Publications by authors named "Thomas Smyrk"

323 Publications

Interobserver agreement and the impact of mentorship on the diagnosis of inflammatory bowel disease-associated dysplasia among subspecialist gastrointestinal pathologists.

Virchows Arch 2021 Jan 3. Epub 2021 Jan 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

The diagnosis of inflammatory bowel disease (IBD)-associated dysplasia is challenging, and past studies have demonstrated considerable interobserver variability in such diagnoses. This study aimed to assess interobserver agreement in IBD dysplasia diagnoses among subspecialty GI pathologists and to explore the impact of mentorship on diagnostic variability. Twelve GI pathologist mentees and 7 GI pathologist mentors reviewed 163 digitized slides. Participants rendered a diagnosis of negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, or high-grade dysplasia and provided a confidence level for each case. Interobserver agreement and reliability were assessed using Cohen's and Fleiss' kappa (κ) statistics and intraclass correlation coefficient (ICC) analysis. The overall κ coefficient was 0.42 (95% CI: 0.38-0.46). The overall ICC was 0.67 (95% CI: 0.62-0.72). Κ coefficients ranged from 0.31 to 0.49 for mentor/mentee pairs and from 0.34 to 0.55 for pairs of mentees of the same mentor. The combined κ coefficient was 0.44 (95% CI: 0.39-0.48) for all mentees and 0.39 (95% CI: 0.34-0.43) for all mentors. Common features in low agreement cases included mucosal atrophy, areas of stark contrast, serrations, decreased goblet cells, absent surface epithelium, and poor orientation. Participants were confident in most diagnoses, and increased confidence levels generally correlated with higher interobserver agreement. Interobserver agreement among subspecialist GI pathologists in this curated cohort of IBD dysplasia cases was fair to moderate. Mentorship during GI pathology fellowship does not appear to be a significant factor contributing to interobserver variability, but increased experience also does not seem to improve interobserver agreement.
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http://dx.doi.org/10.1007/s00428-020-02998-zDOI Listing
January 2021

Novel methylated DNA markers accurately discriminate Lynch syndrome associated colorectal neoplasia.

Epigenomics 2020 12 22;12(24):2173-2187. Epub 2020 Dec 22.

Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA.

Acquired molecular changes in Lynch syndrome (LS) colorectal tumors have been largely unstudied. We identified methylated DNA markers (MDMs) for discrimination of colorectal neoplasia in LS and determined if these MDMs were comparably discriminant in sporadic patients. For LS discovery, we evaluated DNA from 53 colorectal case and control tissues using next generation sequencing. For validation, blinded methylation-specific PCR assays to the selected MDMs were performed on 197 cases and controls. was the most discriminant MDM with areas under the receiver operating characteristic curve ≥0.97 for colorectal neoplasia in LS and sporadic tissues. , was uniquely hypermethylated in LS neoplasms. Highly discriminant MDMs for colorectal neoplasia in LS were identified with potential use in screening and surveillance.
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http://dx.doi.org/10.2217/epi-2020-0132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923255PMC
December 2020

A Broad-Based Submucosal Polyp.

Gastroenterology 2020 Dec 18. Epub 2020 Dec 18.

Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, MN, USA.

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http://dx.doi.org/10.1053/j.gastro.2020.12.027DOI Listing
December 2020

Prognostic variables in low and high risk stage III colon cancers treated in two adjuvant chemotherapy trials.

Eur J Cancer 2021 Feb 17;144:101-112. Epub 2020 Dec 17.

Department of Gastroenterology and GI Oncology, Sorbonne Paris Cité, Université Paris Descartes, Hopital Européen Georges Pompidou, Paris, France.

Background: Stratification of patients with stage III colon cancer into low (TN) and high (T and/or N) risk groups is used to guide the duration of adjuvant chemotherapy. We determined the relative contribution of clinical and molecular features to survival by risk group.

Materials & Methods: Stage III colon cancer (N = 5337) patients from two adjuvant trials of FOLFOX ± cetuximab [N0147 (Alliance), PETACC-8] were risk grouped, then subgrouped by clinical features and molecular variables [KRAS and BRAF/mismatch repair (MMR) combined variable]. Distributions of disease-free survival (DFS), overall survival (OS), and survival after recurrence (SAR) were estimated. In multivariable Cox models, backward elimination was performed for analysis of candidate predictors of outcomes. Relative contributions of model-selected variables to outcomes by risk group were calculated using χ2.

