Outcomes of endoscopic submucosal dissection in cirrhotic patients: First American cohort.

BACKGROUND: Among patients with cirrhosis and pre-malignant or early malignant mucosal lesions, surgical intervention carries a much higher bleeding risk. When such lesions are discovered, endoscopic submucosal dissection (ESD) may offer curative therapy with lower risks than surgery and improved outcomes compared to traditional endoscopic resection. AIM: To evaluate the outcomes of ESD in patients with cirrhosis. METHODS: Patients with cirrhosis undergoing ESD between July 2015 and August 2022 were retrospectively matched in 1:2 fashion to controls based on lesion location, size, and anticoagulation use. Procedural outcomes were compared between groups. RESULTS: A total of 64 Lesions from 59 patients were included (16 cirrhosis, 43 control). There were no differences in patient or lesion characteristics between groups. En bloc and curative resection was achieved in 84.21%, 78.94% of the cirrhosis group and 88.89%, 68.89% of controls, respectively, with no significant differences. Cirrhotic patients had significantly higher rates of intra-procedural coagulation grasper use for control of bleeding (47.37% vs 20%; P = 0.02). There were otherwise no significant differences in adverse event rates. In the 29 patients with follow up, we found higher rates of recurrence in the cirrhosis group compared to controls (40% vs 5.26%; P = 0.019), however this effect did not persist on multivariable analysis controlling for known confounders. CONCLUSION: ESD may be safe and effective in patients with cirrhosis. Most procedure related outcomes were not significantly different between groups. Intra-procedural bleeding requiring use of the coagulation grasper use was expectedly higher in the cirrhosis group given the known effects of liver disease on hemostasis.

Factors associated with radiological misstaging of pancreatic ductal adenocarcinoma: A retrospective observational study.

PURPOSE: Accurate staging of disease is vital in determining appropriate care for patients with pancreatic ductal adenocarcinoma (PDAC). It has been shown that the quality of scans and the experience of a radiologist can impact computed tomography (CT) based assessment of disease. The aim of the current study was to evaluate the impact of the rereading of outside hospital (OH) CT by an expert radiologist and a repeat pancreatic protocol CT (PPCT) on staging of disease. METHODS: Patients evaluated at the our institute's pancreatic multidisciplinary clinic (2006 to 2014) with OH scan and repeat PPCT performed within 30 days were included. In-house radiologists staged disease using OH scans and repeat PPCT, and factors associated with misstaging were determined. RESULTS: The study included 100 patients, with a median time between OH scan and PPCT of 19 days (IQR: 13-23 days.) Stage migration was mostly accounted for by upstaging of disease (58.8 % to 83.3 %) in all comparison groups. When OH scans were rereviewed, 21.5 % of the misstaging was due to missed metastases, however, when rereads were compared to the PPCT, occult metastases accounted for the majority of misstaged patients (62.5 %). Potential factors associated with misstaging were primarily related to imaging technique. CONCLUSION: A repeat PPCT results in increased detection of metastatic disease that rereviews of OH scans may otherwise miss. Accessible insurance coverage for repeat PPCT imaging even within 30 days of an OH scan could help optimize delivery of care and alleviate burdens associated with misstaging.

A case of mosaic deletion of paternally-inherited PLAGL1 and two cases of upd(6)mat add to evidence for PLAGL1 under-expression as a cause of growth restriction.

PLAGL1 is one of a group of imprinted genes, whose altered expression causes imprinting disorders impacting growth, development, metabolism, and behavior. PLAGL1 over-expression causes transient neonatal diabetes mellitus (TNDM type 1) and, based on murine models, under-expression would be expected to cause growth restriction. However, only some reported individuals with upd(6)mat have growth restriction, giving rise to uncertainty about the role of PLAGL1 in human growth. Here we report three individuals investigated for growth restriction, two with upd(6)mat and one with a mosaic deletion of the paternally-inherited allele of PLAGL1. These cases add to evidence of its involvement in pre- and early post-natal human growth.

Discovery of ginisortamab, a potent and novel anti-gremlin-1 antibody in clinical development for the treatment of cancer.

