Publications by authors named "Suresh T Chari"

258 Publications

Quality gaps in public pancreas imaging datasets: Implications & challenges for AI applications.

Pancreatology 2021 Apr 2. Epub 2021 Apr 2.

Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. Electronic address:

Objective: Quality gaps in medical imaging datasets lead to profound errors in experiments. Our objective was to characterize such quality gaps in public pancreas imaging datasets (PPIDs), to evaluate their impact on previously published studies, and to provide post-hoc labels and segmentations as a value-add for these PPIDs.

Methods: We scored the available PPIDs on the medical imaging data readiness (MIDaR) scale, and evaluated for associated metadata, image quality, acquisition phase, etiology of pancreas lesion, sources of confounders, and biases. Studies utilizing these PPIDs were evaluated for awareness of and any impact of quality gaps on their results. Volumetric pancreatic adenocarcinoma (PDA) segmentations were performed for non-annotated CTs by a junior radiologist (R1) and reviewed by a senior radiologist (R3).

Results: We found three PPIDs with 560 CTs and six MRIs. NIH dataset of normal pancreas CTs (PCT) (n = 80 CTs) had optimal image quality and met MIDaR A criteria but parts of pancreas have been excluded in the provided segmentations. TCIA-PDA (n = 60 CTs; 6 MRIs) and MSD(n = 420 CTs) datasets categorized to MIDaR B due to incomplete annotations, limited metadata, and insufficient documentation. Substantial proportion of CTs from TCIA-PDA and MSD datasets were found unsuitable for AI due to biliary stents [TCIA-PDA:10 (17%); MSD:112 (27%)] or other factors (non-portal venous phase, suboptimal image quality, non-PDA etiology, or post-treatment status) [TCIA-PDA:5 (8.5%); MSD:156 (37.1%)]. These quality gaps were not accounted for in any of the 25 studies that have used these PPIDs (NIH-PCT:20; MSD:1; both: 4). PDA segmentations were done by R1 in 91 eligible CTs (TCIA-PDA:42; MSD:49). Of these, corrections were made by R3 in 16 CTs (18%) (TCIA-PDA:4; MSD:12) [mean (standard deviation) Dice: 0.72(0.21) and 0.63(0.23) respectively].

Conclusion: Substantial quality gaps, sources of bias, and high proportion of CTs unsuitable for AI characterize the available limited PPIDs. Published studies on these PPIDs do not account for these quality gaps. We complement these PPIDs through post-hoc labels and segmentations for public release on the TCIA portal. Collaborative efforts leading to large, well-curated PPIDs supported by adequate documentation are critically needed to translate the promise of AI to clinical practice.
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http://dx.doi.org/10.1016/j.pan.2021.03.016DOI Listing
April 2021

Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review.

Pancreas 2021 Mar;50(3):251-279

Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA.

Abstract: Despite considerable research efforts, pancreatic cancer is associated with a dire prognosis and a 5-year survival rate of only 10%. Early symptoms of the disease are mostly nonspecific. The premise of improved survival through early detection is that more individuals will benefit from potentially curative treatment. Artificial intelligence (AI) methodology has emerged as a successful tool for risk stratification and identification in general health care. In response to the maturity of AI, Kenner Family Research Fund conducted the 2020 AI and Early Detection of Pancreatic Cancer Virtual Summit (www.pdac-virtualsummit.org) in conjunction with the American Pancreatic Association, with a focus on the potential of AI to advance early detection efforts in this disease. This comprehensive presummit article was prepared based on information provided by each of the interdisciplinary participants on one of the 5 following topics: Progress, Problems, and Prospects for Early Detection; AI and Machine Learning; AI and Pancreatic Cancer-Current Efforts; Collaborative Opportunities; and Moving Forward-Reflections from Government, Industry, and Advocacy. The outcome from the robust Summit conversations, to be presented in a future white paper, indicate that significant progress must be the result of strategic collaboration among investigators and institutions from multidisciplinary backgrounds, supported by committed funders.
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http://dx.doi.org/10.1097/MPA.0000000000001762DOI Listing
March 2021

Pancreatic cancer in patients with autoimmune pancreatitis: A scoping review.

Pancreatology 2021 Mar 18. Epub 2021 Mar 18.

CLINTEC, Karolinska Institute, Stockholm, Sweden; Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.

Background: Chronic pancreatitis is a known risk factor of pancreatic cancer (PDAC). A similar association has been suggested but not demonstrated for autoimmune pancreatitis (AIP).

Objective: The aim of our study was to identify and analyse all published cases of AIP and PDAC co-occurrence, focusing on the interval between the diagnoses and the cancer site within the pancreas.

Methods: Relevant studies were identified through automatic searches of the MEDLINE, EMBASE, Scopus, and Web of Science databases, and supplemented by manual checks of reference lists in all retrieved articles. Missing/unpublished data were obtained from the authors of relevant publications in the form of pre-prepared questionnaires.

Results: A total of 45 cases of PDAC in AIP patients were identified, of which 12 were excluded from the analysis due to suspicions of duplicity or lack of sufficient data. Thirty-one patients (94%) had type 1 AIP. Synchronous occurrence of PDAC and AIP was reported in 11 patients (33%), metachronous in 22 patients (67%). In the metachronous group, the median period between diagnoses was 66.5 months (2-186) and a majority of cancers (86%) occurred more than two years after AIP diagnosis. In most patients (70%), the cancer originated in the part of the pancreas affected by AIP.

Conclusions: In the literature, there are reports on numerous cases of PDAC in AIP patients. PDAC is more frequent in AIP type 1 patients, typically metachronous in character, and generally found in the part of the pancreas affected by AIP.
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http://dx.doi.org/10.1016/j.pan.2021.03.007DOI Listing
March 2021

Two-stage deep learning model for fully automated pancreas segmentation on computed tomography: Comparison with intra-reader and inter-reader reliability at full and reduced radiation dose on an external dataset.

Med Phys 2021 Feb 17. Epub 2021 Feb 17.

Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Purpose: To develop a two-stage three-dimensional (3D) convolutional neural networks (CNNs) for fully automated volumetric segmentation of pancreas on computed tomography (CT) and to further evaluate its performance in the context of intra-reader and inter-reader reliability at full dose and reduced radiation dose CTs on a public dataset.

