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Background: Postoperative fluid-related complications, such as hematoma and seroma formation, are common concerns in breast surgery, adversely affecting surgical outcomes and patient recovery. Topical tranexamic acid (TXA) has emerged as a promising intervention to minimize bleeding while reducing systemic adverse effects linked to intravenous administration. However, evidence on the efficacy of topical TXA in breast surgery remains sparse. Methods: This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. English-language databases were searched through April 2024 to identify randomized controlled trials and cohort studies assessing the effects of topical TXA on postoperative outcomes in breast surgery, including hematoma, seroma, infection rates, and drain output/duration. Results: Six studies, encompassing 823 patients and 1477 breasts, were included. Subgroup meta-analysis demonstrated a statistically significant reduction in hematoma rates in patients who underwent mastectomy (risk ratio [RR] = 0.14; 95% confidence interval [CI], 0.03–0.78; P = 0.02), but not in patients who underwent breast reduction (RR = 0.76; 95% CI, 0.08–7.08; P = 0.24). No significant differences were found in overall hematoma rates (RR = 0.32; 95% CI, 0.08–1.195; P = 0.09), seroma formation (RR = 1.22; 95% CI, 0.99–1.51; P = 0.07), or infection rates (RR = 0.85; 95% CI, 0.46–1.56; P = 0.59). Conclusions: Topical TXA significantly reduced hematoma rates in patients who underwent mastectomy but showed no significant effect on other outcomes. Larger studies with standardized methodologies are required to fully establish the role of topical TXA in optimizing breast surgery outcomes.

AbstractEUS-guided gallbladder drainage (EUS-GBD) using lumen apposing metal stents (LAMS) has excellent technical and short-term clinical success for acute cholecystitis (AC). The goals of this study were to determine the long-term clinical outcomes and adverse events (AEs) of EUS-GBD with LAMS.A multicenter, retrospective study was conducted at 18 US tertiary care institutions. Inclusion criteria: any AC patient with attempted EUS-GBD with LAMS and minimum 30-day post-procedure follow-up. Long-term clinical success was defined as absence of recurrent acute cholecystitis (RAC) > 30 days and long-term AE was defined as occurring > 30 days from the index procedure.A total of 109 patients were included. Technical success was achieved in 108 of 109 (99.1%) and initial clinical success in 106 of 109 (97.2%). Long-term clinical success was achieved in 98 of 109 (89.9%) over a median follow-up of 140 days (range 30–1188). On multivariable analysis (MVA), acalculous cholecystitis (odds ratio [OR] 15.93, 95% confidence interval [CI] 1.22–208.52, P = 0.04) and the occurrence of a LAMS-specific AE (OR 63.60, 95% CI 5.08–799.29, P <0.01) were associated with RAC. AEs occurred in 38 of 109 patients (34.9%) at any time, and in 10 of 109 (9.17%) > 30 days from the index procedure. Most long-term AEs (7 of 109; 6.42%) were LAMS-specific. No technical or clinical factors were associated with occurrence of AEs. LAMS were removed in 24 of 109 patients (22%). There was no difference in RAC or AEs whether LAMS was removed or not.EUS-GBD with LAMS has a high rate of long-term clinical success and modest AE rates in patients with AC and is a reasonable destination therapy for high-risk surgical candidates.

