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.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is unresponsive to immune checkpoint therapies largely due to immunosuppression mediated by myeloid and lymphoid cells. Effective treatment strategies require, in addition to immune stimulation, the depletion of these immunosuppressive cells and their interactions. Here, we demonstrate for the first time, that a single verteporfin-based photodynamic therapy (PDT) treatment triples median survival in a KPC-PDAC model when combined with anti-PD1 therapy. Mechanistically, apart from reducing CK19 + tumor cells, PDT depletes immunosuppressive myeloid (CD11c+) and lymphoid (FOXP3+) cell populations, by ~ 4- and ~ 18.4-folds, respectively. PDT further disrupts interactions between these immunosuppressive cells, attenuating a key immune-tolerance axis. At the systemic level, PDT reduces splenic immunosuppression through modulation of tumor-derived cytokines. Within this reprogrammed immune-landscape, anti–PD-1 therapy elicits robust CD8 + T-cell responses, reflected by an ~ 6.7-fold increase in the intratumoral CD8+/Treg ratio. Collectively, these findings establish verteporfin-PDT as an immune-priming strategy that complements anti–PD-1 therapy by alleviating immunosuppression in PDAC.

Summary Central obesity is a risk factor for esophageal adenocarcinoma (EAC) independent of acid reflux. However, about a quarter of patients with Barrett’s esophagus (BE) and EAC have a normal body mass index (BMI). One hypothesis is that chronic systemic inflammation is as critical to the cancer pathway than the BMI alone. Therefore, we hypothesized that lean patients with BE/EAC would have a high prevalence of metabolic diseases. We aimed to compare metabolic diseases among lean patients with BE/EAC and overweight/obese BE/EAC and lean control without BE/EAC. We performed a propensity score–matched case–control study including patients with BE/EAC and a control group without BE/EAC from the Rochester Epidemiology Project (REP). The groups were compared using chi-square χ 2 and Student t-test as appropriate. Adjusted logistic regression models were used to compare the association with metabolic diseases. We included a total of 2504 patients (631 EAC, 621 BE, and 1252 controls). A quarter of patients (24.6%) with BE/EAC were lean. When compared to controls without BE/EAC, lean patients with BE were more likely to have diabetes (32.2% vs. 11.2%, P < 0.001) and hyperlipidemia (76.2% vs. 53%, P < 0.001). When comparing lean EAC patients to controls without BE/EAC, lean patients had a higher association with smoking (73.3% vs. 58.6%, P: 0.002) and diabetes (18.7% vs. 11.2%, P: 0.03). When compared to overweight/obese BE patients, lean BE were less likely to have NASH (7.7% vs. 20.3%, P: 0.001), diabetes (32.3% vs. 42.1%, P: 0.03), hyperlipidemia (77.2% vs. 87%, P: 0.003), and metabolic syndrome (24% vs. 54%, P < 0.001). Similarly, when compared to overweight/obese patients with EAC, lean EAC patients were less likely to have NASH (0% vs. 15.5%, P < 0.001), diabetes (18.7% vs. 34.1%, P < 0.001), hyperlipidemia (37.3% vs. 51.8%, P: 0.002), hypertension (37.3% vs. 55.3%, P < 0.001), and metabolic syndrome (8% vs. 37.6%, P < 0.001). A quarter of patients with BE/EAC are lean. Although lean BE/EAC patients have a more favorable metabolic profile compared to overweight/obese BE/EAC patients, diabetes and smoking are more common among lean patients with EAC compared to lean controls. The higher association with smoking and diabetes among lean EAC challenges traditional risk factor paradigms, suggesting a significant role for insulin resistance and chronic inflammation in EAC pathogenesis, especially in patients without typical risk factors. BMI-determined obesity may need to be supplemented with inflammatory metabolic diseases to improve assessment of BE/EAC risk in lean patients.

AbstractAlthough endoscopic submucosal dissection (ESD) is associated with higher en-bloc and R0 resection rates than cap-assisted endoscopic mucosal resection (cEMR), its comparative impact on achieving complete remission of dysplasia (CRD) and intestinal metaplasia (CRIM) in BE endoscopic eradication therapy (EET) is not well defined. We aimed to compare the journey of patients from initial endoscopic resection (ER) with ESD and cEMR to achieving CRD and CRIM.Patients undergoing ESD or cEMR followed by ablation for BE neoplasia at two academic institutions in the United States were included. Primary outcomes included CRD and CRIM rates following ER in the two groups. Secondary outcomes included the number of resection/ablative procedures from initial ER to achieving CRD and CRIM. Inverse probability treatment weighting (IPTW) was used to balance confounding variables between groups.A total of 801 patients (606 cEMR, 195 ESD) were included. ESD group patients had higher en-bloc resection rates (ESD 94.4%, cEMR 44.7%). Higher rates of CRD were observed in patients undergoing initial ESD (HR 1.53, P < 0.01). With time-to-event and IPTW analyses, rates of achieving CRD and CRIM were comparable between the groups. There were no significant differences in mean number of endoscopic resection or ablative procedures among patients undergoing initial cEMR resection compared with those treated with initial ESD.Despite larger lesion sizes and more cancers in patients undergoing ESD, the EET journey to achieving CRD and CRIM was comparable to that in patients receiving cEMR. Prospective studies are required to further study differences between these two treatment approaches.

