Citations

Photodynamic priming (PDP), a fallout of photodynamic therapy, transiently modulates the tumor microenvironment (TME), enhances therapeutic susceptibility, and promotes immunogenic cell death through the release of damage-associated molecular patterns (DAMPs). Pancreatic ductal adenocarcinoma (PDAC) remains non-responsive to current therapies with a desmoplastic and immunosuppressive TME that limits drug delivery and blunts responses to immune checkpoint blockade. We investigated whether PDP could enhance anti-PD1 therapy responses in PDAC using patient-derived organoids (PDOs). PDOs were treated with Visudyne and red light (25, 75, and 100 J/cm²), followed by assessment of cytotoxicity, DAMP expression (HSP60, calreticulin, HMGB1), and transcriptomic changes. Monocyte-derived dendritic cells (mDCs) from healthy donors were cocultured with PDP-treated (25 J/cm 2 ) PDOs, then with matched naïve T cells. mDC and T cell activation markers were analyzed. Pembrolizumab (anti-PD1) was added to PDO-mDC-T cell cocultures to evaluate combined effects on PDO viability and T cell activation. PDP induced dose-dependent cytotoxicity and upregulated DAMPs. Gene profiling in PDOs showed increased IFN-γ , TNF-α , and CXCL12 , with reduced PD-L1 , TGF-β1 , and FOXP1 expression. mDCs exposed to PDP-treated PDOs upregulated CD40, CD86, and MHC-II, driving activation of CD4 + and CD8 + T cells, evidenced by elevated PD1 expression. Addition of pembrolizumab further decreased PDO viability and amplified effector cytokines ( IFN-γ , TNF-α , FASLG , granzyme B, IL-2 , IL-21 ). PDP was associated with modulation of the PDAC TME toward a more immunogenic phenotype by enhancing tumor immunogenicity, activating dendritic cells and T cells, and potentiating PD1 blockade. These findings provide mechanistic support for further preclinical and clinical evaluation of PDP combined with checkpoint inhibition in PDAC.

Healthcare Systems Science (HSS) is an important part of medical education because it helps physicians understand how healthcare systems work and how to improve them. However, it is not commonly included in graduate medical training. This manuscript describes the creation and use of a radiation oncology (RO) HSS curriculum that was built with medical school faculty and adapted to the needs of residents in our residency program. The curriculum included sixteen sessions over ten months and covered six domains: person centered care, population centered care, team-based care, high value care, leadership, and health policy economics and technology. Each session included a short lecture and a case discussion on topics such as financial toxicity, telemedicine, workflow improvement, burnout, health equity, and billing. The curriculum was used successfully with regular participation from residents and faculty, showing that it can fit into an existing residency schedule. Residents completed pre- and post-intervention surveys assessing understanding, consideration, confidence, and satisfaction related to HSS domains using 5-point Likert-scale items. Among residents with paired survey data, scores for understanding of HSS, incorporation of HSS into care planning, confidence applying HSS principles, and satisfaction with HSS integration all improved following curriculum completion. This experience shows that adding HSS to RO residency training is practical and useful, and it may also be a helpful model for other residency programs.