Gremlin-1, a high-affinity antagonist of bone morphogenetic proteins (BMP)-2, -4, and -7, is implicated in tumor initiation and progression. Increased gremlin-1 expression, and therefore suppressed BMP signaling, correlates with poor prognosis in a range of cancer types. A lack of published work using therapeutic modalities has precluded the testing of the hypothesis that blocking the gremlin-1/BMP interaction will provide benefits to patients. To address this shortfall, we developed ginisortamab (UCB6114), a first-in-class clinical anti-human gremlin-1 antibody, currently in clinical development for the treatment of cancer, along with its murine analog antibody Ab7326 mouse immunoglobulin G1 (mIgG1). Surface plasmon resonance assays revealed that ginisortamab and Ab7326 mIgG1 had similar affinities for human and mouse gremlin-1, with mean equilibrium dissociation constants of 87 pM and 61 pM, respectively. The gremlin-1/Ab7326 antigen-binding fragment (Fab) crystal structure revealed a gremlin-1 dimer with a Fab molecule bound to each monomer that blocked BMP binding. In cell culture experiments, ginisortamab fully blocked the activity of recombinant human gremlin-1, and restored BMP signaling pathways in human colorectal cancer (CRC) cell lines. Furthermore, in a human CRC - fibroblast co-culture system where gremlin-1 is produced by the fibroblasts, ginisortamab restored BMP signaling in both the CRC cells and fibroblasts, demonstrating its activity in a relevant human tumor microenvironment model. The safety and efficacy of ginisortamab are currently being evaluated in a Phase 1/2 clinical trial in patients with advanced solid tumors (NCT04393298).

Bacterial second messenger cyclic di-AMP in streptococci.

Cyclic dimeric adenosine monophosphate (c-di-AMP) has been well studied in bacteria, including those of the genus Streptococcus, since the first recognition of this dinucleotide in 2008. Streptococci possess a sole diadenylate cyclase, CdaA, and distinct c-di-AMP phosphodiesterases. Interestingly, cdaA is required for viability of some streptococcal species but not all when streptococci are grown in standard laboratory media. Bacteria of this genus also have distinct c-di-AMP effector proteins, diverse c-di-AMP-signaling pathways, and subsequent biological outcomes. In streptococci, c-di-AMP may influence bacterial growth, morphology, biofilm formation, competence program, drug resistance, and bacterial pathogenesis. c-di-AMP secreted by streptococci has also been shown to interact with the mammalian host and induces immune responses including type I interferon production. In this review, we summarize the reported c-di-AMP networks in seven species of the genus Streptococcus, which cause diverse clinical manifestations, and propose future perspectives to investigate the signaling molecule in these streptococcal pathogens.

Development of Cationic Lipid LAH4-L1 siRNA Complexes for Focused Ultrasound Enhanced Tumor Uptake.

RNAi has considerable potential as a cancer therapeutic approach, but effective and efficient delivery of short interfering RNA (siRNA) to tumors remains a major hurdle. It remains a challenge to prepare a functional siRNA complex, target enough dose to the tumor, and stimulate its internalization into tumor cells and its release to the cytoplasm. Here, we show how these key barriers to siRNA delivery can be overcome with a complex─comprising siRNA, cationic lipids, and pH-responsive peptides─that is suited to tumor uptake enhancement via focused ultrasound (FUS). The complex provides effective nucleic acid encapsulation, nuclease protection, and endosomal escape such that gene silencing in cells is substantially more effective than that obtained with either equivalent lipoplexes or commercial reagents. In mice bearing MDA-MB-231 breast cancer xenografts, both lipid and ternary, lipid:peptide:siRNA complexes, prepared with near-infrared fluorescently labeled siRNA, accumulate in tumors following FUS treatments. Therefore, combining a well-designed lipid:peptide:siRNA complex with FUS tumor treatments is a promising route to achieve robust in vivo gene delivery.

An Analysis of the Availability of Health Education Materials for Migrant and Seasonal Farmworkers.

