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e17027 Background: Guidelines recommend active surveillance for low-risk prostate cancer and definitive therapy for high-risk disease. We evaluated national patterns of risk-misaligned care and the survival consequences of undertreatment. Methods: National Cancer Database prostate cancer cases diagnosed from 2010–2022 were analyzed. Low-risk disease was defined as clinical T1–T2, Grade Group 1, and PSA < 10; overtreatment was definitive treatment vs active surveillance or no treatment. High-risk disease was defined as Grade Group ≥4, PSA ≥20, or clinical T3–T4; undertreatment was no definitive local therapy or incomplete definitive therapy. Multivariable logistic regression evaluated factors associated with misalignment. Overall survival (OS) among high-risk patients was assessed using multivariable Cox regression. Results: Among low-risk patients (N = 124,562), overtreatment occurred in 40% of cases. Overtreatment was more common among young men (adjusted odds ratio [aOR] 0.982; p < 0.001) and less common at academic centers (aOR 0.414; p = 0.015). Compared with White men, odds of overtreatment were lower among Black men (aOR 0.946; p = 0.002) and Asian men (aOR 0.827; p < 0.001), with additional variation by education and region (all p < 0.001). Among high-risk patients (N = 318,532), undertreatment affected 27.3% of patients and was more common among older men (aOR 1.061; p < 0.001). Compared with White men, undertreatment was higher among Black men (aOR 1.479; p < 0.001) and lower among Asian patients (aOR 0.863; p < 0.001) (overall race p < 0.001). Compared with private insurance, undertreatment was higher in Medicaid (aOR 2.038; p < 0.001) and uninsured patients (aOR 2.649; p < 0.001), and slightly lower with Medicare (aOR 0.931; p < 0.001) (overall insurance p < 0.001). Multiple comorbidities were associated with higher undertreatment (≥2 vs 0: aOR 1.252; p < 0.001). Facility type was not independently associated (p = 0.490), while region remained significant (overall p < 0.001). In the survival cohort (high risk) (N = 338,919), undertreatment was associated with substantially worse OS (HR 2.745, 95% CI 2.706–2.784; p < 0.001), adjusted for age (HR 1.056; p < 0.001), race (p = 0.001), insurance (p < 0.001), comorbidity (p < 0.001), income (overall p < 0.001), education (overall p < 0.001), and facility region (overall p < 0.001). Conclusions: Low-risk overtreatment remains common nationwide and varies across patient and health-system factors. In high-risk disease, undertreatment affects over one-quarter of patients and disproportionately impacts Black men and those with Medicaid or no insurance. Undertreatment confers a nearly threefold mortality hazard (adjusted HR 2.75; p < 0.001), highlighting a major national quality gap and the urgent need for system-level interventions to ensure equitable, guideline-concordant delivery of definitive therapy.

e13611 Background: Decentralized cancer care models may reduce treatment burden for patients with advanced prostate cancer (CaP), particularly those facing mobility, transportation, of scheduling challenges. However, prospective patient-reported experience and quality-of-life data comparing home- versus clinic-based oncology care remain limited. Mayo Clinic Cancer CARE Beyond Walls (CCBW) is a patient-centered program designed to deliver selected standard-of-care cancer therapies in the home with virtual clinical oversight. This observational study evaluated patient-reported experience, feasibility, safety, and quality of life among men with advanced or metastatic CaP receiving care at home. Methods: Men with advanced/metastatic CaP receiving active standard-of-care therapy including hormone-based treatments, oral anticancer therapies, anti-bone resorptive agents, or intravenous chemotherapy who were participating in a CCBW randomized trial were enrolled into a companion observational study. After confirmation of treatment tolerance in clinic, patients received home-based care for 24 weeks (Arm A) or in-clinic care for 8 weeks followed by home-based care for 16 weeks (Arm B). Patient-reported outcomes were collected at baseline and Weeks 8, 16, and 24, using CAHPS-based measures and CCBW-specific surveys assessing overall cancer care experience, patient preference for site of care, comfort with home infusions, functional/symptom assessment and quality of life. Descriptive analyses were performed. Results: Eighteen participants were analyzed (Arm A n = 10; Arm B n = 8). Participants were medically stable, and predominantly insured by Medicare. Survey completion was 100% at baseline and 83% at all follow-up time points. At Weeks 16 and 24 when all respondents had received home-based care, 100% and 92% reported being “quite a bit” or “very much” comfortable receiving treatment at home. Communication with at-home and remote nursing teams was rated highly, and most respondents reported transition, scheduling, and equipment use easy or very easy. At Weeks 16 and 24, 45% and 40% of respondents reported improved quality of life from receiving home-based care, with no reports of worsening. No emergency department visits, hospitalizations, or urgent care visits occurred in either arm. Conclusions: In this prospective, observational study, home-based oncology care delivered through CCBW was feasible, safe, and associated with high patient satisfaction among men with advanced CaP receiving diverse systemic therapies. These findings support further evaluation and expansion of decentralized care integrating home-based treatment with virtual clinical oversight.

