Diagnosis and Management of Pancreatic Cysts.

As pancreatic cyst incidence rises, likely due to the ubiquitous increase in cross-sectional imaging, their management presents multiple challenges for both the practitioner and patient. It is critical that all pancreatic cysts are appropriately characterized, as treatment decisions depend on an accurate diagnosis. Diagnostic modalities such as cytology, biopsy, and cyst fluid biomarkers allow for definitive diagnosis of virtually all lesions. Some cysts, such as intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and cystic pancreatic endocrine neoplasms, have malignant potential and must be surveyed. Other cysts, such as serous cystadenomas and pancreatic fluid collections, do not have malignant potential. Surveillance strategies vary widely depending on cyst type and size and while multiple medical societies advocate surveillance, their published surveillance guidelines are heterogenous. Cysts with high-risk stigmata or worrisome features are usually resected, depending on the patient's surgical fitness. In patients unfit for resection, newer endoscopic ablative techniques are advocated. Controversial aspects regarding cyst management include whether surveillance can be stopped, how surveillance should be performed, and the extensive financial burden cyst management places on the health care system. Further study into the natural history of cystic lesions, including definitive determination of the rate of malignant transformation for each cyst type, is essential.

Distinct Serum Immune Profiles Define the Spectrum of Acute and Chronic Pancreatitis From the Multicenter Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) Study.

BACKGROUND & AIMS: Pancreatitis is a disease continuum, starting with acute pancreatitis (AP) and progressing in some cases to recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). Currently, there are no approved therapies or early diagnostic or prognostic biomarkers for pancreatitis. The current study examined whether patient serum immune profiling could identify noninvasive biomarkers and provide mechanistic insight into the disease continuum of pancreatitis. METHODS: Using Olink immunoassay, we assessed the protein levels of 92 immune markers in serum samples from participants enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study of the Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) consortium. Samples (N = 231) were obtained from individuals without pancreatic disease (n = 56) and from those with chronic abdominal pain (CAP) (n = 24), AP (n = 38), RAP (n = 56), and CP (n = 57). RESULTS: A total of 33 immune markers differentiated the combined pancreatitis groups from controls. Immune markers related to interleukin (IL) 17 signaling distinguished CP from AP and RAP. Similarly, the serum level of IL17A and C-C motif chemokine ligand 20 differentiated CP from CAP, suggesting the involvement of T helper 17 cells in CP pathogenesis. The receiver operator characteristic curve with 2 immune markers (IL17A and sulfotransferase 1A1) could differentiate CP from CAP (optimistic area under the curve = 0.78). The macrophage classical activation pathway elevated along the continuum of pancreatitis, suggesting an accumulation of proinflammatory signals over disease progression. Several immune markers were associated with smoking, alcohol, and diabetes status. CONCLUSIONS: Immune profiling of serum samples from a large pancreatitis cohort led to identifying distinct immune markers that could serve as potential biomarkers to differentiate the varying pancreatitis disease states. In addition, the finding of IL17 signaling in CP could provide insight into the immune mechanisms underlying disease progression.

Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations That Improve the Clinical Management of Pancreatic Cysts.

BACKGROUND & AIMS: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. METHODS: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. RESULTS: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. CONCLUSIONS: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.

Development of clinical screening tool for exocrine pancreatic insufficiency in patients with definite chronic pancreatitis.

BACKGROUND/OBJECTIVES: No simple, accurate diagnostic tests exist for exocrine pancreatic insufficiency (EPI), and EPI remains underdiagnosed in chronic pancreatitis (CP). We sought to develop a digital screening tool to assist clinicians to predict EPI in patients with definite CP. METHODS: This was a retrospective case-control study of patients with definite CP with/without EPI. Overall, 49 candidate predictor variables were utilized to train a Classification and Regression Tree (CART) model to rank all predictors and select a parsimonious set of predictors for EPI status. Five-fold cross-validation was used to assess generalizability, and the full CART model was compared with 4 additional predictive models. EPI misclassification rate (mRate) served as primary endpoint metric. RESULTS: 274 patients with definite CP from 6 pancreatitis centers across the United States were included, of which 58 % had EPI based on predetermined criteria. The optimal CART decision tree included 10 variables. The mRate without/with 5-fold cross-validation of the CART was 0.153 (training error) and 0.314 (prediction error), and the area under the receiver operating characteristic curve was 0.889 and 0.682, respectively. Sensitivity and specificity without/with 5-fold cross-validation was 0.888/0.789 and 0.794/0.535, respectively. A trained second CART without pancreas imaging variables (n = 6), yielded 8 variables. Training error/prediction error was 0.190/0.351; sensitivity was 0.869/0.650, and specificity was 0.728/0.649, each without/with 5-fold cross-validation. CONCLUSION: We developed two CART models that were integrated into one digital screening tool to assess for EPI in patients with definite CP and with two to six input variables needed for predicting EPI status.

