Citations

Abstract INTRODUCTION Monoclonal anti‐amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD). METHODS In the DIAN‐TU‐001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [ 11 C]‐Pittsburgh compound‐B (PiB) positron emission tomography (PET), [ 18 F]‐fluoro‐2‐deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI). RESULTS Gantenerumab significantly reduced PiB‐PET uptake overall and in most regions and showed no changes in FDG‐PET or MRI measures. Drug effects were associated with baseline PiB‐PET uptake, and the largest effects occurred in medial regions. DISCUSSION Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB‐PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design. Highlights Gantenerumab unevenly decreased Aβ burden as measured by PiB‐PET across brain regions. The strongest decrease in PiB‐PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG‐PET metabolism or MRI volumetrics after 4 years.

Abstract The Centiloid scale is the standard for Amyloid (Aβ) PET quantification, widely used in research, clinical settings, and trial stratification. However, variability between tracers and scanners remains a challenge. This study introduces DeepSUVR, a deep learning method to correct Centiloid quantification, by penalising implausible longitudinal trajectories during training. The model was trained using data from 2,098 participants (6,762 Aβ PET scans) in AIBL/ADNI and validated using 15,806 Aβ PET scans from 10,543 participants across 10 external datasets. DeepSUVR increased correlation between tracers, and reduced variability in the Aβ-negatives. It showed the strongest association with cognition, highest AUC against visual reads and best longitudinal consistency between studies. DeepSUVR also increased the effect size for detecting lower Centiloid increase per year in the A4 study. DeepSUVR advances Aβ PET quantification, outperforming standard approaches, which is particularly important for consistent decision making and to detect subtle and early changes in clinical interventions.

Abstract This review explores the pivotal role of preanalytical variables in bringing liquid biopsy approaches into the clinic for brain tumors. Preanalytical variables encompass a range of critical issues, from blood sample collection and handling to the impact of tumor heterogeneity and patient-specific factors. These variables introduce challenges such as false positives, false negatives, and variability in the analysis of tumor signals, which can hinder the diagnostic and prognostic utility of liquid biopsies. Understanding the nuances of preanalytical variables is essential for the successful implementation of liquid biopsy in clinical settings. This paper delves into strategies aimed at mitigating the influence of preanalytical variables by emphasizing the importance of standardized sample collection protocols, optimized sample processing and storage, quality control measures, and the integration of multiple liquid biopsy modalities.

Background: Periarticular local infiltration analgesia has become an important mainstay of multimodal analgesia after elective total hip arthroplasty (THA). However, the role of novel motor-sparing fascial plane blocks—with or without periarticular local infiltration analgesia—has not been fully elucidated for patients undergoing THA. The authors conducted a network meta-analysis evaluating the relative analgesic effectiveness of motor-sparing fascial plane blocks (quadratus lumborum, erector spinae, and pericapsular nerve group blocks) and periarticular local infiltration analgesia for adult patients undergoing THA. Methods: Randomized trials examining single-injection quadratus lumborum, erector spinae, or pericapsular nerve group blocks, or periarticular local infiltration analgesia, for THA were sought. The primary outcome was area under the curve (AUC) rest pain scores during the period from 0 to 24 h. Secondary outcomes included rest pain scores at 0, 6, 12, and 24 h; postoperative function at 6, 12, and 24 h; analgesic consumption at 0 to 24 h; incidence of opioid-related side effects; and incidence of block-related complications. Network meta-analysis was performed using a frequentist approach. Results: A total of 44 trials (3,579 patients) evaluating the quadratus lumborum block, erector spinae block, pericapsular nerve group block, or periarticular local infiltration analgesia for THA were considered. Network meta-analysis was used to derive the probability of each intervention being the most effective as compared to the others (P score). For AUC 0 to 24 h rest pain, periarticular local infiltration analgesia was the most effective intervention, as demonstrated by a P score of 89%. For postoperative analgesic consumption, the quadratus lumborum block was the most effective intervention, with a P score of 88%. This was followed by the pericapsular nerve group block (74%), the erector spinae block (38%), and periarticular local infiltration analgesia (42%). Conclusions: Periarticular local infiltration analgesia alone provides the most consistent improvements in postoperative rest pain, analgesic consumption, and functional recovery after THA. The addition of a quadratus lumborum block or pericapsular nerve group block to periarticular local infiltration may further improve analgesic outcomes.