Background: Symptomatic intracranial hemorrhage (sICH) is the most dreaded complication after reperfusion therapy for acute ischemic stroke. We performed a meta-analysis of randomized controlled trials to estimate and compare risks of sICH after mechanical thrombectomy (MT) depending on the location of the large vessel occlusion, concomitant use of intravenous thrombolysis, timing of treatment, and core size. Methods: Randomized controlled trials were included, following a comprehensive search of different databases from inception to 1 March 2024. Random-effect models in a meta-analysis were employed to obtain the pooled risk ratios (RRs) and their corresponding 95% confidence intervals (95% CI) for sICH with MT, and were then compared to other reperfusion treatment regimens, including best medical treatment and intravenous thrombolysis (IVT). Results: MT in the anterior circulation was associated with a significantly higher risk of sICH as compared with no-MT (RR: 1.46; 95%CI: 1.03–2.07; p = 0.037). The risk of sICH was comparable between the MT and MT+IVT groups (RR: 0.77; 95%CI: 0.57–1.03; p = 0.079). There was no difference in sICH risk with MT as compared with no-MT within 6 h of last known well (RR: 1.14; 95%CI: 0.78–1.66; p = 0.485) and beyond that time (RR: 1.29; 95%CI: 0.80–2.08; p = 0.252); the risk of sICH was also comparable between MT conducted within 6 h of last known well and MT conducted beyond that time (p = 0.512). The sICH risk for MT in the posterior circulation (RR: 7.48; 95%CI: 2.27–24.61) was significantly higher than for MT in the anterior circulation (RR: 1.18; 95%CI: 0.90–1.56) (p = 0.003). MT was also associated with a significantly higher sICH risk than no-MT among patients with large core strokes (RR: 1.71; 95%CI: 1.09–2.66, p = 0.018). Conclusions: When evaluating cumulative evidence from randomized controlled trials, the risk of sICH is increased after MT compared with patients not treated with MT. Yet, the difference is largely driven by the greater risk of sICH in patients treated with MT for posterior circulation occlusions and, to a lesser degree, large core strokes. Concomitant use of intravenous thrombolysis and the use of MT in the extended therapeutic window do not raise the risk of sICH.

AbstractBackgroundWe previously identified the novel mechanism of pathological tau transfer via extracellular vesicles (EVs) in Alzheimer’s disease (AD). Targeting EV secretion to mitigate tau transfer is therefore a promising therapeutic approach for AD. P2X purinoreceptor 7 (P2RX7), an ATP‐gated cationic channel, regulates microvesicle shedding or secretion of multivesicular body‐derived exosomes. We aim to investigate the effect of P2rx7 deficiency on disease progression in PS19 tauopathy mouse model in vivo and by proteomic profiling of brain EVs.MethodPS19:P2rx7–/– mice at 9 months of age were tested for the fear conditioning, and pathology assessment of the brain atrophy and tau using immunofluorescence against aggregated tau (Alz50) or phosphorylated tau (AT8) and ELISA. Mice were intracranially injected with viral vectors expressing mEmerald‐CD9 in microglia and P301L tau in neurons to visualize the secretion of microglial EV and extracellular tau in vivo. Brain EV samples were subjected to proteomic profiling by data independent acquisition mass‐spectrometry.ResultPS19:P2rx7–/– mice showed significant improvement in contextual and cued memory compared to age‐matched PS19 mice, which was accompanied by preserved cortical and hippocampal volume, and significant reduction of hippocampal tau pathology and pS396 tau in sarkosyl‐insoluble fraction of brain tissues. The number of GFP+ microglial EVs were significantly reduced in P2rx7–/– compared to WT mice. Gene ontology pathway analysis of EV proteome showed significant enrichment of mitochondrial pathways in PS19 group compared to WT group, which was significantly downregulated in PS19:P2rx7–/– group.ConclusionOur study demonstrated that P2rx7 deficiency ameliorates cognitive dysfunction and tau pathology development in PS19 mice by dampening microglial EV secretion and EV‐mediated mitochondria transfer, further indicating the therapeutic potential of targeting P2RX7, an EV regulatory molecule, to ameliorate AD progression.

Cardiac amyloidosis (CA) is a progressive condition resulting from the deposition of amyloid fibrils in the heart, which leads to severe diastolic dysfunction and restrictive cardiomyopathy. The disease has two main subtypes: light-chain and transthyretin (TTR) CA, with the latter subdivided into wild-type and hereditary forms. Despite advances in diagnostic imaging, early detection remains a challenge due to non-specific symptoms that mimic other cardiac conditions. Treatment has evolved significantly with targeted therapies like TTR stabilizers, gene silencers, and RNA interference, showing promise in altering disease progression. However, barriers such as high costs, limited availability of genetic testing, and inadequate multidisciplinary care continue to impede comprehensive management. Future strategies should focus on integrating novel gene-editing therapies, expanding access to diagnostics, and enhancing multidisciplinary care models to improve outcomes. Overall, early diagnosis, equitable access to therapies, and personalized management plans are crucial to advancing care for CA patients.

