantation.MethodsWe conducted a prospective, multicenter observational study of obtaining peripheral blood at five timepoints during the first post‐transplant year to perform a GEP assay. The cohort was stratified based on the pattern of the peripheral blood GEP results: Tx‐all GEP results normal, 1 Not‐TX had one GEP result abnormal and >1 Not‐TX two or more abnormal GEP results. We correlated the GEP results with outcomes after transplantation.ResultsWe enrolled 240 kidney transplant recipients. The cohort was stratified into the three groups: TX n = 117 (47%), 1 Not‐TX n = 59 (25%) and >1 Not‐TX n = 64 (27%). Compared to the TX group, the >1 Not‐TX group had lower eGFR (p < .001) and more chronic changes on 1‐year surveillance biopsy (p = .007). Death censored graft survival showed inferior graft survival in the >1 Not‐TX group (p < .001) but not in the 1 Not‐TX group. All graft losses in the >1 Not‐TX group occurred after 1‐year post‐transplant.ConclusionsWe conclude that a pattern of persistently Not‐TX GEP assay correlates with inferior graft survival.

Abstract CD19 directed chimeric antigen receptor T (CART19) cell therapy has resulted in remarkable outcomes in B cell malignancies and was FDA approved in multiple indications. However, durable remissions are limited to 40% of treated patients. Inhibitory myeloid cells in tumor microenvironment have been found to suppress T cell expansion and contribute to failure of CART19 cell therapy. In this study, we aimed to unravel the interactions between monocytes, CART19 cells and tumor cells to understand how monocytes-CART19 cell interactions impact CART19 cell effector functions and clinical outcomes. Two sets of experiments were conducted, 1) use of healthy CART19 cells, CD19+ tumor cells, and healthy monocytes; 2) use of brexu-cel products from ZUMA-2 clinical trial treating mantle cell lymphoma (MCL), patient-matched monocytes and circulating MCL tumor cells (n = 11; 6 durable responders, 2 relapsed after initial response and 3 non-responders). CD28 costimulated CART19 (CART19-28ζ) cells generated in the lab from healthy donors were co-cultured with donor freshly isolated monocytes in the presence of Jeko-1 cells (a CD19+ MCL cell line). CART19 antigen specific proliferation was not inhibited by freshly isolated monocytes. When monocytes were co-cultured with CART19 and tumor cells, higher levels of eotaxin, GRO, MCP-3 and IL-7 were detected. When CART19 cells were co-cultured with the CD19+ JeKo-1 cells in the presence of ex vivo M2 polarized macrophages, CART19 antigen specific proliferation was inhibited (p=0.0045). Transwell experiments demonstrate that M2-induced CART19 inhibition is not contact dependent. Cytokine profile analysis indicated increased level of IL-1ra, IP-10 and MCP-1 and decreased level of IL-17A, sCD40L, IL-9 and MIP-1α when M2 macrophages were co-cultured with CART19 and tumor cells compared to co-cultures of tumor cells and CART19. Then we conducted ex vivo co-cultures of brexu-cel products, autologous monocytes and circulating MCL tumor cells from MCL patients (ZUMA-2) collected prior to CART19 cell infusion. Here we observed trends of elevation of IL-13 and IL-5 and reduction of GRO, MCP-3, MIP-1β and IL-8 in non-responders, compared to responders (durable responses or relapsed patients). Our results support that monocyte- and macrophage-dependent cytokine release could modulate CART19 effector and trafficking functions, and thus CART19 clinical outcomes. This warrants further investigation around strategies to improve durable responses to CART cell therapy. Citation Format: Kun Yun, Reona Leo Sakemura, Michelle J. Cox, Truc Huynh, Claudia Manriquez-Roman, Olivia Sirpilla, Carli M. Stewart, James H. Girsch, Ekene J. Ogbodo, Ismail Can, Brooke Kimball, Lionel A. Kankeu Fonkoua, Mehrdad Hefazi, Michael W. Ruff, Elizabeth L. Siegler, Mike Mattie, Sao-Mai Nguyen-Mau, Simone Filosto, Saad S. Kenderian. Impact of immunosuppressive monocytes on CART19 cell effector functions and outcomes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4082.

