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Introduction Alzheimer’s disease and related dementias (ADRD) are conditions with progressive cognitive decline. Still, people living with late-stage ADRD (PLWD) have been reported to exhibit transient recovery of communication or behavioural abilities that had seemingly been lost. These lucid episodes (LEs) are underinvestigated and poorly understood. This study aims to advance scientific understanding of the incidence, prevalence and predictors of LEs and assess from family caregivers if LEs are associated with changes they make in care planning or experiences with burden, distress or grief. Methods This study recruited 545 caregivers from five ADRD-related registries in the USA. Eligibility included caregivers over 18 years who currently provide care to someone with moderate to very severe ADRD and can complete online questionnaires. Using a longitudinal observational study design, consented caregivers will be assessed monthly for 1 year using online questionnaires that inquire about witnessing LEs. If witnessed, the context and content of the LE is reported. Changes in caregiver decision-making about care for the PLWD, and caregiver burden, distress and grief are assessed at baseline, 6 and 12 months. Analysis Analysis of baseline data will assess descriptive aspects of LEs that are currently unknown (eg, prevalence, content, antecedents, duration). Longitudinal analysis will examine the incidence of LEs, characteristics of PLWD and caregivers that are predictors of episodes, and the associations between LEs and caregiver outcomes (eg, burden, distress, grief). Ethics and dissemination This study is being conducted in accordance with all Federal Policies for the Protection of Human Subjects. The protocol has been approved by the Mayo Clinic Institutional Review Board (ID 22-006861). Findings will be presented at scientific conferences and disseminated through journal publications and outreach efforts with collaborating partners invested in brain health and caregiver support.

Abstract Background The CCDC26 germline variant rs55705857 is causal for development of IDH mutant (IDHmut) adult glioma. However, ~60% of IDHmut patients do not carry the rs55705857 risk allele. We aimed to identify variants associated with developing IDHmut glioma among patients that do not have the rs55705857 risk allele and to further understand development of IDHwt glioma. Methods We used three datasets that included 1216 IDHmut and 1442 IDHwt glioma patients and a case–case design to perform genome-wide association (GWAS) analyses comparing IDHmut versus IDHwt glioma. Analyses were performed overall and stratified by rs55705857 genotype and sex. Multivariable logistic regression and regression trees were used to develop models to predict IDH status using germline variants, age, and contrast enhancement on MRI. Results Three regions were identified comparing IDHmut versus IDHwt: rs55705857 (meta P-value [P] = 1.35 × 10−43), PHLDB1 (rs7125115, P = 3.46 × 10−17), and D2HGDH (rs71430382, P = 2.43 × 10−12). When analyzing only patients that do not have the rs55705857 risk allele, PHLDB1 (rs7125115, P = 1.73 × 10−13) and D2HGDH (rs71430382, P = 8.86 × 10−10) were identified. Among patients who have the rs55705857 risk allele, four variants between ROBO1 and ROBO2 (rs4680975, P = 4.65 × 10−7) increased the likelihood of having an IDHwt tumor. Tumor expression of ROBO1 was associated with rs4680975 genotype in IDHwt patients that have the rs55705857 risk allele (P = 0.034). Multivariable logistic analysis demonstrated that rs55705857, rs71430382 (D2HGDH), and age predicted IDH mutation status. Conclusions To understand the development of adult glioma, we demonstrate that D2HGDH and PHLDB1 should be prioritized for functional studies in IDHmut tumors. The ROBO1 region warrants further investigation in IDHwt tumors.

Background: High-grade gliomas (HGGs), particularly glioblastoma (GBM), are associated with exceptionally high mortality and inevitable recurrence. In considering novel treatment options for these devastating diseases, immunotherapies represent promising candidates. Immunotherapies have demonstrated efficacy for several advanced tumors outside the central nervous system, highlighting a potential role for these agents in treating HGGs. However, multiple challenges to immunotherapy efficacy have tempered therapeutic benefit in practice, including local and systemic immunosuppression, intratumoral heterogeneity, and various mechanisms of intrinsic and acquired resistance. In the past 30 years, diverse immunotherapeutic subclasses have been assessed for benefit against HGGs. Methods: We performed a PubMed search for randomized clinical trials performed within the last 30 years evaluating the following immunotherapy agents for high-grade gliomas: immune checkpoint inhibitors, vaccines, oncologic viruses, cytokines, and CAR T-cells. The present review offers a critical analysis of key pre-clinical and clinical trials that have shaped the immunotherapy landscape for high-grade gliomas over the past two decades. Results/Conclusions: Across the different immunotherapeutic methods and modalities explored thus far, a recurring theme emerges: while therapeutic strategies with a compelling conceptual basis are continually under development and even demonstrate a benefit in preclinical and early-phase trials, larger and later-phase trials consistently fail to produce concordantly significant outcomes. To date, no large-scale clinical trial has demonstrated a benefit of sufficient consequence to change practice. Continued critical appraisal of the strengths and pitfalls of prior investigative work, optimization of treatment development and delivery, and innovative approaches to combination therapy design will collectively be integral to future therapeutic advancement.