Introduction: Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Some patients (pts) proceed with a consolidative allogeneic hematopoietic cell transplant (HCT) after breux cel. We do not know which pts can safely avoid a consolidative HCT and its associated morbidity. Methods: We conducted a retrospective cohort study utilizing the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) dataset. ROCCA is a registry of brexu cel pts in 32 centers in North America. We defined complete remission (CR) as &lt; 5% blasts in the bone marrow and no central nervous system (CNS) or extramedullary (EM) disease on or around D28 after brexu cel. We defined measurable residual disease negative (MRD-) CR as CR and no abnormal blasts in the bone marrow by multiparameter flow cytometry, quantitative polymerase chain reaction, ClonoSeq next generation sequencing (NGS), or other sequencing modalities with lower sensitivity. ClonoSeq NGS has a sensitivity of 10-6, while the other modalities have a sensitivity of at least 10-4. We defined progression free survival (PFS) as the time from CAR-T infusion to relapse or death, censored at the date of last follow-up. Statistical analyses were performed in R. Univariable Cox proportional hazards regression analyses were performed to determine the association of pre-specified variables with PFS. Variables known to be associated with CAR T outcomes in ALL were entered into a multivariable model. HCT was incorporated as a time-varying covariate. Results: During the study period, 281 pts were infused with brexu cel. We focused our analysis on 172 (61%) pts with confirmed MRD- CR on D28, as that is the group with clinical equipoise regarding maintenance strategy. 38 (22%) of those pts received a consolidative HCT, 30 (17%) received another form of maintenance therapy (primarily tyrosine kinase inhibitors for Philadelphia (Ph)-chromosome positive ALL), and 104 (60%) pts received no maintenance therapy. Pts who underwent consolidative HCT were younger (median age 35 years) than those who received no maintenance (42y) (p = 0.023) and were less likely to have a history of prior HCT (13% vs. 47%, p &lt; 0.001). No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel. We performed univariable Cox proportional hazard regression analyses among pts in MRD- CR on D28, excluding those who received other maintenance therapy besides HCT; the median follow up was 8.1 months. In univariable analyses, D28 MRD negativity by ClonoSeq NGS (versus MRD negativity by other, less sensitive methods), development of CRS, and pre-CAR BM blasts &lt; 5% were associated with improved PFS; prior ino exposure was negatively associated with PFS (p &lt; 0.05). Age, sex, Ph status, TP53 status, and neurotoxicity development were not associated with PFS. In a multivariable model incorporating ALL type, prior HCT, prior ino/blina, and pre-CAR blast burden, as well as consolidative HCT as a time-varying covariate, only MRD negativity by ClonoSeq NGS with at least 10-6 sensitivity retained statistical significance (PFS hazard ratio 0.34, 95% confidence interval (CI) 0.15-0.77, p = 0.005). Pts who were MRD- by ClonoSeq NGS on D28 and received no maintenance had favorable 6m PFS of 76% (95% CI: 59-98%) and OS of 100% with a median follow up of 6.3 months in this subgroup. Among those in MRD- CR by NGS, HCT as a time-varying covariate was not associated with improved PFS (HR 0.6, p = 0.6). Conclusions: In a large real-world cohort of adults with R/R B-ALL infused with brexu cel, we identified practice variation regarding the use of consolidative HCT. Among brexu cel recipients who entered an MRD- CR, we identified ClonoSeq NGS MRD negativity as a novel predictive factor of favorable oncologic outcomes, even without a consolidative HCT. Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022). Longer follow-up is needed to validate the safety of omitting consolidative HCT in such pts, but these results encourage the potential for definitive therapy with brexu cel when D28 ClonoSeq NGS MRD is negative.