Objectives To compare electrical stimulation and speech perception in vestibular schwannoma (VS) patients across treatment modalities and standard cochlear implant (CI) patients. Study Design Retrospective review. Setting Tertiary academic center. Patients Sixty-seven CI ears consisting of 23 standard CI controls and 44 VS patients with ipsilateral CI. VS patients were separated by treatment modality: 24 microsurgical resection, 15 radiation therapy, and 5 observation. Eleven VS patients with CI did not receive auditory sensation from electrical stimulation. Interventions VS microsurgical resection, radiation therapy, and observation. Main Outcome Measures Threshold (T-levels), comfort (C-levels), consonant-nucleus-consonant (CNC) word score, and AzBio sentence recognition scores. Results Patients who underwent microsurgical resection required significantly higher (p < 0.001) T-levels and C-levels compared with the standard CI group. Stimulation levels in the VS radiation therapy and observation groups were higher but not significantly different compared with standard CI controls. Overall rate of CI nonstimulation across all VS patients was 25%: 38% for microsurgery and 13% for radiation. Average CNC score for microsurgery group was 18% compared with 44% for radiation, 55% for observation, and 68.5% for standard CI controls. CNC word and AzBio scores were significantly lower (p < 0.001) for the microsurgery group compared with standard CI group. Conclusions Resection may negatively affect auditory nerve function, leading to higher stimulation levels, increased risk of nonstimulation, and poorer postoperative CI speech outcomes compared with observation or radiosurgery. When medically appropriate, nonsurgical VS management may be used to allow for optimization of CI programming and postoperative hearing outcomes.

Background Given the low haemorrhagic risk of intracranial low-grade dural arteriovenous fistulas (dAVFs), the benefits of routine intervention remain controversial. This study compares patient outcomes treated with stereotactic radiosurgery (SRS) versus conservative management. Method Multicentre retrospective analysis of the Consortium for Dural Arteriovenous Fistula Outcomes Research and the International Radiosurgery Research Foundation data. Inclusion criteria were (1) intracranial low-grade dAVF diagnosed by catheter-based angiography, (2) no prior dAVF-related haemorrhage and (3) management with upfront SRS (intervention group) or conservative management (observation group). The primary outcome was symptomatic improvement. Secondary outcomes included dAVF obliteration, up-conversion, haemorrhage, improvement and favourable modified Rankin Scale (mRS) at follow-up. Results 304 patients with a mean age of 56 years (SD 13.5) and a follow-up of 46.7 months (SD 45.5) were included. 135 (44.4%) were managed conservatively and 169 (55.6%) had upfront SRS. Compared with the observation group, symptomatic and mRS Score improvement (≥1-point decrease in baseline score) was more likely in the intervention group (95.1% vs 58.5%; OR=13.75 (5.61–33.69) and 37.0% vs 24.0%; OR=1.85 (1.09–3.15), respectively). These findings remained significant after multiple imputation and propensity score matching. Remaining outcomes were similar between groups. The all-cause mortality rate was 5.4% (n=16), unrelated to the dAVF or treatment. Five (3.0%) SRS-related complications were reported and resolved during the follow-up period. Conclusions SRS was associated with increased symptomatic and mRS Score improvement for low-grade dAVFs compared with conservative management. SRS had a low complication risk and did not appear to alter dAVF obliteration or haemorrhage. Future prospective trials on SRS as a first-line intervention for symptomatic low-grade dAVFs should be considered.

