Citations

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Abstract Bruton tyrosine kinase inhibitors (BTKis) that target B-cell receptor signaling have led to a paradigm shift in chronic lymphocytic leukemia (CLL) treatment. BTKis have been shown to reduce abnormally high CLL-associated T-cell counts and the expression of immune checkpoint receptors concomitantly with tumor reduction. However, the impact of BTKi therapy on T-cell function has not been fully characterized. Here, we performed longitudinal immunophenotypic and functional analysis of pretreatment and on-treatment (6 and 12 months) peripheral blood samples from patients in the phase 3 E1912 trial comparing ibrutinib-rituximab with fludarabine, cyclophosphamide, and rituximab (FCR). Intriguingly, we report that despite reduced overall T-cell counts; higher numbers of T cells, including effector CD8+ subsets at baseline and at the 6-month time point, associated with no infections; and favorable progression-free survival in the ibrutinib-rituximab arm. Assays demonstrated enhanced anti-CLL T-cell killing function during ibrutinib-rituximab treatment, including a switch from predominantly CD4+ T-cell:CLL immune synapses at baseline to increased CD8+ lytic synapses on-therapy. Conversely, in the FCR arm, higher T-cell numbers correlated with adverse clinical responses and showed no functional improvement. We further demonstrate the potential of exploiting rejuvenated T-cell cytotoxicity during ibrutinib-rituximab treatment, using the bispecific antibody glofitamab, supporting combination immunotherapy approaches.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

Importance Bleeding is the most common cause of preventable death after trauma. Objective To determine the effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) when used in the emergency department along with standard care vs standard care alone on mortality in trauma patients with exsanguinating hemorrhage. Design, Setting, and Participants Pragmatic, bayesian, randomized clinical trial conducted at 16 major trauma centers in the UK. Patients aged 16 years or older with exsanguinating hemorrhage were enrolled between October 2017 and March 2022 and followed up for 90 days. Intervention Patients were randomly assigned (1:1 allocation) to a strategy that included REBOA and standard care (n = 46) or standard care alone (n = 44). Main Outcomes and Measures The primary outcome was all-cause mortality at 90 days. Ten secondary outcomes included mortality at 6 months, while in the hospital, and within 24 hours, 6 hours, or 3 hours; the need for definitive hemorrhage control procedures; time to commencement of definitive hemorrhage control procedures; complications; length of stay; blood product use; and cause of death. Results Of the 90 patients (median age, 41 years [IQR, 31-59 years]; 62 [69%] were male; and the median Injury Severity Score was 41 [IQR, 29-50]) randomized, 89 were included in the primary outcome analysis because 1 patient in the standard care alone group declined to provide consent for continued participation and data collection 4 days after enrollment. At 90 days, 25 of 46 patients (54%) had experienced all-cause mortality in the REBOA and standard care group vs 18 of 43 patients (42%) in the standard care alone group (odds ratio [OR], 1.58 [95% credible interval, 0.72-3.52]; posterior probability of an OR >1 [indicating increased odds of death with REBOA], 86.9%). Among the 10 secondary outcomes, the ORs for mortality and the posterior probabilities of an OR greater than 1 for 6-month, in-hospital, and 24-, 6-, or 3-hour mortality were all increased in the REBOA and standard care group, and the ORs were increased with earlier mortality end points. There were more deaths due to bleeding in the REBOA and standard care group (8 of 25 patients [32%]) than in standard care alone group (3 of 18 patients [17%]), and most occurred within 24 hours. Conclusions and Relevance In trauma patients with exsanguinating hemorrhage, a strategy of REBOA and standard care in the emergency department does not reduce, and may increase, mortality compared with standard care alone. Trial Registration isrctn.org Identifier: ISRCTN16184981

Abstract Background The efficacy of pembrolizumab monotherapy in metastatic castration-resistant prostate cancer patients when stratified by MSI-H and/or TMB-H is poorly defined. Additionally, outcomes based on sequencing source (i.e., tissue or liquid biopsy) have not been well described. We sought to assess outcomes of pembrolizumab monotherapy in patients with mCRPC and compare efficacy based on MSI-H and/or TMB-H when identified by tissue or liquid biopsy. Methods A retrospective analysis was performed of mCRPC patients treated at Mayo Clinic with pembrolizumab monotherapy between 2018 and 2023. Objective response rates (ORR), median progression-free survival (mPFS), and overall survival (mOS), were determined by RECIST v1.1 criteria. Results Twenty-two patients with mCRPC received pembrolizumab monotherapy for at least 3 cycles for an MSI-H or TMB-H indication. All patients had next generation sequencing (NGS) performed via tissue (n = 11) or liquid (n = 10) biopsy source. The ORR was 50% (27.3% complete response and 22.7% had partial response). The mPFS for TMB 10-14.9 mut/Mb (n = 4), TMB 15-24.9 mut/Mb (n = 6), and TMB ≥ 25 mut/Mb (n = 10) was 2.1, not reached (NR), and NR, respectively (p = 0.0003). The mOS for these same groups was 5.1 months, 20.5 months, and not reached, respectively. Among patients with TMB-H without co-occurring MSI-H or CDK12 (n = 6), none experienced a response and only one patient had stable disease compared to patients with MSI-H (n = 12) for whom the ORR was 75%. Immunotherapy responsive alterations such as ATRX and PTCH1 mutations were frequently noticed among patients who had complete response (CR). Conclusions Our study highlights that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12. This study further demonstrates the utility of liquid biopsy NGS for identifying MSI-H and/or TMB-H disease.