Community health workers (CHWs) have reported a paucity of farmworker-specific education materials for use during health outreach to farmworkers. To improve our understanding of the availability of topically and culturally relevant health education materials for farmworkers, we identified 15 key health topics to examine across four major online health information services: MedlinePlus.gov, Migrant Clinicians Network, National Agricultural Safety Database, and National Center for Farmworker Health. We established inter-coder reliability and conducted coding for health education materials by topic and identified the percentage of materials specifically designed for farmworkers. The availability of materials ranged from, on the low end, accessing clinic services, having one health education material total across all four online services, to alcohol, tobacco, and other drugs, having 50 materials across the four online services. Online health information services ranged from 0.6% of the materials designed specifically for farmworkers (MedlinePlus.gov) to 42.9% (Migrant Clinicians Network). The findings from this study underscore the need to support community-based projects centering CHWs' roles as advocates and facilitators to develop educational materials for farmworker health outreach.

Oncologic resection of pancreatic cancer with isolated liver metastasis: Favorable outcomes in select patients.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) and liver metastasis are treated with palliative chemotherapy, whereas similar patients with metastatic colorectal cancer are considered for aggressive surgery. METHODS: Using an institutional database, PDAC patients undergoing liver resection for isolated metastasis were identified. Their overall survival (OS), treatment factors, and clinicopathological variables associated with survival were also evaluated. RESULTS: Forty-seven patients underwent curative-intent surgery for metastatic PDAC to the liver between 2000 and 2019. Median OS was 21.9 months from diagnosis. Fourteen patients underwent unplanned resection of radiographically occult liver metastasis during pancreatectomy with median OS of 8.7 months. On the other hand, 29 patients received systemic chemotherapy followed by planned resection; this cohort had the most favorable prognosis following aggressive surgery with median OS being 38.1 months from diagnosis and 24.1 months from surgery. Preoperative chemotherapy (HR = 7.1; p = .002) and moderate to well differentiation of the primary tumor (HR = 3.7; p = .003) were associated with prolonged survival in multivariate analysis, whereas lymph node metastases, response to preoperative therapy, number of liver metastasis, and extent of liver surgery were not. CONCLUSIONS: In select patients with PDAC and isolated liver metastasis, curative-intent surgery can result in meaningful survival. This aggressive approach seems most beneficial in patients following induction chemotherapy.

Solid Pseudopapillary Neoplasms of the Pancreas Across Races Demonstrate Disparities with Comparably Good Prognosis.

BACKGROUND: Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare with low-grade malignancy and unclarified clinicopathological features. This study aimed to examine their characteristics and re-evaluate current treatments. METHODS: Databases from three sources were screened for patients with SPNs. We compared the perioperative variables, clinical data, overall survival (OS), and prognostic factors for recurrence among the three corresponding cohorts. RESULTS: We identified 286 patients diagnosed with SPNs between 1988 and 2020. Patients were mostly women (81%; median age: 38 years), and peak incidence was observed in women of 20-29 years of age. SPNs had a peak incidence in Asian men at 50-59 years of age (p = 0.002) and a delayed peak incidence in Asian women at 30-39 years of age (p < 0.001). Treatment strategies differed significantly across the institutions and included variations in the number of harvested lymph nodes and rates of vascular resection. Lymph node positivity was the only predictor of postoperative recurrence (odds ratio, 2.2; 95% confidence interval, 1.38-2.99; p = 0.007). Higher rates of lymphovascular invasion (p = 0.02), perineural invasion (p < 0.001), and R1 margin involvement (p < 0.001), as seen in one institution, did not result in poorer long-term survival in terms of the overall (p = 0.43), SPN-specific (p = 0.69), and recurrence-free survivals (p = 0.067). CONCLUSIONS: In contrast to previous findings that SPNs are prevalent in young women, a racial predilection for middle-aged Asian men and a delayed female peak incidence were noted. Parenchyma-preserving pancreatectomy may be an acceptable treatment. Non-radical surgery may be appropriate in patients with multiple comorbidities.

Optimising care and follow-up of adults with achondroplasia.

