Citations

Background: Artificial intelligence (AI) stroke imaging software is becoming mainstay in many hub-and-spoke hospitals. Brainomix 360 Stroke software is the market leader in Europe focused on leveraging simple imaging (non-contrast computerized topography (NCCT) and CT angiography (CTA)) and has recently been FDA-cleared for use in the USA. We evaluated the implementation of Brainomix 360 AI Stroke software in the 17 spoke, multi-state Mayo Clinic Health System (MCHS) telestroke network. Methods: This prospective study compared decision and treatment times before and after Brainomix AI implementation, as well as clinician feedback and simulated decision making to better understand any changes seen. Patients were included if they underwent telestroke evaluation at an MCHS emergency department within 90 days of implementation (2/9/2024-8/8/2024), and excluded if they were already admitted to the hospital or if video evaluation was not performed. Data collection included demographics, clinical decisions and treatment times. Qualitative surveys were conducted at baseline and evaluation end, as well as simulated decision making in 20 de-identified cases randomized to with/without AI through an online portal. Results: A total of 907 patients were included (444 pre- and 463 post-implementation, 287 (32%) with ischemic stroke final diagnosis). Median NIHSS was 2. IVT was recommended in 20.3% (27/148 ischemic stroke patients) pre- and 25.9% (36/139) post-implementation. EVT was recommended in 16.2% (24/148) pre and 14.4% (20/139) post. AI use was associated with trends of faster telestroke activation to IVT decision (36 vs 32 mins, p=0.6), IVT administration (47 vs 40 minutes, p=0.6), and EVT decision (36 vs 33 minutes, p=0.5). In the simulation, imaging interpretation was significantly faster when randomized to AI use (3.4 vs 2.1 mins, p<0.001) and associated with improved physician confidence (62 vs 88%, p=0.004). Qualitative feedback from 14/24 neurologists showed the greatest perceived value was improved confidence of treatment decisions (43%) and faster triaging (36%). Most value was gained from e-ASPECTS (NCCT) and LVO modules. Conclusion: This service evaluation highlighted the opportunity to improve efficiency of decision making even in the setting of a well-developed telestroke system. The impact was underpinned by the improved speed and confidence of imaging interpretation reflected in an offline simulation and qualitative feedback.

Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson’s disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation. In addition, we observe that a pool of the Rab-specific, protein phosphatase family member 1H phosphatase, is transcriptionally up-regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signaling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioral studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived-neurotrophic factor transcription. This is not exacerbated in double-mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism toward PD. Our data suggest that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients, whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.