Results: Among low risk tumours, mutant KRAS and male gender were significantly associated with poorer OS multivariately. In high risk tumours, significantly poorer OS was observed for right sidedness and for mutant KRAS and BRAF/pMMR, subgroups. Specifically, BRAF/pMMR (OS: HR = 1.75; 95% CI: 1.36-2.24; P<.0001) and right- versus left-sidedness were associated with significantly poorer DFS, OS (HR = 1.56; 95% CI: 1.31-1.83; P<.0001), and SAR (HR = 1.64; 95% CI: 1.37-1.95; P<.0001). Poor prognosis of mutant KRAS for DFS and OS was similar among risk groups. BRAF/MMR and sidedness were associated with poorer SAR in both low and high risk tumours. Age, gender, and KRAS were the top three relative contributors to DFS and OS among low risk tumours; sidedness ranked first for DFS and OS, and second to BRAF/MMR for SAR among high risk tumours.

Conclusion: Sidedness and BRAF/MMR contributed the most to survival outcomes among high risk tumours and should be interpreted in the context of risk group.
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http://dx.doi.org/10.1016/j.ejca.2020.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855426PMC
February 2021

The novel form of amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) preferentially affects the lower gastrointestinal tract of elderly females.

Histopathology 2021 Feb 28;78(3):459-463. Epub 2020 Nov 28.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Aims: To characterise the clinicopathological features of amyloidosis due to EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1), a newly described amyloid type.

Methods And Results: We identified cases by searching the Mayo Clinic amyloid liquid chromatography and tandem mass spectrometry typing database for specimens with the universal amyloid signature proteins, abundant EFEMP1 spectra and absence of other specific amyloid precursor proteins. We also developed an immunohistochemical stain for EFEMP1 applicable to formalin-fixed tissue sections and performed electron microscopy in one case. We identified 33 specimens from 32 patients with EFEMP1 amyloid. Most patients were female (91%) with a mean age of 75 years, and most specimens (94%) were from the bowel. EFEMP1 amyloid was incidentally identified in specimens biopsied/resected for a variety of clinical indications. In bowel specimens, EFEMP1 amyloid involved blood vessels and interstitium of the lamina propria, submucosa and/or muscularis propria. Although the EFEMP1 deposits were weakly to moderately Congo red-positive with absent to weak birefringence, they were strongly positive for EFEMP1 by immunohistochemistry, had the characteristic fibrillar ultrastructure of amyloid and were readily identified by mass spectrometry.

Conclusions: EFEMP1 amyloid is a recently described novel amyloid type that predominantly affects the bowel of elderly females. Because EFEMP1 amyloid is only weakly Congo red-positive, it may be overlooked without a high index of suspicion. However, its characteristic microanatomical distribution is highlighted by immunohistochemistry and its identity is readily confirmed by mass spectrometry. Based on its distinctive features, we propose that EFEMP1 amyloidosis be considered a new amyloid type.
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http://dx.doi.org/10.1111/his.14276DOI Listing
February 2021

Methylated DNA Markers of Esophageal Squamous Cancer and Dysplasia: An International Study.

Cancer Epidemiol Biomarkers Prev 2020 Dec 18;29(12):2642-2650. Epub 2020 Sep 18.

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

Background: Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices.

Methods: MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons.

Results: Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia ( < 0.004).

Conclusions: MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results.

Impact: MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710574PMC
December 2020

Clinical Outcomes in Patients With Colon Cancer With Microsatellite Instability of Sporadic or Familial Origin Treated With Adjuvant FOLFOX With or Without Cetuximab: A Pooled Analysis of the PETACC8 and N0147 Trials.

JCO Precis Oncol 2020 26;4. Epub 2020 Feb 26.

Department of Medicine, Mayo Clinic, Rochester, MN.

Purpose: The microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually regarded as a single biologic entity, given the absence of comparative analyses regarding prognosis and response to chemotherapy between sporadic and familial dMMR cancers.

Patients And Methods: Patients with stage III colon cancers were randomly assigned to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without cetuximab in 2 large adjuvant phase III trials (N = 5,577). Among patients with MSI and exon 2 wild-type (WT) tumors, the prognostic and predictive impacts of sporadic versus familial dMMR cancers and V600E mutational status were determined. Multivariable Cox proportional hazards models were used to assess disease-free survival (DFS) by treatment arm, adjusting for age, sex, tumor grade, Eastern Cooperative Oncology Group performance status, pT/pN stage, and primary tumor location.