BACKGROUND: Achondroplasia is a genetic condition that can cause complications across the lifespan. While complications in childhood are well documented, the natural history of achondroplasia in adults has, until recently, been relatively lacking, and little is known about the care they receive or how they access it. The European Achondroplasia Forum undertook two exploratory surveys, one for healthcare professionals (HCPs) and one for patient advocacy group (PAG) representatives, to gain an understanding of current practices of the transition process of individuals with achondroplasia from paediatric to adult services and how adults perceive their care. RESULTS: Most HCP respondents followed up more children than adults, and 8/15 responded that individuals did not transition to an adult multidisciplinary team (MDT) after paediatric care. Of 10 PAG respondents, none considered the experience of transition to adult services as good or very good and 50% considered it to be poor or very poor. A total of 64% (7/11) described the coordination of transition to adult services as "Not satisfactory" or "Poor". HCPs and PAG representatives largely agreed on the core specialists involved in adult care (orthopaedic surgeons, physiotherapists, rehabilitation specialists, rheumatologists, clinical geneticists). However, there was a discrepancy in the understanding of healthcare needs outside of this, with PAG representatives selecting neurosurgeons and genetic counsellors, while HCPs selected pulmonologists and obstetricians/gynaecologists. There was agreement between HCP and PAG respondents on the key barriers to effective care of adults with achondroplasia, with lack of an adult MDT, lack of interest from individuals in accessing care, and less experience in adult than paediatric MDTs ranking highly. CONCLUSIONS: This study indicates that the care and follow up of adults with achondroplasia is challenging. Individuals are often lost to, or decline, follow up as they leave paediatric care, and it is largely unknown how, where, and why adults with achondroplasia access care later in life. Lifelong, multidisciplinary specialist care led by an identified physician should be accessible to all individuals with achondroplasia. It is important to ensure barriers to optimal care are addressed to enable access to appropriate care for all individuals with achondroplasia.

Literature review and expert opinion on the impact of achondroplasia on medical complications and health-related quality of life and expectations for long-term impact of vosoritide: a modified Delphi study.

BACKGROUND: Achondroplasia is associated with disproportionate short stature and significant and potentially severe medical complications. Vosoritide is the first medicine to treat the underlying cause of achondroplasia and data from phase 3 and phase 2 extension studies showed effects on growth and body proportions. However, there are currently no long-term data available on the direct impact on endpoints such as medical complications and health-related quality of life (HRQoL). This study explored the perceived impact of achondroplasia on medical complications, HRQoL, healthcare resource use and mortality, and potential modifying effects of vosoritide, based on published evidence and expert opinion. Structured expert opinion was obtained by an international modified Delphi study among 14 experts in managing achondroplasia performed on a virtual platform and consisting of an explorative phase followed by an anonymous individual rating round. RESULTS: Overall, the panelists expect that in individuals starting long-term treatment between 2 years of age and puberty, growth velocity increases observed in the clinical trials will be maintained until final height is reached (92% agreement) and will likely result in clinically meaningful improvements in upper-to-lower body segment ratio (85%). Earlier treatment initiation will likely result in a greater final height (100%) and more likely improve proportionality (92%) than later treatment. Although current data are limited, ≥ 75% of panelists find it conceivable that the earlier long-term treatment is started, the greater the probability of a positive effect on the lifetime incidence of symptomatic spinal stenosis, kyphosis, obstructive sleep apnea, and foramen magnum stenosis. These are among the most clinically important complications of achondroplasia because of their high impact on comorbidity, mortality, and/or HRQoL. A positive effect of vosoritide on the incidence of surgeries through lifetime was considered more likely with earlier long-term treatment (90%). CONCLUSIONS: This explorative study, based on international expert opinion, provides further insight into the medical and functional impacts of achondroplasia and how these might be modified through long-term use of vosoritide. The results can be used to guide the direction and design of future research to validate the assumptions and to discuss potential treatment outcomes with disease modifying therapies with families and clinicians.

RAD51B Harbors Germline Mutations Associated With Pancreatic Ductal Adenocarcinoma.

