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This guideline has been updated. This ASCO Living Guideline is reviewed on an eight-week cycle. Please see the online dynamic version for the latest updates. Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information ( Appendix 1 and Appendix 2 ). Updates are published regularly and can be found on the ASCO Publications website .

Introduction Lynch syndrome (LS) is a hereditary cancer syndrome that increases risk for colorectal and other cancers. We hypothesize that vaccines against tumor-associated antigens CEA, MUC1, and brachyury, simultaneously delivered in an adenovirus serotype-5 vector (Tri-Ad5) combined with the immune-enhancing IL-15 receptor superagonist nogapendekin-alfa-inbakicept (NAI) will reduce the incidence of colorectal neoplasms in LS carriers. Methods In this ongoing phase IIB double-blind placebo-controlled trial, two open-label safety phases (SPs) assessed safety of Tri-Ad5 alone (SP1, n=10) and with added NAI (SP2, n=10). A randomized controlled trial (RCT) follows the SPs. After baseline colonoscopy, vaccine dosing occurs at weeks 0, 4 and 8; Tri-Ad5 alone in SP1 and Tri-Ad5 plus NAI in SP2, with identical boosters at Week 52. The RCT phase participants (n=138) were randomized to receive Tri-Ad5 plus NAI or placebo. All participants complete colonoscopy at Weeks 52 and 104 for assessment of the primary endpoint: cumulative colorectal neoplasm incidence. Secondary endpoints include safety, tolerability, and immunogenicity. Results All 20 SP participants (median age 57.5 (range 42–75), 70% female, 15% minority) received all prime and booster series. SP1 participants reported 139 adverse events (AEs) and SP2 participants reported 178. AEs were predominantly grade 1; no treatment-related serious adverse events (SAEs) occurred. The most common treatment-related AEs were reactogenic events including grade 3 rash (without skin necrosis or breakdown) at NAI injection site (100% of SP2 participants). The RCT phase (n=138) recently completed accrual. Discussion In LS carriers without active cancer, the combination of Tri-Ad5 + NAI was well-tolerated; the RCT phase is ongoing. Clinical Trial Registration https://clinicaltrials.gov/study/ , identifier NCT05419011.

Abstract Rationale Lymphangioleiomyomatosis (LAM) is a rare, progressive, cystic lung disease affecting women. Sirolimus has been shown to stabilize lung function in women with LAM, but real-world data on long-term safety and efficacy are limited. Methods The NIH Multicenter Safety and Durability of Sirolimus for LAM (MIDAS, NCT02432560) observational registry was launched in 2015. All adult (≥18 years) women with LAM (treated or untreated) were eligible to enroll at any of the 20 U.S. sites and followed longitudinally with serial assessments of lung function, health-related quality of life, and treatment related adverse event (TRAEs). Baseline cohort characteristics and TRAEs are summarized using descriptive analyses. Marginal structural models (MSMs) with inverse probability of treatment weighting estimated the causal effect of sirolimus on annualized forced expiratory volume in one-second (FEV1) decline, adjusting for age at LAM diagnosis, prior treatment with sirolimus, menopausal status, race, presence of angiomyolipomas, supplemental oxygen use; time-varying covariates included diffusing capacity for carbon monoxide (DLCO) and serum vascular endothelial growth factor-D (VEGF-D) levels. Results Longitudinal data was available in 350 LAM patients, most of whom (246, 70.3%) had sporadic LAM. The median age at the baseline pulmonary function test (PFT) measurement was 46 years (range: 19 - 74) and the median (IQR) number of serial PFTs obtained per patient was 3 (1 - 5). The average follow-up duration per patient was 2.8 years. Over half of the patients (196, 56%) were treated with sirolimus during the MIDAS observation period for a median (IQR) treatment duration of 4.9 (2.4 - 7.5) years. MSM analysis demonstrated that sirolimus treatment was durably effective and reduced FEV₁ decline by 74.36 mL/year (95% CI: 15.87 - 132.85) compared with no treatment (-85.31 mL/year for the untreated group vs. -10.95 mL/year for the treated group, p = 0.01). Sirolimus was generally well tolerated; treatment interruption ≥3 months was observed in 38 (19.4%) of the 196 sirolimus treated patients. Logistic regression analysis showed that higher levels of FEV1 (odds ratio: OR = 3.12 [1.45 - 7.11], p = 0.005), VEGF-D (OR = 1.0007 [1.0004 - 1.001], p < 0.001), and DLCO (OR = 1.023 [1.0053 - 1.0413, p = 0.01]), were associated with treatment interruption. Conclusions In the MIDAS cohort, sirolimus treatment resulted in durable stabilization of lung function with a favorable safety profile over a 5-year period. These real-world data support sirolimus as a chronic suppressive therapy for LAM, demonstrating durable efficacy in slowing lung disease progression and tolerability with long-term use. This abstract is funded by: National Institutes of Health

