Citations

385 Background: Tyrosine kinase inhibitors (TKI) and immuno-oncology (IO) agents alone or in combination have revolutionized the landscape of management for untreated metastatic renal cell carcinoma (mRCC). Baseline quality of life (QOL) outside of interventional clinical trials and rationale for management decisions in mRCC are poorly understood. Methods: In this prospective observational study of 800 mRCC pts in the US, pts must: have a diagnosis of mRCC (any histology) with no prior systemic therapy (ST) for mRCC; be age ≥19 at informed consent; be able to comply with completion of PROs. Exclusion criteria include being treated for active malignancy other than mRCC or not intending to follow up at a study site within PCORnet. Pts undergo consent and baseline assessments by the study site team, with subsequent follow up by the central coordinating center. The primary objective is to determine distinct patterns of change in QOL and symptom burden of mRCC pts. A key secondary objective is to identify patterns of clinical management in the real world setting of mRCC across treatment regimens. Minimally important differences are defined as 3- and 7-points for FKSI-19 and FACT-G respectively. ClinicalTrials.gov ID: NCT04919122. Results: As of 9/1/2023, 173 pts have been enrolled (126 ST, 47 no ST [NST]): 75% male, 87% white, 73% clear cell, 52% intermediate risk and 47% poor risk. 47% had radical nephrectomy and 22% another solid tumor. ST pts as compared to NST pts were more likely to be poor risk (52% vs 16%); but differences in baseline pain were not significant. Of ST pts, 44 were treated with IO-IO (ipilimumab + nivolumab), 50 with IO-TKI (cabozantinib + nivolumab 38%, axitinib + pembrolizumab 38%, lenvatinib + pembrolizumab 24%) and 32 other (IO alone 34%, TKI alone 31%, investigational drug 25%). Reasons for NST included active surveillance (AS, 50%), other (21%), local therapy (13%). Mean differences between ST and NST for baseline FKSI-19 and FACT-G were 5.7 (95% CI: 1.2 – 10.2) and 3.3 (-2.6 – 9.3). There were no differences in pain or PROs between IO-IO and IO-TKI pts. Mean differences in FKSI-19 and FACT-G between AS vs IO-IO were 10.6 (4.8 – 16.4) and 8.6 (1.1 – 16.0); and vs IO-TKI were 11.0 (4.9 – 17.0) and 10.3 (3.5 – 17.1). On physician surveys, primary reasons for treatment selection were (in order of % selected): complete response (CR), prolonged survival (OS), prognostic factors (Px), treatment-free interval for IO-IO; versus delaying progression (PFS), OS, CR, Px for IO-TKI. Conclusions: Our data suggest differences in baseline QoL in pts treated with ST vs NST, as well as AS vs IO-IO or IO-TKI, in the real world. Reasons for selection of ST regimen differed among combination regimen classes. Completion of ODYSSEY will clarify baseline and longitudinal differences in pain and PROs among management strategies and give novel insights into the rationale for real world management of untreated pts with mRCC. Clinical trial information: NCT04919122 .

Abstract Objectives Since the 1970s, a plethora of tools have been introduced to support the medication use process. However, automation initiatives to assist pharmacists in prospectively reviewing medication orders are lacking. The review of many medications may be protocolized and implemented in an algorithmic fashion utilizing discrete data from the electronic health record (EHR). This research serves as a proof of concept to evaluate the capability and effectiveness of an electronic prospective medication order review (EPMOR) system compared to pharmacists’ review. Materials and methods A subset of the most frequently verified medication orders were identified for inclusion. A team of clinical pharmacist experts developed best-practice EPMOR criteria. The established criteria were incorporated into conditional logic built within the EHR. Verification outcomes from the pharmacist (human) and EPMOR (automation) were compared. Results Overall, 13 404 medication orders were included. Of those orders, 13 133 passed pharmacist review, 7388 of which passed EPMOR. A total of 271 medication orders failed pharmacist review due to order modification or discontinuation, 105 of which passed EPMOR. Of the 105 orders, 19 were duplicate orders correctly caught by both EPMOR and pharmacists, but the opposite duplicate order was rejected, 51 orders failed due to scheduling changes. Discussion This simulation was capable of effectively discriminating and triaging orders. Protocolization and automation of the prospective medication order review process in the EHR appear possible using clinically driven algorithms. Conclusion Further research is necessary to refine such algorithms to maximize value, improve efficiency, and minimize safety risks in preparation for the implementation of fully automated systems.

