Citations

Background: Multicellular programs in the tumor microenvironment (TME) drive cancer pathogenesis and response to therapy but remain challenging to identify and profile clinically. Here, we present Spatial EcoTyper, a multimodal machine learning framework for large-scale profiling of spatially dependent cell states and multicellular ecosystems, termed spatial ecotypes (SEs). Methods and Findings: By integrating five million single-cell and spot-level spatial transcriptomes from 10 diverse human neoplasms, including carcinomas and melanomas, we identified a rich tapestry of conserved regional plasticity across nine TME cell types. We then applied Spatial EcoTyper to deeply dissect these data, revealing nine novel SEs with broad conservation - each with unique biology, TME cell states, geospatial features, and clinical outcome associations. SEs were linked to specific biogeographic domains, including the tumor core, margin, and adjacent stroma, and were remarkably well-validated in 235 held-out tumor samples profiled by either single-cell RNA sequencing, sequencing-based spatial transcriptomics (10x Visium), or high-resolution imaging-based spatial transcriptomics (Vizgen MERSCOPE and NanoString CosMx). By deconvolving SEs from over 1,200 bulk tumor RNA-seq profiles, we discovered striking associations between SE levels and response to immune checkpoint inhibitors (ICIs), outperforming nearly 40 potential correlates of ICI response, including previously described signatures of tertiary lymphoid structures and tumor tissue PD-L1 expression. Notably, baseline levels of a proinflammatory SE - localized to the tumor core and defined by a hub of unique T cell, macrophage, fibroblast, and endothelial cell states - strongly forecasted ICI benefit, while another SE - localized to the tumor margin and defined by myofibroblast and hypoxia-associated endothelial cell states - portended ICI resistance. Conclusion: Our data reveal fundamental units of TME organization and demonstrate a platform for large-scale profiling of spatial cellular ecosystems in any tissue, with implications for improved forecasting of immunotherapy response and the development of novel therapeutic strategies. Citation Format: Wubing Zhang,Erin L. Brown,Abul Usmani,Noah Earland,Hyun Soo Jeon,Irfan Alahi,Nicholas P. Semenkovich,Janella C. Schwab,Chloé B. Steen,Chloe M. Sachs,Bilge Gungoren,Faridi Qaium,Peter K. Harris,Jacqueline Mudd,Qingyuan Cai,Antonella Bacchiocchi,Ryan C. Fields,Mario Sznol,Ruth Halaban,David Y. Chen,Aadel A. Chaudhuri,Aaron M. Newman. High-resolution profiling of the tumor microenvironment with spatial ecotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 153.

ABSTRACTObjectiveWhile endoscopic laser wedge excision (LWE) for iSGS demonstrated lower surgical recurrence rates compared to endoscopic dilation (ED), ED remains the primary technique employed. Additionally, serial intralesional steroid injections (SILSIs) also demonstrate benefits in controlling disease. We aimed to compare surgical recurrence rates following ED, ED + SILSI, and LWE following a patient's first operation.MethodsThis was a two‐center retrospective analysis of iSGS patients who underwent either ED, ED + SILSI, or LWE. Patients were followed to their last follow‐up date or reoperation. Kaplan–Meier analysis and Cox proportional hazards were used to evaluate the recurrence times across the different surgical groups with additional stratification by age, compliance to medical adjuvant therapy, and percentage of stenosis rated at reoperation.ResultsA total of 126 patients from Institution 1 underwent LWE, while at Institution 2, ED and ED + SILSI were performed on 32 and 23 patients, respectively. One‐year recurrence estimates were 9%, 53%, and 0% for LWE, ED, and ED + SILSI, respectively, while 5‐year recurrence estimates were 45%, 90%, and 19%, respectively. Adjusted Cox‐proportional hazard ratios demonstrated a greater risk of surgical recurrence with ED compared to LWE (2.25; 95% confidence interval [CI]: 1.31–3.88) and no difference between ED + SILSI and LWE (0.84; 95% CI: 0.32–2.25).ConclusionLWE demonstrates reduced recurrence times compared to ED when controlling for surgery number, age, triple therapy compliance, and percentage of stenosis at reoperation. The application of postoperative SILSI appears to similarly reduce recurrence rates comparable to LWE and warrants further investigation.

