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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 We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

ABSTRACT The local treatment of bladder and prostate rhabdomyosarcoma is a multidisciplinary decision, incorporating elements of patient age, tumor size and location, nodal involvement, and access to local expertise and technology. The relative absence of long‐term bladder and bowel function outcome data complicates discussions, particularly given improved survival rates and development of new surgical and radiotherapy techniques. These INSTRuCT guidelines, a collaboration of the Children's Oncology Group, Soft Tissue Sarcoma Committee, European Pediatric Soft Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe, reflect international expert consensus and are intended to inform practice, generate discussion, and highlight areas of future inquiry.

Abstract Background Sensitive, accessible biomarkers of the pathologies underlying Alzheimer's disease and related dementias (ADRD) are critical for accurate diagnosis, deeper understanding of disease mechanisms, and development of new therapies with validated target engagement. The retina is connected to the brain via the optic nerve, which may facilitate the transmission and spread of amyloid beta (Aβ) and tau species. In postmortem studies, retinal Aβ deposits have been associated with neuritic Aβ‐plaque and neurofibrillary tangle burden, particularly in the entorhinal and temporal cortices. The goal of the current study was to evaluate associations between retinal perivascular amyloid and cognition, as well as to explore effect modification by hippocampal volumetry. Method Participants, aged ≥40 years, underwent retinal imaging, brain MRI, FDG‐PET, and a comprehensive neuropsychological assessment. Retinal amyloid imaging was conducted following curcumin ingestion and pupil dilation using a confocal scanning laser ophthalmoscope. Perivascular Aβ plaque counts were quantified in the superotemporal peripheral region following manual identification and tracking of retinal arteries and veins. Associations between retinal perivascular Aβ plaque counts with cognitive domains were evaluated using linear regression models adjusted for age, sex, and estimated premorbid functioning. Where significant associations were detected ( p ‐value<0.05), effect modification by hippocampal volumetry was examined with additional adjustment for intracranial volume. Result The sample included 26 participants (mean age 65±7 years, 50% female). Higher amyloid plaque counts in the perivascular secondary small and tertiary branches and in the periarteriolar tertiary branch were associated with poorer verbal and visual memory (Table 1). Significant interactions were observed between amyloid plaque count in the perivascular secondary small branch (β(95% Confidence Interval) = 0.397(0.037‐0.756), p = 0.033) and periarteriolar tertiary branch (β(95% Confidence Interval) = 0.756(0.165–1.346), p = 0.017) with hippocampal volumetry for visual memory. Conclusion Our pilot study provides preliminary evidence that perivascular Aβ accumulation in smaller vessels of the superotemporal retina may be a marker of memory impairment that may interact synergistically with hippocampal atrophy. Longitudinal studies consisting of multimodal ophthalmic assessments, brain imaging, ADRD biofluid markers, and cognitive testing will be necessary to capture the temporal sequence of retinal pathological changes and their associations with those in the brain.

Abstract Background The interplay between vascular dysfunction and brain amyloidosis in driving Alzheimer's disease (AD) pathogenesis and cognitive decline is increasingly recognized. The retina, sharing an embryonic origin with the brain, offers an accessible CNS organ for high‐resolution, noninvasive imaging of AD‐related vascular pathology. However, the exact nature of retinal vascular damage in AD—especially in early disease stages—and its relationship with cerebral amyloid angiopathy (CAA) and cognitive impairment remain understudied. Method We examined vascular abnormalities in retinas of MCI and AD via histopathology and in‐vivo imaging studies. Postmortem retinas from 53–62 individuals (CN: 22; MCI/AD: 31–40) underwent immunohistochemistry for pericyte integrity, vascular Aβ42/40, and endothelial TJ proteins, with dysregulated proteins quantified by mass spectrometry in 12 additional AD/CN cases. Retinal curcumin‐amyloid imaging by scanning‐laser ophthalmoscope in 28–34 live participants (CN[MOCA>26]: 8–15; MCI/AD[MOCA≤26]: 13–19) assessed peri‐arteriolar/venular amyloid plaques (APs). Perivascular AP burden was correlated with MRI measures (hippocampal volume, WMH lesions) and cognitive/neuropsychiatric parameters. Result Retinal pericyte loss, reflected by PDGFRβ deficiency and apoptosis, was evident in MCI and AD patients and correlated with vascular Aβ42/40 accumulation and CAA severity (r=0.68–0.84; p <0.01–0.0001). Retinal endothelial ZO‐1 and claudin‐5 levels were significantly reduced, correlating with arteriolar Aβ40 deposition, suggesting impaired retinal Aβ clearance. Retinal capillary claudin‐5 and arteriolar Aβ40 strongly associated with CAA (r=0.75–0.77, p <0.0001), while ZO‐1 moderately correlated with brain amyloidosis/tauopathy, CAA, and cognitive decline (r=0.43–0.57, p <0.01–0.001). Both histological and in‐vivo imaging studies revealed greater Aβ deposition in retinal arterioles, particularly in secondary and tertiary branches, compared to venules or capillaries ( p <0.01–0.0001). Retinal perivascular APs in secondary/tertiary branches imaged in living patients correlated with cognitive impairment (global CDR, MOCA), hippocampal atrophy, and WMH lesions (r=0.51–0.66, p <0.05–0.001). Perivascular APs in the secondary (β=0.397, p = 0.033) and tertiary (β=0.756, p = 0.017) arteriolar branches showed significant interactions with hippocampal volumetry for visual memory. Conclusion Retinal arteriolar Aβ accumulation, pericyte loss, and TJ dysfunction contribute to early AD vascular pathology. If validated in larger cohorts, these findings support retinal vascular biomarkers as tools for predicting cognitive decline, monitoring AD progression, and assessing CAA severity.