PURPOSE: Genetic alterations in many components of the homologous recombination, DNA damage response, and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes, including familial pancreatic cancer. HR-DDR genes beyond BRCA1, BRCA2, ATM, and PALB2 may also mutate and confer the HR-DDR deficiency in pancreatic ductal adenocarcinoma (PDAC). METHODS: We conducted a study to examine the genetic alterations using a companion diagnostic 15-gene HR-DDR panel in PDACs. HR-DDR gene mutations were identified and characterized by whole-exome sequencing and whole-genome sequencing. Different HR-DDR gene mutations are associated with variable homologous recombination deficiency (HRD) scores. RESULTS: Eight of 50 PDACs with at least one HR-DDR gene mutation were identified. One tumor with BRCA2 mutations is associated with a high HRD score. However, another tumor with a CHEK2 mutation is associated with a zero HRD score. Notably, four of eight PDACs in this study harbor a RAD51B gene mutation. All four RAD51B gene mutations were germline mutations. However, currently, RAD51B is not the gene panel for germline tests. CONCLUSION: The finding in this study thus supports including RAD51B in the germline test of HR-DDR pathway genes.

Evaluating Age as a Predictor of Postoperative Opioid Use and Prescribing Habits in Older Adults With Cancer.

OBJECTIVE: To assess the narcotic use of older patients after oncologic resection. DESIGN: Retrospective review. SETTING AND PARTICIPANTS: Adults with neoplasms undergoing resection at a tertiary academic medical center. METHODS: Open and minimally invasive resections of the pancreas, bowel, rectum, lung, breast, and skin were included. Emergent procedures, chronic opioid users, and benign pathology were excluded. Narcotic use was measured using morphine equivalents (MEQs, milligrams of morphine) at multiple time points and compared between younger and older (aged ≥65 years) patients. Refill requests were within 30 days of index procedure. RESULTS: A total of 445 patients were eligible, and 245 were ≥65 years old. Despite longer length of stay (3 vs 2 days, P = .01), older patients used less narcotic medication [39.8 (150) mg vs 84 (229) mg, P = .004], and reported lower pain scores [1.3 (3.3) vs 2.8 (4.5), P = .0001] over the course of their hospitalization. Additionally, older patients had lower normalized narcotic use [15.3 (150) mg vs 77.4 (240) mg, P = .0001] in the last 48 hours of their admission. Following discharge, older patients had a lower median discharge MEQ (DC MEQ) compared with younger patients, 75 (150) mg vs 112.5 (102.5) mg, P = .002. Further stratifying older patients into age cohorts (65-74 years, 75-84 years, ≥85 years) revealed progressively less narcotic use as measured by total inpatient MEQ and final 48 hours. Additionally, progressively older patients were discharged with progressively lower DC MEQ compared with younger patients, 90 (112.5) mg, 50 (131.3) mg, and 0 (60) mg vs 112.5 (102.5) mg, P < .0001, respectively. Finally, older patients requested refills less often than younger counterparts, 6.5% vs 14.5%, P = .006. CONCLUSIONS AND IMPLICATIONS: Older patients with cancer reported lower pain scores, consumed less narcotics, were discharged with significantly less narcotics, and called for refills less often compared with younger patients after surgery. These data suggest this population may require less opioids for satisfactory pain control, and development of a guideline targeting postoperative multimodal analgesia in older adults is warranted.

Phase-shift nanodroplets as an emerging sonoresponsive nanomaterial for imaging and drug delivery applications.

Nanodroplets - emerging phase-changing sonoresponsive materials - have attracted substantial attention in biomedical applications for both tumour imaging and therapeutic purposes due to their unique response to ultrasound. As ultrasound is applied at different frequencies and powers, nanodroplets have been shown to cavitate by the process of acoustic droplet vapourisation (ADV), causing the development of mechanical forces which promote sonoporation through cellular membranes. This allows drugs to be delivered efficiently into deeper tissues where tumours are located. Recent reviews on nanodroplets are mostly focused on the mechanism of cavitation and their applications in biomedical fields. However, the chemistry of the nanodroplet components has not been discussed or reviewed yet. In this review, the commonly used materials and preparation methods of nanodroplets are summarised. More importantly, this review provides examples of variable chemistry components in nanodroplets which link them to their efficiency as ultrasound-multimodal imaging agents to image and monitor drug delivery. Finally, the drawbacks of current research, future development, and future direction of nanodroplets are discussed.