668 Background: After the approval of 177Lu DOTATATE, a new generation of radiopharmaceutical therapies (RPT) utilizing alpha-emitting radiometals is being developed as front-line therapies for advanced NETs with the hope of higher clinical efficacy. In this Phase I study, [ 212 Pb]VMT-α-NET, a novel targeted alpha radionuclide therapy (TAT) to SSTR2, is being evaluated in SSTR2-expressing NETs tumors in patients with no prior PRRT treatment. Here we present interim safety and the first efficacy results from dose escalation cohorts 1 and 2. Methods: In this first-in-human dose-escalation study, safety, PK, and efficacy of [ 212 Pb]VMT-α-NET were investigated in a population of well-differentiated adult NETs of any grade which progressed after prior standard of care therapy as assessed by RECIST v1.1 (NCT05636618). No patient may have received prior 177 Lu-DOTATATE or PRRT. The dose escalation design includes four cohorts, 3 mCi, 5 mCi, 7.5 mCi and 10 mCi based on a Bayesian modified toxicity probability interval (mTPI-2) design. Subjects in cohorts 1 and 2 underwent dosimetry evaluations using the therapeutic surrogate [ 203 Pb]VMT-a-NET. Therapeutic [ 212 Pb]VMT-a-NET was administered for 4 cycles Q8W in combination with reno-protective amino acids. The DLT assessment period is defined as the first 6 weeks of cycle 1. The primary objectives include the evaluation of safety and tolerability, the PK and RP2D of [ 212 Pb]VMT-a-NET as well as ORR as assessed by RECIST 1.1 criteria. Results: The current data cut occurred on September 19 th , 2024. A total of 9 patients were enrolled (2 in cohort 1 and 7 in cohort 2). Median exposure for cohort 1 was 2.5 mCi (2.5 mCi, 2.5 mCi) and for cohort 2 was 5.1 mCi (4.7 mCi, 5.2 mCi). No DLTs were observed. Two grade 3 AEs occurred in Cohort 2 (diarrhea, syncope). The most frequent related TEAE were alopecia, fatigue, anemia, lymphopenia and nausea (all grade 1 or 2). One subject in Cohort 2 was discontinued due to progressive disease. Landmark PFS at 9 months is 89%. ORR is not yet mature and will be shown at the time of the meeting. Safety Monitoring Committee (SMC) meeting was held on July 17 th , 2024, recommended dose escalation to cohort 3 at 7.5 mCi. No nephrotoxicity was reported in either cohort. Conclusions: [ 212 Pb]VMT-α-NET is safe up to 185 MBq (5 mCi) dose level, and the SMC supported dose escalate to cohort 3 at 277.5 MBq (7.5 mCi) following a mandated FDA review in fall. Cohort 2 remains open for dose level expansion. Early efficacy results demonstrate encouraging progression-free survival. Clinical trial information: NCT05636618 .

572 Background: Guidelines recommend systemic therapy for uHCC ineligible for locoregional therapy. Until the approval of tremelimumab + durvalumab for uHCC, in Oct 2022, 1L systemic therapies in the US included multikinase inhibitors and atezolizumab (A) + bevacizumab (B). It is crucial to understand factors driving real-world treatment decisions and outcomes in uHCC. Characteristics, treatment patterns, and outcomes were assessed in US pts with uHCC treated with 1L systemic therapy. Methods: Data were collected from electronic medical records from US Mayo Clinic sites. Pts with uHCC who initiated an NCCN-recommended 1L systemic therapy between Jun 2020–Oct 2022 (A + B was the only approved 1L immunotherapy (IO)-based regimen) with ≥2 follow-up visits, were included. Index was the date of first 1L systemic therapy. Pts were assessed by risk of post-index gastrointestinal (GI) bleeding (pts with Child-Pugh class B or C, pre-index GI bleeding, uncontrolled hypertension [HTN] [≥2 anti-HTN drugs or ≥2 vital entries of SBP >140 mmHg or DBP >90 mmHg]), or significant varices and band ligation). Treatment patterns, overall survival (OS), and post-index GI bleeding were assessed. Results: A total of 186 pts met the inclusion criteria. Most common etiologies of liver disease were metabolic dysfunction-associated steatohepatitis (42.7%) and hepatitis C virus (40.2%). Pre-index GI bleeding was reported in 29.0% of pts, of which 46.3% occurred within 6 months (mo) pre-index; 62.4% of pts had EGD, of which 72.4% had varices. There were 128 (68.8%) pts with GI bleeding risk and 58 (31.2%) pts without GI bleeding risk. The most common 1L systemic therapies for pts with GI bleeding risk were A + B (72.7%) and A only (9.4%), while for pts without GI bleeding risk, A + B (29.3%), nivolumab + ipilimumab (13.8%), and B + chemotherapy (13.8%) were the most common. Median OS and OS rates at 12, 18, and 24 mo were lower, and post-index GI bleeding rate was higher in pts with vs without GI bleeding risk (Table). For pts treated with A + B, median OS and OS rates at 12, 18, and 24 mo were lower in pts with vs without GI bleeding risk (Table). Conclusions: In this network, prior to the approval of other 1L IO-based regimens for uHCC, many pts received A + B, despite risk of post-index GI bleeding. Median OS with A + B was shorter in pts with vs without GI bleeding risk. Data highlight the complexity of uHCC and the unmet need for guidance on characteristics-driven treatment decisions. Full cohort A + B cohort All ptsN=186 GI bleeding risk N=128 No GI bleeding risk N=58 All pts N=110 GI bleeding risk N=93 No GI bleeding risk N=17 Median follow-up, mo 20.6 20.9 20.4 21.3 21.6 20.3 Median OS, mo 14.4 11.4 40.3 13.9 12.8 Not reached OS rates, % 12 mo 55.2 48.9 68.9 55.2 52.3 70.6 18 mo 45.3 38.1 61.1 44.1 41.6 57.8 24 mo 39.4 31.8 56.8 37.1 34.6 51.3 Post-index GI bleed, % 17.2 23.4 3.4 17.3 19.4 5.9