Introduction: Brexucabtagene Autoleucel (brexu-cel) is the first CD19-targeting chimeric antigen receptor (CD19.CAR) T-cell therapy approved for the treatment of relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in adult (≥18 yo) patients (pts) based on results from the ZUMA-3 trial. However, data on the safety and efficacy of CAR-T cells in older pts (≥60 yo) remains limited, with only 8 pts &gt;65 yo enrolled in the ZUMA-3 trial. We evaluated the treatment characteristics and outcomes with use of brexu-cel amongst patients ≥60 yo in the Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database. Methodology: ROCCA is a consortium of over 30 U.S.-based institutions with a database of adult pts with B-ALL who received brexu-cel as standard of care therapy. We identified pts ≥60 yo and further stratified them into two cohorts: 60-69 yo and ≥70 yo. Outcomes of interest included OS, PFS, ORR, and toxicities (CRS and ICANS). Both OS and PFS were calculated from the day of brexu-cel infusion. Response assessment occurred on day +28, and MRD evaluation was per institutional practices. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria. Results: Of 280 brexu-cel recipients in the ROCCA database, 73 (26%) were ≥60 yo, of which 58 (79%) were between 60-69 yo and 15 (21%) were ≥70 yo. Among pts ≥60 yo, the median age at infusion was 65 (range 60-81). Pts were heavily pretreated with a median of 3 prior lines of therapy (range 2-9). Prior therapies included: allogeneic HSCT (38%), inotuzumab ozogamicin (41%), and blinatumomab (62%). Forty pts (55%) had Ph-negative B-ALL, 24 (33%) had Ph+ B-ALL and 9 (12%) had Ph-like B-ALL. When grouped by HCT-CI equal to 0, 1-2 or ≥3, a higher proportion of pts ≥60 yo had HCT-CI ≥3 (19% vs. 7% in &lt;60 yo; p=0.004). Pre-apheresis, 33 pts (45%) had active disease (&gt;5% marrow blasts or extramedullary disease), 34 (47%) were in CR (of whom 14 were MRD-negative) and 6 had unknown disease status. Following brexu-cel, 43 (59%) achieved MRD-negative CR, 20 (27%) had MRD + or CR with unknown MRD status, 6 (8%) had refractory disease and 5 had no disease evaluation available. The ORR was similar between pts 60-69 and ≥70 yo (MRD-negative CR rate: 58% vs 61%, r/r to brexu-cel: 9% vs 6%) and was comparable to pts &lt;60 yo (MRD-negative CR 66%; r/r disease of 9%). The rate of all grade ICANS was higher in pts ≥70 (77%) than in pts 60-69 (47%) or pts &lt;60 (49%), with grade 1-2 ICANS occurring at a significantly higher rate in pts ≥70 (44% vs. 20% in 60-69 and 20% in &lt;60, p=0.049). Grade 3-4 ICANS were similar between the groups: 33%, 27% and 29% in the ≥70, 60-69, and &lt;60 groups, respectively. Conversely, rates of CRS were similar across age groups (80-84%). There was no statistically significant difference in the rate of grade 3-4 CRS which was 17% in pts ≥70, 4% in pts 60-69, and 11% in pts &lt;60 yo. With a median follow-up of 332 days (range 8-936 days) from infusion, pts ≥60 yo had a median PFS of 395 days compared to 547 days in pts &lt;60 yo. Median PFS was lower in the ³70 yo (231 days) compared to 677 in the 60-69 yo cohort. No statistically significant difference was found between the &lt;60 and ≥60groups in 6- and 12-month PFS rates (6 months PFS: 66% vs 64%, p=0.77 and 12 months PFS: 57% vs 57%, p=1.00). When pts ≥60 yo were stratified by age, pts ≥70 yo had similar 6-month PFS compared to other age groups but significantly lower 12-month PFS (38%; vs. 64% in pts 60-69and 57% in pts &lt;60, p=0.001). Median OS was not reached in any of the age groups, and there was no statistically significant difference in 6-month OS (72% in ≥ 70 vs. 82% in the 60-69 vs. 82% in &lt;60, p=0.14) or 12-months OS (61% in ≥ 70 vs. 69% in 60-69 vs. 73% in &lt;60, p=0.18). Conclusion: This is the largest study to date of older B-ALL pts receiving CAR-T cells. We observed that older pts, particularly those aged 60-69, have similar outcomes to younger pts. However, pts ≥70 yo had lower median and 12-month PFS when compared to younger patients. Additionally, pts ≥70 yo had higher rates of grades 1-2 ICANS. An important limitation of this analysis is the potential selection bias among clinicians when selecting older patients for this treatment. Longer follow-up, including inclusion of additional pts ≥70 yo is needed to confirm these results, and further studies are needed to identify the optimal approach for use of CAR T-cell therapy in patients in this age group.