Methods: A dataset of 1994 abdomen CT scans (portal venous phase, slice thickness ≤ 3.75-mm, multiple CT vendors) was curated by two radiologists (R1 and R2) to exclude cases with pancreatic pathology, suboptimal image quality, and image artifacts (n = 77). Remaining 1917 CTs were equally allocated between R1 and R2 for volumetric pancreas segmentation [ground truth (GT)]. This internal dataset was randomly divided into training (n = 1380), validation (n = 248), and test (n = 289) sets for the development of a two-stage 3D CNN model based on a modified U-net architecture for automated volumetric pancreas segmentation. Model's performance for pancreas segmentation and the differences in model-predicted pancreatic volumes vs GT volumes were compared on the test set. Subsequently, an external dataset from The Cancer Imaging Archive (TCIA) that had CT scans acquired at standard radiation dose and same scans reconstructed at a simulated 25% radiation dose was curated (n = 41). Volumetric pancreas segmentation was done on this TCIA dataset by R1 and R2 independently on the full dose and then at the reduced radiation dose CT images. Intra-reader and inter-reader reliability, model's segmentation performance, and reliability between model-predicted pancreatic volumes at full vs reduced dose were measured. Finally, model's performance was tested on the benchmarking National Institute of Health (NIH)-Pancreas CT (PCT) dataset.

Results: Three-dimensional CNN had mean (SD) Dice similarity coefficient (DSC): 0.91 (0.03) and average Hausdorff distance of 0.15 (0.09) mm on the test set. Model's performance was equivalent between males and females (P = 0.08) and across different CT slice thicknesses (P > 0.05) based on noninferiority statistical testing. There was no difference in model-predicted and GT pancreatic volumes [mean predicted volume 99 cc (31cc); GT volume 101 cc (33 cc), P = 0.33]. Mean pancreatic volume difference was -2.7 cc (percent difference: -2.4% of GT volume) with excellent correlation between model-predicted and GT volumes [concordance correlation coefficient (CCC)=0.97]. In the external TCIA dataset, the model had higher reliability than R1 and R2 on full vs reduced dose CT scans [model mean (SD) DSC: 0.96 (0.02), CCC = 0.995 vs R1 DSC: 0.83 (0.07), CCC = 0.89, and R2 DSC:0.87 (0.04), CCC = 0.97]. The DSC and volume concordance correlations for R1 vs R2 (inter-reader reliability) were 0.85 (0.07), CCC = 0.90 at full dose and 0.83 (0.07), CCC = 0.96 at reduced dose datasets. There was good reliability between model and R1 at both full and reduced dose CT [full dose: DSC: 0.81 (0.07), CCC = 0.83 and reduced dose DSC:0.81 (0.08), CCC = 0.87]. Likewise, there was good reliability between model and R2 at both full and reduced dose CT [full dose: DSC: 0.84 (0.05), CCC = 0.89 and reduced dose DSC:0.83(0.06), CCC = 0.89]. There was no difference in model-predicted and GT pancreatic volume in TCIA dataset (mean predicted volume 96 cc (33); GT pancreatic volume 89 cc (30), p = 0.31). Model had mean (SD) DSC: 0.89 (0.04) (minimum-maximum DSC: 0.79 -0.96) on the NIH-PCT dataset.

Conclusion: A 3D CNN developed on the largest dataset of CTs is accurate for fully automated volumetric pancreas segmentation and is generalizable across a wide range of CT slice thicknesses, radiation dose, and patient gender. This 3D CNN offers a scalable tool to leverage biomarkers from pancreas morphometrics and radiomics for pancreatic diseases including for early pancreatic cancer detection.
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http://dx.doi.org/10.1002/mp.14782DOI Listing
February 2021

High Detection Rates of Pancreatic Cancer Across Stages by Plasma Assay of Novel Methylated DNA Markers and CA19-9.

Clin Cancer Res 2021 Feb 16. Epub 2021 Feb 16.

Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota.

Purpose: We have previously identified tissue methylated DNA markers (MDMs) associated with pancreatic ductal adenocarcinoma (PDAC). In this case-control study, we aimed to assess the diagnostic performance of plasma MDMs for PDAC.

Experimental Design: Thirteen MDMs (, and ) were identified on the basis of selection criteria applied to results of prior tissue experiments and assays were optimized in plasma. Next, 340 plasma samples (170 PDAC cases and 170 controls) were assayed using target enrichment long-probe quantitative amplified signal method. Initially, 120 advanced-stage PDAC cases and 120 healthy controls were used to train a prediction algorithm at 97.5% specificity using random forest modeling. Subsequently, the locked algorithm derived from the training set was applied to an independent blinded test set of 50 early-stage PDAC cases and 50 controls. Finally, data from all 340 patients were combined, and cross-validated.

Results: The cross-validated area under the receiver operating characteristic curve (AUC) for the training set was 0.93 (0.89-0.96) for the MDM panel alone, 0.91 (95% confidence interval, 0.87-0.96) for carbohydrate antigen 19-9 (CA19-9) alone, and 0.99 (0.98-1) for the combined MDM-CA19-9 panel. In the test set of early-stage PDAC, the AUC for MDMs alone was 0.84 (0.76-0.92), CA19-9 alone was 0.87 (0.79-0.94), and combined MDM-CA19-9 panel was 0.90 (0.84-0.97) significantly better compared with either MDMs alone or CA19-9 alone ( = 0.0382 and 0.0490, respectively). At a preset specificity of 97.5%, the sensitivity for the combined panel in the test set was 80% (28%-99%) for stage I disease and 82% (68%-92%) for stage II disease. Using the combined datasets, the cross-validated AUC was 0.9 (0.86-0.94) for the MDM panel alone and 0.89 for CA19-9 alone (0.84-0.93) versus 0.97 (0.94-0.99) for the combined MDM-CA19-9 panel ( ≤ 0.0001). Overall, cross-validated sensitivity of MDM-CA19-9 panel was 92% (83%-98%), with an observed specificity of 92% at the preset specificity of 97.5%.

Conclusions: Plasma MDMs in combination with CA19-9 detect PDAC with significantly higher accuracy compared with either biomarker individually.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0235DOI Listing
February 2021

An international study of interobserver variability of "string sign" of pancreatic cysts among experienced endosonographers.

Endosc Ultrasound 2021 Jan-Feb;10(1):39-50

Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background And Objectives: No single optimal test reliably determines the pancreatic cyst subtype. Following EUS-FNA, the "string sign" test can differentiate mucinous from nonmucinous cysts. However, the interobserver variability of string sign results has not been studied.