Abstract3D stem cell spheroids have immense potential for various tissue engineering applications. However, current spheroid fabrication techniques encounter cell viability issues due to limited oxygen access for cells trapped within the core, as well as nonspecific differentiation issues due to the complicated environment following transplantation. In this study, functional 3D spheroids are developed using mesenchymal stem cells with 2D hetero‐nanostructures (HNSs) composed of single‐stranded DNA (ssDNA) binding carbon nanotubes (sdCNTs) and gelatin‐bind black phosphorus nanosheets (gBPNSs). An osteogenic molecule, dexamethasone (DEX), is further loaded to fabricate an sdCNTgBP‐DEX HNS. This approach aims to establish a multifunctional cell‐inductive 3D spheroid with improved oxygen transportation through hollow nanotubes, stimulated stem cell growth by phosphate ions supplied from BP oxidation, in situ immunoregulation, and osteogenesis induction by DEX molecules after implantation. Initial transplantation of the 3D spheroids in rat calvarial bone defect shows in vivo macrophage shifts to an M2 phenotype, leading to a pro‐healing microenvironment for regeneration. Prolonged implantation demonstrates outstanding in vivo neovascularization, osteointegration, and new bone regeneration. Therefore, these engineered 3D spheroids hold great promise for bone repair as they allow for stem cell delivery and provide immunoregulative and osteogenic signals within an all‐in‐one construct.

Abstract Background Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD).1 The U-ENDURE (NCT03345823) maintenance study and long-term extension (LTE) evaluate the long-term efficacy and safety of UPA maintenance therapy. Here, we report the results of the U-ENDURE LTE. Methods Patients (pts) completing the U-ENDURE 52-week (wk) maintenance study were eligible to participate in the LTE and continue their previously assigned treatment (placebo [PBO], UPA 15 mg [UPA15] once daily [QD], or UPA 30 mg [UPA30] QD; blinded until the last pt completed maintenance wk52). Clinical response, clinical remission, endoscopic response, endoscopic remission, as well as high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP) were evaluated as-observed up to wk48 of the LTE among pts (PBO [N = 89], UPA15 [N = 107], UPA30 [N = 173]); excluding pts who received open-label UPA30 rescue therapy. Safety was assessed in all pts (PBO [N = 223], UPA15 [N = 221], UPA30 [N = 229]) from wk0 of the maintenance study up to LTE wk204 (cut-off date: 01 Aug 2023). Results At LTE wk0, the SF/APS clinical remission rates were 73.0%, 78.3%, and 80.3% for PBO, UPA15, and UPA30, respectively (Figure 1A). Similar rates were reported at LTE wk0 for CDAI clinical remission (PBO 75.3%, UPA15 81.3%, UPA30 80.9%; Figure 1B) and clinical response (CR-100: PBO 79.5%, UPA15 84.9%, UPA30 84.4%). Rates of clinical remission were stable through wk48 of the LTE. Endoscopic response (PBO 32.9%, UPA15 59.6%, UPA30 66.5%) and remission rates (PBO 27.8%, UPA15 42.4%, UPA30 47.3%) at LTE wk0 were sustained through wk48 with UPA while decreased with PBO (Figure 1C-D). At LTE wk0, the mean [95% CI] change from induction BL in hs-CRP was 1.8 [–0.4, 4.1], –13.2 [–17.9, –8.6], and –12.8 [–16.8, –8.9] for PBO, UPA15, and UPA30, respectively; sustained through wk48. Similar results were observed with FCP (mean [95% CI] change from induction BL: PBO 126 [–103, 356], UPA15 –2946 [–4121, –1772], UPA30 –1871 [–2577, –1165]). Severe adverse events (AEs) and serious AEs were lower with UPA treatment compared with PBO (Table 1). The rates of most AEs of special interest were similar between UPA and PBO; however, numerically higher rates of herpes zoster, adjudicated gastrointestinal perforations, neutropenia, lymphopenia, creatine phosphokinase elevation, and hepatic disorders were reported in pts treated with UPA vs PBO (Table 1). Conclusion In pts completing wk48 of the LTE, sustained efficacy was observed in clinical and endoscopic endpoints with over 2 years of UPA treatment, while maintaining an overall positive safety profile in pts with CD. Reference: 1. Loftus EV Jr, et al. N Engl J Med. 2023;388:1966–80

