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Abstract Background The tumor, node, metastasis (TNM) classification at pathological evaluation determines prognosis following cancer treatment. For rectal cancer patients undergoing neoadjuvant therapy, whether ypTNM likely confers different prognosis than pTNM. We compared survival outcomes of patients classified by ypTNM vs pTNM staging. Methods Patients with resected locoregional rectal cancer from the National Cancer Database who underwent upfront surgery (pTNM) and had ≥5 years follow-up (2010-2017) were compared with those receiving neoadjuvant therapy followed by surgery (ypTNM). To address treatment selection bias, analyses were stratified by receipt of guideline-concordant care. Overall survival (OS) was compared using Kaplan-Meier and multivariable Cox regression analyses. Results Of 50 436 patients (median age = 60; 61.4% male), 11 732 (23.3%) underwent upfront surgery and 38 704 (76.7%) received neoadjuvant therapy; 78.8% of the upfront surgery group received guideline-concordant care. In analyses stratified by guideline-concordant care, overall survival was similar for stage 0-I (hazard ratio [HR] = 1.05; 95% CI = 0.96 to 1.15) but significantly worse for ypTNM vs pTNM in stage II (HR = 1.50; 95% CI = 1.27 to 1.77; 5-year OS = 75.6% vs 83.2%) and stage III (HR = 1.60; 95% CI = 1.46 to 1.75; 5-year OS = 67.0% vs 78.2%). Multivariable analysis confirmed ypTNM was associated with worse survival at each stage (stage 0-I: HR = 1.14, P = .004; stage II: HR = 1.49, P < .001; stage III: HR = 1.60, P < .001). Conclusion Stage for stage, ypTNM classification is associated with worse survival than pTNM classification, with increasing difference at higher stages. Future staging systems and management guidelines should account for these differences to optimize prognostication and stratification for clinical trials and surveillance strategies.

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

e15557 Background: In metastatic colorectal cancer (mCRC), systemic chemotherapy can enable conversion surgery in a subset of patients with initially unresectable disease. Although R0 resection considered a key determinant of long-term survival, its clinical impact across heterogeneous trial populations and treatment strategies remains insufficiently defined. We aimed to clarify the survival benefit of R0 resection after first-line chemotherapy using large-scale individual patient data. Methods: Using the ARCAD database, which comprises 67 randomized clinical trials and approximately 47,000 patients, we conducted a pooled analysis of individual patient data from six first-line randomized clinical trials (COIN, COIN-B, 03-TTD-01, ATOM, SOFT and PARADIGM) for which data on R0 resection were available. Patients with initially unresectable mCRC and available surgical data were categorized into three groups: R0 resection, non-R0 resection, and no surgery. All R0 cases were included, comprising liver-only, lung-only, combined liver and lung metastases, and peritoneal dissemination or other metastatic sites. Overall survival (OS) and progression-free survival (PFS) were evaluated using multivariable Cox proportional hazards models adjusted for age, sex, and performance status. Pre-specified subgroup analyses examined the consistency of outcomes according to tumor response, metastatic site, primary tumor sidedness, RAS status, and targeted therapy class. Results: Among 4,445 eligible patients, 263 underwent R0 , 233 underwent non-R0 resection, and 3,949 received no surgical intervention. The R0 resection group comprised patients with liver-only metastases (n = 176), lung-only metastases (n = 23), and combined liver and lung metastases (n = 27). R0 resection was associated with significantly improved OS and PFS compared with both non-R0 resection and no surgery. These survival benefits were consistently observed across key clinical subgroups, including patients achieving complete or partial response to chemotherapy, those with liver or lung metastases, left- and right-sided primary tumors, and both RAS wild-type and mutant disease. Importantly, the benefit of R0 resection was maintained irrespective of anti-EGFR– or anti-VEGF–based first-line therapy. Conclusions: R0 resection following systemic chemotherapy is strongly associated with durable survival benefits in patients with initially unresectable mCRC across diverse clinical settings. These findings support the pivotal role of conversion strategies and highlight the importance of multidisciplinary evaluation to identify appropriate candidates for curative-intent resection.