Results: Among patients with MSI status with complete data for dMMR mechanism analysis (n = 354), 255 (72%) had sporadic ( mutation and/or methylation) and 99 (28%) had familial tumors ( WT and unmethylated or loss of MSH2/MSH6/PMS2 protein expression). A large proportion of dMMR sporadic tumors were mutated for (n = 200). In patients treated with FOLFOX, DFS did not differ statistically by dMMR mechanism, whereas in patients treated with FOLFOX plus cetuximab, those with sporadic tumors had worse DFS than those with familial cancers (multivariable hazard ratio, 2.69; 95% CI, 1.02 to 7.08; = .04). Considering the predictive utility, the interaction between treatment and dMMR mechanism was significant ( = .03). Furthermore, a nonsignificant trend toward a deleterious effect of adding cetuximab to FOLFOX was observed in patients with -mutant but not WT tumors.

Conclusion: The addition of cetuximab to adjuvant FOLFOX was associated with shorter DFS in patients with sporadic dMMR colon cancer. Additional studies are needed to validate these results in metastatic disease.
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http://dx.doi.org/10.1200/PO.19.00237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446392PMC
February 2020

Targeting of the Hedgehog/GLI and mTOR pathways in advanced pancreatic cancer, a phase 1 trial of Vismodegib and Sirolimus combination.

Pancreatology 2020 Sep 14;20(6):1115-1122. Epub 2020 Jul 14.

Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA; Department of Medical Oncology, Department of Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55902, USA. Electronic address:

Background/objectives: Preclinical data indicated a functional and molecular interaction between Hedgehog (HH)/GLI and PI3K-AKT-mTOR pathways promoting pancreatic ductal adenocarcinoma (PDAC). A phase I study was conducted of Vismodegib and Sirolimus combination to evaluate maximum tolerated dose (MTD) and preliminary anti-tumor efficacy.

Methods: Cohort I included advanced solid tumors patients following a traditional 3 + 3 design. Vismodegib was orally administered at 150 mg daily with Sirolimus starting at 3 mg daily, increasing to 6 mg daily at dose level 2. Cohort II included only metastatic PDAC patients. Anti-tumor efficacy was evaluated every two cycles and target assessment at pre-treatment and after a single cycle.

Results: Nine patient were enrolled in cohort I and 22 patients in cohort II. Twenty-eight patients were evaluated for dose-limiting toxicities (DLTs). One DLT was observed in each cohort, consisting of grade 2 mucositis and grade 3 thrombocytopenia. The MTD for Vismodegib and Sirolimus were 150 mg daily and 6 mg daily, respectively. The most common grade 3-4 toxicities were fatigue, thrombocytopenia, dehydration, and infections. A total of 6 patients had stable disease. No partial or complete responses were observed. Paired biopsy analysis before and after the first cycle in cohort II consistently demonstrated reduced GLI1 expression. Conversely, GLI and mTOR downstream targets were not significantly affected.

Conclusions: The combination of Vismodegib and Sirolimus was well tolerated. Clinical benefit was limited to stable disease in a subgroup of patients. Targeting efficacy demonstrated consistent partial decreases in HH/GLI signaling with limited impact on mTOR signaling. These findings conflict with pre-clinical models and warrant further investigations.
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http://dx.doi.org/10.1016/j.pan.2020.06.015DOI Listing
September 2020

Duodenal mucosal secretory disturbances in functional dyspepsia.

Neurogastroenterol Motil 2021 01 9;33(1):e13955. Epub 2020 Aug 9.

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

Background: There is increased recognition of duodenal disturbances (inflammation, altered mucosal protein expression, and chemosensitivity) in functional dyspepsia (FD). Besides sensorimotor functions, enteric submucosal neurons also regulate epithelial ion transport. We hypothesized that duodenal mucosal ion transport and expression of associated genes are altered in FD.

Methods: Duodenal mucosal ion transport (basal and acetylcholine- and glucose-evoked changes in short-circuit current [Isc]) and expression of associated genes and regulatory miRNAs were evaluated in 40 FD patients and 24 healthy controls.

