Wang, Kenneth K

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.

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.

Abstract Radiofrequency ablation (RFA) is the first-line treatment for flat Barrett’s esophagus (BE) with dysplasia, however its role for persistent Barrett’s esophagus (PBE) is unclear. PBE requires additional RFA sessions or application of cryotherapy to improve therapeutic response. We performed a retrospective cohort study evaluating cases of PBE treated by endoscopic eradication programs, with and without spray cryotherapy, and evaluated their safety and efficacy. We retrospectively identified patients with PBE, defined as ≤50% BE reduction or unchanged dysplasia after at least two RFA sessions. PBE was treated either by continued RFA (RFA Group) or converting to spray cryotherapy (CRYO Group), both followed by surveillance period. The rate of adverse events (AE), complete response of intestinal metaplasia (CRIM) and complete response of dysplasia (CRD) were recorded. A total of 46 patients, 23 per group, underwent 622 endoscopic therapies. Circumferential BE length was longer in the CRYO Group, but other baseline characteristics were similar, including maximal BE length. Esophageal strictures accounted for 14/16 total AE, 71% of which were RFA related, compared with 14% related to spray cryotherapy (P = 0.02). Overall CRIM/CRD rates in CRYO (83%) and RFA (96%) groups were not statistically different (P = 0.16), however cases in the CRYO Group required more treatment encounters (Median 19 vs. 12, P ≤ 0.01). Multimodal endotherapy is effective for eradicating PBE. Treatment programs incorporating spray cryotherapy are associated with less esophageal strictures but may require more treatment sessions to achieve eradication.

Summary Introduction Esophageal adenocarcinoma (EAC) is an aggressive cancer, associated with reflux esophagitis and intestinal metaplasia (IM). One underlying biological mechanism, which possibly drives the development of EAC, is the dysregulated expression of Bone Morphogenetic Proteins (BMPs). Aim To investigate if local delivery of Noggin, a BMP antagonist, reduced EAC. Methods After obtaining proof of principal on local delivery of a Noggin/Sucralfate substance, a randomized controlled trial to test the effects of Noggin on EAC development was performed in a surgical rat model. In the model, an esophago-jejunostomy leads to development of reflux-esophagitis, IM and eventually EAC. Rats were treated by Noggin/Sucralfate or Sucralfate alone. Treatment was administered from 26 to 29 weeks after the operation. Results Of the 112 operated rats, 52 survived beyond 26 weeks. Finally, 25 rats treated with Noggin/Sucralfate and 21 with Sucralfate, were evaluated. At the end, 39 (85%) of the animals had IM while 28 (61%) developed cancer. There were significantly more cancers in the Noggin/Sucralfate arm (50%) versus the Sucralfate group (73%) (Chi square, P < 0.05). Most cancers were mucous producing T3 adenocarcinomas. There were no significant differences in the amount of IM, size or grade of the cancers, or expression of columnar and squamous markers between the two groups. Conclusion In this study, we demonstrated that inhibition of BMPs by Noggin reduced development of EAC in a surgical esophagitis-IM-EAC rat model. In future, effective targeting of the BMP pathway with selective BMP-inhibitors could become an important asset to improve EAC patient outcome.

Abstract Background Dysphagia is the most common symptom in advanced esophageal cancer patients. Esophageal stent placement (SP) is a common palliation method but can be associated with significant morbidity. Limited data exist regarding the ability of spray cryotherapy (SC) prolong time to SP. Methods A Mayo Clinic (Rochester, MN) patient database was reviewed for cases with a SC indication of esophageal cancer palliation from 2007–2019. Procedures were performed using a liquid nitrogen SC system to apply 2–5 separate 20 second freeze and 60 second thaw cycles based on tumor characteristics. Primary outcome was time to subsequent palliative SP. Results Of 56 patients (71.4% male, mean age 77.8 ± 10.2 years) who underwent a total of 199 SC sessions (mean 3.6 ± 2.7, range 1–12 per patient), 41 had adenocarcinoma and 15 squamous cell carcinoma (SCC). Overall, 13 patients underwent subsequent SP within a mean duration of 15.7 ± 11.0 months over a mean follow-up duration of 25.6 ± 29.4 months. Treatment did produce stenosis in 16 patients, who required dilation within a mean period of 193.1 ± 294.1 days; notably, 10 patients had a history of preceding malignant strictures requiring dilation. Two patients experienced bleeding requiring transfusion, whereas 1 experienced perforation at the start of SC. Prior chemotherapy and/or radiation was not associated with developing an SC-related complication (risk ratio (RR) 1.5; 95% CI 0.6–3.7, P > 0.4). Conclusions SC appears to be an effective and safe modality to palliate esophageal cancer in appropriate candidates. Majority of patients who undergo SC avoid the need for future SP. If patients eventually require SP, they are able to, on average, defer stenting for >1 year from SC initiation.