Abstract Electroconvulsive therapy (ECT) is an effective treatment for severe depression, especially in treatment-resistant cases. However, its potential cognitive side effects necessitate careful dosing to balance therapeutic benefits and cognitive stability. Recent advances in electric field (E-field) modeling offer promising avenues to optimize ECT dosing. This review synthesizes current knowledge on E-field modeling in ECT and explores its clinical applications. It examines the variability in E-field strengths and distributions induced by ECT and their impact on clinical outcomes. Additionally, the relationship between E-field strengths, neuroplasticity, and therapeutic efficacy is discussed. Translational studies of E-field-informed ECT are highlighted, emphasizing individualized optimal amplitude dosing and potential clinical applications. This review provides useful insights into how E-field modeling can improve the effectiveness of ECT while minimizing adverse effects, helping guide future research and clinical practice.

Abstract Background Vedolizumab (VDZ) is a gut selective, monoclonal anti-α4β7 integrin antibody approved for the treatment of moderate to severe ulcerative colitis (UC) or Crohn’s disease (CD). The subcutaneous (SC) formulation of VDZ was evaluated during the Phase 3 VISIBLE 1 and 2 studies. We report the long-term efficacy among patients (pts) with UC or CD treated with VDZ SC in the VISIBLE open-label extension (OLE) study. Methods Pts with UC or CD in VISIBLE 1/2 could enrol in VISIBLE OLE (NCT02620046). Pts in VISIBLE 1/2 who completed 52 weeks(W) of treatment with VDZ or placebo (randomised completers) and pts without clinical response at W6 who responded at W14 (non-randomised responders) received VDZ SC 108mg every 2W (Q2W) in the OLE. Pts with worsening disease were escalated to QW dosing. Clinical remission (partial Mayo score ≤2, no subscore &gt;1 in UC; HBI score ≤4 in CD) up to W168 was assessed (pts with missing data or escalated to QW dosing were imputed as non-response, irrespective of clinical status). The number of pts who regained clinical response when escalated to QW dosing was also assessed. Results were summarized by prior VISIBLE 1/2 treatment groups. Results Data from 231 pts with UC and 344 pts with CD were included. In pts with UC, baseline OLE clinical remission rates were 55.0%, 91.3% and 77.1% among randomised completers (N=124) previously treated with placebo, VDZ SC and VDZ IV in VISIBLE 1, respectively. At W168, 40.0%, 56.5% and 62.9%, respectively, were in clinical remission on Q2W dosing. In non-randomised responders with UC (N=107), 57.0% were in clinical remission at baseline and 29.9% at W168 (Figure). In pts with CD, baseline OLE clinical remission rates were 60.3% and 62.0% among randomised completers (N=226) previously treated with placebo and VDZ SC in VISIBLE 2. At W168, 32.4% and 37.3% were in clinical remission on Q2W dosing. In non-randomised responders with CD (N=118), 57.6% were in clinical remission at baseline and 27.1% at W168 (Figure). In pts with UC escalated to QW dosing, 22.2% and 38.1% achieved clinical remission and response at W8 after transitioning to QW. Among pts with CD escalated to QW dosing, 38.6% and 53.5% achieved clinical remission and response by W8 after transitioning to QW. Higher rates of remission and response were noted in VDZ completers than non-randomised responders. No new long-term safety signals were noted with VDZ SC vs IV, except for injection site reactions. Conclusion The clinical benefit of VDZ SC was maintained long-term during VISIBLE OLE. A subset of pts who escalated to QW dosing regained response. Findings support VDZ SC as a treatment option for patients with UC or CD who require long-term maintenance therapy.

