Levy, Michael J.

AbstractA crucial mutational mechanism in malignancy is structural variation, in which chromosomal rearrangements alter gene functions that drive cancer progression. Herein, the presence and pattern of structural variations were investigated in twelve prospectively acquired treatment‐naïve pancreatic cancers specimens obtained via endoscopic ultrasound (EUS). In many patients, this diagnostic biopsy procedure and specimen is the only opportunity to identify somatic clinically relevant actionable alterations that may impact their care and outcome. Specialized mate pair sequencing (MPseq) provided genome‐wide structural variance analysis (SVA) with a view to identifying prognostic markers and possible therapeutic targets. MPseq was successfully performed on all specimens, identifying highly rearranged genomes with complete SVA on all specimens with > 20% tumour content. SVA identified chimeric fusion proteins and potentially immunogenic readthrough transcripts, change of function truncations, gains and losses of key genes linked to tumour progression. Complex localized rearrangements, termed chromoanagenesis, with broad pattern heterogeneity were observed in 10 (83%) specimens, impacting multiple genes with diverse cellular functions that could influence theragnostic evaluation and responsiveness to immunotherapy regimens. This study indicates that genome‐wide MPseq can be successfully performed on very limited clinically EUS obtained specimens for chromosomal rearrangement detection and potential theragnostic targets.

Objective The diagnosis of autoimmune pancreatitis (AIP) is challenging. Sonographic and cross-sectional imaging findings of AIP closely mimic pancreatic ductal adenocarcinoma (PDAC) and techniques for tissue sampling of AIP are suboptimal. These limitations often result in delayed or failed diagnosis, which negatively impact patient management and outcomes. This study aimed to create an endoscopic ultrasound (EUS)-based convolutional neural network (CNN) model trained to differentiate AIP from PDAC, chronic pancreatitis (CP) and normal pancreas (NP), with sufficient performance to analyse EUS video in real time. Design A database of still image and video data obtained from EUS examinations of cases of AIP, PDAC, CP and NP was used to develop a CNN. Occlusion heatmap analysis was used to identify sonographic features the CNN valued when differentiating AIP from PDAC. Results From 583 patients (146 AIP, 292 PDAC, 72 CP and 73 NP), a total of 1 174 461 unique EUS images were extracted. For video data, the CNN processed 955 EUS frames per second and was: 99% sensitive, 98% specific for distinguishing AIP from NP; 94% sensitive, 71% specific for distinguishing AIP from CP; 90% sensitive, 93% specific for distinguishing AIP from PDAC; and 90% sensitive, 85% specific for distinguishing AIP from all studied conditions (ie, PDAC, CP and NP). Conclusion The developed EUS-CNN model accurately differentiated AIP from PDAC and benign pancreatic conditions, thereby offering the capability of earlier and more accurate diagnosis. Use of this model offers the potential for more timely and appropriate patient care and improved outcome.

Abstract Background Endoscopic intervention for pancreatic fluid collections (PFCs) with disconnected pancreatic duct syndrome (DPDS) has been associated with failures and increased need for additional endoscopic and non-endoscopic interventions. The primary aim of this study was to determine the outcomes of endoscopic ultrasound (EUS)-guided transmural drainage of PFCs in patients with DPDS. Methods In patients undergoing EUS-guided drainage of PFCs from January 2013 to January 2018, demographic profiles, procedural indications and details, adverse events, outcomes, and subsequent interventions were retrospectively collected. Overall treatment success was determined by PFC resolution on follow-up imaging or stent removal without recurrence. Results EUS-guided drainage of PFCs was performed in 141 patients. DPDS was present in 57 of them (40 %) and walled-off necrosis was the most frequent type of PFC (55 %). DPDS was not associated with lower clinical success, increased number of repeat interventions, or increased time to PFC resolution. Patients with DPDS were more likely to be treated with permanent transmural plastic double-pigtail stents (odds ratio [OR] 6.4; 95 % confidence interval [CI] 2.5 – 16.5; P < 0.001). However, when stents were removed, DPDS was associated with increased PFC recurrence after stent removal (OR 8.0; 95 %CI 1.2 – 381.8; P = 0.04). Conclusions DPDS frequently occurs in patients with PFCs but does not negatively impact successful resolution. DPDS is associated with increased PFC recurrence after stent removal.