ImportanceImplementing multidisciplinary teams for treatment of complex brain tumors needing awake craniotomies is associated with significant costs. To date, there is a paucity of analysis on the cost utility of introducing advanced multidisciplinary standardized teams to enable awake craniotomies.ObjectiveTo assess the cost utility of introducing a standardized program of awake craniotomies.Design, Setting, and ParticipantsA retrospective economic evaluation was conducted at Mayo Clinic Florida. All patients with single, unilateral lesions who underwent elective awake craniotomies between January 2016 and December 2021 were considered eligible for inclusion. The economic perspective of the health care institution and a time horizon of 1 year were considered. Data were analyzed from October 2022 to May 2023.ExposureTreatment with an awake craniotomy before standardization (2016-2018) compared with treatment with awake craniotomy after standardization (2018-2021).Main Outcomes and MeasuresPatient demographics, perioperative, and postoperative outcomes, including length of stay, intensive care (ICU) admission, extent of resection, readmission rates, and 1-year mortality were compared between patients undergoing surgery before and after standardization. Direct medical costs were estimated from Medicare reimbursement rates for all billed procedures. A cost-utility analysis was performed considering differences in direct medical costs and in 1-year mortality within the periods before and after standardization of procedures. Uncertainty was explored in probability sensitivity analysis.ResultsA total of 164 patients (mean [SD] age, 49.9 [15.7] years; 98 [60%] male patients) were included in the study. Of those, 56 underwent surgery before and 108 after implementation of procedure standardization. Procedure standardization was associated with reductions in length of stay from a mean (SD) of 3.34 (1.79) to 2.46 (1.61) days (difference, 0.88 days; 95% CI, 0.33-1.42 days; P = .002), length of stay in ICU from a mean (SD) of 1.32 (0.69) to 0.99 (0.90) nights (difference, 0.33 nights; 95% CI, 0.06-0.60 nights; P = .02), 30-day readmission rate from 14% (8 patients) in the prestandardization cohort to 5% (5 patients) (difference, 9%; 95% CI, 19.6%-0.3%; P = .03), while extent of resection and intraoperative complication rates were similar between both cohorts. The standardized protocol was associated with mean (SD) savings of $7088.80 ($12 389.50) and decreases in 1-year mortality (dominant intervention). This protocol was found to be cost saving in 75.5% of all simulations in probability sensitivity analysis.Conclusions and RelevanceIn this economic evaluation of standardization of awake craniotomy, there was a generalized reduction in length of stay, ICU admission time, and direct medical costs with implementation of an optimized protocol. This was achieved without compromising patient outcomes and with similar extent of resection, complication rates, and reduced readmission rates.

PURPOSE Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC. PATIENTS AND METHODS PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981 ). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion. RESULTS Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively). CONCLUSION Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

OBJECTIVES: To provide guidance on the reporting of norepinephrine formulation labeling, reporting in publications, and use in clinical practice. DESIGN: Review and task force position statements with necessary guidance. SETTING: A series of group conference calls were conducted from August 2023 to October 2023, along with a review of the available evidence and scope of the problem. SUBJECTS: A task force of multinational and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. INTERVENTIONS: The implications of a variation in norepinephrine labeled as conjugated salt (i.e., bitartrate or tartrate) or base drug in terms of effective concentration of norepinephrine were examined, and guidance was provided. MEASUREMENTS AND MAIN RESULTS: There were significant implications for clinical care, dose calculations for enrollment in clinical trials, and results of datasets reporting maximal norepinephrine equivalents. These differences were especially important in the setting of collaborative efforts across countries with reported differences. CONCLUSIONS: A joint task force position statement was created outlining the scope of norepinephrine-dose formulation variations, and implications for research, patient safety, and clinical care. The task force advocated for a uniform norepinephrine-base formulation for global use, and offered advice aimed at appropriate stakeholders.

Objective Open science is a movement and set of practices to conduct research more transparently. Implementing open science will significantly improve public access and supports equity. It also has the potential to foster innovation and reduce duplication through data and materials sharing. Here, we survey an international group of researchers publishing in cardiovascular journals regarding their perceptions and practices related to open science. Methods We identified the top 100 ‘Cardiology and Cardiovascular Medicine’ subject category journals from the SCImago journal ranking platform. This is a publicly available portal that draws from Scopus. We then extracted the corresponding author’s name and email from all articles published in these journals between 1 March 2021 and 1 March 2022. Participants were sent a purpose-built survey about open science. The survey contained primarily multiple choice and scale-based questions for which we report count data and percentages. For the few text-based responses we conducted thematic content analysis. Results 198 participants responded to our survey. Participants had a mean response of 6.8 (N=197, SD=1.8) on a 9-point scale with endpoints, not at all familiar (1) and extremely familiar (9), when indicating how familiar they were with open science. When asked about where they obtained open science training, most participants indicated this was done on the job self-initiated while conducting research (n=103, 52%), or that they had no formal training with respect to open science (n=72, 36%). More than half of the participants indicated they would benefit from practical support from their institution on how to perform open science practices (N=106, 54%). A diversity of barriers to each of the open science practices presented to participants were acknowledged. Participants indicated that funding was the most essential incentive to adopt open science. Conclusions It is clear that policy alone will not lead to the effective implementation of open science. This survey serves as a baseline for the cardiovascular research community’s open science performance and perception and can be used to inform future interventions and monitoring.

Background The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5 / CCL5 expression in CRC and to determine whether CCR5 / CCL5 levels could impact treatment outcomes. Methods 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. Results CCR5 / CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5 / CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5 / CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5 / CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone. Conclusions Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.