9558 Background: Ipilimumab 3 mg/kg plus nivolumab 1 mg/kg (Ipi3+Nivo1) is the standard immunotherapy regimen for metastatic melanoma with brain metastases (MBM) but is associated with significant immune-related toxicity, particularly neurologic toxicity. Ipilimumab 1 mg/kg plus nivolumab 3 mg/kg (Ipi1+Nivo3) has demonstrated improved tolerability in extracranial melanoma, though comparative data in MBM are limited. We compared efficacy and toxicity of these dosing strategies in a multisite real-world cohort. Methods: We retrospectively identified patients with MBM treated with ipilimumab plus nivolumab across three Mayo Clinic sites between 2016 and 2024. Patients were classified by induction dosing as Ipi1+Nivo3 or Ipi3+Nivo1. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method and compared using log-rank tests. Best overall response (BOR) and toxicity outcomes were summarized descriptively. Results: Among 147 patients (Ipi1+Nivo3 n=32; Ipi3+Nivo1 n=115), 144 were evaluable for survival. Median age was higher in the Ipi1+Nivo3 group (69.5 vs 66.0 years); males predominated in both groups (71.9% vs 61.7%), and the cohort was predominantly White (>96%). Most patients had ECOG 0–1 in both groups (84.4% in Ipi1+ Nivo3 and 90.4% in Ipi3+Nivo1). BRAF mutation status was balanced between regimens, with approximately half of patients harboring BRAF-mutant disease (51.6% vs 53.2%). Median OS was 18.5 months (95% CI, 5.7–54.7) with Ipi1+Nivo3 versus 10.6 months (95% CI, 6.5–19.1) with Ipi3+Nivo1 (log-rank p=0.25). Two-year OS was 45.9% and 35.0%, and five-year OS was 24.5% and 19.2%, respectively. Median PFS was 7.3 months (95% CI, 1.8–10.9) versus 2.8 months (95% CI, 2.1–4.4) (log-rank p=0.16). BOR was available for 138 patients; objective response rates were 35.5% and 31.8%, respectively. 3–5 adverse events occurred in 24.1% of Ipi1+Nivo3 versus 30.5% of Ipi3+Nivo1 patients. Hospitalizations were less frequent (16.7% vs 36.1%), and neurologic adverse events occurred only with Ipi3+Nivo1 (11.9% vs 0%). Conclusions: In this multisite real-world MBM cohort, Ipi1+Nivo3 demonstrated comparable efficacy, numerically longer survival, and a more favorable toxicity profile compared with standard Ipi3+Nivo1. Notably, no neurologic toxicity was observed with the Ipi1+Nivo3 regimen. These findings support further prospective evaluation of lower dose ipilimumab strategies. Response and survival outcomes. Outcome Ipi1 + Nivo3 Ipi3 + Nivo1 Complete response (CR) 2 / 31 (6.5%) 8 / 107 (7.5%) Partial response (PR) 9 / 31 (29.0%) 26 / 107 (24.3%) Objective response rate (ORR = CR+PR) 11 / 31 (35.5%) 34 / 107 (31.8%) Disease control rate (DCR = CR+PR+SD) 18 / 31 (58.1%) 51 / 107 (47.7%) Median PFS, months (95% CI) 7.3 (1.8–10.9) 2.8 (2.1–4.4) 2-year PFS 27.6% 22.3% Median OS, months (95% CI) 18.5 (5.7–54.7) 10.6 (6.5–19.1) 2-year OS 45.9% 35.0% 5-year OS 24.5% 19.2%

Patients with advanced liver disease challenge anesthesiologists, especially those providing regional anesthesia for postoperative pain management. Coagulopathy, encephalopathy, sepsis and other comorbidities complicate care. Liver failure lowers albumin and α1-acid glycoprotein and slows hepatic clearance, increasing the unbound fraction and effective exposure to amide local anesthetics. Risks are magnified by acidosis, low cardiac output, low body mass index, sepsis, and concurrent renal dysfunction. Neuraxial options are often limited by coagulopathy and the risk of catastrophic neurologic complications while superficial, compressible peripheral blocks are generally considered safer than deep plexus targets. Safe practice includes the use of ultrasound guidance, incremental injection with frequent aspirations, avoidance of unnecessary high-dose multiple-site injections, and conservative dosing and infusion strategies. Regional anesthesia is feasible in patients with hepatic failure when dose and technique are adjusted to disease biology and when local anesthetic systemic toxicity (LAST) preparedness is routine. Catheters should run at lower concentrations and rates with scheduled reassessment and clearly communicated stop times. Teams should keep 20% lipid emulsion immediately available for treatment of neurologic or cardiovascular signs of LAST. We provide a practical pathway to select the block, choose the agent, and set doses that keep a reasonable safety margin for local anesthetics.