Abstract Background Adults with congenital heart disease (ACHD) represent a rapidly expanding population with evolving mortality patterns. Despite improved survival, excess mortality persists. Objective To evaluate the incidence, causes, and predictors of mortality in a contemporary ACHD cohort. Methods We performed a retrospective cohort study of adults (≥18 years) first evaluated at Mayo Clinic from 2002–2023. Baseline clinical, imaging, and electrocardiographic data were analyzed. Vital status was determined using institutional records and the Accurint national mortality database. Kaplan-Meier analysis and Cox proportional hazard models were used to evaluate mortality and identify independent predictors of mortality Results A total of 7,678 ACHD patients were included, with median age of 36.8 years and median follow-up of 11.4 years. During 78,768 patient-years of follow-up, 1,116 patients died (median age at death 57.2 years), corresponding to an annual mortality rate of 1.4%. The cumulative rate of all-cause mortality at 5, 10, 15, and 20 years was 6.9%, 12.0%, 19.0%, and 26.2%, respectively. When stratified by CHD complexity, the annual death rate in patients with severe CHD (2.4%/year) was twice that of patients with moderate or mild CHD (both 1.2%/year). Older age and ACHD subtypes, specifically, cyanotic heart disease (HR 3.9, 95% CI 2.9–5.3) and Fontan physiology (HR 3.2, 95% CI 2.3–4.4), were strongly associated with increased mortality. Additional independent predictors included male sex, ventricular dysfunction, advanced NYHA class, prior heart failure hospitalization, hypertension, smoking, coronary artery disease, renal dysfunction, and abnormal hemoglobin levels. Cardiovascular causes accounted for 57.7% of deaths with known etiology, predominantly heart failure (48.9%) and sudden cardiac death (21.9%), while non-cardiovascular causes were driven mainly by infection and malignancy. Conclusions In this large contemporary ACHD cohort, mortality was driven by ventricular dysfunction, heart failure, and systemic end-organ involvement in addition to the underlying congenital anatomy. Both cardiovascular and non-cardiovascular causes contributed significantly to mortality. These findings underscore the need for comprehensive multidisciplinary ACHD care focused on early recognition of cardiac functional decline, management of acquired comorbidities, and end-organ dysfunction.

Background/Objectives: Retained airway secretions are a common complication of mechanical ventilation and a major contributor to ventilator-associated pneumonia. Airway Pressure Release Ventilation following a Time-Controlled Adaptive Ventilation protocol (APRV-TCAV) has been anecdotally observed to improve secretion clearance, but the mechanism is not well established. Because TCAV sets the release time (TLow) from each patient’s own expiratory flow decay, we hypothesized that the resulting expiratory-dominant flow profile would generate a net antegrade force on secretions. This bench study compared secretion movement between APRV-TCAV and conventional Volume-Control Continuous Mandatory Ventilation (VC-CMV), with and without an in-line oscillatory device. Methods: A critical care ventilator was connected to a 3 L test lung via a 7 mm endotracheal tube (ETT). Simulated mucus (1% guar gum) was instilled into the ETT, and secretion movement was measured under VC-CMV (positive end-expiratory pressure (PEEP) 5, 10, 15 cmH2O) and APRV-TCAV (PHigh 20, 25, 30 cmH2O; PLow 0 cmH2O). Each condition was repeated with an in-line oscillatory device. Results: All VC-CMV settings produced retrograde secretion movement toward the test lung; all APRV-TCAV settings produced antegrade movement. The largest antegrade movement was observed at the widest PHigh-to-PLow differential. Adding the oscillatory device raised peak expiratory flow above peak inspiratory flow in every condition, yet abolished antegrade movement under APRV-TCAV. Conclusions: In this bench study, APRV-TCAV reversed the direction of secretion movement within the ETT, with larger antegrade movement at wider PHigh-to-PLow differentials. This suggests a potential mechanism by which the ventilator flow profile itself may influence secretion movement. The directional effect depended on the intact release-phase waveform and was abolished by in-line oscillatory therapy despite preserved peak flow asymmetry.

PURPOSE Hematology care delivery is changing rapidly for patients, care teams, and health care institutions. This study simultaneously evaluated utilization data for synchronous/real-time patient appointments, asynchronous/time-delayed patient communications, and provider preferences in a large academic hematology practice to inform sustainable care delivery and workflows in the digital era. METHODS We conducted a retrospective analysis of aggregated adult hematology appointment and patient communication data at Mayo Clinic (Rochester, MN) from January 2023 to January 2025. Data were stratified by appointment modality, patient characteristics, and electronic health record (EHR) message volumes. Additionally, a voluntary, anonymous survey assessed hematology provider preferences regarding appointment modalities, in-basket burdens, and billing practices. RESULTS Among 83,713 completed appointments, 80.8% were in-person, 12.9% video, and 6.4% telephone. Patients age 80 years and older and rural cohorts used virtual modalities at rates comparable with younger and metropolitan cohorts. Asynchronous communication volume was considerable, with 155,036 patient-initiated telephone calls generating a digital cascade of 407,578 EHR messages (a 1:2.6 ratio) and 49,798 patient-initiated advice request in-basket messages generating 343,030 additional EHR messages (a 1:6.9 ratio). Providers (n = 53) strongly preferred in-person appointments for new consults (92.5%) and active therapy management (90.6%) but favored virtual appointments for surveillance (52.8%). Although 86.8% of providers reported spending >30 minutes daily on in-basket management, 94.3% reported not billing for this time. CONCLUSION Telehealth is a substantial component of modern hematology practice, used across all age groups. However, digital cascading and proliferation of asynchronous communications present an invisible and uncaptured workload. Optimizing care delivery could include implementation of a stratified hybrid model, prioritizing in-person appointments for high-acuity needs and virtual appointments for low-acuity needs, alongside standardized workflows to mitigate burdens of the digital era.