Methods: An experienced endosonographer performed EUS-FNA of pancreatic cysts on different patients and was recorded on video performing the string sign test for each. The videos were shared internationally with 14 experienced endosonographers, with a survey for each video: "Is the string sign positive?" and "If the string sign is positive, what is the length of the formed string?" Also asked "What is the cutoff length for string sign to be considered positive?" Interobserver variability was assessed using the kappa statistic (κ).

Results: A total of 112 observations were collected from 14 endosonographers. Regarding string sign test positivity, κ was 0.6 among 14 observers indicating good interrater agreement (P < 0.001) while κ was 0.38 when observers were compared to the index endosonographer demonstrating marginal agreement (P < 0.001). Among observations of the length of the string in positive samples, 89.8% showed >5 mm of variability (P < 0.001), indicating marked variability. There was poor agreement on the cutoff length for a string to be considered positive.

Conclusion: String sign of pancreatic cysts has a good interobserver agreement regarding its positivity that can help in differentiating mucinous from nonmucinous pancreatic cysts. However, the agreement is poor on the measured length of the string and the cutoff length of the formed string to be considered a positive string sign.
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http://dx.doi.org/10.4103/eus.eus_73_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980687PMC
January 2021

Memorial Tribute to Rakesh Kumar Tandon, MD, PhD (1941-2020).

Pancreas 2021 Jan;50(1):1-2

Department of Surgery, University of Miami, Miami, FL.

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http://dx.doi.org/10.1097/MPA.0000000000001699DOI Listing
January 2021

A single center randomized double blind controlled trial of pentoxifylline in acute pancreatitis: Challenges and opportunities.

Pancreatology 2020 Dec 3;20(8):1592-1597. Epub 2020 Oct 3.

Division of Gastroenterology and Hepatology (Drs Vege, Horibe, Chari [emeritus Member], and Loftus and Ms Clemens) and Division of Biomedical Statistics and Informatics (Dr Enders), Mayo Clinic, Rochester, MN, USA.

Objectives: Despite substantial morbidity and mortality associated with acute pancreatitis (AP), only one small randomized controlled drug trial (RCT) is available in the past few decades from the United States. Hence, we conducted a single-center, double-blind, placebo-controlled RCT of pentoxifylline in AP.

Methods: A total of 9 doses of oral pentoxifylline 400 mg or placebo tablet, three times daily, was administered within 72 h of diagnosis, using randomization blocks by pharmacy. Primary outcome was a composite outcome including any of the following: death, peripancreatic and/or pancreatic necrosis, infected pancreatic necrosis, persistent organ failure, persistent systemic inflammatory response syndrome, hospital stay longer than 4 days, need for intensive care, and need for intervention for necrosis.

Results: Between July 7, 2015, and April 4, 2017, we identified 685 patients with AP, 233 met eligibility criteria and 176 were approached for the study. Of these, 91 (51.7%) declined and finally 45 in pentoxifylline group and 38 in placebo group (83 total) were compared. There were no significant differences in primary outcome (27 [60.0%] vs 15 [39.5%]; P = .06). Pentoxifylline group was not associated with any benefit, but withlonger stay (42% vs. 21%; P = .04) and higher readmission rates (16 %vs 3%; P = .047).

Conclusions: We could not demonstrate superiority of pentoxifylline over placebo. Smaller sample size and inclusion of all types of severity might be the reasons for lack of efficacy. The challenges observed in the present study indicate that, in order to conduct a successful drug trial in AP, a multi center collaboration is essential.
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http://dx.doi.org/10.1016/j.pan.2020.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704646PMC
December 2020

Utilisation of artificial intelligence for the development of an EUS-convolutional neural network model trained to enhance the diagnosis of autoimmune pancreatitis.

Gut 2020 Oct 7. Epub 2020 Oct 7.

Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA

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.
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http://dx.doi.org/10.1136/gutjnl-2020-322821DOI Listing
October 2020

Computerized tomography scan in pre-diagnostic pancreatic ductal adenocarcinoma: Stages of progression and potential benefits of early intervention: A retrospective study.

Pancreatology 2020 Oct 11;20(7):1495-1501. Epub 2020 Aug 11.

Division of Gastroenterology and Hepatology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: The frequency, nature and timeline of changes on thin-slice (≤3 mm) multi-detector computerized tomography (CT) scans in the pre-diagnostic phase of pancreatic ductal adenocarcinoma (PDAC) are unknown. It is unclear if identifying imaging changes in this phase will improve PDAC survival beyond lead time.

Methods: From a cohort of 128 subjects (Cohort A) with CT scans done 3-36 months before diagnosis of PDAC we developed a CTgram defining CT Stages (CTS) I through IV in the radiological progression of pre-diagnostic PDAC. We constructed Cohort B of PDAC resected at CTS I and II and compared survival in CTS I and II in Cohort A (n = 22 each; control natural history cohort) vs Cohort B (n = 33 and 72, respectively; early interception cohort).

Results: CTs were abnormal in 16% and 85% at 24-36 and 3-6 months respectively, before PDAC diagnosis. The PDAC CTgram stages, findings and median lead times (months) to clinical diagnosis were: CTS I: Abrupt duct cut-off/duct dilatation (-12.8); CTS II: Low density mass confined to pancreas (-9.5), CTS III: Peri-pancreatic infiltration (-5.8), CTS IV: Distant metastases (only at diagnosis). PDAC survival was better in cohort B than in cohort A despite inclusion of lead time in Cohort A: CTS I (36 vs 17.2 months, p = 0.03), CTS II (35.2 vs 15.3 months, p = 0.04).

Conclusion: Starting 12-18 months before PDAC diagnosis, progressive and increasingly frequent changes occur on CT scans. Resection of PDAC at the time of pre-diagnostic CT changes is likely to provide survival benefit beyond lead time.
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http://dx.doi.org/10.1016/j.pan.2020.07.410DOI Listing
October 2020

Development of a volumetric pancreas segmentation CT dataset for AI applications through trained technologists: a study during the COVID 19 containment phase.

Abdom Radiol (NY) 2020 12 16;45(12):4302-4310. Epub 2020 Sep 16.

Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Purpose: To evaluate the performance of trained technologists vis-à-vis radiologists for volumetric pancreas segmentation and to assess the impact of supplementary training on their performance.