Background and Aims Presence of malignant regional lymph nodes (MRLNs) precludes curative oncological resection or liver transplantation for cholangiocarcinoma (CCA). Limited data support the utility of endoscopic ultrasound (EUS)/fine needle aspiration (FNA) for detection of MRLNs in extrahepatic CCA, but there are no data for its role in intrahepatic CCA (iCCA). The aim of this study is to evaluate the staging impact of EUS for CCA, including analysis by subtype. Approach and Results We identified consecutive patients with CCA who underwent EUS staging at a single tertiary care center from October 2014 to April 2018. Among this cohort, we abstracted clinical demographic, radiographical, procedural, cytopathological, and surgical data. STATA 15 software was used for comparative analysis calculations (StataCorp LP, College Station, TX). The study cohort included 157 patients; 24 (15%), 124 (79%), and 9 (6%) with intrahepatic, perihilar, and distal CCA, respectively. EUS was able to identify regional lymph nodes (RLNs) in a higher percentage of patients compared to cross‐sectional imaging (86% vs. 47%; P < 0.001). FNA was performed in 133 (98.5%) patients with RLNs, with a median of three passes per node. EUS‐FNA identified MRLN in 27 of 31 (87.1%) patients ultimately found to have MRLNs. For iCCA, EUS detected a higher percentage of RLN compared to cross‐sectional imaging (83% vs. 50%; P = 0.048), with MRLNs identified in 4 (17%) patients. Among the entire cohort, identification of at least one MRLN by EUS was associated with lower median survival (353 vs. 1,050 days; P < 0.001) and increased risk of death (hazard ratio = 4.1; P < 0.001). Conclusions EUS‐FNA is effective for identifying MRLN in patients with CCA, and should be routinely incorporated into staging of all CCA subtypes given the impact of MRLN on prognosis and management decisions.

BACKGROUND: There is lack of consensus on post-operative surveillance for resected non-invasive intraductal papillary neoplasms (IPMNs). In this study we explored risk factors for subsequent PC in patients with MD-IPMN undergoing partial pancreatectomy. METHODS: We searched the Mayo Clinic surgical pathology database for all cases of resected MD-IPMN between 1997 and 2014. Cases with histologically confirmed main pancreatic duct involvement either isolated or in a mixed pattern with branch-duct involvement were included. Outcomes of PC in the remnant pancreas, and death related to MD-IPMN were assessed with survival analyses (Kaplan–Meier and Cox regression). RESULTS: Among the 179 patients with resected MD-IPMN the incidence of concomitant PC and high-grade dysplasia (HGD) in the resected specimen was 23 and 14%, respectively. The mean duration of follow-up was 4.31 years (range 0.12–13.5 years). Excluding 28 subjects who either underwent initial total pancreatectomy or partial pancreatectomy with surgical margins positive for PC/HGD, the 5-year incidence of subsequent PC was 12%, including 60.6% and 15.6% in those with initial PC and HGD, respectively. The 10-year incidence of PC was 21.2% overall, 60.6% for PC, 38.3% for HGD, and 3.0% for LGD. Risk of subsequent PC was significantly higher for those with initial PC compared with HGD (HR = 4.95, 95% CI: 1.63–15.03, p = 0.005 and for HGD compared with LGD (HR = 11.30, 95% CI: 1.55–82.26, p = 0.017). CONCLUSIONS: Patients with MD-IPMN with PC or HGD undergoing segmental pancreatectomy are at higher risk of subsequent PC and may benefit from post-operative surveillance. The post-operative surveillance intervals in resected MD-IPMNs need to be tailored based on dysplasia grade.

Abstract Background and study aims The US FDA recently approved a cancer treatment with pembrolizumab based upon the tumor biomarker status of deficient mismatch repair (dMMR) rather than a specific disease-based approach. We sought to determine if endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) could determine dMMR and quantification of PD-L1 expression to potentially guide the delivery of tumor agnostic immunotherapy. Patients and methods Immunohistochemistry was performed on archived pancreas core biopsy specimens. Tumors with absent nuclear staining of DNA mismatch repair proteins represented dMMR. Tumors were considered to have any or high PD-L1 expression, if expressed in ≥ 1 % or ≥ 50 % of tumor cells. Results Histologic specimen adequacy for MMR status assessment was satisfactory in 97.2 % of tumors. dMMR and high PD-L1 expression was identified in 3 % and 8.1 % of the cohort. Conclusion In the setting of tumor type agnostic immunotherapy, it is projected that at least 3 % of malignant pancreas lesions will be sensitive to pembrolizumab and up to 8 % sensitive to the family of immune checkpoint inhibitors. This highlights the expanding role of EUS-FNB in the field of precision immuno-oncology.

Abstract Background and study aims Little consideration has been given to selection of endoscopic ultrasound-guided fiducials for proton radiotherapy and the resulting perturbations in the therapy dose and pattern. Our aim was to assess the impact of perturbations caused by six fiducials of different composition and dimensions in a phantom gel model. Materials and methods The phantom was submerged in a water bath and irradiated with a uniform 10 cm × 10 cm field of 119.7 MeV monoenergetic spot scanning protons delivered through a 45 mm range shifter. The proton “Bragg Peak” was evaluated. Results Dose perturbations manifesting as dose reductions up to 30 % were observed. A carbon composite (1 × 5 mm) and gold (0.4 × 10 mm) fiducial with backload potential rather than dedicated EUS pre-loaded gold fiducial needles had the best performance in terms of minimizing the dose perturbation. Conclusions Our data demonstrate that a carbon composite fiducial has a less untoward effect on proton therapy dose distribution than dedicated EUS pre-loaded gold fiducial needles. Such information is important to consider when selecting fiducials specifically for proton therapy.