3525 Background: Tumor microenvironment (TME) features of colorectal cancer (CRC) may influence detection of circulating tumor DNA (ctDNA) and further refine prognosis. We applied a deep learning histopathologic algorithm to quantify TME features in stage III colon cancers and evaluated their association with postoperative ctDNA status among participants in a phase III FOLFOX-based adjuvant trial (NCCTG N0147). Methods: QuantCRC (Aiforia Technologies) was applied to digitized hematoxylin and eosin-stained whole-slide images of stage III colon adenocarcinomas to extract quantitative histopathologic features. Among cases where data met quality control (N=1817), associations between 15 distinct pathologist-defined features and clinical outcomes—time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS)—were evaluated, stratified by postoperative ctDNA status assessed by a tissue-free assay (Guardant Reveal). Relationships were analyzed using univariate and multivariable Cox proportional hazards models that were adjusted for clinicopathologic and molecular features ( KRAS , BRAF V600E , MMR status). Interaction testing was performed. Results: We found statistically significant quantitative differences for histopathological features by ctDNA status. Features associated with ctDNA positivity(+) included lymphovascular invasion (LVI), and increased %high grade, %tumor budding, %necrosis, and %stroma. ctDNA+ cases had lower %inflammatory stroma and fewer %signet ring cells (all p< 0.006). Multivariable analyses, irrespective of ctDNA status, identified %tumor budding, %mucin, %signet ring cells, %inflammatory tumor bed, and %inflammatory stroma as significantly associated with adverse outcomes (TTR, DFS, OS). Within ctDNA+ cases, higher %immature tumor bed was associated with adverse outcome for all 3 variables. Among ctDNA-negative cases, significantly poorer outcomes (TTR, DFS, OS) were observed for tumors with lower tumor infiltrating lymphocyte (TIL) density and reduced %necrosis. After adjustment, significant interactions with ctDNA status were observed for LVI (p< 0.006) and %signet ring cells (p< 0.035) across all outcome variables, for %necrosis with DFS, OS (p<0.040), and for TILs with TTR (p<0.015). Analysis is ongoing for ctDNA tumor fraction as well as tumor genotyping data (739 genes; Guardant360). Conclusions: QuantCRC identifies TME features associated with postoperative ctDNA status that enable risk-stratification within ctDNA groups. Among ctDNA-negative patients, reduced intratumoral TIL density and reduced tumor necrosis identify high-risk subgroups with inferior clinical outcomes, and may have clinical utility.

12007 Background: YAs with cancer, defined as those diagnosed prior to the age of 40, may experience greater symptom burden compared to those diagnosed at older ages. We evaluated the impact of an ePROM-triggered, CC-based, supportive care intervention on symptom burden in YAs with cancer. Methods: The Enhanced, Electronic Health Record-facilitated Cancer Symptom Control (E2C2) trial was a cluster-randomized, pragmatic trial (NCT03892967) that enrolled oncology patients seen at Mayo Clinic Rochester and within the Mayo Clinic Health System (sites in Minnesota and Wisconsin) between March 2019 and January 2023. Patients routinely reported the severity of six SPPADE symptoms (Sleep deficit, Pain, Physical function impairment, Anxiety, Depression, and Energy deficit/fatigue) on 11-point numerical rating scales. Symptom severity was classified as none to mild (0-3), moderate (4-6), or severe (7-10). Those with moderate or severe symptoms were offered symptom management education, while those with severe symptoms were also offered the option to work virtually with a symptom care manager. In this post hoc analysis, we examined the effects of the intervention on change in symptom scores among YAs and time to improvement to a mild/moderate level in those with at least one severe symptom. Results: Among 40,659 patients who responded to at least one survey, 2,598 were YAs and 38,061 were adults ≥ 40 years. Among YAs, 10.7%, 24.3%, and 65.1% were 18-24 years, 25-31 years, and 32-39 years, respectively. A greater proportion of YA patients were female (61.5% vs 57.0%), of a non-white race (12.4% vs 5.3%), living in an urban setting (65.7% vs 55.1%), single (36.4% vs 9.6%), on non-government insurance (78.1% vs 36.6%), employed (72.6% vs 37.4%), and had a Bachelor’s degree or greater (37.8% vs 28.3%, p < 0.001 for all). Fewer YA patients had metastatic disease compared to older patients (24.2% vs 35.2%, p < 0.001). Compared to a pre-intervention baseline, the mean change in symptom score for YA patients following the intervention demonstrated improvements in anxiety (-0.195) and depression (-0.168, p < 0.0001 for both), while physical function impairment worsened over the intervention period (0.101, p = 0.014). Compared to adults ≥ 40 years, YAs experienced greater intervention effects for management of depression ( p < 0.001), fatigue ( p = 0.01), pain ( p < 0.0001), and physical function impairment ( p < 0.0001). Among YAs with a severe symptom during the intervention period, median time to improvement to a mild/moderate level was longer for anxiety compared to those ≥ 40 years (3.5 vs 2.7 months, p = 0.009). Conclusions: Routine ePROM surveillance, coupled with CC-based symptom management, led to improvements in anxiety and depression among YAs with cancer, although, time to improvement was longer for anxiety compared to adults ≥ 40 years.