Abstract Meaningful benefit is a much‐debated concept in Alzheimer's disease (AD). Research to date has primarily focused on change thresholds that are anchored in clinicians’ or care partners’ impressions; however, these thresholds are not inherently meaningful to people living with AD (PLWAD) and may not take their perspectives into account. By overlaying the lived experience of AD through the eyes of individual PLWAD and their care partners with clinical outcomes, we offer an important framework in which to consider meaningful benefit in terms of symptoms, functioning, and outcomes. The PLWAD and care partner interviews and surveys of the What Matters Most (WMM) research program have identified treatment‐related needs, preferences, and priorities of people at risk of or living with AD and their care partners across the AD continuum. A WMM conceptual model of disease—created and refined through interviews with PLWAD and care partners across the AD severity spectrum—includes 50 concepts across six domains (social life/activities, thought processing, communication, daily activities, mood/emotion, and general independence) considered important to all PLWAD and care partners. From the PLWAD and care partner perspectives, an increase in time to the onset, development, or worsening of the symptoms in any of these meaningful concepts was considered a meaningful benefit. No single commonly used clinical outcome assessment captures all concepts of importance, nor the importance of time in AD; considering the lived experience and priorities of individuals affected by AD is crucial to put the “meaning” in “meaningful.”

Abstract Rationale: Prior studies report association between pulmonary artery (PA) dilation on computed tomography (CT) imaging and pulmonary hypertension (PH). These studies predate expansion of PH hemodynamic diagnostic criteria and do not report patient mortality. As such, little is known about the presence of vascular changes in mild PH or their association with survival. We sought to investigate these relationships in individuals without significant parenchymal lung disease. Methods: We obtained CT images for subjects with group 1 or 2 PH, disease comparators, and healthy controls enrolled in the Pulmonary Vascular Disease Phenomics (PVDOMICS) study. We used Osirix imaging software to measure the main, left, and right PA (MPA, LPA, and RPA) and MPA:aorta (PA:Ao) ratio by diameter and cross-sectional area at locations consistent with prior studies. We evaluated associations with mortality and mean PA pressure (mPAP) using multivariable Cox and linear regression models adjusting for age, sex, and BMI. Descriptive statistics are presented as mean ± SD. Results: We identified 558 subjects (59 controls, 138 comparators, and 361 PH [267 group 1, 94 group 2]). 79 subjects had mPAP < 21 mmHg, 39 had mPAP 21-24 mmHg, and 371 had mPAP ≥ 25 mmHg. Increased MPA, LPA, and RPA diameter and area, PA:Aodia, and PA:Aoarea were associated with decreased survival (all p < 0.001) after multivariable adjustment. First versus third quantiles of all measurements were associated with mortality, with adjusted hazard ratio of 2.99 [95% CI 1.77, 5.05] for MPA diameter (2.84 vs 3.82 cm), 3.74 [2.07, 6.74] for MPA area (7.26 vs 12.74 cm2) and 5.24 [2.58, 10.66] for LPA area (4.55 vs 7.03 cm2). All measures significantly increased alongside PH severity from mPAP < 20 to 21-24 to ≥ 25 mmHg (see figure 1 for MPA diameter). All measures positively correlated with mPAP, including MPA diameter (ρspearman = 0.55) and PA:Aodia (ρ = 0.56). After multivariable adjustment, Q1 to Q3 increments in MPA diameter and PA:Aodia were associated with mPAP increase of 12.5 [10.7, 14.4] and 13.9 [11.9, 15.8] mmHg, respectively. BMI showed no correlation with PA size (ρ = 0.076 for MPA area, -0.051 for PA:Aodia). Conclusions: PA size increases alongside PH severity using updated hemodynamic criteria and is associated with incremental increases in PA pressure and mortality. LPA dilation demonstrates particularly strong association with mortality. PA size does not correlate with BMI. These novel findings enhance our understanding of vascular changes across the PH disease spectrum.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more . PURPOSE To provide evidence-based recommendations for patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS An Expert Panel including patient representation completed a systematic review of the evidence and made recommendations. RESULTS Depending upon prior treatment received, androgen receptor pathway inhibitors (ARPIs: enzalutamide, abiraterone with prednisone), poly(ADP-ribose) polymerase inhibitors (PARPi), chemotherapeutic agents (docetaxel, cabazitaxel), radiopharmaceuticals (radium 223, 177 Lu-prostate-specific membrane antigen [PSMA]-617), and sipuleucel-T have demonstrated an overall survival (OS) benefit for patients with mCRPC. For patients with BRCA1 / 2 alterations who did not receive prior ARPI, the combination of PARPi and ARPI (talazoparib + enzalutamide, olaparib and/or niraparib + abiraterone) has shown clinical benefit. For patients with BRCA1 / 2 alterations who received prior ARPI or ARPI followed by docetaxel, olaparib showed OS benefit. In select patients with microsatellite instability-high/mismatch repair-deficient, pembrolizumab showed clinical efficacy. RECOMMENDATIONS Prior systemic therapy for castration-sensitive prostate cancer will determine subsequent therapy used for mCRPC. Continue androgen-deprivation therapy for patients with mCRPC indefinitely. Early adoption of somatic genetic testing and palliative care is recommended. Patients with mCRPC and bony metastases should receive a bone-protective agent. The panel recommends the combination of ARPI with PARPi in patients with BRCA1 / 2 alterations who did not receive prior ARPI. For patients who received prior ARPI, the panel recommends docetaxel chemotherapy. The panel recommends 177 Lu-PSMA-617 or cabazitaxel chemotherapy for patients who receive prior ARPI and docetaxel chemotherapy. For patients with BRCA1 / 2 alterations who received prior ARPI, the panel recommends PARPi monotherapy. Radium 223 is recommended for patients with symptomatic bone–only disease. Evidence for optimal sequencing for mCRPC regimens is lacking. Additional information is available at www.asco.org/genitourinary-cancer-guidelines .

