Citations

Abstract Colorectal cancer develops through a normal-adenoma-carcinoma sequence, yet only 5-10% of adenomas progress to malignancy, and the cellular programs governing that sequence remain poorly defined. Here we generate a spatial multi-omics atlas of human colon adenomas, combining Visium CytAssist and protein co-detection across 24 nonadvanced and advanced tubular adenomas with single-cell resolution Xenium Prime 5K profiling of 101 patient-matched normal, adenoma, and carcinoma cores from 16 patients. Integrating whole-transcriptome and 31-plex protein data identifies nine spatial clusters and two dysplastic epithelial populations that co-express stemness, proliferation, and senescence programs. These programs occupy a shared, spatially confined epithelial niche that expands from adenoma to carcinoma. Spatial analysis revealed GDF15, a senescence-associated secretory factor, mediated the coupling between senescence and stemness in advanced adenomas, and that GDF15-high epithelium locally excludes CD8+ T cells in adenoma and, more broadly, in carcinoma. These findings position senescence as a spatially instructive rather than merely tumor-suppressive program during colorectal carcinogenesis and suggest GDF15 might be a potential candidate target for cancer prevention and interception in the colon.

Abstract Background Peritumoral brain edema (PTBE) is a frequent complication of CNS tumors and radiation therapy (RT). PTBE is primarily treated with corticosteroids, but prolonged use is associated with severe toxicities including myopathy and immunosuppression. Bevacizumab, an alternative treatment, is not recommended in patients with thromboembolic events and intracerebral hemorrhage. Plasma kallikrein is a key driver of tumor-related edema. By targeting this pathogenic enzyme, the orally delivered inhibitor, RZ402, may provide therapeutic value by controlling edema and decreasing corticosteroid use. Methods In this single-patient investigational new drug protocol, we report results from use of RZ402 for treatment of cerebral edema related to metastatic melanoma and RT. Results A 74-year-old man with BRAF-wildtype melanoma had a right frontal and basal ganglia hemorrhagic metastasis not amenable to resection, treated with stereotactic RT (30 Gy, 5 fractions), followed by ipilimumab and nivolumab. MRI obtained 5 months after RT showed increased edema associated with midline shift. After 12 weeks of treatment with high-dose dexamethasone (16 mg daily), edema remained persistent and patient was unable to tolerate dose reduction below 4 mg daily. Course was complicated by a pulmonary embolus prompting initiation of anticoagulation, leading to deferral of bevacizumab. Patient was treated with RZ402, which was tolerated well with no reported toxicities. Dexamethasone was discontinued over 4 weeks. Follow up imaging 6 weeks after RZ402 initiation and off dexamethasone demonstrated stability without rebound edema. Patient did experience adrenal insufficiency characterized by severe fatigue, managed with low-dose prednisone. RZ402 was discontinued after 8 weeks of treatment with patient remaining clinically stable. Conclusion Despite persistent edema after prolonged use of corticosteroids, the selective plasma kallikrein inhibitor RZ402 was associated with radiographic stabilization and discontinuation of dexamethasone for this patient. These findings support prospective evaluation of RZ402 in treatment of symptomatic cerebral edema related to CNS tumors.