Introduction: Although the role of cardiometabolic risk factors (CMRF) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed to evaluate the impact of CMRF on mortality. Methods: Multinational prospective cohort study (2015–2024) including hospitalized patients with severe AH across 32 centers in 14 countries. Diagnosis of AH was made using the NIAAA criteria. Analyses included adjusted competing-risk models by age, sex, ethnicity, history of cirrhosis, CMRF, corticosteroid use, MELD, and ACLF grade, with liver transplantation as a competing risk. Results: 936 participants were included; mean age 48±11.2 years, and 88.9% were male. At least one CMRF was present in 46.6%; median body mass index (BMI) was 24.2 kg/m 2 [IQR: 22.8–28.2], prevalence of diabetes 17.6%, hypertension 16.5%, and dyslipidemia 5.8%. Median MELD was 24.4 [19.3–31.4], 86.7% had severe AH, and 180-day survival was 72.9%. Survival did not differ by CMRF status (log-rank p =0.453). In adjusted competing-risk models, higher age (sHR 1.02; 95%CI:1.01–1.04), greater alcohol intake (per g/day; sHR 1.001; 95%CI:1.000–1.002), MELD (sHR 1.04; 95%CI:1.01–1.06), and ACLF grade 2–3 (sHR 2.34 and 4.34) predicted mortality. However, no individual CMRF independently increased mortality. A prespecified non-linear BMI analysis showed modestly lower mortality between 25–40 kg/m², with a higher risk above 40 kg/m². Conclusion: Among patients with severe AH, metabolic dysfunction was not associated with increased mortality. Although a higher BMI was associated with slightly lower mortality in AH, this may reflect better nutritional status rather than a true protective effect.

ABSTRACT Background Metabolic dysfunction‐associated steatotic liver disease (MASLD) exhibits marked heterogeneity in fibrosis progression and liver‐related outcomes. Liver biopsy is not feasible for longitudinal risk stratification at scale, creating a need for validated non‐invasive biomarkers, particularly imaging biomarkers, that can predict clinically meaningful disease progression and liver‐related outcomes. Aims To describe the design and rationale of the GOLDMINE study, established to determine whether non‐invasive imaging biomarkers predict MASLD progression and liver‐related clinical outcomes. Methods GOLDMINE is an investigator‐initiated, multi‐centre, international longitudinal cohort enrolling up to 1000 adults with either biopsy‐proven MASLD or MASLD cirrhosis across the full fibrosis spectrum. Participants are recruited from 15 sites in the US and 4 international sites (Japan, Singapore and France). At baseline, participants undergo clinical phenotyping, vibration‐controlled transient elastography, and advanced magnetic resonance imaging (MRI), including proton‐density‐fat‐fraction and magnetic resonance elastography (MRE). MRI (and biospecimen banking) is repeated at 2‐year intervals (years 2 and 4), with annual follow‐up visits for up to 10 years. Baseline liver histology is centrally processed, digitized and reviewed by a single expert hepatopathologist; all MRI/MREs are centrally interpreted. Results The prespecified clinical outcomes include progression to cirrhosis, clinically significant portal hypertension, major adverse liver‐related outcomes (ascites, hepatic encephalopathy, portal hypertensive bleeding, liver transplantation/qualification), hepatocellular carcinoma, major adverse cardiovascular events, and all‐cause mortality, with independent central adjudication of all events. Conclusions GOLDMINE establishes a rigorously phenotyped MASLD cohort integrating centralized histology, advanced MRI‐based biomarkers, longitudinal biobanking, and adjudicated outcomes, providing a platform to validate imaging and blood‐based prognostic biomarkers in MASLD.