Circulating immune signatures in chronic pancreatitis with and without preceding acute pancreatitis: A pilot study.

OBJECTIVE: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP). METHODS: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups. RESULTS: In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10. CONCLUSION: CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP.

Utilization of Pancreatic Endotherapy in Patients with Chronic Pancreatitis: Results From a Multicenter Cohort Study in the United States.

BACKGROUND AND AIMS: Although commonly used for treating complications of chronic pancreatitis (CP), data on the frequency and factors associated with the use of pancreatic endotherapy (PET) are limited. Our aim was to define the utilization and factors predictive for receiving PET in a well-characterized CP cohort. METHODS: This is a cross-sectional analysis of data from PROCEED, a multicenter US cohort study of CP. PET modalities primarily consisted of ERCP. A treatment course was defined as the number of sessions performed for a specific indication. A repeat course was defined as PET >1 year after completion of the last course. Multivariable logistic regression identified predictive factors for receiving PET, and proportional rates model assessed risk factors for repeat PET. RESULTS: Of a total of 681 subjects, 238 (34.9%) received PET. Factors associated with receiving PET included female sex (OR: 1.26, 95% CI: 1.03-1.53), lower education (OR: 1.30, 95% CI: 1.04-1.62), income ≤ $50,000 per year (OR: 1.35, 95% CI: 1.07-1.71) and prior acute pancreatitis (AP) (OR: 1.74, 95% CI: 1.31, 2.32). 103/238 subjects (43.3%) underwent repeat PET at a median duration of 2 years with 23.1% receiving 2 courses, 9.7% receiving 3 courses, and 10.4% receiving 4+ courses. CONCLUSIONS: Nearly half of patients with CP who undergo PET received one or more repeat courses within 2-3 years. In addition to a prior history of AP, demographic and socioeconomic factors were associated with receiving PET.

Changes in Glomerular Volume, Sclerosis, and Ischemia at 5 Years after Kidney Transplantation: Incidence and Correlation with Late Graft Failure.

SIGNIFICANCE STATEMENT: Glomerular volume, ischemic glomeruli, and global glomerulosclerosis are not consistently assessed on kidney transplant biopsies. The authors evaluated morphometric measures of glomerular volume, the percentage of global glomerulosclerosis, and the percentage of ischemic glomeruli and assessed changes in these measures over time to determine whether such changes predict late allograft failure. All three features increased from transplant to five-year biopsy. Kidneys with smaller glomeruli at 5 years had more global glomerulosclerosis and a higher percentage of ischemic-appearing glomeruli. Smaller glomeruli and increasing percentages of global glomerulosclerosis and ischemic glomeruli at 5 years predicted allograft failure. Only increased percentage of ischemic glomeruli predicted allograft failure at 5 years independent of all Banff scores. Glomerular changes reflect pathologic processes that predicted allograft loss; measuring them quantitatively might enhance the current Banff system and provide biomarkers for intervention trials. BACKGROUND: Histology can provide insight into the biology of renal allograft loss. However, studies are lacking that use quantitative morphometry to simultaneously assess changes in mean glomerular volume and in the percentages of globally sclerosed glomeruli (GSG) and ischemic-appearing glomeruli in surveillance biopsies over time to determine whether such changes are correlated with late graft failure. METHODS: We used digital scans of surveillance biopsies (at implantation and at 1 and 5 years after transplantation) to morphometrically quantify glomerular volume and the percentages of GSG and ischemic-appearing glomeruli in a cohort of 835 kidney transplants. Cox proportional hazards models assessed the risk of allograft failure with these three glomerular features. RESULTS: From implantation to 5 years, mean glomerular volume increased by nearly 30% (from 2.8×10 6 to 3.6×10 6 µm 3 ), mean percentage of GSG increased from 3.2% to 13.2%, and mean percentage of ischemic-appearing glomeruli increased from 0.8% to 9.5%. Higher percentages of GSG and ischemic-appearing glomeruli at 5-year biopsy predicted allograft loss. The three glomerular features at 5-year biopsy were related; the percentage of GSG and the percentage of ischemic glomeruli were positively correlated, and both were inversely correlated to glomerular volume. At 5 years, only 5.3% of biopsies had ≥40% ischemic glomeruli, but 45% of these grafts failed (versus 11.6% for <40% ischemic glomeruli). Higher Banff scores were more common with increasing percentages of GSG and ischemia, but at 5 years, only the percentage of ischemic glomeruli added to predictive models adjusted for Banff scores. CONCLUSIONS: Glomerular changes reflect important pathologic processes that predict graft loss. Measuring glomerular changes quantitatively on surveillance biopsies, especially the proportion of ischemic-appearing glomeruli, may enhance the current Banff system and be a useful surrogate end point for clinical intervention trials. PODCAST: This article contains a podcast at.