Abstract Disclosure: M. Dhanasekaran: None. A.A. Rajwani: None. M.R. Castro: None. J.C. Morris: None. J. Schmitz: None. R.A. Lee: None. M. Callstrom: None. M. Stan: None. Context: Autonomously functioning thyroid nodules (AFTNs) constitutes 5% of thyroid nodules and is the second most common cause of hyperthyroidism following Graves’ Disease. Untreated hyperthyroidism is associated with adverse cardiovascular and skeletal complications. Currently, radioactive iodine (RAI) and surgery are the standard treatment options for AFTNs, and both incur a risk of post-procedural hypothyroidism. To overcome this and other surgery/radiation-related complications, radiofrequency ablation (RFA) has been utilized in multiple countries (for both toxic and non-toxic thyroid nodules). It has been shown to induce significant nodule volume reduction along with restoration of normal thyroid function in many AFTNs. Methods: We present a single-center experience using RFA as an alternative treatment modality for AFTNs. The study's primary aim was to assess the efficacy of RFA in normalizing thyroid hormone concentration and restoring the euthyroid state. In addition, we analyzed the efficacy of RFA in nodule volume rate reduction (VRR) and its associated adverse events. Results: A total of 22 consecutive patients (17 F and 5 M) underwent RFA for a solitary AFTN (hot nodule in thyroid uptake and scan) under variable degrees of general anesthesia. 72% (n=16) had subclinical hyperthyroidism, 9% (n=2) had overt hyperthyroidism, and 18% (n=4) were biochemically euthyroid on anti-thyroid drugs (ATD). The mean age at the time of ablation was 52.09 years (SD= 14.6), with a mean BMI of 27.36 kg/m2 (SD= 4.67). Average pre-treatment TSH was 0.41 mIU/L (SD= 0.980) and free T4 1.29 ng/dl (SD= 0.33). The thyroid function was assessed after a single RFA session. TSH normalized in all patients within 3-6 months following the ablation. All four patients on ATD pre-treatment discontinued therapy within three months following the procedure. The average VRR (62.54%) was achieved within 3-6 months following the RFA, and importantly, none of the nodules grew back during the follow-up period (up to 24 months). Two patients (9%) developed transient tachycardia requiring short-term beta-blocker therapy, and two (9%) developed mild hypothyroidism requiring levothyroxine therapy. One patient, euthyroid post RFA, developed recurrent hyperthyroidism 45 months later and elected to undergo lobectomy. No serious adverse effects were noted in this cohort. Conclusions - RAI and/or surgery represent the standard of care for toxic adenomas but RFA shows excellent efficacy along with an excellent safety profile. Therefore at centers with RFA expertise it should be considered an alternative treatment strategy, avoiding radiation and surgery-related complications. Presentation Date: Saturday, June 17, 2023