Methods: In this IRB-approved study, 22 technologists were trained in pancreas segmentation on portal venous phase CT through radiologist-led interactive videoconferencing sessions based on an image-rich curriculum. Technologists segmented pancreas in 188 CTs using freehand tools on custom image-viewing software. Subsequent supplementary training included multimedia videos focused on common errors, which were followed by second batch of 159 segmentations. Two radiologists reviewed all cases and corrected inaccurate segmentations. Technologists' segmentations were compared against radiologists' segmentations using Dice-Sorenson coefficient (DSC), Jaccard coefficient (JC), and Bland-Altman analysis.

Results: Corrections were made in 71 (38%) cases from first batch [26 (37%) oversegmentations and 45 (63%) undersegmentations] and in 77 (48%) cases from second batch [12 (16%) oversegmentations and 65 (84%) undersegmentations]. DSC, JC, false positive (FP), and false negative (FN) [mean (SD)] in first versus second batches were 0.63 (0.15) versus 0.63 (0.16), 0.48 (0.15) versus 0.48 (0.15), 0.29 (0.21) versus 0.21 (0.10), and 0.36 (0.20) versus 0.43 (0.19), respectively. Differences were not significant (p > 0.05). However, range of mean pancreatic volume difference reduced in the second batch [- 2.74 cc (min - 92.96 cc, max 87.47 cc) versus - 23.57 cc (min - 77.32, max 30.19)].

Conclusion: Trained technologists could perform volumetric pancreas segmentation with reasonable accuracy despite its complexity. Supplementary training further reduced range of volume difference in segmentations. Investment into training technologists could augment and accelerate development of body imaging datasets for AI applications.
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http://dx.doi.org/10.1007/s00261-020-02741-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493700PMC
December 2020

Management of Immune-Related Colitis During the COVID-19 Pandemic.

Inflamm Bowel Dis 2020 Sep;26(10):e110-e111

Department of Gastroenterology, Hepatology and Nutrition, The University of MD Anderson Cancer Center, Houston, Texas, USA.

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http://dx.doi.org/10.1093/ibd/izaa235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454566PMC
September 2020

The long-term outcomes of patients with immunoglobulin G4-related sclerosing cholangitis: the Mayo Clinic experience.

J Gastroenterol 2020 Nov 8;55(11):1087-1097. Epub 2020 Aug 8.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 1st St SW, Rochester, MN, 55905, USA.

Background: The long-term outcomes of immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) are not well known.

Methods: The outcomes of patients with IgG4-SC at Mayo Clinic (1999-2018) were compared to an age- and gender-matched (1:1 ratio) group of patients with primary sclerosing cholangitis (PSC).

Results: We identified 89 patients with IgG4-SC; median age at diagnosis was 67 years, 81% were males, and the median follow-up was 5.7 years. Seventy-eight patients received prednisone for induction of remission, and 53 received at least one other immunosuppressive agent for maintenance of remission. Of the IgG4-SC group, 10 died (median time from diagnosis until death was 6.5 years): 2 due to cirrhosis, 3 due to cholangiocarcinoma (CCA), and 5 due to non-hepatobiliary causes. Eleven patients in the PSC group underwent liver transplantation, while none did in the IgG4-SC group. The incidence of a hepatobiliary adverse event (cirrhosis or CCA) was 3.4 times greater in the PSC compared to the IgG4-SC group (events per 1000 person-years: 52.6; 95% CI 38-73; vs. 15.6; 95% CI 7-32). The probability of development of a hepatobiliary adverse event within 10 years was 11% in the IgG4-SC compared to 45% in the PSC group (P = 0.0001). The overall survival tended to be higher in the IgG4-SC compared to the PSC group (10-year: 79% vs. 68%, respectively; P = 0.11).

Conclusions: In a cohort of IgG4-SC patients, 88% of whom were treated with immunosuppressive drugs, the risk of cirrhosis and CCA was significantly lower compared to an age- and gender-matched group with PSC.
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http://dx.doi.org/10.1007/s00535-020-01714-7DOI Listing
November 2020

Corrigendum to "Polychlorinated biphenyl exposures differentially regulate hepatic metabolism and pancreatic function: Implications for nonalcoholic steatohepatitis and diabetes" [Toxicology & Applied Pharmacology, 363 (2018) 22-33].

Toxicol Appl Pharmacol 2020 10 20;404:115149. Epub 2020 Jul 20.

Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY 40202, United States; Department of Biochemistry and Molecular Genetics, School of Medicine, University of Louisville, Louisville, KY 40202, United States; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Louisville, Louisville, KY 40202, United States. Electronic address:

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http://dx.doi.org/10.1016/j.taap.2020.115149DOI Listing
October 2020

Early detection of pancreatic cancer.

Curr Opin Gastroenterol 2020 09;36(5):456-461

Division of Gastroenterology and Hepatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Purpose Of Review: Pancreatic cancer is the third leading cause of cancer death and with a dismal 5-year survival of 10%. Poor survival of pancreatic cancer is mostly due to its presentation and diagnosis at a late stage. The present article aims to update clinicians with recent progress in the field of early detection of pancreatic cancer.

Recent Findings: Pancreatic cancer screening is not recommended in the general population due to its low prevalence. In this review, we discuss high-risk groups for pancreatic cancer, including inherited predisposition to pancreatic cancer, new-onset diabetes, mucinous pancreatic cyst, and chronic pancreatitis. We discuss methods of enrichment of high-risk groups with clinical models using electronic health records and biomarkers. We also discuss improvements in imaging modalities and emerging role of machine learning and artificial intelligence in the field of imaging and biomarker to aid in early identification of pancreatic cancer.

Summary: There are still vast challenges in the field of early detection of pancreatic cancer. We need to develop noninvasive prediagnostic validated biomarkers for longitudinal surveillance of high-risk individuals and imaging modalities that can identify pancreatic cancer early.
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http://dx.doi.org/10.1097/MOG.0000000000000663DOI Listing
September 2020

Impact of disconnected pancreatic duct syndrome on endoscopic ultrasound-guided drainage of pancreatic fluid collections.

Endoscopy 2020 Jul 6. Epub 2020 Jul 6.

Division of Gastroenterology and Hepatology, Mayo Clinic at Rochester, Rochester, Minnesota, USA.

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;  < 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;  = 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.
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http://dx.doi.org/10.1055/a-1213-1489DOI Listing
July 2020

Systemic Proteome Alterations Linked to Early Stage Pancreatic Cancer in Diabetic Patients.