A Combined DNA/RNA-based Next-Generation Sequencing Platform to Improve the Classification of Pancreatic Cysts and Early Detection of Pancreatic Cancer Arising From Pancreatic Cysts.

OBJECTIVE: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. BACKGROUND AND AIMS: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. METHODS: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. RESULTS: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. CONCLUSIONS: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

Association of Chronic Pancreatitis Pain Features With Physical, Mental, and Social Health.

BACKGROUND AND AIMS: Pain is a cardinal symptom of chronic pancreatitis (CP). Using Patient-Reported Outcomes Measurement Information System (PROMIS) measures, we characterized physical and mental health and symptom profiles of a well-defined cohort of individuals with CP and compared them with control subjects. Among patients with CP, we also examined associations between pain (intensity, temporal nature) and PROMIS symptom profiles and the prevalence of clinically significant psychological comorbidities. METHODS: We analyzed baseline data in 488 CP patients and 254 control subjects enrolled in PROCEED (Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies), an ongoing longitudinal cohort study. Participants completed the PROMIS-Global Health, which captures global physical and mental health, and the PROMIS-29 profile, which captures 7 symptom domains. Self-reported pain was categorized by severity (none, mild-moderate, severe) and temporal nature (none, intermittent, constant). Demographic and clinical data were obtained from the PROCEED database. RESULTS: Pain was significantly associated with impairments in physical and mental health. Compared with participants with no pain, CP participants with severe pain (but not mild-moderate pain) had more decrements in each PROMIS domain in multivariable models (effect sizes, 2.54-7.03) and had a higher prevalence of clinically significant depression, anxiety, sleep disturbance, and physical disability (odds ratios, 2.11-4.74). Similar results were noted for constant pain (but not intermittent pain) for PROMIS domains (effect sizes, 4.08-10.37) and clinically significant depression, anxiety, sleep disturbance and physical disability (odds ratios, 2.80-5.38). CONCLUSIONS: Severe and constant pain are major drivers for poor psychological and physical health in CP. Systematic evaluation and management of psychiatric comorbidities and sleep disturbance should be incorporated into routine management of patients with CP. (ClinicalTrials.gov, Number: NCT03099850).

ACG Clinical Guideline: Diagnosis and Management of Gastrointestinal Subepithelial Lesions.

Subepithelial lesions (SEL) of the GI tract represent a mix of benign and potentially malignant entities including tumors, cysts, or extraluminal structures causing extrinsic compression of the gastrointestinal wall. SEL can occur anywhere along the GI tract and are frequently incidental findings encountered during endoscopy or cross-sectional imaging. This clinical guideline of the American College of Gastroenterology was developed using the Grading of Recommendations Assessment, Development, and Evaluation process and is intended to suggest preferable approaches to a typical patient with a SEL based on the currently available published literature. Among the recommendations, we suggest endoscopic ultrasound (EUS) with tissue acquisition to improve diagnostic accuracy in the identification of solid nonlipomatous SEL and EUS fine-needle biopsy alone or EUS fine-needle aspiration with rapid on-site evaluation sampling of solid SEL. There is insufficient evidence to recommend surveillance vs resection of gastric gastrointestinal stromal tumors (GIST) <2 cm in size. Owing to their malignant potential, we suggest resection of gastric GIST >2 cm and all nongastric GIST. When exercising clinical judgment, particularly when statements are conditional suggestions and/or treatments pose significant risks, health-care providers should incorporate this guideline with patient-specific preferences, medical comorbidities, and overall health status to arrive at a patient-centered approach.