Abstract Thyroid cancer is the most common endocrine cancer in the US, and its incidence is rising. Most thyroid cancer deaths are attributed to treatment-refractory, metastatic tumors. Thyroid stimulating hormone receptor (TSRH) expression is largely limited to the thyroid gland and is abundantly expressed on thyroid tumor cells, making TSRH a compelling target for advanced thyroid cancer diagnostics and therapeutics. Therefore, we developed a novel TSHR-targeted chimeric antigen receptor (CAR) T cell therapy to treat aggressive thyroid cancers. TSHR-CAR constructs were cloned into a lentiviral CAR construct containing 4-1BB and CD3ζ. First, we demonstrated potent TSHR-CART antigen-specific anti-tumor activity in vitro. Then, NOD-SCID-γ-/- (NSG) mice were inoculated subcutaneously with TSHR+ tumor cells and randomized by tumor volume to treatment with TSHR-CART cells or control Untransduced T cells (UTD). Treatment with TSHR-CART cells resulted in dose-dependent antitumor activity and prolonged survival. De-differentiated anaplastic thyroid cancers (ATC) downregulate TSHR. Our TSHR immunohistochemistry results corroborated these findings and displayed minimal TSHR protein expression, precluding successful TSHR-CART treatment. We therefore sought to sensitize these tumors with MAPK inhibitors, as a strategy to upregulate TSHR expression in patients with metastatic thyroid cancer. TSHR expression was upregulated in patient-derived xenograft (PDX) ATC models after one week of daily administration of the MAPK inhibitors (p=0.0024). After confirming that MAPK inhibition does not dampen TSHR-CART effector functions, we tested sequential and combination therapy of TSHR-CART with MEK and BRAF inhibition in vivo. NSG mice were engrafted with ATC BRAF-mutant PDX tumors and randomized by tumor volume to daily oral treatment with placebo or trametinib (MEK inhibitor) plus dabrafenib (BRAF inhibitor). One week later, mice received either UTD or TSHR-CART. Mice conditioned with trametinib plus dabrafenib (p=0.0018) and subsequently treated with TSHR-CART showed superior antitumor activity. However, the improved antitumor activity in this setting was transient. We therefore tested the durability of TSHR upregulation following MEK/BRAF inhibition and demonstrated that TSHR upregulation lasts less than 48-72 hours after discontinuation. Finally, we tested the combination of TSHR CART cells with MEK/BRAF inhibitors in ATC BRAF-mutant PDX tumors. Here, combining TSHR-CART cells with MEK/BRAF inhibitors result in durable control of the tumors. Collectively, our findings indicate that MEK/BRAF inhibition of de-differentiated thyroid cancers upregulated TSHR expression and enhanced TSHR-CART antitumor activity. This work represents a viable strategy to improve outcomes of patients with aggressive, metastatic thyroid cancers. Citation Format: Claudia Manriquez Roman, Kendall J. Schick, Justyna J. Gleba, Truc N. Huynh, Elizabeth L. Siegler, James L. Miller, Aylin Alasonyalilar Demirer, Matthew L. Pawlush, Ahmet Biligili, Long K. Mai, Erin Tapper, Leo R. Sakemura, Michelle J. Cox, Carli M. Stewart, Ismail Can, Ekene J. Ogbodo, Gaofeng Cui, Georges Mer, Gloria R. Olivier, Yushi Qiu, Robert C. Smallridge, Zubair C. Abba, Han W. Tun, John A. Copland, Saad S. Kenderian. Addition of MAPK inhibitors to prime and sensitize poorly differentiated thyroid cancers as a strategy to improve TSHR-CART cell therapy antitumor activity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5074.

Introduction Maintaining fluid intake sufficient to reduce arginine vasopressin (AVP) secretion has been hypothesised to slow kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, evidence to support this as a clinical practice recommendation is of poor quality. The aim of the present study is to determine the long-term efficacy and safety of prescribed water intake to prevent the progression of height-adjusted total kidney volume (ht-TKV) in patients with chronic kidney disease (stages 1–3) due to ADPKD. Methods and analysis A multicentre, prospective, parallel-group, open-label, randomised controlled trial will be conducted. Patients with ADPKD (n=180; age ≤65 years, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m 2 ) will be randomised (1:1) to either the control (standard treatment+usual fluid intake) or intervention (standard treatment+prescribed fluid intake) group. Participants in the intervention arm will be prescribed an individualised daily fluid intake to reduce urine osmolality to ≤270 mOsmol/kg, and supported with structured clinic and telephonic dietetic review, self-monitoring of urine-specific gravity, short message service text reminders and internet-based tools. All participants will have 6-monthly follow-up visits, and ht-TKV will be measured by MRI at 0, 18 and 36 months. The primary end point is the annual rate of change in ht-TKV as determined by serial renal MRI in control vs intervention groups, from baseline to 3 years. The secondary end points are differences between the two groups in systemic AVP activity, renal disease (eGFR, blood pressure, renal pain), patient adherence, acceptability and safety. Ethics and dissemination The trial was approved by the Human Research Ethics Committee, Western Sydney Local Health District. The results will inform clinicians, patients and policy-makers regarding the long-term safety, efficacy and feasibility of prescribed fluid intake as an approach to reduce kidney cyst growth in patients with ADPKD. Trial registration number ANZCTR12614001216606.