Abstract Rationale Patients with interstitial lung disease related to systemic autoimmune rheumatic diseases (SARD-ILD) may develop progressive pulmonary fibrosis (PPF), characterized by irreversible loss of lung function and high mortality risk. The risk of PPF by SARD subtype is not well characterized in large, representative real-world data sources. We characterized patients with SARD-ILD and compared the risk of PPF by SARD subtype in a multicenter cohort derived from the national Patient-Centered Clinical Research Network (PCORnet). Methods Harmonized electronic health record (EHR) data was collected from seven PCORnet centers. Included patients had at least two ICD-9/ICD-10 codes for ILD between 2015-2021, an ILD diagnosis that persisted following chest CT and/or lung biopsy, at least one year of potential follow-up, and sufficient lung function data to assess PPF. The presence of SARD, subtypes of which were classified by ICD codes, was also required. PPF was defined by ≥ 5% absolute decline in FVC, lung transplantation or death. The incidence of PPF was compared across SARD subtypes using Kaplan Meier estimates and Cox proportional hazards models adjusted for age, sex, enrolling center and baseline FVC. Results The cohort included 6,288 patients with SARD-ILD, of whom 68.4% were female, with a mean (SD) age of 61.2 (13.9) years. The most common underlying SARD was rheumatoid arthritis (RA, 42.8%), followed by systemic sclerosis (SSc, 22.3%), mixed connective tissue disease (MCTD, 21.5%), Sjögren’s syndrome (16.9%), systemic lupus erythematosus (SLE, 14.5%) and polymyositis/dermatomyositis (PM/DM, 12.0%). Mean FVC and DLCO at baseline were 78.7 (22.9) % and 51.9 (21.3) % of predicted, respectively. Patients with PM/DM had the lowest mean FVC (70.4 [SD 21.3]) % of predicted) and DLCO (45.1 [SD 18.5] % of predicted). During the follow-up period, antifibrotic, corticosteroid, and non-steroidal immunosuppressive drugs were used by 7.6%, 89.3% and 77.5% of the overall cohort, respectively. The cumulative incidence of PPF, transplant or death at one year ranged from 20.6% to 29.0%, depending on SARD-ILD subtype, with higher risk among those with RA, SSc or MCTD as compared with PM/DM (figure). Conclusions In a large, harmonized EHR dataset, the risk of PPF at one year among patients with SARD-ILD was high. Variability of PPF risk by SARD-ILD subtype was similar to that observed in traditional cohort studies, with lower risk among patients with myositis despite poorer lung function at baseline. These findings establish the feasibility of PCORnet as a tool to understand PPF among patients with SARD-ILD. This abstract is funded by: Genentech

Abstract Honoring a patient’s wishes for end-of-life care can be challenging if the patient loses decision-making capacity and the identified alternate decision-maker will not respect the patient’s wishes. This article discusses how to proceed ethically and legally when the alternate decision-maker and care team disagree about respecting a patient’s end-of-life preferences.

Abstract M.D.-Ph.D. programs in the United States have traditionally followed a “2- n -2” curricular model, with the graduate phase occurring between the pre-clerkship and clerkship portions of medical training. While well established, this format can limit trainee autonomy in shaping their physician-scientist training trajectories. In response, some programs have introduced a “3- n -1” model, allowing students to complete clerkships before beginning Ph.D. training. Our institution implemented multiple flexible curricula in 2017. Understanding why trainees choose one pathway is important as programs consider implementing more adaptable training structures. To investigate these factors, we surveyed M.D.-Ph.D. students at our institution, which offers multiple flexible curricular alternatives, about contributions to their curricular decisions. Responses supported that trainees weigh considerations across medical education, scientific development, and integrated physician-scientist training domains. Although the traditional pathway was a popular option, most students pursued one of the flexible pathways. Our findings suggest that introducing flexibility in the timing of undergraduate medical education and graduate training can support diverse educational, logistical, and personal priorities while maintaining the rigor of physician-scientist training. Offering multiple pathways empowers trainees to design trajectories that best fit their needs. Continued longitudinal studies are needed to assess the long-term impacts of flexible curricula on physician-scientist career outcomes.