Cancers (Basel) 2020 Jun 11;12(6). Epub 2020 Jun 11.

Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

Background: Diabetes is a risk factor associated with pancreatic ductal adenocarcinoma (PDAC), and new adult-onset diabetes can be an early sign of pancreatic malignancy. Development of blood-based biomarkers to identify diabetic patients who warrant imaging tests for cancer detection may represent a realistic approach to facilitate earlier diagnosis of PDAC in a risk population.

Methods: A spectral library-based proteomic platform was applied to interrogate biomarker candidates in plasma samples from clinically well-defined diabetic cohorts with and without PDAC. Random forest algorithm was used for prediction model building and receiver operating characteristic (ROC) curve analysis was applied to evaluate the prediction probability of potential biomarker panels.

Results: Several biomarker panels were cross-validated in the context of detection of PDAC within a diabetic background. In combination with carbohydrate antigen 19-9 (CA19-9), the panel, which consisted of apolipoprotein A-IV (APOA4), monocyte differentiation antigen CD14 (CD14), tetranectin (CLEC3B), gelsolin (GSN), histidine-rich glycoprotein (HRG), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), plasma kallikrein (KLKB1), leucine-rich alpha-2-glycoprotein (LRG1), pigment epithelium-derived factor (SERPINF1), plasma protease C1 inhibitor (SERPING1), and metalloproteinase inhibitor 1 (TIMP1), demonstrated an area under curve (AUC) of 0.85 and a two-fold increase in detection accuracy compared to CA19-9 alone. The study further evaluated the correlations of protein candidates and their influences on the performance of biomarker panels.

Conclusions: Proteomics-based multiplex biomarker panels improved the detection accuracy for diagnosis of early stage PDAC in diabetic patients.
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http://dx.doi.org/10.3390/cancers12061534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352938PMC
June 2020

Early Detection of Sporadic Pancreatic Ductal Adenocarcinoma: Problems, Promise, and Prospects.

Ann Intern Med 2020 04 17;172(8):558-559. Epub 2020 Mar 17.

University of Texas MD Anderson Cancer Center, Houston, Texas (S.T.C., A.M.).

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http://dx.doi.org/10.7326/M19-2336DOI Listing
April 2020

Validation of the Enriching New-Onset Diabetes for Pancreatic Cancer Model in a Diverse and Integrated Healthcare Setting.

Dig Dis Sci 2021 01 28;66(1):78-87. Epub 2020 Feb 28.

Department of Gastroenterology, Center for Pancreatic Care, Los Angeles Medical Center, Southern California Permanente Medical Group, Los Angeles, CA, USA.

Background: The risk of pancreatic cancer is elevated among people with new-onset diabetes (NOD). Based on Rochester Epidemiology Project Data, the Enriching New-Onset Diabetes for Pancreatic Cancer (END-PAC) model was developed and validated.

Aims: We validated the END-PAC model in a cohort of patients with NOD using retrospectively collected data from a large integrated health maintenance organization.

Methods: A retrospective cohort of patients between 50 and 84 years of age meeting the criteria for NOD in 2010-2014 was identified. Each patient was assigned a risk score (< 1: low risk; 1-2: intermediate risk; ≥ 3: high risk) based on the values of the predictors specified in the END-PAC model. Patients who developed pancreatic ductal adenocarcinoma (PDAC) within 3 years were identified using the Cancer Registry and California State Death files. Area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were estimated.

Results: Out of the 13,947 NOD patients who were assigned a risk score, 99 developed PDAC in 3 years (0.7%). Of the 3038 patients who had a high risk, 62 (2.0%) developed PDAC in 3 years. The risk increased to 3.0% in white patients with a high risk. The AUC was 0.75. At the 3+ threshold, the sensitivity, specificity, PPV, and NPV were 62.6%, 78.5%, 2.0%, and 99.7%, respectively.

Conclusions: It is critical that prediction models are validated before they are implemented in various populations and clinical settings. More efforts are needed to develop screening strategies most appropriate for patients with NOD in real-world settings.
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http://dx.doi.org/10.1007/s10620-020-06139-zDOI Listing
January 2021

New-Onset Diabetes, Longitudinal Trends in Metabolic Markers, and Risk of Pancreatic Cancer in a Heterogeneous Population.

Clin Gastroenterol Hepatol 2020 Jul 4;18(8):1812-1821.e7. Epub 2019 Dec 4.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, Los Angeles, California.

Background & Aims: Observational studies of predominantly white populations have found new-onset diabetes to be associated with increased risk of pancreatic cancer. We sought to determine whether this relationship applies to other races or ethnicities and to identify metabolic profiles associated with increased risk of pancreatic cancer.

Methods: We conducted a population-based cohort study of Asian, black, Hispanic and white patients from Kaiser Permanente Southern California from 2006 through 2016 (n = 1,499,627). Patients with diabetes were identified based on glucose and hemoglobin A1c (HbA1c) measurements. We used Cox regression to assess the relationship between diabetes status and duration and pancreatic cancer. For patients with recent diagnoses of diabetes (1 year or less) we compared longitudinal changes in glucose, HbA1c, and weight, from time of diabetes diagnosis through 3 years prior to the diagnosis, in patients with vs without pancreatic cancer.

Results: We identified 2,002 incident cases of pancreatic cancer from nearly 7.5 million person-years of follow-up. Compared to patients without diabetes, individuals who received a recent diagnosis of diabetes had an almost 7-fold increase in risk of pancreatic cancer (relative risk, 6.91; 95% CI, 5.76-8.30). Among patients with a recent diagnosis of diabetes, those who developed pancreatic cancer had more rapid increases in levels of glucose (Δslope: cases, 37.47 mg/dL vs non-cases, 27.68 mg/dL) and HbA1c (Δslope: cases, 1.39% vs non-cases, 0.86%) in the month preceding the diagnosis of diabetes, and subtle weight loss in the prior years (slope: cases -0.18 kg/interval vs non-cases 0.33 kg/interval). These longitudinal changes in markers of metabolism were stronger for specific race and ethnic groups.

Conclusions: In a study of a large ethnically diverse population, we found risk of pancreatic cancer to be increased among patients with a diagnosis of diabetes in the past year among different races and ethnicities. Weight loss and rapid development of poor glycemic control were associated with increased risk of pancreatic cancer in multiple races.
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http://dx.doi.org/10.1016/j.cgh.2019.11.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269863PMC
July 2020

Significance of peripheral eosinophilia for diagnosis of IgG4-related disease in subjects with elevated serum IgG4 levels.