Results: Basal Isc (FD: 88.2 [52.6] μA/cm vs healthy: 20.3 [50.2] μA/cm ; P ≤ .0001), acetylcholine-evoked Isc (FD: Emax 50.4 [35.8] μA/cm vs healthy: 16.6 [15] μA/cm ; P ≤ .001), and glucose-evoked Isc responses (FD: E 69.8 [42.1] μA/cm vs healthy: 40.3 [24.6] μA/cm ; P = .02) were greater in FD than in controls. The Emax for glucose was greater in FD patients on selective serotonin reuptake inhibitors. In FD, the mRNA expression of SLC4A7 and SLC4A4, which transport bicarbonate into cells at the basolateral surface, and the apical anion exchanger SLC26A3 were reduced (false discovery rate <0.05), the serotonin receptor HTR4 was increased, and the serotonin transporter SLC6A4 was decreased. Selected miRNAs (hsa-miR-590-3p, hsa-miR-32-5p) that target genes associated with ionic transport were upregulated in FD.

Conclusions: Compared to controls, FD patients had greater baseline and agonist-evoked duodenal mucosal secretory responses. These findings may be explained by reduced gene expression, which would be anticipated to reduce luminal bicarbonate secretion. The upregulated miRNAs may partly explain the downregulation of these genes in FD.
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http://dx.doi.org/10.1111/nmo.13955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772227PMC
January 2021

Pancreatic ductal adenocarcinoma is associated with a unique endocrinopathy distinct from type 2 diabetes mellitus.

Pancreatology 2020 Jul 22;20(5):929-935. Epub 2020 May 22.

Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; Department of Medicine, Division of Endocrinology, Metabolism, Diabetes, and Nutrition, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. Electronic address:

Introduction: The majority of patients with pancreatic ductal adenocarcinoma (PC) display either impaired fasting glucose/glucose intolerance or overt diabetes. However, the pathophysiologic basis of this association remains largely unexplained.

Methods: In this case-control study we aimed to study the morphological changes in the islets of patients with PC, compared to control patients with and without type 2 diabetes mellitus (T2DM). T2DM controls and PC cases had a lower β-cell area and average islet size and density compared to non-T2DM controls (p < 0.05).

Results: Compared to both T2DM and non-T2DM controls, mean α-cell area was significantly lower and β/α-ratio was higher in PC cases (p < 0.05). Furthermore, whereas islets in T2DM controls were characterized by disrupted islet architecture and presence of islet amyloid aggregates, islet composition in PC islets was not significantly different compared to non-T2DM controls (p > 0.05 vs. Control).

Conclusions: Our data shows that PC is associated with a unique pattern of islet pathology characterized by preserved architecture, absence of amyloid aggregates, and relative α-cell loss indicating that distinct mechanisms are likely involved in the pathophysiology of islet failure in PC-induced DM. Insights into the mechanisms mediating β-cell failure in PC can be important for our understanding of pathophysiology of PC.
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http://dx.doi.org/10.1016/j.pan.2020.05.010DOI Listing
July 2020

Accurate Nonendoscopic Detection of Barrett's Esophagus by Methylated DNA Markers: A Multisite Case Control Study.

Am J Gastroenterol 2020 08;115(8):1201-1209

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

Introduction: Nonendoscopic Barrett's esophagus (BE) screening may help improve esophageal adenocarcinoma outcomes. We previously demonstrated promising accuracy of methylated DNA markers (MDMs) for the nonendoscopic diagnosis of BE using samples obtained from a capsule sponge-on-string (SOS) device. We aimed to assess the accuracy of these MDMs in an independent cohort using a commercial grade assay.

Methods: BE cases had ≥ 1 cm of circumferential BE with intestinal metaplasia; controls had no endoscopic evidence of BE. The SOS device was withdrawn 8 minutes after swallowing, followed by endoscopy (the criterion standard). Highest performing MDMs from a previous study were blindly assessed on extracted bisulfite-converted DNA by target enrichment long-probe quantitative amplified signal (TELQAS) assays. Optimal MDM combinations were selected and analyzed using random forest modeling with in silico cross-validation.

Results: Of 295 patients consented, 268 (91%) swallowed the SOS device; 112 cases and 89 controls met the pre-established inclusion criteria. The median BE length was 6 cm (interquartile range 4-9), and 50% had no dysplasia. The cross-validated sensitivity and specificity of a 5 MDM random forest model were 92% (95% confidence interval 85%-96%) and 94% (95% confidence interval 87%-98%), respectively. Model performance was not affected by age, gender, or smoking history but was influenced by the BE segment length. SOS administration was well tolerated (median [interquartile range] tolerability 2 [0, 4] on 10 scale grading), and 95% preferred SOS over endoscopy.

Discussion: Using a minimally invasive molecular approach, MDMs assayed from SOS samples show promise as a safe and accurate nonendoscopic test for BE prediction.
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http://dx.doi.org/10.14309/ajg.0000000000000656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415629PMC
August 2020

Contribution of Immunoscore and Molecular Features to Survival Prediction in Stage III Colon Cancer.