Introduction: Thoracic aortic aneurysms (TAA) are a significant health concern, with the true prevalence likely underestimated due to undiagnosed cases. Outcomes in TAA are influenced by factors like age, sex, and comorbidities such as hypertension. This study examines mortality trends and disparities associated with TAA in US adults. Methodology: This study analyzed death certificates from 1999 to 2020 using the CDC WONDER Database to identify TAA-related deaths in individuals aged 25 and older using ICD-10 codes I71.1 and I71.2. Age-adjusted mortality rates (AAMRs) per 1 000 000 and annual percent changes (APCs) were calculated and stratified by year, sex, age group, race/ethnicity, region, and urbanization status. Results: Between 1999 and 2020, 47 136 TAA-related deaths were reported among US adults. The AAMR decreased from 16.2 to 8.2 per 1 000 000, with a significant decline from 1999 to 2013 (APC: −5.00; 95% CI: −5.54 to −4.54; P<0.001). Older adults had the highest AAMRs at 44.6 per 1 000 000. Men had higher AAMRs than women (11.2 vs. 9). AAMRs were highest among non-Hispanic (NH) Black (11), followed by NH White (10.3), NH Asian or Pacific Islander (9.5), NH American Indian or Alaska Native (7.8), and Hispanic (5.2) populations. Nonmetropolitan areas had higher AAMRs than metropolitan areas (11 vs. 9.8). Conclusions: The analysis showed a significant decline in TAA mortality since 1999, with recent stabilization. However, disparities persist, with higher AAMRs among men, older adults, NH Black adults, and nonmetropolitan residents, highlighting the need for targeted and equitable interventions.

Background: Hypertensive heart disease (HHD) poses a growing public health concern. Global data reveal a concerning rise in HHD prevalence, deaths, and disability-adjusted life years (DALYs) between 1990 and 2019. The Framingham Study highlights that hypertension is linked to approximately one-quarter of heart failure cases. This association is even stronger among older adults, in whom hypertension is responsible for up to 68% of heart failure cases. Methods: This study analyzed death certificates within the CDC WONDER database for patients in the United States from 1999 to 2020. We identified deaths among individuals aged 25 years and older caused by HHD and CHF using the International Classification of Diseases, Tenth Revision (ICD-10) code I11.0. Age-adjusted mortality rates (AAMRs) per 1,000,000 individuals and annual percent change (APC) were computed and categorized based on year, gender, race/ethnicity, and urbanization status. Results: Between 1999 and 2020, a total of 302,270 deaths were reported in patients due to HHD with CHF. Overall, AAMR increased from 37.3 to 134.9 per 1,000,000 population between 1999 and 2020, with a significant decrease from 1999 to 2004 (APC: -7.91; 95% CI: -20.16 to -1.04), followed by a significant increase from 2004 to 2007 (APC: 42.47; 95% CI: 21.27 to 55.62), a slight decrease from 2007 to 2014 (APC: -0.9; 95% CI: -9.38 to 2.39), and finally a steep increase from 2014 to 2020 (APC: 14.22; 95% CI: 10.87 to 20.84). Gender-based analysis revealed that men had slightly higher AAMRs than women (Men: 63.1; 95% CI: 62.8 to 63.5 vs. Women: 60.7; 95% CI: 60.5 to 61). Moreover, AAMRs were highest among non-Hispanic African Americans (109.6; 95% CI: 108.6 to 110.6), followed by non-Hispanic American Indian or Alaska Natives (66.6; 95% CI: 63.1 to 70.1), non-Hispanic Whites (58.5; 95% CI: 58.2 to 58.7), Hispanics (53.7; 95% CI: 52.9 to 54.5), and non-Hispanic Asian or Pacific Islanders (39; 95% CI: 38–39.9). In addition, non-metropolitan areas had higher AAMRs than metropolitan areas (non-metropolitan: 65.7; 95% CI: 65.2 to 66.3 vs. metropolitan: 62.1; 95% CI: 61.8 to 62.3) (Figure 1). Conclusions: Despite an initial decline, mortality from combined HHD and CHF has risen significantly since 1999. Notably, mortality was most pronounced among men, non-Hispanic African Americans, and individuals residing in non-metropolitan areas.

PURPOSE On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. METHODS We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). RESULTS At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. CONCLUSION Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.