Ascites development in cirrhosis reduces 5-year survival from 80% to 30%, yet substantial heterogeneity exists among patients with comparable ascites severity. This multicenter retrospective cohort study included adult liver transplant candidates with ascites at 4 United States centers (2015–2024). Latent class analysis was performed using 7 clinical variables: ascites grade, bilirubin, albumin, platelet count, estimated glomerular filtration rate, systolic blood pressure, and portal vein thrombosis. The derivation cohort (n=625) from the University of California San Francisco and Columbia University was randomly split 80/20 for model development and internal validation. External validation was performed at the University of Southern California (n=59) and Mayo Clinic (n=93). Primary outcomes were acute kidney injury (AKI) and waitlist mortality over 365 days. Three phenotypes emerged: “CKD-Metabolic” (30.4%, lowest eGFR 76.5 mL/min/1.73 m 2 ), “Vasodilatory-Synthetic Dysfunction” (38.9%, highest bilirubin 7.03 mg/dL, lowest blood pressure 117.5 mmHg), and “PVT-Intermediate” (30.7%, severe thrombocytopenia 68.1×10 3 /μL, 24.0% PVT). In validation cohorts (n=305), phenotypes demonstrated robust classification (mean posterior probability 0.823–0.855). Vasodilatory-Synthetic Dysfunction showed increased AKI risk versus CKD-Metabolic in derivation (MELD 3.0-adjusted HR 2.95, 95% CI 2.07–4.22, p <0.001) and validation cohorts (HR 3.39, 95% CI 1.93–5.94, p <0.001). Competing risk analysis revealed no mortality differences, but Vasodilatory-Synthetic Dysfunction was associated with higher transplantation rates (validation: HR 1.63, 95% CI 1.19–2.22, p =0.002). Three reproducible clinical phenotypes of ascites were identified with distinct risk profiles. The Vasodilatory-Synthetic Dysfunction phenotype was associated with a 3-fold increase in the risk of AKI that persisted after adjustment for MELD 3.0. No differences in waitlist mortality were observed, likely reflecting effective MELD-based transplant allocation that preferentially removes the highest-acuity patients from the waitlist.

Juvenile Parkinson's disease (JPD) is a rare condition characterized by the onset of parkinsonian motor symptoms before the age of 21. Sixteen patients with JPD who presented to the Mayo Clinic between 1990-2020 were included. The median age of symptoms onset was 18.5 years, and six cases had pathogenic PRKN mutations. Resting tremor was the most frequent initial symptom (81.3%), and non-motor symptoms were notably common, including mild cognitive impairment (56.3%), anxiety (62.5%), and depression (56.3%). Levodopa responsiveness was suboptimal in 9 patients and 14 exhibited motor fluctuations. JPD demonstrates distinct clinical characteristics compared with early-onset and late-onset PD.

Pediatric sarcomas are a heterogeneous group of rare mesodermal malignancies. These cancers, which affect children from infancy through adolescence and young adulthood, are in general challenging to treat with currently available therapies. Biologically, many are characterized by quiet genomes, fusion oncoproteins, immune “cold” microenvironments, and vast epigenetic deregulation that contributes to diverse and complex mechanistic drivers. Multifaceted advancements in research strategies, including high-throughput screening, new model systems, surfaceome profiling, and study of oncogenic fusion condensates have led to new opportunities for understanding the biology of pediatric sarcomas. To continue to make progress for these difficult to treat cancers, it will be critical to continue to improve access to bioinformatic data, approach patient care using innovative clinical trial frameworks, and foster interdisciplinary partnerships among medicinal chemists, scientists, clinicians, advocates, and industry partners.

Background With improvements in in vitro culture techniques, there has been a steady shift in practice to transfer in vitro fertilisation (IVF) embryos at the blastocyst-stage to increase pregnancy rates per embryo transfer (ET) and reduce the risk of multiple pregnancy. In patients with fewer embryos (≤5 zygotes), fresh cleavage-stage ET is still commonly performed to reduce the risk of cycle cancellation if no embryo survives to the blastocyst-stage in vitro. However, evidence for improved outcomes with cleavage-stage embryo transfer in this subgroup of patients is lacking. We will compare blastocyst-stage to cleavage-stage ET with regard to cumulative live birth rates (CLBR) per oocyte retrieval and other patient-centred cycle outcomes in patients with ≤5 zygotes. Methods and analysis Multicentre, randomised pragmatic comparative effectiveness trial with superiority design comparing blastocyst-stage to cleavage-stage ET in patients with ≤5 zygotes. This trial will enrol and randomise 1126 women aged 18–44 undergoing IVF to either fresh cleavage-stage or blastocyst-stage ET at eleven IVF centres. Surplus embryos will be vitrified at the blastocyst-stage. The primary outcome is the CLBR per oocyte retrieval. Secondary outcomes include: multiple pregnancy, pregnancy loss <20 weeks and cycle cancellation. Exploratory outcomes include: live birth per fresh ET, ectopic pregnancy, time to pregnancy, stillbirth, preterm birth, financial burden, patient distress and facilitators and barriers for patient involvement and implementation. All primary analyses will be conducted according to the intent-to-treat principle. We also will report per-protocol analyses as a sensitivity analysis. A multidisciplinary stakeholder team, including a 5-patient stakeholder panel, will participate in study design, conduct and oversight. Ethics and dissemination The Institutional Review Board at Beth Israel Deaconess Medical Center (BIDMC) provides central regulatory oversight. Results will inform timing of embryo transfer in patients with ≤5 zygotes and will be disseminated through academic publications, meeting presentations and communications to advocacy groups and patient participants. Trial registration number NCT06746129 .