1510 Background: The National Comprehensive Cancer Network (NCCN) Harmonized Guidelines for Sub-Saharan Africa (SSA) have emerged as leading cancer treatment guidelines in SSA. The NCCN-SSA guidelines, derived by adapting NCCN guidelines for the SSA context, offer standardized recommendations to guide cancer care and shape policy in SSA. This study examines the evidence cited in support of the NCCN-SSA guidelines, with a focus on population characteristics and generalizability to SSA. Methods: Two reviewers independently examined the NCCN-SSA guidelines for the eight most common cancers in SSA to identify all studies cited in support of treatment/management recommendations. Study selection discrepancies were resolved by discussion. Full-text articles were reviewed and data on age, sex, race, and recruitment geography were abstracted. Descriptive analyses were performed using R statistical software. Results: Overall, 4,589 citations were reviewed, and 2,938 (64.0%) studies with individual-level data were included, representing >10.4 million study participants. Of the 2,061 studies reporting geographic information (70%), 50 (2.4%) recruited in SSA; of these, 39 (83.0%) recruited from South Africa. Three studies (0.2%) recruited exclusively in SSA. Most studies (95.3%) recruited exclusively from high or upper-middle income countries. Only 29.2% of studies with race data included >10% Black study participants. Conclusions: Most studies cited in the NCCN-SSA guidelines were conducted in high-income countries outside SSA. A small minority of all study participants were Black. Our findings underscore potential limitations in the generalizability of the NCCN-SSA guidelines to SSA and highlight a pressing need to generate and incorporate context-specific data to guide care and inform policy. WHO region of recruitment, race, and country-level income of studies included in NCCN-SSA guidelines. Cancer type # (%) studies reporting geography # (%) studies by recruitment region*: Americas # (%) studies by recruitment region*: Europe # (%) studies by recruitment region*: Sub-Sah. Africa % participants, White % participants, Black % participants, Other race # (%) studies representing only HMIC (per World Bank) Overall 2061(70%) 1177 (57%) 921 (45%) 50 (2%) 79% 9% 11% 1964(95%) B-cell 325(57%) 173 (53%) 178 (55%) 5(2%) 82% 7% 10% 307(94%) Breast 206(44%) 123 (60%) 124 (60%) 12 (6%) 80% 9% 11% 179(87%) Cervical 163(90%) 100 (61 %) 44(27%) 3(2%) 64% 14% 22% 158(97%) Colorectal 584(82%) 278 (48%) 292 (50%) 11 (2%) 80% 10% 10% 571 (98%) Hepato-cellular 183(74%) 80(44%) 68(37%) 0(0%) 69% 9% 22% 169(92 %) Kaposi sarcoma 51(80%) 25 (49%) 19(37%) 5(10%) 38% 51% 10% 44(86%) Ovarian 115(56%) 76 (66%) 35 (30%) 0(0%) 83% 4% 13% 115(100%) Prostate 434(88 %) 322 (74 %) 161 (37%) 14 (3%) 79% 9% 12% 421(97%) HMIC = high and upper-middle income countries. *Percent of studies includes as the denominator only the number of studies with reported geographies.