Telehealth may improve access to specialized oncology care for Medicaid beneficiaries with hematological malignancies who face geographic and financial barriers. During the COVID-19 public health emergency, telehealth use expanded rapidly, yet state policies governing telehealth coverage/payment parity varied. Evidence is limited on how these policy differences influenced oncology telehealth use for Medicaid patients. We conducted a cross-sectional analysis of 2020–2021 multistate Medicaid claims. Adult and pediatric oncology specialists were identified based on board certification data. Telehealth video visits were measured monthly at the extensive margin, defined as the proportion of specialists providing any telehealth, and the intensive margin, defined as average monthly telehealth visits among telehealth providing specialists. States were categorized by private insurance telehealth policy environment: coverage and payment parity, coverage parity only, or no or unspecified parity. Telehealth use increased sharply across all states in early 2020, rising from less than 1% of specialists before the pandemic to peak levels by April 2020. Specialists practicing in coverage and payment parity states demonstrated higher and more sustained telehealth use through 2021 compared with those in coverage only or no parity states. By December 2021, 15.1% of adult specialists in coverage and payment parity states provided telehealth, compared with 8.1% in coverage-only states and 7.8% in no-parity states. Pediatric specialists showed similar patterns, though overall telehealth use remained lower. Specialists in parity states also maintained higher monthly telehealth visit volumes over time. State-level coverage and payment parity policies may have been associated with greater and sustained telehealth provision by oncology specialists treating Medicaid beneficiaries with hematologic malignancies. Maintaining supportive telehealth policies may be essential for promoting equitable access to specialized cancer care and reducing disparities among underserved populations. These findings inform future telehealth policy decisions nationally statewide.

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

Background The optimal management of biochemical recurrence (BCR) after radical prostatectomy (RP) remains controversial, particularly in the absence of clinical or radiographic evidence of disease. Salvage radiotherapy (SRT) remains standard of care, but it is unclear whether SRT benefits patients when modern imaging with a multiparametric magnetic resonance imaging (mpMRI) and prostate‐specific membrane antigen‐positron emission tomography/computed tomography (PSMA‐PET/CT) are negative for local recurrence. Retrospective data comparing SRT to observation for such patients is fraught with selection bias, underscoring the need for a prospective randomised controlled trial. Study Design and Methods The Biochemical Recurrence Irradiation or Observation (BRIO) is a randomised study under the DIVINE trial framework (NCT06378866) enrolling men with BCR (prostate‐specific antigen [PSA] level ≥0.2, up to 1.5 ng/mL) after RP with no radiographic evidence of recurrence on mpMRI and PSMA‐PET/CT. Major inclusion criteria include age ≥18 years, biochemically recurrent prostate cancer after RP with a PSA level between 0.2 and 1.5 ng/mL, and no local or metastatic recurrence on imaging. A total of 312 patients will be enrolled. Participants are randomised 1:1 to standard‐of‐care SRT followed by surveillance (Group A), or initial observation with subsequent image‐guided therapy at radiographic progression (Group B). Based on historical analysis, a total of 30 metastasis events provides 80% power to detect a significant improvement (hazard ratio 0.5 corresponding to a 5‐year metastasis‐free proportion of 80.7% in the control group and 89.8% in the experimental group with one‐sided type I error rate of 0.15). All participants undergo baseline blood collection to measure prostate cancer‐extracellular vesicles and cell‐free DNA for biomarker development. Participants are followed in a 16‐week cycle with serial PSA measurements, repeat imaging if PSA doubles, safety assessment, and patient‐reported outcomes. Endpoints The primary endpoint is distant recurrence‐free survival at 5‐years using a 12‐month landmark to mitigate bias arising from differing assessment schedules for patients receiving optional 6 months of androgen deprivation therapy. Key secondary outcomes include time to hormone therapy, quality of life measures, adverse effects, and novel blood and urine biomarkers. Conclusion The BRIO study will clarify the clinical benefit of immediate SRT vs observation with image‐guided intervention in mpMRI and PET‐negative BCR after RP.

Abstract Context Prior reports of plasma estradiol concentrations and their reference ranges in postmenopausal women identified marked variation, in part due to assay method and body mass index (BMI). Objective To develop an international reference range for plasma estradiol in postmenopausal women, support accurate assessment of concentrations during systemic and local (eg, vaginal) estradiol therapy, and improve risk prediction for diseases, including osteoporosis, breast, and endometrial cancers. Methodology Estradiol concentrations were measured using primarily liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays in 5 international cohorts of community-dwelling, postmenopausal women of primarily European ancestry aged 38-100 years who were not using exogenous estrogens (n = 7206). Measurements were harmonized to the Centers for Disease Control and Prevention (CDC) reference measurement procedure (RMP) by re-assaying a subset of samples for each cohort and generating recalibration equations. Reference intervals were determined for all women, non-obese women, and specific BMI categories. Results Estradiol concentrations from separate LC-MS/MS assays correlated closely with the CDC RMP, and harmonization minimized inter-assay variability. Estradiol concentrations correlated with BMI but not with chronological age. The reference range (2.5th-97.5th percentile) was 1.1-18.2 pg/mL (4.0-66.8 pmol/L) with median of 4.9 pg/mL (18.0 pmol/L) for all postmenopausal women and 1.1-12.5 pg/mL (4.0-45.9 pmol/L) with median of 4.1 pg/mL (15.1 pmol/L) for non-obese women (BMI &lt; 30). Reference ranges increased progressively with higher BMI categories. Conclusion Cross-calibration of estradiol measurements with the CDC RP enabled the development of harmonized plasma estradiol reference ranges for postmenopausal women who were not using exogenous estrogens, suitable for future studies to establish clinical utility. Increasing obesity in postmenopausal women was associated with increasing estradiol concentration and BMI category-specific reference ranges.