Pancreatology 2020 Jan 27;20(1):74-78. Epub 2019 Nov 27.

Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, USA. Electronic address:

Objectives: In this study, we aim to assess the diagnostic utility of elevated serum IgG4 (sIgG4) concentration alone and in combination with peripheral eosinophilia (PE) for IgG4-related disease (IgG4-RD).

Methods: From the Mayo Clinic, Rochester electronic medical record database we identified 409 patients with above normal levels of sIgG4 (reference range 121-140 mg/dL) who had sIgG4 measured to differentiate IgG4-RD from another disease.

Results: Among 409 patients with any elevation in sIgG4 levels, 129 (31.5%) had a definite diagnosis of IgG4-RD. The prevalence of PE increased with increasing sIgG4 levels and was more likely to be seen in subjects with IgG4-RD vs. non-IgG4-RD at ≥1X (n = 35/120, 29.2% vs. n = 23/258, 8.9%; p < 0.001), ≥2X (n = 23/64, 35.9% vs. n = 5/54,9.3%; p = 0.001) and ≥3X (n = 18/42, 42.9% vs. n = 0/9, 0%; p = 0.015) of sIgG4 upper limit of normal (ULN), respectively. After adjusting for gender and age, sIgG4 levels ≥ 2X ULN with PE as a predictor, had a higher positive predictive value in predicting IgG4-RD (72.2% vs. 65.9%) with an Area Under the Receiver Operatic Characteristic Curve (AUC) of 0.776, compared to sIgG4 ≥ 2X ULN without PE predictor (AUC = 0.74), p = 0.016. PE, sIgG4≥2X ULN, male gender, and age independently predicted the disease with odds ratio of 4.89 (95% CI:2.51-9.54), 3.78 (95% CI:2.27-6.28), 2.78 (95% CI:1.55-4.97), and 1.03 (95% CI:1.02-1.05), respectively.

Conclusion: Even in subjects in whom IgG4-RD is suspected, only a minority (∼30%) with elevated sIgG4 levels have IgG4-RD. sIgG4 by itself is more specific at higher levels, though never diagnostic. PE increases with increasing sIgG4 and adds diagnostic value at higher sIgG4 levels.
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http://dx.doi.org/10.1016/j.pan.2019.11.016DOI Listing
January 2020

Clinical impact of celiac ganglia metastasis upon pancreatic ductal adenocarcinoma.

Pancreatology 2020 Jan 14;20(1):110-115. Epub 2019 Nov 14.

Division of Gastroenterology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. Electronic address:

Background: Pre-operative staging of pancreatic adenocarcinoma guides clinical decision making. Limited data indicate that metastasis to celiac ganglia (CG) correlates with poor prognosis. We investigated feasibility and safety of endoscopic ultrasound fine needle aspiration (EUS-FNA) detection of CG metastasis and its impact upon tumor stage, resectability, and survival in pancreatic ductal adenocarcinoma (PDAC).

Patients: We reviewed our prospectively maintained EUS and cytopathology databases to identify patients with FNA proven CG metastasis in patients with PDAC from 2004 to 2017. Clinical demographics, EUS, CT, MRI, cytopathology, cancer stage, and resectability data were analyzed. Survival of PDAC patients with CG metastasis was compared to the expected survival of PDAC patients of similar stage as reported by the United States National Cancer Database.

Results: Twenty-one patients with PDAC [median age 73 (IQR63-78); 14 (67%) female)], had CG metastasis confirmed by cytopathologic assessment. CG metastasis resulted in tumor upstaging relative to other EUS findings and cross sectional imaging findings in 12 (57%) and 15 (71%) patients, and converted cancers from resectable to unresectable relative to EUS and cross sectional imaging in 7 (37%) and 7 (37%) patients, respectively. In patients with PDAC, the survival of patients with CG metastasis was not significantly different from the overall survival (hazard ratio 0.71; 95% confidence interval 0.44, 1.13; p = 0.15).

Conclusions: EUS-FNA may safely identify CG metastases. While CG metastasis upstaged and altered the resectability status among this cohort of patients with PDAC, the survival data with regard to PDAC suggest that this may be misguided.
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http://dx.doi.org/10.1016/j.pan.2019.11.003DOI Listing
January 2020

Survival benefit of neoadjuvant therapy in patients with non-metastatic pancreatic ductal adenocarcinoma: A propensity matching and intention-to-treat analysis.

J Surg Oncol 2019 Nov 26;120(6):976-984. Epub 2019 Aug 26.

Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, Minnesota.

Background And Objectives: Conclusive evidence in favor of neoadjuvant therapy for those with non-metastatic pancreatic ductal adenocarcinoma (PDAC) is still lacking. The objective of this study was to evaluate the survival benefit of neoadjuvant therapy vs upfront surgery for patients with non-metastatic PDAC.

Methods: The study involved 565 patients undergoing neoadjuvant therapy or upfront surgery as the primary treatment for PDAC. Propensity score matching was performed between the neoadjuvant therapy group (NAT group) and the upfront surgery group (UFS group) using 20 clinical variables at diagnosis. Overall survival and surgical pathology were compared between the two treatment groups on an intent-to-treat basis.

Results: In the matched cohort, the NAT group (n = 91) had a longer median overall survival than the UFS group (n = 91) (23.1 months vs 18.5 months, P = .043). The rate of patients undergoing surgical resection was lower in the NAT group (58% vs 80%, P = .001). Regarding surgical pathology, the NAT group had smaller tumor size (2.8 cm vs 4.0 cm, P = .001), lower incidence of positive surgical margins (8% vs 30%, P < .002), and less lymph node metastasis (45% vs 78%, P < .001).

Conclusions: The strategy of neoadjuvant therapy before surgical resection appears to offer pathologic effect and survival benefit for the patients presenting with non-metastatic PDAC.
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http://dx.doi.org/10.1002/jso.25681DOI Listing
November 2019

Methylated DNA in Pancreatic Juice Distinguishes Patients With Pancreatic Cancer From Controls.