1015 Background: T-DXd is an antibody-drug conjugate approved for advanced HER2+/low/ultra-low breast cancer and multiple other solid tumors. T-DXd carries a rare but serious risk of ILD (incidence 12-15%), requiring frequent imaging and symptom evaluation. For > grade (G) 2 ILD, guidelines recommend permanent drug discontinuation. For asymptomatic G1 ILD, drug is held with the option for rechallenge (RC) if imaging findings resolve. Limited data exist on outcomes of RC after ILD in diverse real-world patients (pts). Methods: In this multi-center retrospective study, we analyzed pts with T-DXd related ILD treated from 2017-2024. Pts with ILD were identified via chart/ICD code review. Adjudication of T-DXd related ILD was based on treating providers’ assessment and graded via CTCAE v5. We collected pt demographics, T-DXd and steroid dosing, imaging results, and outcomes after RC. Statistical analysis was performed using Wilcoxon rank sum and Fisher’s exact tests. Results: Four centers treated 712 pts with T-DXd, with a 9.1% rate of any grade ILD (n=65). One other center reported only RC data in 18 pts with ILD. In total, 47 pts were RC; 38 after G1 ILD (81%), 9 after G2. Median (med) time to initial ILD was 145 days (d) after 1st dose (interquartile range [IQR] 78-205). Demographics for pts RC are shown in the table. Among 50 pts with G1 ILD, including pts not RC, 28/50 (56%) received steroids for a med of 36d (IQR 27-79). Radiographic improvement was seen at a med of 24d (IQR 19-63) for pts treated with steroids vs 82d (IQR 48-94) without (p<0.01); and a med of 35d (IQR 22-82) for pts RC vs 81d (IQR 68-105) for pts not RC (p=0.01). Among pts with G1 ILD, 38/50 (76%) were RC at a med of 42d (IQR 36-57) from last dose; 23/38 (61%) were dose reduced. After RC, pts remained on T-DXd for a med of 215d (IQR 60-334); 10/38 (26%) developed recurrent ILD (7-G1, 2-G2, 1-G3) at a med of 211d (IQR 47-273) from RC. No statistically significant differences were seen between ILD onset, time to RC, or demographics for pts with recurrent ILD vs not. Of the 9 pts RC after G2 ILD, T-DXd was continued for a med of 129d (IQR 49-171); 2/9 (22%) developed recurrent ILD (1-G2, 1-G3). No G5 toxicity was seen with RC. Conclusions: In this multi-center study, high RC rates were seen after G1 ILD with long duration of clinical benefit. Pts treated with steroids had faster radiographic ILD improvement, highlighting the importance of early steroid use. Among pts RC after G1 ILD, recurrent ILD rates were low, with the majority G1 and no G5 events. Notably, 9 pts with G2 ILD were RC, with a similar rate of recurrent ILD; this must be interpreted cautiously. Our large cohort data further supports the safety of T-DXd RC in diverse real-world settings. RC Pt Characteristics (n=47) n (%) or Median (IQR) Cancer typeBreastGIGyn 43 (91)3 (6)1 (2) Age (yrs) 57 (52-68) Prior # therapy lines in the advanced/metastatic setting 3 (1-5) Renal impairment (CrCl < 60 mL/min) 8 (17)

Abstract Introduction AXS-12 (reboxetine) is a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator under development for narcolepsy. In the Phase 3 SYMPHONY trial, AXS-12 significantly reduced weekly cataplexy attacks from baseline to Week 5 versus placebo in patients with narcolepsy. Here we report the Phase 3 ENCORE trial, assessing long-term efficacy and safety of AXS-12 in participants who completed SYMPHONY. Methods ENCORE included a 24-week open-label extension (OLE) period, followed by a 3-week double-blind randomized-withdrawal (DBRW) period. During the OLE, participants received AXS-12 (5 mg once-daily for 1 week, twice-daily for 23 weeks). Following this, remaining participants were randomized 1:1 to continue twice-daily AXS-12 or switch to once-daily AXS-12 plus placebo for 1 week, then placebo twice-daily for 2 weeks. The primary endpoint was change in frequency of cataplexy attacks from randomization to DBRW Week 3. OLE efficacy outcomes included change in weekly frequency of cataplexy attacks, cataplexy response (≥50% reduction), and change in cataplexy-free days. Additional analyses are ongoing. Results ENCORE enrolled 68 participants; 42 completed the OLE and entered the DBRW (AXS-12, n=22; placebo, n=20). In SYMPHONY, baseline mean weekly frequency of cataplexy attacks was 31.5. At DBRW randomization, mean weekly frequency of cataplexy attacks was 4.2 (AXS-12) and 6.9 (placebo). Participants randomized to placebo experienced a mean increase of 10.29 weekly cataplexy attacks versus 1.32 for AXS-12, at end of DBRW (p=0.017). In the OLE, weekly frequency of cataplexy attacks decreased by 22.3 (71%) and 24.1 (77%) at 1 and 6 months, respectively. Cataplexy response was achieved by 72% and 82% at 1 and 6 months, respectively. Cataplexy-free days increased from 14.3% to 61% and 70% at 1 and 6 months, respectively. Common adverse events (AEs; ≥5%) during the OLE were nausea and tachycardia (both 5.9%); no new safety signals were detected. Discontinuations due to AEs occurred in 17.6% of participants in the OLE. Conclusion AXS-12 significantly reduced the frequency of cataplexy attacks during the DBRW. AXS-12 was well-tolerated and demonstrated maintenance of efficacy with long-term open-label use. These results align with SYMPHONY, supporting the positive therapeutic impact of AXS-12 for narcolepsy. Support (if any) Axsome Therapeutics, Inc.