Abstract Background The first international clinical standards of care for the gender-diverse population were formulated in the late 1970s. In the last 15 years, multiple subspecialty societies within the United States have developed clinical care guidelines for those with gender dysphoria, including gender-affirming hormone therapy (GAHT) and surgical treatments. To date, there are no pathology- and laboratory medicine–specific recommendations in the United States for the gender-diverse population. Content This document outlines pathology- and laboratory medicine–specific recommendations for providing optimal care to the gender-diverse population, with a predominant focus on the adult population. The scope of this document focuses on the following 5 topics: (a) reference intervals and interpretation of laboratory tests impacted by use of GAHT (testosterone for transgender men; estradiol with or without antiandrogens for transgender women), focusing on those stably on GAHT for 6 months or longer; (b) transfusion medicine considerations for the gender-diverse patient population, (c) consideration of gender diversity in autopsy and death investigation, (d) interpretation of histology from tissues that are impacted by GAHT and surgical procedures; and (e) pathology and laboratory medicine informatics challenges and opportunities. Summary A relatively small group of laboratory tests is significantly impacted by GAHT. The histology of some tissues shows changes attributable to GAHT or to nonhormonal medical procedures. Autopsy and transfusion medicine practices for the gender-diverse population currently lack standardization, although this is evolving. The landscape of pathology informatics related to gender diversity is complicated by varying electronic health record and laboratory informatics systems functionality.

OBJECTIVE Essential tremor (ET) is common and disabling in older adults. Many patients aged ≥ 80 years are ineligible for deep brain stimulation due to medical comorbidities. Data on noninvasive alternatives, such as MR-guided high-intensity focused ultrasound (MRgHIFU), remain limited in this population. The aim of this study was to evaluate the safety and efficacy of unilateral MRgHIFU thalamotomy targeting the ventral intermediate nucleus (VIM) for the treatment of ET in patients ≥ 80 years of age. METHODS This retrospective multicenter cohort study included consecutive patients aged ≥ 80 years with medically refractory ET treated with unilateral MRgHIFU VIM thalamotomy between 2016 and 2023 at five academic neurosurgical centers. All patients met skull density ratio criteria and underwent standardized targeting. Clinical assessments were conducted at baseline, immediately posttreatment, and at the 3-month follow-up. The primary outcome was change in tremor severity assessed by using the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS). Secondary outcomes included the Clinical Rating Scale for Tremor (CRST) score, Dynamic Gait Index score, patient-reported tremor relief, and adverse events. RESULTS One hundred twenty-nine patients (76 male, mean age 84 years) were included. At 3 months, the mean TETRAS score improved by 9.2 points (p < 0.001). CRST scores also showed significant improvement. The mean patient-reported tremor relief was 81%. Adverse events were mild and transient, with a 1.6% rate of nonsurgical adverse events. Subgroup analysis comparing patients 80–84 years versus those ≥ 85 years of age showed no significant differences in treatment response. Gait outcomes improved modestly but were not significant in the age ≥ 85 years group. CONCLUSIONS Unilateral MRgHIFU thalamotomy is a safe and effective noninvasive treatment for ET in patients ≥ 80 years of age. It results in significant improvements in tremor and disability, with a low complication rate. These findings support its consideration for older patients who are ineligible for invasive procedures and highlight the importance of age-specific metrics in neuromodulation outcomes research.

Abstract In this systematic review, we aimed to assess the sensitivity of serum immunofixation (SIFE), urine immunofixation (UIFE), and serum free light chain (sFLC) in detecting plasma cell dyscrasia associated with light chain (AL) amyloidosis. We searched the literature using PubMed, Embase, and CENTRAL databases since inception through March 2024. We included studies reporting the diagnostic accuracy of immunofixation and/or sFLC in patients with AL amyloidosis. We used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach to assess the certainty of the evidence and QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) to assess the risk of bias. After deduplication, 29 237 records were screened, and 44 studies (n = 18 071) were included. For the meta-analysis, 28 studies reported sensitivity for SIFE (n = 3390), 24 studies for UIFE (n = 2830), 19 studies for SIFE and UIFE (n = 2819), 21 studies for sFLC ratio (n = 3678), 6 studies for SIFE and sFLC ratio (n = 372), 3 studies for UIFE and sFLC ratio (n = 242), and 10 studies for all 3 tests (n = 1430). Pooled sensitivities were as follows: SIFE, 0.68 (95% confidence interval [CI], 0.62-0.73); UIFE, 0.77 (95% CI, 0.72-0.81); SIFE and UIFE, 0.89 (95% CI, 0.84-0.93); and sFLC ratio, 0.82 (95% CI, 0.78-0.86). When SIFE, UIFE, and sFLC ratio were combined, the sensitivity reached 0.99 (95% CI, 0.96-1.00). The high sensitivity of combining SIFE, UIFE, and sFLC ratio supports their use as a reliable initial testing strategy to raise suspicion for AL amyloidosis and guide decisions regarding future diagnostic modalities.