Citations

501 Background: Targeted treatment options have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), but oncology healthcare professionals (HCPs) who provide care for fewer numbers of patients with CLL are challenged to remain current with continuously changing treatment paradigms. To assess ongoing educational needs, we analyzed the treatment choices made by HCPs in an online survey for select cases of poor-prognosis CLL and compared these with the choices of experts in CLL treatment for the same clinical scenarios. Methods: As part of a CME program, HCPs could access an online algorithm to enter specific characteristics of a CLL case scenario and receive treatment recommendations from 5 US-based CLL experts. Experts made recommendations in July 2024 for 146 possible case patients built into the algorithm. After entering their case characteristics, HCPs were asked to enter their planned treatment prior to viewing the expert recommendations. We compared expert and HCP treatment choices across various case scenarios that were entered into the algorithm, with a focus on previously untreated CLL with del(17p)/mutated TP53 or R/R CLL. Results: Between August 2024 and February 2025, 346 cases were entered into the algorithm by 174 HCPs. Among responding HCPs, 38% were based in the UK/EU, 24% in the US, and 10% in Asia; 62% treated ≤10 patients with CLL per month and 49% sought recommendations for a specific patient in their practice. Among 231 cases of previously untreated CLL entered, 91 (39%) sought recommendations for del(17p)/mutated TP53 disease. For cases with no major comorbidities and previously untreated CLL with del(17p)/mutated TP53 , all experts recommended acalabrutinib or zanubrutinib; in 19 cases submitted by HCPs practicing in locations where second-generation BTK inhibitors (BTKi) are approved for CLL (including the US, EU, and Japan), 58% planned 1 of these treatments for this case scenario, 17% planned ibrutinib-based therapy, and 11% planned venetoclax-based therapy. Among case scenarios requiring third-line therapy after progressing with 2 regimens including a covalent BTKi and venetoclax plus an anti-CD20 Ab (with progression <2 years after completing treatment), all experts would recommend a noncovalent BTKi (eg, pirtobrutinib), with 1 expert indicating they would also consider CAR T-cell therapy. For the same case scenario among 6 US-based HCPs, 1 planned pirtobrutinib and 3 planned CAR T-cell therapy. Overall, after reviewing expert recommendations, 61% of HCP respondents whose planned treatment differed from the experts indicated that they would change their approach, and 20% indicated barriers to implementing the recommendations. Conclusions: Our findings provide insight into potential educational needs among HCPs who manage patients with CLL, suggesting that targeted expert-led education could benefit these HCPs.

Abstract Capgras syndrome is a delusional misidentification syndrome characterized by the recurrent belief that someone, usually a family member, has been replaced by an impostor. Although described over a century ago, its aetiology, clinical features and neuroimaging characteristics remain poorly understood due to its rarity. This study aimed to clarify these aspects through the analysis of a large cohort and to explore its clinical implications and underlying mechanisms. We conducted a retrospective cohort study by reviewing medical records of patients diagnosed with Capgras syndrome at the Mayo Clinic (Rochester, MN) over a 28-year period (January 1995 to December 2022). Clinical, neuropathological and neuroimaging data were analysed. A total of 204 patients were included (median age at onset: 73 years; 44% female). Twelve patients underwent neuropathological examination, all of whom exhibited α-synuclein pathology, including one patient with a clinical diagnosis of Alzheimer’s disease (AD). Regarding clinical diagnoses, neurodegenerative diseases were the most common (69%, n = 140), with dementia with Lewy bodies (DLB) being predominant (58%, n = 118), followed by mixed aetiologies (‘two-hits’) (18%, n = 36) and AD (10%, n = 21). Psychotic disorders accounted for 9% (n = 18) of cases. No case was attributed to a single stroke, although 9% (n = 19) involved coexisting cerebrovascular disease in the context of AD or DLB. In DLB, the timing of Capgras syndrome onset varied: it occurred later than cognitive decline and core clinical features (e.g. visual hallucinations, fluctuating cognition, parkinsonism) in both DLB and mild cognitive impairment-onset prodromal DLB, but earlier in psychiatric-onset prodromal DLB. In both DLB and AD, Capgras syndrome typically targeted a single spouse, whereas in psychotic disorders, it often involved multiple, non-spousal targets. Depression or anxiety was present in 55% (n = 112). Capgras syndrome worsened in the evening or at night (87%, n = 45/52), suggesting a link to negative affective states. Among 82 patients with DLB and AD treated with cholinesterase inhibitors, 15% (n = 12) showed symptomatic improvement. Neuroimaging with MRI and 18F-fluorodeoxyglucose-PET revealed widespread bilateral cortical involvement and prominent right frontal dysfunction in DLB and AD. Capgras syndrome is associated with DLB and could serve as a potential early diagnostic clue. Recognizing its phenomenological features—the number and type of targeted individuals—can help differentiate between neurodegenerative and psychiatric aetiologies. In neurodegenerative diseases, Capgras syndrome may reflect a multifactorial, dynamic process, driven by widespread bilateral cortical dysfunction (particularly involving the right frontal lobe) and psychological factors. Thus, a combined approach involving pharmacological and non-pharmacological interventions may offer effective management strategies.