Abstract Photodynamic therapy (PDT) offers localized focal ablation in unresectable pancreatic tumors while tissues surrounding the treatment volume experience a lower light dose, termed photodynamic priming (PDP). While PDP does not cause tissue damage, it has been demonstrated to promote vascular permeability, improve drug delivery, alleviate tumor cell density, and reduce desmoplasia and the resultant internal pressure in pre-clinical evaluation. Preclinical data supports PDP as a neoadjuvant therapy beneficial to subsequent chemotherapy or immunotherapy, yet it is challenging to quantify PDP effects in clinical treatment without additional imaging and testing. This study investigated the potential of radiomic analysis using CT scans acquired before and after PDT to identify areas experiencing PDT-induced necrosis as well as quantify PDP effects in the surrounding tissues. A total of 235 CT tumor slices from seven patients undergoing PDT for pancreatic tumors were examined. Radiomic features assessed included intensity metrics (CT number in Hounsfield Units) and texture analysis using several gray-level co-occurrence matrix (GLCM) parameters. Pre-treatment scans of tumor areas that resulted in PDT-induced necrosis showed statistically significant differences in intensity and texture-based features that could be used to predict the regions that did respond (paired t-test, response versus no response, p < 0.001). Evaluation of PDP effects on the surrounding tissues also demonstrated statistically significant differences, in tumor mean value, standard deviation, and GLCM parameters of contrast, dissimilarity and homogeneity (t-test, pre versus post, p < 0.001). Using leave-one-out cross validation, six intensity and texture-based features were combined into a support-vector machine model which demonstrated reliable prediction of treatment effects for six out of seven patients (ROC curve, AUC = 0.93). This study provides pilot evidence that texture features extracted from CT scans could be utilized as an effective clinical diagnostic prediction and assessment of PDT and PDP effects in pancreatic tumors. (clinical trial NCT03033225)

INTRODUCTION: Minimally invasive tests for Barrett's esophagus (BE) detection have raised the prospect of broader nonreflux-based testing. Cost-effectiveness studies have largely studied men aged 50 years with chronic gastroesophageal reflux disease (GERD) symptoms. We evaluated the comparative cost effectiveness of BE screening tests in GERD-based and GERD-independent testing scenarios. METHODS: Markov modeling was performed in 3 scenarios in 50 years old individuals: (i) White men with chronic GERD (GERD-based); (ii) GERD-independent (all races, men and women), BE prevalence 1.6%; and (iii) GERD-independent, BE prevalence 5%. The simulation compared multiple screening strategies with no screening: sedated endoscopy (sEGD), transnasal endoscopy, swallowable esophageal cell collection devices with biomarkers, and exhaled volatile organic compounds. A hypothetical cohort of 500,000 individuals followed for 40 years using a willingness to pay threshold of $100,000 per quality-adjusted life year (QALY) was simulated. Incremental cost-effectiveness ratios (ICERs) comparing each strategy with no screening and comparing screening strategies with each other were calculated. RESULTS: In both GERD-independent scenarios, most non-sEGD BE screening tests were cost effective. Swallowable esophageal cell collection devices with biomarkers were cost effective (<$35,000/QALY) and were the optimal screening tests in all scenarios. Exhaled volatile organic compounds had the highest ICERs in all scenarios. ICERs were low (<$25,000/QALY) for all tests in the GERD-based scenario, and all non-sEGD tests dominated no screening. ICERs were sensitive to BE prevalence and test costs. DISCUSSION: Minimally invasive nonendoscopic tests may make GERD-independent BE screening cost effective. Participation rates for these strategies need to be studied.

INTRODUCTION: Esophageal epidermoid metaplasia (EEM) is a rare disease. METHODS: Patients with EEM diagnosed between 2014 and 2020 were reviewed. RESULTS: Forty EEM cases were identified. EEM occurred in 9 (23%) patients before, concordant, or after esophageal squamous cell carcinoma (ESCC). EEM was associated with previous esophageal lichen planus in 5 patients, Barrett's esophagus 7, and esophageal adenocarcinoma 1. EEM was focal in 28 (70%) or diffuse in 12 (30%) and not detected in 45% on recent previous endoscopy. DISCUSSION: EEM is a premalignant underrecognized condition associated with multiple conditions. Close follow-up or endoscopic treatment may be warranted because of its ESCC association.