Accurate Nodal Staging in Pancreatic Cancer in the Era of Neoadjuvant Therapy.

BACKGROUND: Nodal disease is prognostic in pancreatic ductal adenocarcinoma (PDAC); however, optimal number of examined lymph nodes (ELNs) required to accurately stage nodal disease in the current era of neoadjuvant therapy remains unknown. The aim of the study was to evaluate the optimal number of ELNs in patients with neoadjuvantly treated PDAC. METHODS: A retrospective study was performed on patients with PDAC undergoing resection following neoadjuvant treatment between 2011 and 2018. Clinicopathological data were extracted and analyzed. RESULTS: Of 546 patients included, 232 (42.5%) had lymph node metastases. The median recurrence free survival (RFS) was 10.6 months (95% confidence interval: 9.7-11.7) and nodal disease was independently associated with shorter RFS (9.1 vs 11.9 months; p < 0.001). A cutoff of 22 ELNs was identified that stratified patients by RFS. Patients with N1 and N2 disease had similar median RFS (9.1 vs 8.9 months; p = 0.410). On multivariable analysis, ELN of ≥ 22 was found to be significantly associated with longer RFS among patients with N0 disease (14.2 vs. 10.9 months, p = 0.046). However, ELN has no impact on RFS for patients with N1/N2 disease (9.5 vs. 8.4 months, p = 0.190). Adjuvant therapy was associated with RFS only in patients with residual nodal disease. CONCLUSIONS: Lymph node metastases remain prognostic in PDAC patients after neoadjuvant treatment. Among N0 patients, a cutoff of 22 ELN was associated with improved RFS and resulted in optimal nodal staging.

X-Ray Phase Contrast 3D Virtual Histology: Evaluation of Lung Alterations After Microbeam Irradiation.

PURPOSE: This study provides the first experimental application of multiscale 3-dimensional (3D) x-ray phase contrast imaging computed tomography (XPCI-CT) virtual histology for the inspection and quantitative assessment of the late-stage effects of radio-induced lesions on lungs in a small animal model. METHODS AND MATERIALS: Healthy male Fischer rats were irradiated with x-ray standard broad beams and microbeam radiation therapy, a high-dose rate (14 kGy/s), FLASH spatially fractionated x-ray therapy to avoid beamlet smearing owing to cardiosynchronous movements of the organs during the irradiation. After organ dissection, ex vivo XPCI-CT was applied to all the samples and the results were quantitatively analyzed and correlated to histologic data. RESULTS: XPCI-CT enables the 3D visualization of lung tissues with unprecedented contrast and sensitivity, allowing alveoli, vessel, and bronchi hierarchical visualization. XPCI-CT discriminates in 3D radio-induced lesions such as fibrotic scars and Ca/Fe deposits and allows full-organ accurate quantification of the fibrotic tissue within the irradiated organs. The radiation-induced fibrotic tissue content is less than 10% of the analyzed volume for all microbeam radiation therapy-treated organs and reaches 34% in the case of irradiations with 50 Gy using a broad beam. CONCLUSIONS: XPCI-CT is an effective imaging technique able to provide detailed 3D information for the assessment of lung pathology and treatment efficacy in a small animal model.

Discovery proteomics defines androgen-regulated glycoprotein networks in prostate cancer cells, as well as putative biomarkers of prostatic diseases.