Abstract Historically, cancers diagnosed via the emergency department (ED) portend a poor prognosis. Recent data from the United States are sparse, and analyses of cancers detected in the years following ED visits are lacking. Thus, we analyzed data from nine rural U.S. Midwest counties included within the population-based Rochester Epidemiology Project (2015–2021). Participants without a history of cancer (N = 42,074) who did not receive ED care were matched 1:1 to ED participants on the date of ED visit, age, sex, race, ethnicity, and county of residence. Analyses were restricted to participants with records ≤2 years prior to ED or index visit and ≥30 days after. HRs and 95% confidence intervals (CI) comparing cancer incidence and deaths among ED and non-ED participants were estimated from Cox proportional hazards regression models, either unadjusted or adjusted for covariates. Cumulative cancer incidence curves accounting for competing risks of death and survival (all cause and cancer-specific) were estimated. The median follow-up was 6.3 years, with 2,719 (6.46%) cancers diagnosed among ED participants and 3,139 (7.46%) among non-ED participants. ED participants experienced lower cancer risk overall (HRAdjusted = 0.70; 95% CI, 0.66–0.74; P = 8.89 × 10−31), specifically for breast cancer, prostate cancer, melanoma, and secondary cancers. Cancer-specific mortality was higher among ED participants (HRAdjusted = 1.76; 95% CI, 1.49–2.08; P = 3.62 × 10−11). Compared with non-ED participants, ED participants experienced a lower incidence of cancer but higher overall cancer-specific mortality, suggesting that subsets of ED patients may benefit from postvisit preventive interventions. Prevention Relevance: This cohort analysis shows that cancer incidence over 6 years was lower among participants after an ED visit than among matched non-ED participants, whereas cancer-specific mortality was higher in the ED group (HRAdjusted = 1.76; 95% CI, 1.49–2.08; P = 3.62 × 10−11), suggesting the potential benefit of preventive interventions.

Purpose of review Pain during cesarean delivery (PDCD) has been overlooked and underreported and is associated with a traumatic birth experience and long-term morbidity. We review the studies reporting on PDCD and summarize available guidance providing roadmaps for anesthesiologists caring for patients during cesarean delivery. Recent findings PDCD is a patient-reported outcome and should not be defined by interventions mitigating insufficient neuraxial anesthesia, such as supplemental analgesic medication or general anesthesia. Depending on the cohorts studied and definitions used, current reported rates of PDCD range between 2 and 36%. Preoperative patient counseling, risk stratification, and testing of neuraxial block are mitigating strategies; ultimately, if pain occurs, it should be managed skillfully applying shared decision-making with a supportive follow-up to reduce psychological trauma. Statements from three international organizations offer guidance to prevent and treat PDCD. Summary This review provides strategies to mitigate the occurrence of PDCD, with targeted approaches to better prevent and manage PDCD.

Abstract Emphysema’s significant morbidity and mortality underscore the need for reliable outcome metrics in clinical trials. However, commonly accepted chronic obstructive pulmonary disease outcome measures do not adequately capture emphysema severity or progression. Computed tomography (CT) metrics have been validated as accurate indicators of pathological emphysema and predictors of chronic obstructive pulmonary disease progression, exacerbations, and mortality. This position paper reviews the evidence supporting CT densitometry as a biomarker for emphysema, establishes implementation standards, and highlights areas for future research. A systematic literature review addressed three key questions: whether CT densitometry can be used as a diagnostic biomarker of emphysema, whether CT densitometry can be used as a prognostic biomarker, and whether longitudinal change in densitometry can be used as a disease progression monitoring biomarker. Emphysema metrics, such as the percentage of low attenuation areas below −950 Hounsfield units, are validated, highly reproducible diagnostic and prognostic biomarkers. Volume-adjusted lung density is recommended for disease monitoring. Both metrics demonstrate a scan–rescan intraclass correlation coefficient of 0.99 with proper technique. The paper also discusses relevant CT physics, techniques, and sources of variation, including technical factors, physiological changes, and software analysis. Key recommendations for clinical trials include using standardized CT techniques, proper subject selection, and longitudinal evaluation with volume-adjusted lung density.

Abstract INTRODUCTION Cognition is reduced at low and high glucose, reflecting cognitive vulnerability to glucose (CVG) fluctuations. The impact of glucose fluctuations on the aging brain remains unclear. We examined whether CVG is associated with plasma biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration. METHODS Participants included N = 114 adults with type 1 diabetes assessed for processing speed and sustained attention using ecological momentary assessment (EMA) combined with continuous glucose monitoring (CGM). We characterized associations between CVG and amyloid beta (Aβ) 42/40, phosphorylated tau (p‐tau) 181 and 217, neurofilament light chain, and glial fibrillary acidic protein. RESULTS CVG was associated with all plasma biomarkers, except Aβ 42/40. CVG for sustained attention exhibited strong associations with p‐tau biomarkers that persisted across covariate specifications. DISCUSSION CVG may be a useful digital phenotype of AD. It remains unclear whether CVG contributes to versus arises from neurodegeneration. We consider possible mechanisms linking cognitive vulnerability and long‐term glucose variability to the development of neuropathology. Highlights Cognitive vulnerability to glucose (CVG) may be a useful digital phenotype of neurodegeneration. We used cognitive ecological momentary assessment and continuous glucose monitoring to investigate CVG's associations with plasma biomarkers. Associations of CVG for sustained attention and phosphorylated tau 181 remained significant across covariates. We discuss possible mechanisms relating glucose variability, cognition, and neurodegeneration.