Background: Coronary artery disease (CAD) is common among liver transplantation (LT) candidates, yet whether pre-transplant percutaneous coronary intervention (PCI) improves post-LT outcomes remains uncertain. Methods: We conducted a single-center, Institutional Review Board-approved cohort study of adults undergoing LT from 2005 to 2025. Asymptomatic candidates with significant stenosis on invasive angiography were included; prior coronary artery bypass grafting was excluded. The primary endpoint was major adverse cardiovascular events (MACE: myocardial infarction [MI], stroke/transient ischemic attack, new systolic dysfunction, post-LT coronary revascularization, or all-cause death). Results: Among 111 patients (median age 65 years; 84% male), 66 (59%) underwent PCI and 45 (41%) were managed medically. Over a median 32 months of follow-up, 61 patients (55%) experienced MACE. Composite MACE did not differ between PCI and non-PCI groups (52% vs. 60%, p = 0.40; log-rank p = 0.59). Fine–Gray modeling showed no association of PCI with MACE; independent predictors were prior MI (HR 1.81, 95% CI 1.01–3.24) and pre-transplant dialysis (HR 2.13, 95% CI 1.07–4.24). Major bleeding occurred in 7%. Matched and era-stratified analyses were concordant. Conclusions: In asymptomatic LT candidates with angiographically severe CAD, pre-LT PCI was not associated with a lower incidence of post-LT MACE.

Background: Chronic nonspecific low back pain (CNLBP) is a prevalent, disabling condition worldwide. Tuina, a traditional Chinese manual therapy, has shown potential benefits, but evidence remains limited. Objective: This study evaluated the effectiveness and safety of Tuina therapy in managing CNLBP in a U.S. population. Methods: A prospective, single-blind, randomized controlled trial was conducted at Mayo Clinic Rochester campus (February 2020-April 2024). 204 participants with CNLBP were randomized into 3 groups: Tuina (N = 68), physical therapy (N = 68), or a combination of both (N = 68). Each group received 6 treatments over 2 months. The primary outcome was pain intensity (VAS); secondary outcomes included disability (ODI), quality of life (SF-36), and adverse events. Additionally, participants completed a satisfaction survey at the end of the trial. Research Electronic Data Capture (REDCap) was used for survey data collection. Data was assessed by analysis of variance (ANOVA) for the multiple repeated measurements, Kruskal-Wallis tests, while Chi-square tests, and Bonferroni correction in SAS software. Results: 185 subjects completed the study. Significant decreases in VAS, ODI, and SF-36 Overall Physical scores were found from baseline, to post treatment and follow-up in all groups ( P < .05), while there were no significant differences in VAS, ODI, or SF-36 outcomes between the Tuina group and the other 2 groups. There were 4 adverse events observed in the trial, 1 in the Physical therapy group and 3 in the Mixed group. Only 1 transient low back pain after Tuina therapy was observed in the Mixed group but did not require treatment. The high percentage of patients who received the Tuina program was extremely helpful (n = 94/126, 77.0%). The willingness to recommend was significantly higher for Tuina compared to physical therapy (Mixed group [N = 59/62, 95.2%], Tuina group [N = 57/64, 91.9%], and physical therapy group [N = 31/59, 59.6%] ( P < .05). Conclusion: Tuina therapy showed comparable benefits to physical therapy and combined treatment of both in improving pain, function, and quality of life in patients with CNLBP. With high patient satisfaction and a favorable safety profile, Tuina appears to be a safe and acceptable non-invasive treatment option. Further studies are needed to validate these findings in the future.