Accurate Identification of Mucinous Pancreatic Cystic Lesions Using Small-Volume Analytes.

INTRODUCTION: The accurate identification of mucinous pancreatic cystic lesions (PCLs) is paramount for cancer risk stratification. Cyst fluid carcinoembryonic antigen (CEA), the only routinely used test, requires high volumes and has low sensitivity. We aimed to compare the performance of two investigational small-volume biomarkers, glucose and the protease gastricsin, to CEA for PCL classification. METHODS: We obtained cyst fluid samples from 81 patients with pathologically confirmed PCLs from four institutions between 2003 and 2016. Gastricsin activity was measured using an internally quenched fluorescent substrate. Glucose levels were measured with a standard glucometer. CEA levels were obtained from the medical record. Models using Classification and Regression Trees were created to predict mucinous status. Model performance was evaluated using nested cross-validation. RESULTS: Gastricsin activity, CEA, and glucose levels from patients with mucinous (n = 50) and nonmucinous (n = 31) PCLs were analyzed. Area under the curve (AUC) was similar for individual classifiers (gastricsin volume normalized [GVN] 0.88; gastricsin protein concentration normalized [GPN] 0.95; glucose 0.83; CEA 0.84). The combination of two classifiers did not significantly improve AUC, with CEA + GVN (0.88) performing similarly to CEA + GPN (0.95), GVN + glucose (0.87), GPN + glucose (0.95), and CEA + glucose (0.84). The three-analyte combination performed similarly to single and dual classifiers (GPN + glucose + CEA AUC 0.95; GVN + glucose + CEA AUC 0.87). After multiple comparison corrections, there were no significant differences between the individual, dual, and triple classifiers. CONCLUSIONS: Gastricsin and glucose performed similarly to CEA and required <5% of the volume required for CEA; these classifiers may be useful in patients with limited cyst fluid. Future multicenter prospective studies are needed to validate and compare these novel small-volume biomarkers.

Automated scoring of total inflammation in renal allograft biopsies.

BACKGROUND: Computer-assisted scoring is gaining prominence in the evaluation of renal histology; however, much of the focus has been on identifying larger objects such as glomeruli. Total inflammation impacts graft outcome, and its quantification requires tools to identify objects at the cellular level or smaller. The goal of the current study was to use CD45 stained slides coupled with image analysis tools to quantify the amount of non-glomerular inflammation within the cortex. METHODS: Sixty renal transplant whole slide images were used for digital image analysis. Multiple thresholding methods using pixel intensity and object size were used to identify inflammation in the cortex. Additionally, convolutional neural networks were used to separate glomeruli from other objects in the cortex. This combined measure of inflammation was then correlated with rescored Banff total inflammation classification and outcomes. RESULTS: Identification of glomeruli on biopsies had high fidelity (mean pixelwise dice coefficient of .858). Continuous total inflammation scores correlated well with Banff rescoring (maximum Pearson correlation .824). A separate set of thresholds resulted in a significant correlation with alloimmune graft loss. CONCLUSIONS: Automated scoring of inflammation showed a high correlation with Banff scoring. Digital image analysis provides a powerful tool for analysis of renal pathology, not only because it is reproducible and can be automated, but also because it provides much more granular data for studies.

Multiple abnormal peripheral blood gene expression assay results are correlated with subsequent graft loss after kidney transplantation.

BACKGROUND: The aim of this study was to correlate peripheral blood gene expression profile (GEP) results during the first post-transplant year with outcomes after kidney transplantation. METHODS: We conducted a prospective, multicenter observational study of obtaining peripheral blood at five timepoints during the first post-transplant year to perform a GEP assay. The cohort was stratified based on the pattern of the peripheral blood GEP results: Tx-all GEP results normal, 1 Not-TX had one GEP result abnormal and >1 Not-TX two or more abnormal GEP results. We correlated the GEP results with outcomes after transplantation. RESULTS: We enrolled 240 kidney transplant recipients. The cohort was stratified into the three groups: TX n = 117 (47%), 1 Not-TX n = 59 (25%) and >1 Not-TX n = 64 (27%). Compared to the TX group, the >1 Not-TX group had lower eGFR (p < .001) and more chronic changes on 1-year surveillance biopsy (p = .007). Death censored graft survival showed inferior graft survival in the >1 Not-TX group (p < .001) but not in the 1 Not-TX group. All graft losses in the >1 Not-TX group occurred after 1-year post-transplant. CONCLUSIONS: We conclude that a pattern of persistently Not-TX GEP assay correlates with inferior graft survival.