OBJECTIVE Severe (level 3) hypoglycemia is a life-threatening complication of diabetes associated with substantial risk of recurrence and long-term morbidity. This study examined how adults with diabetes interpreted severe hypoglycemic events and why they declined participation in a community paramedicine program (Diabetes Rescue, Engagement, and Management [Diabetes-REM]) designed to prevent recurrence. RESEARCH DESIGN AND METHODS We conducted semistructured qualitative interviews with adults with type 1 or type 2 diabetes who experienced severe hypoglycemia requiring emergency medical services and declined enrollment in Diabetes-REM. Interviews explored hypoglycemia management experiences and reasons for nonparticipation and were explored using thematic analysis. RESULTS Sixteen adults (44% female; mean age 60 years, range 25–83) participated. Four interrelated themes emerged. First, participants normalized glucose variability as a baseline condition of diabetes and interpreted severe events as situational and correctable when a cause was identifiable, or as inevitable when it was not, rather than as evidence of increased risk. Second, participants relied on prevention systems encompassing habitual routines, caregiver involvement, and glucose-monitoring technologies. Third, severe episodes were frightening and disruptive but typically prompted adjustments to personal management over pursuit of additional clinical support. Finally, reasons for declining Diabetes-REM included time constraints (56%), perceived lack of benefit (25%), and privacy concerns or discomfort with home visits (25%). CONCLUSIONS Among adults who declined a community paramedicine hypoglycemia prevention intervention, severe events were absorbed into existing self-management frameworks rather than viewed as signals of increased risk. Programs targeting hypoglycemia recurrence should account for patients’ risk perceptions and existing management systems, positioning support as complementary rather than corrective.

Objective: To evaluate the relationship between race and social determinants of health and receipt of hysterectomy versus uterine-preserving fibroid treatment. Methods: A retrospective cohort study using deidentified claims and longitudinal health data from OptumLabs ® Data Warehouse. Patients aged 15–55 years with newly diagnosed fibroids between 2010 and 2023 were included. Menopausal individuals and those with gynecological cancer were excluded. The primary outcome was hysterectomy by any route versus uterine-preserving fibroid surgery within 180 days of fibroid diagnosis. We used logistic regression to assess associations between socioeconomic factors and receipt of hysterectomy after adjusting for pertinent covariates. Results: A total of 73,479 individuals were included; 50,645 received hysterectomy, 22,834 received a uterine-preserving treatment. Race, income, education level, and rurality were independently associated with the probability of hysterectomy. Odds of hysterectomy were lower for all people of color compared with White individuals (Asian odds ratio [OR] 0.61 [95% confidence interval (CI): 0.56–0.66], Black OR: 0.70 [95% CI: 0.67–0.73], and Hispanic OR: 0.90 [95% CI: 0.86–0.95]). Individuals with household income <$40,000, less than high school education, and rural address were more likely to undergo hysterectomy compared with those with income >$124,999 (OR: 1.15, 95% CI: 1.09–1.21), bachelor’s degree or higher (OR: 2.55, 95% CI: 1.78–3.65), and metropolitan address (OR: 1.70, 95% CI: 1.44–2.01). All associations were significant at p < 0.05. Conclusion: People with fewer socioeconomic advantages, such as lower household income, lower educational attainment, and rural address were more likely to receive hysterectomy rather than uterine-preserving fibroid treatment. After controlling for age, surgery year, and socioeconomic factors, people of color were less likely to receive hysterectomy rather than uterine-preserving fibroid treatment.

Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379