Esophageal squamous cell carcinoma (ESCC) remains a significant global health challenge, being the sixth leading cause of cancer mortality with pronounced geographic variability. The incidence rates range from 125 per 100,000 in northern China to 1–1.5 per 100,000 in the United States, driven by environmental and lifestyle factors such as tobacco and alcohol use, dietary habits, and pollution. Major modifiable risk factors include tobacco and alcohol consumption, with a synergistic risk increase when combined. Nonmodifiable risk factors include previous diagnoses of head and neck squamous cell carcinoma (H&N SCC), achalasia, and prior radiotherapy. Prevention strategies must be tailored to specific regional burdens to efficiently allocate medical and financial resources. Gastrointestinal endoscopy is crucial in reducing ESCC burden through early detection and characterization of neoplastic changes, such as high‐grade dysplasia. Early diagnosis significantly improves survival rates, while endoscopic resection of noninvasive dysplasia can prevent ESCC onset, reducing treatment burden for advanced disease. Postresection surveillance can detect high‐risk metachronous lesions. Despite these benefits, endoscopic prevention faces challenges, including the lack of high‐level evidence supporting its efficacy, opportunity costs, the need for specialized training and techniques, and the requirement for advanced technology investments. This Position Statement from the World Endoscopy Organization (WEO) aims to address these challenges, supplying recommendations for the exploitation of endoscopic resources regarding the possible role of screening, quality, and training for the detection, characterization, resection, and surveillance of ESCC.

INTRODUCTION: Reflux bile acids are believed to promote esophageal adenocarcinoma (EAC), but the role of systemic bile acids is unknown. This study aimed to assess associations between systemic bile acids and stages of Barrett's esophagus (BE) progression. METHODS: Subjects with and without BE were enrolled in this multicenter cross-sectional study. Targeted serum bile acid profiling was performed, and a subset of subjects completed a validated food frequency questionnaire. RNA sequencing was performed on BE or gastric cardia tissue to assess bile acid associations with gene expression. RESULTS: A total of 141 subjects were enrolled with serum bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia, 25 indefinite/low grade dysplasia, 23 high-grade dysplasia/EAC). Lower Healthy Eating Index score, older age, higher body mass index, and no proton pump inhibitor use were associated with increased levels of multiple bile acids. Global bile acid pools were distinct between non-BE and stages of BE neoplasia ( P = 0.004). Increasing cholic acid was associated with high-grade dysplasia/EAC compared with non-BE, even after adjusting for EAC risk factors (adjusted odds ratio 2.03, 95% confidence interval 1.11–3.71) as was the combination of unconjugated primary bile acids (adjusted odds ratio 1.81, 95% confidence interval 1.04–3.13). High cholic acid levels were associated with tissue gene expression changes including increased DNA replication and reduced lymphocyte differentiation genes. DISCUSSION: Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes, proneoplastic effects of bile acids, and whether these bile acids, particularly cholic acid, represent potential biomarkers or viable therapeutic targets for advanced neoplasia in BE.

INTRODUCTION: Esophageal adenocarcinoma (EAC) is the second-most lethal cancer in the United States, with Barrett esophagus (BE) being the strongest risk factor. Assessing the future risk of neoplastic progression in patients with BE is difficult; however, high-grade dysplasia (HGD) and early EAC are treatable by endoscopic eradication therapy (EET), with survival rates of 90%. Thus, it would be beneficial to develop a molecular assay to identify high-risk patients, who merit more frequent endoscopic surveillance or EET, as well as low-risk patients, who can avoid EET and undergo less frequent surveillance. METHODS: Deidentified endoscopic biopsies were acquired from 240 patients with BE at 6 centers and confirmed as future progressors or nonprogressors. Tissues were analyzed by a set of methylation-specific biomarker assays. Test performance was assessed in an independent validation set using 4 stratification levels: low risks, low-moderate risks, high-moderate risks, and high risks. RESULTS: Relative to patients in the low-risk group, high-risk patients were 15.2 times more likely to progress within 5 years to HGD or EAC. For patients in the high-risk category, the average risk of progressing to HGD or EAC within 5 years was 21.5%, 4-fold the BE population prevalence within 5 years, whereas low-risk patients had a progression risk of only 1.85%. DISCUSSION: This clinical assay, Esopredict, stratifies future neoplastic progression risk to identify higher-risk patients with BE who can benefit from EET or more frequent surveillance and lower-risk patients who can benefit from reduced surveillance.

INTRODUCTION: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. Although effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease. METHODS: We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre-treatment and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups. RESULTS: The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway ( P = 0.01), amplifications of oncogenes ( P = 0.01), and deletions of tumor suppressor genes ( P = 0.02). These associations were no longer significant after adjusting for patient age and BE length. More than half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre-treatment and post-treatment samples that shared at least 50% of their driver mutations. DISCUSSION: Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. Although it was expected to find shared driver mutations in pre-treatment and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.