Novel Circulating and Tissue Monocytes as Well as Macrophages in Pancreatitis and Recovery.

BACKGROUND AND AIMS: Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality. Uncovering inflammatory pathways that lead to progression and recovery will inform ways to monitor and/or develop effective therapies. METHODS: We performed single-cell mass Cytometry by Time Of Flight (CyTOF) analysis to identify pancreatic and systemic inflammatory signals during mild AP (referred to as AP), severe AP (SAP), and recovery using 2 independent experimental models and blood from patients with AP and recurrent AP. Flow cytometric validation of monocytes subsets identified using CyTOF analysis was performed independently. RESULTS: Ly6C+ inflammatory monocytes were the most altered cells in the pancreas during experimental AP, recovery, and SAP. Deep profiling uncovered heterogeneity among pancreatic and blood monocytes and identified 7 novel subsets during AP and recovery, and 6 monocyte subsets during SAP. Notably, a dynamic shift in pancreatic CD206+ macrophage population was observed during AP and recovery. Deeper profiling of the CD206+ macrophage identified 7 novel subsets during AP, recovery, and SAP. Differential expression analysis of these novel monocyte and CD206+ macrophage subsets revealed significantly altered surface (CD44, CD54, CD115, CD140a, CD196, podoplanin) and functional markers (interferon-γ, interleukin 4, interleukin 22, latency associated peptide-transforming growth factor-ß, tumor necrosis factor-α, T-bet, RoRγt) that were associated with recovery and SAP. Moreover, a targeted functional analysis further revealed distinct expression of pro- and anti-inflammatory cytokines by pancreatic CD206+ macrophage subsets as the disease either progressed or resolved. Similarly, we identified heterogeneity among circulating classical inflammatory monocytes (CD14+CD16-) and novel subsets in patients with AP and recurrent AP. CONCLUSIONS: We identified several novel monocyte/macrophage subsets with unique phenotype and functional characteristics that are associated with AP, recovery, and SAP. Our findings highlight differential innate immune responses during AP progression and recovery that can be leveraged for future disease monitoring and targeting.

High Prevalence of Osteopathy in Chronic Pancreatitis: A Cross-sectional Analysis From the PROCEED Study.

BACKGROUND & AIMS: Chronic pancreatitis (CP) is associated with osteopathy (osteoporosis or osteopenia). However, existing literature is mostly limited to retrospective or administrative studies that have not clearly defined the prevalence and risk factors. Our aim was to identify patient- and disease-related associations with osteopathy in a prospective cohort study of CP. METHODS: We studied 282 subjects with definitive CP enrolled in the PROCEED study who had a baseline dual-energy X-ray absorptiometry (DXA) scan. Osteopenia and osteoporosis were defined using the lowest T-scores. Clinical data were collected using standardized case report forms. Comparisons were performed with a multivariate logistic regression model with forward selection to identify risk factors for osteopathy. RESULTS: The majority of subjects had osteopathy on DXA scan (56.0%; 17.0% osteoporosis; 39.0% osteopenia). Subjects with osteopathy had a higher prevalence of traumatic (40.0% vs 26.4%; P = .02) and spontaneous fractures (3.9% vs 0; P = .04). On multivariate analysis, older age (odds ratio [OR], 1.29 per 5 years; 95% confidence interval [CI], 1.15-1.45), female sex (OR, 3.08; 95% CI, 1.75-5.43), white race (OR, 2.68; 95% CI, 1.20-6.01), and underweight body mass index category (OR, 7.40; 95% CI, 1.56-34.99) were associated with higher probability of osteopathy. There were no significant associations between osteopathy and other patient and disease-related features of CP. CONCLUSION: In the largest study of patients with CP who underwent DXA screening, the majority had osteopathy. There are overlapping risk factors with osteopathy in the general population, but the high prevalence in men and younger women supports the need for future investigations into the mechanisms of bone loss in CP. CLINICALTRIALS: gov number, NCT03099850.

Management of Incidentally Detected Gallbladder Polyps: Society of Radiologists in Ultrasound Consensus Conference Recommendations.