Background: Exogenous and endogenous polyamines are critical for gastrointestinal (GI) barrier integrity, of which putrescine, spermidine and spermine are most well studied. Our recent work shows n-acetylputrescine, a putrescine derivative, correlates with increased intestinal permeability and loss of microbial diversity. Despite this, bacterial mechanisms of n-acetylputrescine production or direct effects on barrier integrity are unknown. Aim: Determine the role of microbiota in shaping n-acetylputrescine abundance and the effect on barrier integrity. Methods: N-acetylputrescine effects on barrier were assessed both in vitro using Caco-2 and ex vivo in Ussing using colonic strips from conventional mice. Germ-free (GF) mice were monocolonized with wild-type E. coli (SK929) or E.coli SK930 (2-weeks, n=4mice/group), strains given by Dr. Shin Kurihara. E. coli SK930 is deficient in SpeC, SpeF and SpeB, genes generating putrescine, required for n-acetylputrescine production. Untargeted metabolomics (Metabolon) was performed on fecal pellets. Targeted isotope tracing with [13C6, 15N4]-arginine delivered via enema was done to track bacterial production of n-acetylputrescine by Fusobacterium varium, a known producer, in vivo with isotopolog labeling measured by LC/HRMS. Results: In vitro n-acetylputrescine (100mM) addition to Caco-2 monolayers caused significant barrier disruption compared to controls (%Baseline TER, 13.7±6.7 vs 102.8±9.4, 3h postexposure, n=3 p=0.0002), not seen at lower (10mM) concentration. N-acetylputrescine caused increased flux of 300Da fluorescein (12.6±2.0 vs 6.0±0.2 mg/mL, n=3 p=0.004) and 4kDa FITC-Dextran flux on Ussing compared to untreated controls (999±94 vs 562±121 ng/hr/cm2, n=3 p= 0.01). Mutant E. coli SK930 monocolonized mice had similar fecal n-acetylputrescine to GF animals. In contrast, wild type E. coli SK929 monocolonization led to significantly greater n-acetylputrescine (5-fold, FDR< 0.001) compared to SK930, indicating a bulk of n-acetylputrescine production is driven by bacterial mechanisms. Pathway enrichment analysis predicted decreased spermidine and spermine biosynthesis in SK930 monocolonization, indicative of impaired polyamine metabolism, compared to SK929 (FDR< 0.01). Targeted metabolomics on fecal pellets showed a shift in the production of isotopolog [13C1, 15N0]-N-acetylputrescine to increased isotopolog [13C4, 15N2]-N-acetylputrescine concentration after monocolonization with F. varium compared to GF mice (5.9±5.0 vs. 2.1±3.6 pg/mg stool, n=3mice/group p=0.05) suggesting microbiota driven shifts in n-acetylputrescine metabolism. Conclusion: Luminal n-acetylputrescine production and profile is driven by bacteria in the GI tract. Concentration dependent effects of n-acetylputrescine suggest insufficient regulation by intestinal microbiota can lead to accumulation of n-acetylputrescine and the intestinal barrier disruption seen in human studies. Ongoing studies aim to identify bacterial taxa critical for n-acetylputrescine suppression, the mechanisms involved, and impact on GI health. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Importance Chronic pain is a leading cause of disability, and many affected patients rely on long-term opioid therapy despite its unfavorable adverse effect profile. Spinal cord stimulation is an established therapy for chronic pain that may secondarily reduce opioid consumption by providing sustained analgesia. Objective To quantify changes in opioid use following spinal cord stimulation implantation for the treatment of chronic pain through a systematic review and meta-analysis. Data sources We conducted a comprehensive search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus from each database’s inception to July 1, 2024. Study selection We included studies describing patients who underwent spinal cord stimulator implantation for the treatment of chronic pain. A total of 2,784 potential studies were identified and screened by multiple independent reviewers, yielding a final total of 43 studies included in the systematic review. Data extraction and synthesis Data extraction was completed by multiple independent reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analysis and Meta-analysis Of Observational Studies in Epidemiology guidelines. A random effects model with Hartung-Knapp-Sidik-Jonkman adjustment was used to estimate pooled estimates. Certainty assessment was performed following the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Main outcome(s) and measure(s) The primary outcomes were change in continuous opioid use (ie, morphine milligram equivalent (MME)) and categorical opioid use (yes/no) from preimplantation to 12 months following spinal cord stimulator implantation. Results Meta-analysis of 12 month continuous MME use comprising 22 study comparisons (1,666 individuals) revealed a weighted mean difference of −18.06 MME (95% CI −24.41 to −11.70; 95% prediction interval −38.29 to 2.17; p<0.001). Meta-analysis of categorical opioid use at 12 months comprising 24 study comparisons (1,527 individuals) revealed an OR of 0.47 (95% CI 0.30 to 0.75; 95% prediction interval 0.10 to 2.11; p=0.003), signifying lower odds of opioid continuation. Conclusions and relevance Spinal cord stimulation is associated with reduced opioid dose consumption and increased odds of opioid cessation at 12 months postimplantation compared with baseline in patients with chronic pain; however, both of these conclusions are supported by evidence of very low GRADE certainty. PROSPERO registration number CRD42024574921.

This secondary analysis of a nonrandomized clinical trial identifies which participant characteristics were associated with selection of centralized or remote trial engagement.