Clin Gastroenterol Hepatol 2020 03 16;18(3):676-683.e3. Epub 2019 Jul 16.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Background & Aims: Precursors of pancreatic cancer arise in the ductal epithelium; markers exfoliated into pancreatic juice might be used to detect high-grade dysplasia (HGD) and cancer. Specific methylated DNA sequences in pancreatic tissue have been associated with adenocarcinoma. We analyzed these methylated DNA markers (MDMs) in pancreatic juice samples from patients with pancreatic ductal adenocarcinomas (PDACs) or intraductal papillary mucinous neoplasms (IPMNs) with HGD (cases), and assessed their ability to discriminate these patients from individuals without dysplasia or with IPMNs with low-grade dysplasia (controls).

Methods: We obtained pancreatic juice samples from 38 patients (35 with biopsy-proven PDAC or pancreatic cystic lesions with invasive cancer and 3 with HGD) and 73 controls (32 with normal pancreas and 41 with benign disease), collected endoscopically from the duodenum after secretin administration from February 2015 through November 2016 at 3 medical centers. Samples were analyzed for the presence of 14 MDMs (in the genes NDRG4, BMP3, TBX15, C13orf18, PRKCB, CLEC11A, CD1D, ELMO1, IGF2BP1, RYR2, ADCY1, FER1L4, EMX1, and LRRC4), by quantitative allele-specific real-time target and signal amplification. We performed area under the receiver operating characteristic curve analyses to determine the ability of each marker, and panels of markers, to distinguish patients with HGD and cancer from controls. MDMs were combined to form a panel for detection using recursive partition trees.

Results: We identified a group of 3 MDMs (at C13orf18, FER1L4, and BMP3) in pancreatic juice that distinguished cases from controls with an area under the receiver operating characteristic value of 0.90 (95% CI, 0.83-0.97). Using a specificity cut-off value of 86%, this group of MDMs distinguished patients with any stage of pancreatic cancer from controls with 83% sensitivity (95% CI, 66%-93%) and identified patients with stage I or II PDAC or IPMN with HGD with 80% sensitivity (95% CI, 56%-95%).

Conclusions: We identified a group of 3 MDMs in pancreatic juice that identify patients with pancreatic cancer with an area under the receiver operating characteristic value of 0.90, including patients with early stage disease or advanced precancer. These DNA methylation patterns might be included in algorithms for early detection of pancreatic cancer, especially in high-risk cohorts. Further optimization and clinical studies are needed.
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http://dx.doi.org/10.1016/j.cgh.2019.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984349PMC
March 2020

Novel Methylated DNA Markers Discriminate Advanced Neoplasia in Pancreatic Cysts: Marker Discovery, Tissue Validation, and Cyst Fluid Testing.

Am J Gastroenterol 2019 09;114(9):1539-1549

Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL.

Objectives: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND).

Methods: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs.

Results: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2).

Discussion: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.
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http://dx.doi.org/10.14309/ajg.0000000000000284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294458PMC
September 2019

Pancreatobiliary Versus Head and Neck Manifestations in Immunoglobulin G4-related Disease: Distinct Subsets of the Same Disease?

Pancreas 2019 07;48(6):799-804

Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN.

Objectives: We compared the clinical profiles and organ manifestations of the commonly encountered immunoglobulin G4-related diseases (IgG4-RDs) on either side of the diaphragm: head and neck (HN) versus pancreatobiliary (PB) in IgG4-RD.

Methods: From the Mayo Clinic, Rochester, database, we identified 53 HN and 88 PB IgG4-RD based on the first affected organ manifestation.

Results: Compared with HN IgG4-RD, subjects with PB IgG4-RD were likely to be older (median, 64.8 vs 50.2 years; P < 0.0001), male (83% vs 60.4%; P = 0.003), and with a shorter duration of follow-up (24.4 vs 48.7 months; P < 0.0001). In HN versus PB-IgG4-RD orbital, lacrimal gland, submandibular, parotid gland, asthma, and sinusitis manifestations were more common (77% vs 4.5%, 21% vs 0%, 32% vs 8%, 13% vs 0%, 36% vs 9%, and 51% vs 6.8%; P < 0.0001, respectively), whereas lung manifestations were similar (13.2% vs 5.6%; P = 0.12). In contrast, in PB versus HN IgG4-RD, pancreas and biliary were more frequent (98.8% vs 15%, 56.8% vs 3.7%; P < 0.0001), whereas renal lesions were similar (12.5% vs 7.5%; P = 0.36).

Conclusion: Pancreatobiliary and HN IgG4-RD have distinct clinical profiles. Proximity matters in other organ involvement in IgG4-RD, and organs involved tend to cluster close to each.
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http://dx.doi.org/10.1097/MPA.0000000000001332DOI Listing
July 2019

Pancreatic Cysts and Intraductal Papillary Mucinous Neoplasm in Autosomal Dominant Polycystic Kidney Disease.

Pancreas 2019 May/Jun;48(5):698-705

Division of Nephrology and Hypertension.

Objectives: Pancreatic lesions in autosomal dominant polycystic kidney disease (ADPKD) are primarily cysts. They are increasingly recognized, with isolated reports of intraductal papillary mucinous neoplasia (IPMN).

Methods: Retrospective study to determine prevalence, number, size, and location of pancreatic abnormalities using abdominal magnetic resonance imaging (MRI) of genotyped ADPKD patients (seen February 1998 to October 2013) and compared with age- and sex-matched non-ADPKD controls. We evaluated presentation, investigation, and management of all IPMNs among individuals with ADPKD (January 1997 to December 2016).

Results: Abdominal MRIs were examined for 271 genotyped ADPKD patients. A pancreatic cyst lesion (PCL) was detected in 52 patients (19%; 95% confidence interval, 15%-23%). Thirty-seven (71%) had a solitary PCL; 15 (28%) had multiple. Pancreatic cyst lesion prevalence did not differ by genotype. Intraductal papillary mucinous neoplasia was detected in 1% of ADPKD cases. Among 12 IPMN patients (7 branch duct; 5 main duct or mixed type) monitored for about 140 months, 2 with main duct IPMNs required Whipple resection, and 1 patient died of complications from small-bowel obstruction after declining surgical intervention.

Conclusions: With MRI, PCLs were detected in 19% and IPMNs in 1% of 271 ADPKD patients with proven mutations, without difference across genotypes. Pancreatic cyst lesions were asymptomatic and remained stable in size.
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http://dx.doi.org/10.1097/MPA.0000000000001306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521861PMC
February 2020

Cyclooxygenase-2 and Cytosolic Phospholipase A2 Are Overexpressed in Mucinous Pancreatic Cysts.