Abstract Background Children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency typically have height, weight, and body mass index (BMI) growth patterns that differ from the general population due to increased androgen and/or glucocorticoid exposures. With the recent surge in the development of new therapies, CAH-specific growth charts are needed to evaluate the effectiveness of these new treatments. Methods Retrospective data from patients aged 0 to 20 years with classic CAH, confirmed by hormonal testing and/or CYP21A2 genotyping, from 2 large clinical databases were analyzed. Specialized charts were developed using the lamda-mu-sigma semiparametric modeling method to generate CAH-specific percentile curves from 0 to 20 years. Nodal-point analyses were conducted to assess differences in incremental growth at 4, 8, 12, 16, and 20 years of age relative to Centers for Disease Control and Prevention (CDC) 2000 normative charts using 1-sided quantile tests and age of adiposity rebound estimated with curve derivative solutions. Results A total sample of 8692 visits from 515 patients was used. Growth (height-, weight-, BMI-for-age) channels of CAH patients were significantly different over the entire growing period and characterized by diminished pubertal spurt relative to the CDC reference. Onset of adiposity rebound based on BMI-for-age occurred earlier for CAH patients (females 3.3 years, males 3.9 years) compared to their normative counterparts (5-8 years). Conclusion Our study showed that at incremental time points throughout childhood, children with CAH collectively follow specific differences in growth trajectories as compared to unaffected children. These variations highlight the need for CAH-specific charts to assist in clinical management, appraisal of growth trajectories, and assessment of the impact of new therapies.

Abstract Objectives To implementation an automated multi-institutional pipeline that delivers breast-cancer risk integrated with polygenic risk scores, monogenic variants, family history, and clinical factors, emphasizing operational challenges and their solutions. Materials and Methods A five-stage process was executed at ten sites. Data streams from REDCap surveys, PRS and monogenic reports, and MeTree pedigrees were normalized and forwarded through a REDCap plug-in to the CanRisk API. Results Integrated risk was returned to &gt;10 000 women; 3.6% were ≥25 % lifetime risk and 0.9% carried pathogenic variants. Pipeline generated score aligns well with manual generated ones. Major barriers such as heterogeneous pedigree formats, missing data, edge-case handling, and evolving model versions were identified and resolved through mapping rules, imputations, and iterative testing. Discussion Cross-platform data harmonization and stakeholder alignment were decisive for success. Borderline-risk communication and model-version drift remain open issues. Conclusion Large-scale PRS-integrated breast-cancer risk reporting is feasible but requires robust interoperability standards and iterative governance.

ABSTRACT Background The Geriatric Emergency Department (ED) guidelines recommend screening older adults for delirium using evidence‐based screening tools, but these tools are often underutilized. We aimed to identify barriers and facilitators to implementing an electronic health record (EHR)‐based delirium screening tool as intended. Methods This mixed methods and focused ethnographic study combined a review of structured delirium screening data with observations of real‐time delirium screenings and semi‐structured in‐person interviews at an academic ED that previously implemented the Delirium Triage Screen (DTS) and Brief Confusion Assessment Method (bCAM) tool. Content analysis of field notes from observations and interview transcripts was guided by the Exploration, Preparation, Implementation, and Sustainment implementation framework. Results From a total of 40,818 ED visits, 6196 (15.2%) had incomplete screens (i.e., without fidelity). We observed 62 encounters, of which 25 (40.3%) screenings were implemented without fidelity due to (1) not asking the required screening questions, (2) assuming patient responses, or (3) not completing the screen due to uncertainty regarding a patient's baseline mentation. We conducted 32 interviews. Identified barriers included staff prioritization of other tasks (e.g., stroke code, cleaning patients), limited knowledge of the screen's importance and utility, and language discordance. Facilitators included care partners providing baseline mental status information and nurses prefacing the screening to increase patient engagement. Conclusion The fidelity of ED delirium screening is influenced by an interplay of environmental, patient, provider, and caregiver factors. Fidelity may be improved by focusing education on the importance of screening, training screeners on how to determine whether a patient's mentation is acutely changed, providing clear action steps when a patient screens positive, and addressing how to administer the delirium screen to patients who do not speak English fluently.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Background: Variable terminology is used in the literature to describe facial synkinesis and hypertonicity following incomplete recovery from facial paralysis and its associated medical and surgical treatments. Study Objectives: Establish a nomenclature consensus for this condition among a group of facial nerve experts. Design Type: Consensus study. Methods: Using modified Delphi methodology, an international, multidisciplinary group of facial nerve experts reviewed the terminology for the name of the clinical condition and treatments of interest. Online surveys and a virtual discussion were performed to establish consensus, defined a priori as agreement by 80% of the group. Results: Twenty-five facial nerve experts established consensus after three Delphi rounds. Consensus terminology for the condition is “facial synkinesis” with 84% agreement. Medical treatment is termed “chemodenervation” with 100% agreement. Surgical treatments including “selective facial neurectomy,” “selective facial neurotomy,” “selective facial myectomy,” and “selective facial myotomy,” were defined and reached agreement of 100%. Conclusions: This international group of facial nerve experts has recommended standardized nomenclature for the condition of facial synkinesis and its various treatments. While “facial synkinesis” reached consensus as the preferred term, some experts noted it may insufficiently describe the full clinical spectrum, which includes muscle hypertonicity, weakness, and spontaneous twitching.

Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in KRAS -mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.