Gallbladder polyps (also known as polypoid lesions of the gallbladder) are a common incidental finding. The vast majority of gallbladder polyps smaller than 10 mm are not true neoplastic polyps but are benign cholesterol polyps with no inherent risk of malignancy. In addition, recent studies have shown that the overall risk of gallbladder cancer is not increased in patients with small gallbladder polyps, calling into question the rationale for frequent and prolonged follow-up of these common lesions. In 2021, a Society of Radiologists in Ultrasound, or SRU, consensus conference was convened to provide recommendations for the management of incidentally detected gallbladder polyps at US. See also the editorial by Sidhu and Rafailidis in this issue.

Pilot-phase PET/CT study targeting integrin αvß6 in pancreatic cancer patients using the cystine-knot peptide-based 18F-FP-R01-MG-F2.

PURPOSE: A novel cystine-knot peptide-based PET radiopharmaceutical, 18F-FP-R01-MG-F2 (knottin), was developed to selectively bind to human integrin αvß6 which is overexpressed in pancreatic cancer. The purpose of this study is to evaluate the safety, biodistribution, dosimetry, and lesion uptake of 18F-FP-R01-MG-F2 in patients with pancreatic cancer. METHODS: Fifteen patients (6 men, 9 women) with histologically confirmed pancreatic cancer were prospectively enrolled and underwent knottin PET/CT between March 2017 and February 2021 (ClinicalTrials.gov Identifier NCT02683824). Vital signs and laboratory results were collected before and after the imaging scans. Maximum standardized uptake values (SUVmax) and mean SUV (SUVmean) were measured in 24 normal tissues and pancreatic cancer lesions for each patient. From the biodistribution data, the organ doses and whole-body effective dose were calculated using OLINDA/EXM software. RESULTS: There were no significant changes in vital signs or laboratory values that qualified as adverse events or serious adverse events. At 1 h post-injection, areas of high 18F-FP-R01-MG-F2 uptake included the pituitary gland, stomach, duodenum, kidneys, and bladder (average SUVmean: 9.7-14.5). Intermediate uptake was found in the normal pancreas (average SUVmean: 4.5). Mild uptake was found in the lungs and liver (average SUVmean < 1.0). The effective dose was calculated to be 2.538 × 10-2 mSv/MBq. Knottin PET/CT detected all known pancreatic tumors in the 15 patients, although it did not detect small peri-pancreatic lymph nodes of less than 1 cm in short diameter in two of three patients who had lymph node metastases at surgery. Knottin PET/CT detected distant metastases in the lungs (n = 5), liver (n = 4), and peritoneum (n = 2), confirmed by biopsy and/or contrast-enhanced CT. CONCLUSION: 18F-FP-R01-MG-F2 is a safe PET radiopharmaceutical with an effective dose comparable to other diagnostic agents. Evaluation of the primary pancreatic cancer and distant metastases with 18F-FP-R01-MG-F2 PET is feasible, but larger studies are required to define the role of this approach. TRIAL REGISTRATION: NCT02683824.

Characterizing gastrointestinal dysfunction after pancreatic resection: a single-center retrospective study.

BACKGROUND: There are many well-described potential gastrointestinal (GI) side effects of pancreatic resection that can cause patients to suffer from chronic malabsorption, diarrhea, and persistent nausea. These GI symptoms can affect postoperative recovery, initiation of adjuvant therapy, and overall quality of life (QOL). The purpose of this study is to quantify the incidence of post-procedural complications and identify patients at higher risk for experiencing GI dysfunction after pancreatectomy. METHODS: A retrospective review of patients who underwent pancreatic resection at a single institution between January 2014 and December 2019 was performed. Demographics, operative factors, and postoperative gastrointestinal symptomatology and treatments were obtained by chart review. Significance tests were performed to compare GI dysfunction between patient subgroups. RESULTS: A total of 545 patients underwent pancreatic resection; within the cohort 451 patients (83%) underwent a pancreaticoduodenectomy (PD) and the most common indication was pancreatic adenocarcinoma. Two-thirds of patients (67%) reported gastrointestinal symptoms persisting beyond hospitalization. Only 105 patients (20%) were referred to gastroenterology for evaluation with 30 patients (5.5%) receiving a formal diagnosis. Patients who underwent PD were more likely to report GI symptoms and patients who identified as Caucasian were more likely to be referred to gastroenterology for evaluation. CONCLUSIONS: Gastrointestinal dysfunction after pancreatic resection occurs frequently yet only a small percentage of patients are referred for formal testing and diagnosis. There also appears to be a racial difference in referral patterns. Patients would benefit if earlier attention was dedicated to the diagnosis and corresponding treatment for postoperative digestive health disorders to optimize treatment planning and QOL.