Abstract Background There is growing evidence that low-density lipoprotein-triglyceride (LDL-TG) may be a better biomarker to define atherosclerotic cardiovascular disease (ASCVD) risk than LDL-cholesterol (LDL-C), which is currently used to stratify risk and as a treatment goal. Because LDL-TG typically requires additional advanced lipid testing, we developed an equation for estimating LDL-TG (eLDL-TG) from the results of the standard lipid panel. Methods Results from a general dyslipidemic population (N = 40 202), which were obtained with beta-quantification (BQ) reference method, were randomly divided into a training and validation datasets and used to develop the equation for estimating LDL-TG shown in Fig. 1A. Association of Sampson-NIH-LDL-C (NIH-LDL-C) and eLDL-TG with ASCVD risk markers was done in the National Heart and Nutrition Examination Survey (NHANES) (N = 37 053) and with ASCVD events in the Atherosclerosis Risk in Communities (ARIC) study (N = 14 749). Results The comparison between eLDL-TG and measured LDL-TG was only modest (R2 = 0.601, slope = 0.611), but eLDL-TG (Fig. 1B) showed better risk stratification than NIH-LDL-C (Fig. 1C) by survival curve analysis in ARIC. Moreover, receiver-operating characteristic (ROC) analysis showed that eLDL-TG was better than all other lipid-marker tests for ASCVD events (AUC: eLDL-TG = 0.633, HDL-C = 0.627, sdLDL-C = 0.621, remnant-cholesterol = 0.613, NonHDL-C = 0.613, TG = 0.603, apoB = 0.598, NIH-LDL-C = 0.590, TC = 0.568). In NHANES, eLDL-TG was more strongly associated with hypertriglyceridemia, obesity, diabetes, metabolic syndrome and increased high-sensitivity C-reactive protein than NIH-LDL-C. Inclusion of eLDL-TG in a Cox-Proportional Hazards Model along with other conventional risk factors (age, sex, race, diabetes, systolic blood pressure, smoking, HDL-C, and total cholesterol) did not further improve risk prediction. Conclusions Like LDL-C, LDL-TG can also be estimated from the results of the standard lipid panel. It is a better univariate risk marker than LDL-C and hence can be useful for initial ASCVD risk stratification.

Abstract Background Low-density lipoprotein cholesterol (LDL-C) is used to assess atherosclerotic cardiovascular disease (ASCVD) risk and to manage lipid-lowering therapy. Proprotein convertase subtilisin/kexin (type 9) serine protease (PCSK9) inhibitors decrease LDL-C by up to 70% when used in conjunction with statins. Due to cost, insurance companies restrict their use. To be eligible for PCSK9 therapy, a patient must have pre-existing ASCVD and LDL-C > 70 mg/dL, while on a maximally tolerated dose of statins. Most clinical laboratories calculate LDL-C by the Friedewald Equation (FWLDL-C), which utilizes results from the standard lipid panel (total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C)). However, this often leads to an underestimation of LDL-C, especially when TG concentrations are elevated. More accurate equations have recently been developed, such as the Martin (MLDL-C), Sampson-NIH (SLDL-C) and extended Martin (ext-MLDL-C) equations. Using LDL-C determined by the beta-quantification reference method (BQ), we developed the following enhanced version of the Sampson-NIH Equation (eSLDL-C), which includes apoB as an independent variable: eSLDL-C = TC/1.15-(HDL-C)/1.25-TG/6.98-(TG × NonHDL-C)/1115 + TG2/8903.23 + (TG × ApoB)/1237 + ApoB/4.54–4.73 Methods Results for clinically ordered ApoB, BQ, and lipid panels were used. To test the accuracy of the various equations, we compared BQLDL-C to FWLDL-C, MLDL-C, extMLDL-C, SLDL-C and eSLDL-C by regression analysis (N = 12 101, TG < 800). Accuracy of each equation was compared to the BQ reference method for classifying patients (LDL-C ≤ 150, n = 9374) as either being below or above the 70 mg/dL treatment decision threshold for PCSK9 therapy. Results The eSLDL-C equation performed substantially better than the other equations for estimating low LDL-C (BQLDL-C ≤ 100 mg/dL, TG 5–800 mg/dL, n = 4115), with a mean absolute difference (MAD) of 3.80 mg/dL (compared to SLDL-C: 6.05; FWLDL-C: 8.71; MLDL-C: 6.43; extMLDL-C: 6.39). It also had the best overall normalized Matthew’s Correlation Coefficient (nMCC) for the best balance of sensitivity and specificity for identifying patients that are above the 70 mg/dL treatment threshold (eSLDL-C-94.7% (92.2% spec, 98.5% sen), SLDL-C-90.7% (94.8% spec, 95.5% sen), FWLDL-C-88.2% (98.0% spec, 92.7% sen), MLDL-C-90.3% (88.9% spec, 96.5% sen), and extMLDL-C-90.1% (88.4% spec, 96.5% sen)). In our dataset with 1125 subjects being below the 70 mg/dL threshold by BQLDL-C, FWLDL-C misclassified an additional 601 subjects below this threshold (Negative Predictive Value 65%). MLDL-C and extMLDL-C misclassified 289 subjects falsely low, whereas eSLDL-C only has 126 subjects falsely classified lower than the 70 mg/dL threshold. Conclusion We show that the enhanced Sampson-NIH equation, which includes apoB, estimates low LDL-C more accurately than other equations. The use of the new equation would improve access to those patients who might benefit from PCSK9 therapy but have falsely low LDL-C by the FWLDL-C equation or other LDL-C equations. The new equation is also more specific than the MLDL-C and extMLDL-C equations and would, therefore, also reduce the overutilization of PCSK9 therapy by these particular equations for those patients who do not require it, according to the reference BQ method and current guidelines.