Supraphysiologic androgen (SPA) inhibits cell proliferation in prostate cancer (PCa) cells by transcriptional repression of DNA replication and cell-cycle genes. In this study, quantitative glycoprotein profiling identified androgen-regulated glycoprotein networks associated with SPA-mediated inhibition of PCa cell proliferation, and androgen-regulated glycoproteins in clinical prostate tissues. SPA-regulated glycoprotein networks were enriched for translation factors and ribosomal proteins, proteins that are known to be O-GlcNAcylated in response to various cellular stresses. Thus, androgen-regulated glycoproteins are likely to be targeted for O-GlcNAcylation. Comparative analysis of glycosylated proteins in PCa cells and clinical prostate tissue identified androgen-regulated glycoproteins that are differentially expressed prostate tissues at various stages of cancer. Notably, the enzyme ectonucleoside triphosphate diphosphohydrolase 5 was found to be an androgen-regulated glycoprotein in PCa cells, with higher expression in cancerous versus non-cancerous prostate tissue. Our glycoproteomics study provides an experimental framework for characterizing androgen-regulated proteins and glycoprotein networks, toward better understanding how this subproteome leads to physiologic and supraphysiologic proliferation responses in PCa cells, and their potential use as druggable biomarkers of dysregulated AR-dependent signaling in PCa cells.

Reliable Detection of Somatic Mutations for Pancreatic Cancer in Endoscopic Ultrasonography-Guided Fine Needle Aspirates with Next-Generation Sequencing: Implications from a Prospective Cohort Study.

BACKGROUND OR PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, the diagnostic adequacy of EUS-FNA is often limited by low cellularity leading to inconclusive results. We aimed to investigate the feasibility and added utility of targeted next-generation sequencing (NGS) on PDAC EUS-FNAs. METHODS: EUS-FNAs were prospectively performed on 59 patients with suspected PDAC (2014-2017) at a high-volume center. FNAs were analyzed for the presence of somatic mutations using NGS to supplement cytopathologic evaluations and were compared to surgical specimens and circulating tumor DNA (ctDNA). RESULTS: Fifty-nine patients with suspected PDAC were evaluated, and 52 were diagnosed with PDAC on EUS-FNA. Four of the remaining seven patients had inconclusive EUS-FNAs and were ultimately diagnosed with PDAC after surgical resection. Of these 56 cases of PDAC, 48 (85.7%) and 18 (32.1%) harbored a KRAS and/or TP53 mutation on FNA NGS, respectively. Particularly, in the four inconclusive FNA PDAC diagnoses (false negatives), half harbored KRAS mutations on FNA. No KRAS/TP53 mutation was found in remaining three non-PDAC cases. All EUS-FNA detected KRAS mutations were detected in 16 patients that underwent primary tumor NGS (100% concordance), while 75% KRAS concordance was found between FNA and ctDNA NGS. CONCLUSION: Targeted NGS can reliably detect KRAS mutations from EUS-FNA samples and exhibits high KRAS mutational concordance with primary tumor and ctDNA. This suggests targeted NGS of EUS-FNA samples may enable preoperative ctDNA prognostication using digital droplet PCR and supplement diagnoses in patients with inconclusive EUS-FNA.

Autoimmune Pancreatitis: A Critical Analysis of the Surgical Experience in an Era of Modern Diagnostics.

OBJECTIVE: The aim of this study was to critically analyze the surgical experience of managing autoimmune pancreatitis (AIP) in an era of modern diagnostics and compare these patients with those who were managed conservatively. METHODS: Two prospectively maintained databases were used to retrospectively identify patients with AIP who were either managed conservatively or underwent pancreatectomy. RESULTS: Eighty-eight patients were included in the study, of which 56 (63.6%) underwent resection and 32 (36.4%) were managed conservatively. Patients who underwent resection were more likely to present with jaundice (64.3% vs 18.1%, P < 0.001) and weight loss (53.6% vs 15.6%, P = 0.005). The cohort who underwent resection had a significantly higher median carbohydrate antigen 19-9 (40.0 vs 18.6 U/mL, P = 0.034) and was less likely to have elevated immunoglobulin G4 (26.1% vs 50.0%, P < 0.001). The most frequent initial diagnosis in the cohort who underwent resection was ductal adenocarcinoma (82.1%). Nine patients (28.1%) in the conservatively managed cohort experienced AIP relapse compared with 6 patients (10.7%) in the cohort who underwent resection. CONCLUSIONS: The most frequent reason for surgical resection of AIP is concern for malignancy. Carbohydrate antigen 19-9 elevations were more common than immunoglobulin G4 in our cohort, suggesting that this laboratory profile is suboptimal for this population.