OBJECTIVE The purpose of this study was to determine risk factors for distal junctional failure (DJF) following three-column osteotomy (3CO) for the correction of cervical deformity. METHODS A retrospective review was performed of patients who underwent a cervical or upper thoracic 3CO for cervical deformity correction by the senior author from 2008 to 2023. The main outcome of interest was DJF, defined as revision surgery with extension of the distal end of the fusion construct. Patients were excluded if the lowest instrumented vertebra (LIV) was the sacrum/pelvis, and if patients had prior autofusion throughout the distal part of the spine to the sacrum (e.g., ankylosing spondylitis). The minimum follow-up duration was 1 year. RESULTS One hundred fourteen patients were identified who underwent a cervical or upper thoracic 3CO for cervical deformity correction, 41 of whom met inclusion criteria for this study. The median patient age was 66 years, median BMI was 27, and 61% were male. Ten patients (24%) experienced DJF, requiring reoperation and distal extension of the construct to the pelvis in 9 cases and to L1 in 1 case. On univariable analysis, patients who experienced DJF compared with those who did not were more likely to be female (80% vs 35%, p = 0.007), had lower LIV Hounsfield units (HUs; 127 vs 167, p = 0.041), were less likely to have an LIV in a small autofused segment (10% vs 45%, p = 0.02), had an LIV that was closer to the first lordotic level (one level above vs three, p = 0.043), and had a longer length of fusion (17 vs 13 levels, p = 0.033). A stepwise multivariable regression model showed that having an LIV closer to the first lordotic vertebra was the only statistically significant predictor of DJF (OR 0.49, p = 0.013) and low LIV HUs did not reach statistical significance (OR 0.97, p = 0.09). CONCLUSIONS Patients with cervical deformity undergoing a 3CO are at higher risk for DJF with constructs terminating near the first lordotic vertebra. While LIV selection is complex and patient specific, choosing an LIV at least two levels above the first lordotic vertebra may help prevent DJF.

Background: Cognitive change is an important factor in understanding dementia. Estimating effects of exposures on cognitive change requires choosing an analytical timescale, typically time on study or current age. There is limited consensus regarding timescale choice in epidemiologic cognitive aging research. Methods: Using a coordinated analytic approach in 10 cohorts of older adults, we evaluated whether estimated effects of two exposures on memory change differed depending on timescale (time on study or current age). We modeled effects of apolipoprotein-E (APOE) ε4 genotype (a time-invariant exposure) and diabetes (a potentially time-varying/acquired exposure evaluated at baseline) using mixed-effects models with linear and nonlinear time specifications for both timescales. Results: Among APOE ε4 carriers, model-estimated memory scores at baseline (time on study timescale) or at each cohort’s median baseline age (current age timescale) were lower, and the average rate of decline was faster than among APOE ε4 noncarriers. Model-estimated memory scores at baseline or at median baseline age were generally similar across baseline diabetes status, with variability across cohorts in the diabetes-memory change association. In some cohorts, trends in diabetes-memory change associations differed in direction across timescales. Conclusions: Timescale was largely inconsequential for estimated effects of APOE genotype, but yielded differences in estimated diabetes effects, raising questions about the appropriate scale. The current age scale may be problematic because diabetes was measured heterogeneously in age across individuals, a common issue in aging cohorts. Our work demonstrates approaches to evaluate alternative timescales, including in multicohort analyses, and highlights potential implications for estimated exposure effects on cognitive change.