PURPOSE Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (<50 years, named early-onset CRC [eoCRC]) has been increasing. PATIENTS AND METHODS Individual patient data on 13,365 patients with metastatic CRC enrolled between 2000 and 2012 in 17 first-line randomized trials in the Aide et Recherche en Cancérologie Digestive database were pooled. The distribution of demographics, clinicopathologic features, biomarkers, and outcome data were summarized and compared by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group on clinical outcomes was evaluated by testing interaction effect between treatment and age variables. RESULTS Overall, 2,045 patients with eoCRC (median age, 42.5) and 11,320 patients with average-onset CRC (aoCRC; median age, 63.8) were included in this analysis. Within the eoCRC population, treatment with bevacizumab in addition to chemotherapy improved PFS (9.9 v 6.8 months; hazard ratio [HR], 0.66 [95% CI, 0.54 to 0.80]; P < .0001), which was similar to the findings in aoCRC population (9.4 v 7.3 months; HR, 0.73 [95% CI, 0.67 to 0.80]; P < .001; interaction P = .5415). However, epithelial growth factor receptor inhibitor (EGFRi) did not improve PFS in RAS wild-type (WT) patients with eoCRC who had left-sided primary tumors (8.3 v 8.9 months; HR, 1.20 [95% CI, 0.81 to 1.77]; P = .36), whereas EGFRi significantly improved PFS in the aoCRC population (9.9 v 8.5 months; HR, 0.74 [95% CI, 0.64 to 0.86]; P < .0001; interaction P = .083). CONCLUSION Treatment-naïve patients with metastatic eoCRC appear to derive similar benefit from bevacizumab as patients with aoCRC. However, patients with eoCRC with left-sided RAS/RAF WT tumors did not appear to derive benefit from first-line EGFRi.

AbstractINTRODUCTIONGiven the close interactions between the retina and the brain, retinal amyloid imaging may serve as a diagnostic and prognostic tool for Alzheimer's disease and related dementias. This retrospective study investigated multivariable associations between retinal perivascular amyloid and cognitive domains.METHODSIntegrated analysis of retinal perivascular amyloid imaging, neuropsychological assessment, and brain magnetic resonance imaging in adults with and without cognitive impairment (N = 26; mean age: 65 ± 7 years; 50% female). Correlations between perivascular amyloid plaque burden and cognitive domains were evaluated with linear regression and interactions with hippocampal volumetry were explored.RESULTSHigher perivascular and periarteriolar amyloid plaque count in the secondary small and tertiary branches were associated with poorer verbal and visual memory in this cohort (p = 0.005–0.009). Higher perivascular amyloid burden interacted with hippocampal atrophy to worsen visual memory (p = 0.033).DISCUSSIONRetinal perivascular amyloid may serve as a non‐invasive marker for cognitive impairment and may shed insight into pathological changes in the brain.Highlights In vivo retinal perivascular amyloid plaque counts are associated with poorer memory. Retinal perivascular amyloid interacted with hippocampal atrophy to worsen memory. Retinal amyloid imaging is a potential biomarker for neurodegenerative diseases.