ImportanceAcute promyelocytic leukemia (APL) is an acute illness that presents with cytopenia, infections, and disseminated intravascular coagulation. Achieving remission has been shown to make a major difference in patient outcomes; however, early death rates in the first month have been as high as 30% due to acute presentation, comorbidities, the rarity of APL, and clinician inexperience.ObjectiveTo develop treatment strategies that would decrease estimated 1-month mortality from 30% to below 15%.Design, Setting, and ParticipantsIn this nonrandomized clinical trial, a treatment algorithm that focused on supportive care was used to prevent early death in patients with APL treated at academic and community health centers between August 2017 and July 2021. Because of the rarity of the disease, expert support was available 24/7 from 7 designated APL experts at 6 participating academic lead centers, and included an additional 293 community centers. When a patient presented with APL, an expert was contacted and a consensus treatment plan was developed using the algorithm and expert suggestions. There were no exclusion criteria and all patients with a confirmed diagnosis of APL regardless of age or comorbid conditions were enrolled. Expert support was provided throughout induction. Initial data analysis was conducted May 2023.Main Outcomes and MeasuresOne-month mortality; additional objectives were to compare outcomes in academic and community centers and assess 1-year and overall survival.ResultsA total of 201 patients were enrolled from 43 centers; 62 at lead centers and 139 from 37 community centers. The median age was 53 years (range, 18-91 years), with 72 patients (35.8%) who were aged 60 years or older; 105 patients (52.2%) were male. Fifty-two patients (26.4%) were diagnosed with high-risk APL. The 1-month mortality rate was 6 deaths of 201 patients (3.0%; 95% CI, 1.1%-6.4%) after adjusting for 1 interim analysis. In a secondary analysis using the Kaplan-Meier method, the 1-month overall survival (OS) rate was 97.0% (95% CI, 93.5%-98.6%) and the 1-year OS rate was 94.5% (95% CI, 90.3%-96.9%).Conclusions and RelevanceIn this nonrandomized clinical trial, use of an algorithm combined with expert support resulted in a dramatic decrease in early death in academic and community centers. Population-wide survival improved in this highly curable disease, which suggests that implementing an accessible support system with APL experts for comanagement is the most logical next step.Trial RegistrationClinicalTrials.gov Identifier: NCT03253848

OBJECTIVE Sepsis is associated with significant morbidity and mortality in pediatric hematology, oncology, and transplant (PHOT) patients. This study characterized PHOT patients who developed hospital-onset sepsis more than 12 hours after admission and identified risk factors for 30-day sepsis-attributable (SA) mortality. PATIENTS AND METHODS We analyzed an existing multicenter database of sepsis collected prospectively over 5 years (2017–2021) as part of the Improving Pediatric Sepsis Outcomes Collaborative. Sepsis was defined using operational elements documented in the health records based on International Classification of Diseases, Tenth Revision codes, treatment, diagnostic tests, and sepsis screen, huddle, or order set use. RESULTS A total of 9604 sepsis episodes in PHOT patients from 49 hospitals were analyzed: 70.5% were identified in the emergency department (ED), 10.9% in inpatient settings less than or equal to 12 hours from admission, and 18.6% were hospital onset. Only 52.5% of patients with hospital-onset sepsis were identified using a sepsis recognition method compared with 87.2% in the ED (P < .001). The overall 30-day SA mortality was 2.2%, with a higher rate (6.9%) among those with hospital-onset sepsis compared with those who developed sepsis at presentation or less than or equal to 12 hours (1.1%, P < .001). CONCLUSIONS Although the difference in SA mortality between hospitalized and nonhospitalized patients may be impacted by nonmeasurable confounders inherent to the type of patients presenting in the different care settings, we reported system-based improvements that may reduce mortality. The 30-day SA mortality was lower in hospitalized PHOT patients when sepsis was detected by early recognition methods, supporting the need for efforts to implement sepsis recognition tools in the inpatient setting.