JNCI Cancer Spectr 2020 Jun 5;4(3):pkaa023. Epub 2020 Apr 5.

Division of Oncology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.

Background: The American Joint Committee on Cancer staging and other prognostic tools fail to account for stage-independent variability in outcome. We developed a prognostic classifier adding Immunoscore to clinicopathological and molecular features in patients with stage III colon cancer.

Methods: Patient (n = 559) data from the FOLFOX arm of adjuvant trial NCCTG N0147 were used to construct Cox models for predicting disease-free survival (DFS). Variables included age, sex, T stage, positive lymph nodes (+LNs), N stage, performance status, histologic grade, sidedness, , mismatch repair, and Immunoscore (CD3, CD8 T-cell densities). After determining optimal functional form (continuous or categorical) and within Cox models, backward selection was performed to analyze all variables as candidate predictors. All statistical tests were two-sided.

Results: Poorer DFS was found for tumors that were T4 vs T3 (hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.19 to 2.60;  = .004), right- vs left-sided (HR = 1.52, 95% CI = 1.14 to 2.04;  = .005), (HR = 1.74, 95% CI = 1.26 to 2.40;  < .001), mutant (HR = 1.66, 95% CI = 1.08 to 2.55;  = .02), and low vs high Immunoscore (HR = 1.69, 95% CI = 1.22 to 2.33; = .001) (all <.02). Increasing numbers of +LNs and lower continuous Immunoscore were associated with poorer DFS that achieved significance (both s<.0001). After number of +LNs, T stage, and , Immunoscore was the most informative predictor of DFS shown multivariately. Among T N tumors, Immunoscore was the only variable associated with DFS that achieved statistical significance. A nomogram was generated to determine the likelihood of being recurrence-free at 3 years.

Conclusions: The Immunoscore can enhance the accuracy of survival prediction among patients with stage III colon cancer.
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http://dx.doi.org/10.1093/jncics/pkaa023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236783PMC
June 2020

Phase 1 trial of Vismodegib and Erlotinib combination in metastatic pancreatic cancer.

Pancreatology 2020 Jan 21;20(1):101-109. Epub 2019 Nov 21.

Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background/objectives: Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients.

Methods: Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers.

Results: Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2-7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels.

Conclusions: Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.
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http://dx.doi.org/10.1016/j.pan.2019.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195700PMC
January 2020

Mesenchymal Hamartoma in Children: A Diagnostic Challenge.

Case Rep Pediatr 2019 16;2019:4132842. Epub 2019 Sep 16.

Division of Pediatric Gastroenterology & Hepatology, Department of Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.

Mesenchymal hamartoma is a benign tumor of the liver with a poorly understood pathogenesis. It is uncommon in older children, especially after 2 years of age. The signs and symptoms may be nonspecific; therefore, a high index of suspicion is required for diagnosis and treatment. We report a 5-year-old previously healthy male who presented with acute abdominal pain, fatigue, and fever. He was diagnosed with pneumonia initially and treated with antibiotics. A computed tomography (CT) scan done for evaluation of his persistent abdominal pain demonstrated a hepatic mass. Follow-up magnetic resonance imaging (MRI) of the liver demonstrated multiple serpiginous tubular-type structures, read as possible Caroli syndrome. He had a normal abdominal examination and normal biochemistries including alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and alpha-fetoprotein. He was referred to our institution for second opinion. On further review of his imaging studies, the lesion was thought to be a mesenchymal hamartoma. He subsequently underwent resection of the mass. Pathology confirmed the diagnosis of mesenchymal hamartoma.
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http://dx.doi.org/10.1155/2019/4132842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766091PMC
September 2019

Biliary Amyloidoma as a Cause for Pancreatitis.

Clin Gastroenterol Hepatol 2019 10;17(11):A25-A26

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

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http://dx.doi.org/10.1016/j.cgh.2018.06.029DOI Listing
October 2019

Discovery, Validation, and Application of Novel Methylated DNA Markers for Detection of Esophageal Cancer in Plasma.

Clin Cancer Res 2019 12 16;25(24):7396-7404. Epub 2019 Sep 16.

Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Purpose: The burden of esophageal cancer continues to rise, and noninvasive screening tools are needed. Methylated DNA markers (MDM) assayed from plasma show promise in detection of other cancers. For esophageal cancer detection, we aimed to discover and validate MDMs in tissue, and determine their feasibility when assayed from plasma.