Background: Historically, the standard of care for advanced biliary tract cancers (aBTCs) was gemcitabine plus cisplatin (GemCis). Immunotherapy plus GemCis is now recommended as a first-line treatment for aBTCs. Whether patients can tolerate eight cycles of GemCis in clinical practice, as per the Advanced Biliary Cancer (ABC)-02 study, remains to be assessed. We performed a retrospective observational cohort study to assess real-world treatment patterns and overall survival (OS) in patients with de novo or recurrent aBTCs treated with first-line gemcitabine-based chemotherapy in the United States. Methods: This retrospective observational cohort study used Optum’s de-identified Market Clarity Data (Market Clarity). Adults diagnosed with de novo or recurrent aBTCs in the United States who began first-line gemcitabine-based chemotherapy from January 2016–March 2022 were identified and followed from index until death, the end of continuous enrolment, or the end of study period. Treatment patterns and OS were assessed. Results: Overall, 559 patients were included (de novo, n = 462; recurrent, n = 97). GemCis was the most common first-line therapy received (de novo: 73.8%; recurrent: 57.7%). Most patients received approximately five cycles of GemCis; median (95% CI) time to discontinuation was 4.6 (4.3–5.1) months. Most patients died over the follow-up period (de novo: 70.3%; recurrent: 62.9%). Median OS (95% CI) was 14.2 (12.1–16.1) months (de novo) and 18.5 (15.6–26.9) months (recurrent). Conclusions: GemCis was the most common first-line therapy received during the study period; most patients were unable to receive eight cycles of GemCis. Survival was limited over the follow-up period, highlighting the need for new treatments for aBTCs. Future studies are warranted to understand the real-world impact of first-line immunotherapy plus GemCis for patients with aBTCs.

Abstract INTRODUCTION Greater white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) are seen with transactive response DNA‐binding protein 43 (TDP‐43) pathology in frontotemporal lobar degeneration (FTLD‐TDP). WMH associations with TDP‐43 pathology in Alzheimer's disease (AD‐TDP) remain unclear. METHODS A total of 157 participants from Mayo Clinic Rochester with autopsy‐confirmed AD, known TDP‐43 status, and antemortem fluid‐attenuated inversion recovery (FLAIR) MRI were included. Vascular risk factors were assessed. A semi‐automated WMH segmentation‐quantification process produced total and regional WMH volumes. Penalized linear regression models adjusting for age at MRI analyzed TDP‐43 associations (status and typing) with WMHs. RESULTS TDP‐43‐positive status was not associated with WMH burden overall because opposite effects were seen based on AD‐TDP typing. Despite similar antemortem vascular risk factors and postmortem vascular pathologies, AD‐TDP type‐ α showed greater total and regional WMH burden (particularly in subcortical frontotemporal and basal ganglia regions) than TDP‐43 negatives and AD‐TDP type‐ β . DISCUSSION AD‐TDP types may have different WMH pathomechanisms, with type‐ α having associations more like FTLD‐TDP than AD. Highlights In transactive response DNA‐binding protein 43 (TDP‐43) pathology in Alzheimer's disease (AD‐TDP), TDP‐43 status alone is not associated with total or regional WMH burden AD‐TDP type‐ α shows greater total, frontotemporal subcortical, and basal ganglia white matter hyperintensities (WMHs) AD‐TDP type‐ β shows less total and subcortical occipital WMHs AD‐TDP type‐ α effect on WMH burden closely mimics the effects of frontotemporal lobar degeneration with TDP‐43 (FTLD‐TDP) rather than AD Different relationships of AD‐TDP types with WMHs suggest different pathomechanisms