Quality metrics in the performance of EUS: a population-based observational cohort of the United States.

BACKGROUND AND AIMS: There are few data on the quality of EUS in the community setting. We characterized EUS performance at the individual facility level in 3 large American states, using need for repeat biopsy (NRB) as a metric for procedural failure, and the rate of unplanned hospital encounters (UHEs) as a metric for adverse events. METHODS: We collected data on 76,614 EUS procedures performed at 166 facilities in California, Florida, and New York (2009-2014). The endpoints for the study were 7-day rate of UHEs after EUS, and 30-day rate of NRB after EUS with fine-needle aspiration. Facility-level factors analyzed included annual procedure volume, urban/rural location, and free-standing status (facilities not attached to a larger hospital). Predictors for UHE and NRB were analyzed in both multivariable regression and nonparametric local regression. RESULTS: Facility volume did not predict risk for UHEs. However, high facility volume protected against NRB (P trend <.001) even after adjustment for other facility-level factors. When regressing facility volume against risk for NRB in local regression, a join point (inflection point) was identified at 97 procedures per annum. Once facilities reached this threshold volume, there appeared little additional protective effect of higher volume. Rural facility location (odds ratio, 1.81; 95% confidence interval, 1.36-2.40) and free-standing status (odds ratio, 1.57; 95% confidence interval, 1.16-2.13) were also associated with NRB. CONCLUSION: Facility volume does not predict risk for adverse events after EUS. However, high facility volume is associated with decreased rates of technical failure (as assessed by NRB). These data provide one of the first descriptions of EUS practice in community settings and highlight opportunities to improve endoscopic quality nationally.

Novel rigidizing overtube for colonoscope stabilization and loop prevention (with video).

BACKGROUND AND AIMS: Loop formation can impede endoscope advancement, destabilize the tip, and cause pain. Strategies to mitigate looping include torque-based reduction maneuvers, variable stiffness shafts, and abdominal splinting. In some cases, these strategies are insufficient, and there is need for novel instruments. Loop formation is of particular concern in colonoscopy, but it can also impact performance of other endoscopic procedures such as enteroscopy and altered-anatomy ERCP. In this case series we demonstrate the utility of a novel rigidizing overtube (Pathfinder; Neptune Medical, Burlingame, Calif, USA) in colonoscopy and other endoscopic procedures where loop management is critical. METHODS: We describe our initial experience with the Pathfinder overtube in 29 patients. The overtube is 85 cm long and can accommodate a pediatric colonoscope. In its native state, the overtube is extremely flexible. Once the overtube is advanced to the desired location, application of a vacuum to the device causes the device to become 15 times stiffer. The endoscope can then be advanced through the overtube without loop formation in the region that the overtube traverses. RESULTS: The overtube was used in 29 patients to assist with difficult procedures. Patients were predominantly men (n = 18; 62.1%), with a median age of 66 years (interquartile range, 57-72). One patient received an upper endoscopy (3.4%), 24 received colonoscopy (82.8%), and 4 received enteroscopy (13.8%). The overtube was used in 12 procedures for incomplete colonoscopy (41.4%), 6 for depth (20.7%), and 11 for stability (37.9%). Colonoscopy was performed in the setting of screening (n = 3), surveillance given polyp history (n = 7), referrals for polyp removal (n = 10), workup of iron deficiency anemia (n = 2), and incomplete colonoscopy (n = 1). The lower endoscopy cases had a median cecal intubation time of 5 minutes (interquartile range, 4.25-7). Enteroscopy was performed in 4 patients: In one patient the distal 60 cm of the ileum was examined with a pediatric colonoscope to exclude ileitis, in another the overtube was used to stabilize a 6-mm endoscope to traverse a tight Crohn's ileocolonic stricture, in a third patient altered-anatomy ERCP was performed using an enteroscope through the overtube to reach a hepaticojejunostomy, and in the final patient upper enteroscopy was performed and the mid-jejunum was reached. We present 4 cases that demonstrate the use of the overtube. There were no adverse events. CONCLUSIONS: Initial experience with a novel rigidizing overtube suggests that this tool can be useful in colonoscopy and other endoscopic procedures affected by looping.