Clin Transl Gastroenterol 2019 04;10(4):e00028

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Objectives: Expression of prostaglandin biosynthetic pathway enzymes in mucinous pancreatic cysts is unknown. Cyclooxygenase-2 (COX-2) inhibition is a potential cancer chemoprevention strategy for these lesions. We evaluated the expression of COX-2, cytosolic phospholipase A2 (cPLA2), and protein kinase B (AKT) in the epithelium of pancreatic cysts and correlated enzyme expression with aspirin (ASA) use and cyst fluid prostaglandin E2 (PGE2) concentration.

Methods: Pathology of 80 resected pancreatic cysts was reviewed. Expression of COX-2, cPLA2, and AKT was quantified by tissue immunohistochemistry immunoreactivity scores (IRSs). IRS values were compared between cyst types and (in 30 cases) with matched cyst fluid PGE2 concentrations.

Results: The mean IRS was higher in the epithelium of mucinous vs nonmucinous cysts for COX-2 (6.1 ± 4.7 vs 3.2 ± 2.8, P = 0.01) and cPLA2 (6.9 ± 3.0 vs 2.9 ± 2.9, P < 0.001). Cyst epithelial COX-2 expression was higher in mucinous cysts with low-grade dysplasia vs those with high-grade dysplasia or invasive carcinoma (IRS 8.0 ± 3.9 vs 1.5 ± 2.9, P < 0.001), whereas the opposite was found for cPLA2 (6.2 ± 3.0 vs 8.6 ± 2.3, P = 0.005). Cyst fluid PGE2 concentrations did not correlate with either the IRS or a history of low- to moderate-dose ASA use.

Conclusions: COX-2 and cPLA2 are overexpressed in the epithelium of mucinous pancreatic cysts. COX-2 and/or cPLA2 inhibition might prevent the emergence or progression of mucinous pancreatic cysts, but higher doses of ASA or nonsteroidal anti-inflammatory drugs may be necessary to substantially inhibit cyst epithelial COX-2 activity.
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http://dx.doi.org/10.14309/ctg.0000000000000028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602781PMC
April 2019

Safety, Diagnostic Accuracy, and Effects of Endoscopic Ultrasound Fine-Needle Aspiration on Detection of Extravascular Migratory Metastases.

Clin Gastroenterol Hepatol 2019 11 3;17(12):2533-2540.e1. Epub 2019 Apr 3.

Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background & Aims: Tumor cells can migrate via diminutive perivascular cuffing to distant sites along blood vessels to form extravascular migratory metastases (EVMM). These metastases usually are identified during surgery or autopsies. We aimed to evaluate the feasibility and safety of endoscopic ultrasound fine-needle aspiration (EUS-FNA) of perivascular soft-tissue cuffs to detect EVMM. We compared findings from EUS with those from noninvasive cross-sectional imaging (reference standard) of patients who underwent EUS-FNA to assess suspected EVMM and studied the effects on pancreatic tumor staging and determination of resectability.

Methods: We performed a retrospective analysis of 253 patients (mean age, 62 ± 12 y) who underwent EUS-FNA of 267 vessels for evaluation of suspected EVMM, from April 2001 through May 2018. EUS findings were compared with those from computed tomography (CT) and magnetic resonance imaging (MRI) as the reference standard. Lesions were considered to be malignant based on cytology analysis of FNA samples, histology analyses of surgical or biopsy specimens, or vascular abnormalities detected by CT or MRI that clearly indicate EVMM.

Results: Thirty patients were found to have benign lesions. The remaining 223 patients who had malignancies (166 with pancreatic ductal adenocarcinomas [PDACs]), underwent further analyses. A median of 4 FNAs (range, 1-20 FNAs) were obtained from 4-mm perivascular soft-tissue cuffs (range, 2-20 mm). FNA and cytology analysis showed malignant cells in 163 vessels (69.4%) from 157 patients (70.4%). CT or MRI did not detect EVMM in 44 patients (28%) with malignancies, including 24 patients (24%) with newly diagnosed PDAC. Detection of EVMM by EUS-FNA resulted in upstaging of 15 patients and conversion of 14 patients with PDAC from resectable (based on CT or MRI) to unresectable. No adverse events were reported during a follow-up period of 3.9 months (range, 0-117 mo).

Conclusions: EUS-FNA and cytologic analysis of perivascular soft-tissue cuffs can detect EVMM that were not found in 28% of patients by CT or MRI. Detection of EVMM affects tumor staging and determination of tumor resectability.
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http://dx.doi.org/10.1016/j.cgh.2019.03.043DOI Listing
November 2019

Classic chronic pancreatitis is associated with prior acute pancreatitis in only 50% of patients in a large single-institution study.

Pancreatology 2019 Mar 12;19(2):224-229. Epub 2019 Feb 12.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

Background: The sentinel acute pancreatitis event (SAPE) hypothesis for pathogenesis of chronic pancreatitis (CP) postulates that acute pancreatitis (AP), especially recurrent AP (RAP), precedes development of CP. However, in a recent population-based study, 52/89 (58.4%) of CP had no prior episodes of AP. In a large clinic-based CP cohort, we aimed to determine the incidence and timing of prior AP in patients diagnosed with CP.

Methods: We retrospectively identified 499 consecutive patients with classic CP diagnosed at our institution from January 2013 through December 2015. We abstracted their demographic and clinical data, especially regarding prior AP.

Results: We identified 3 cohorts: 1) CP with no AP (n = 231 [46.3%]), 2) AP before CP (n = 250 [50.1%]), and 3) AP after CP (n = 18 [3.6%]). At CP diagnosis, 249 patients (49.9%) had no prior AP. Compared with the "CP preceded by AP" cohort, the "CP without AP"' cohort was older (59.2 ± 13.9 vs 48.6 ± 15.7 years; P < .001), had a higher prevalence of diabetes mellitus (30.3% vs 12.4%; P < .001), reported less pain (52.8% vs 87.6%; P < .001), and had a lower rate of endoscopic interventions (16.0% vs 39.2%; P < .001). In the "CP preceded by AP" cohort, 117 (46.8%) had a single episode of AP and 133 (53.2%) had RAP.

Conclusion: Nearly half the patients with classic CP did not have prior AP. Only a quarter of patients had CP that could potentially have evolved from prior RAP. Development of CP may be attributable to an altogether different pathogenesis (a non-SAPE pathway) for a considerable proportion of patients.
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http://dx.doi.org/10.1016/j.pan.2019.02.004DOI Listing
March 2019