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 Introduction Patients with metastatic spine disease (MSD) present with varying degrees of systemic illness and frailty. Given the palliative intent of surgery and radiation treatment for MSD, treatment risks must be judiciously weighed against potential benefits. We sought to examine the impact of peroperative nutritional status as measured by the PG-SGA on survival in patients undergoing surgery and radiation for MSD. Methods This study involved an international, multicenter prospective, observational registry of patients with MSD: AO Knowledge Forum Tumor’s Metastatic Tumor Research and Outcomes Network (MTRON). Variables including baseline demographics, oncologic data, adverse events (medical adverse events and surgical complications), length of stay, and nutritional status were prospectively collected. The Patient-Generated Subjective Global Assessment (PG-SGA) was used to evaluate nutritional status. Results A total of 589 patients were included in this study; 469 (80%) of whom underwent surgery and radiation and 120 (20%) of whom underwent radiation alone. The majority of patients (362, 61%) were classified as well nourished, however, 68 patients (12%) were classified as severely malnourished. Among patients that underwent surgery and radiation, the median overall survival of well nourished patients was 491 days compared to 117 days in the severely malnourished patients (p < 0.001). A multivariate analysis demonstrated severe malnourishment and ECOG performance status of 3 or 4 were associated with worse overall survival. Conclusion Malnutrition as measured by the PG-SGA demonstrated to be significantly and independently associated with perioperative survival in patients with MSD. Further studies that investigate optimal pre-treatment optimization for patients with MSD in order to mitigate morbidity and mortality risk are essential.

Abstract Introduction As the incidence of metastatic spine disease (MSD) increases, treatments to manage refractory pain, pathologic vertebral body fractures, and spinal cord compression are becoming increasingly common. Given the palliative nature of surgical intervention used to achieve tumor control and thus mitigate loss of neurologic function and compromised ambulatory function, it is essential to mitigate the risk of such procedures. Methods The AO Spine Knowledge Forum Tumor’s Metastatic Tumor Research and Outcomes Network (MTRON), an international, prospective registry for patients with spinal metastases, was used for this query. Prospective collection included baseline health and demographic information, oncologic data (including Spinal Instability Neoplastic Score (SINS) score and Bilksy epidural compression classification), and baseline functional status (preoperative American Spinal Injury Association (ASIA) and ECOG scores). Health related quality of life (HRQoL) data included Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ2.0) and Euro-QoL measures. Surgery related adverse events (AE’s) were collected using the Spine Adverse Events Severity (SAVES V2) framework. Kaplan-Meir curves were used to assess survival. Results The cohort consisted of 1267 patients, 701 male (55.3%). A total of 245 (19.3%) experienced at least one postoperative AE, the majority of which were considered minor (grade 3 or less). Among the most common were deep wound infections (3.2%), wound dehiscence (2.5%), and urinary infections (2.4%). A multivariate analysis demonstrated that age, smoking status, ECOG performance, prior radiotherapy, presence of multiple metastases at other sites, and multiple spine metastases were significant risk factors for a postoperative AE. Postoperative AE’s (p = 0.049) and major postoperative AE’s (p = 0.0038) were found to be related to survival as well as a significant change in HRQoL scores (p < 0.001). Conclusion Postoperative AE’s are extremely relevant to the care of patients with MSD and impact both HRQoL and survival.