Experimental Design: Whole-methylome sequencing was performed on DNA extracted from 37 tissues (28 EC; 9 normal esophagus) and 8 buffy coat samples. Top MDMs were validated by methylation specific PCR on tissue from 76 EC (41 adeno, 35 squamous cell) and 17 normal esophagus. Quantitative allele-specific real-time target and signal amplification was used to assay MDMs in plasma from 183 patients (85 EC, 98 controls). Recursive partitioning (rPART) identified MDM combinations predictive of esophageal cancer. Validation was performed by bootstrapping.

Results: From discovery, 23 candidate MDMs were selected for independent tissue validation; median area under the receiver operating curve (AUC) for individual MDMs was 0.93. Among 12 MDMs advanced to plasma testing, rPART modeling selected a 5 MDM panel () which achieved an AUC of 0.93 (95% CI, 0.89-0.96) on best-fit and 0.81 (95% CI, 0.75-0.88) on cross-validation. At 91% specificity, the panel detected 74% of esophageal cancer overall, and 43%, 64%, 77%, and 92% of stages I, II, III, and IV, respectively. Discrimination was not affected by age, sex, smoking, or body mass index.

Conclusions: Novel MDMs assayed from plasma detect esophageal cancer with moderate accuracy. Further optimization and clinical testing are warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911634PMC
December 2019

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

Albumin In Situ Hybridization Can Be Positive in Adenocarcinomas and Other Tumors From Diverse Sites.

Am J Clin Pathol 2019 07;152(2):190-199

Division of Anatomic Pathology, Mayo Clinic, Rochester, MN.

Objectives: Albumin messenger RNA (mRNA) expression is a marker of hepatocellular differentiation. Most published data are from review of tissue microarrays, and albumin in situ hybridization (ISH) expression across several tumor types is incompletely characterized.

Methods: Sections from 221 tumors were evaluated for albumin mRNA. Immunohistochemistry was used to confirm diagnoses. Albumin ISH was performed according to manufacturer-provided instructions. Fifty-nine cases were evaluated with both commercial ISH assays.

Results: Albumin mRNA was detected in all hepatocellular carcinomas (HCCs) and 81% of intrahepatic cholangiocarcinomas. Lung (20%), gallbladder (39%), hepatoid pancreatic (n = 1 of 1) adenocarcinoma, breast invasive ductal carcinoma (18%), yolk sac tumor (25%), and acinar cell carcinoma (29%) showed expression. Both assays were concordant in 93% of cases.

Conclusions: Albumin ISH was expressed in all HCCs studied. It was also positive in intrahepatic cholangiocarcinoma and patchy positive in gallbladder adenocarcinoma and a subset of other neoplasms, which can be a potential pitfall.
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http://dx.doi.org/10.1093/ajcp/aqz032DOI Listing
July 2019

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

Solid Pseudopapillary Neoplasms of the Pancreas: A Large American Cohort.

Pancreas 2019 04;48(4):e21-e22

Division of Medical Oncology Mayo Clinic Rochester, MN Department of Oncology Clinica Santa Maria Santiago, Chile Department of Internal Medicine Mayo Clinic Rochester, MN Division of Medical Oncology Mayo Clinic Rochester, MN Department of Laboratory Medicine and Pathology Mayo Clinic Rochester, MN Division of Medical Oncology Mayo Clinic Rochester, MN

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http://dx.doi.org/10.1097/MPA.0000000000001288DOI Listing
April 2019

Staging of T1 esophageal adenocarcinoma with volumetric laser endomicroscopy: a feasibility study.

Endosc Int Open 2019 Apr 21;7(4):E462-E470. Epub 2019 Mar 21.

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

Precise staging in T1 esophageal adenocarcinoma (EAC) is critical in determining candidacy for curative endoscopic resection. High-frequency endoscopic ultrasound (EUS) has demonstrated suboptimal accuracy in T1 EAC staging due to insufficient spatial resolution. Volumetric laser endomicroscopy (VLE) allows for high-resolution wide-field visualization of the esophageal microstructure. We aimed to investigate the role of VLE in staging T1 EAC. Patients undergoing endoscopic mucosal resection (EMR) were prospectively enrolled and only T1 EAC cases were included. EMR specimens were imaged using second-generation VLE immediately after resection. VLE images were analyzed for signal intensity by depth and signal attenuation (dB/mm) in both cross-sectional and en-face orientation. A decision tree model was constructed to combine measured VLE parameters and delineate diagnostic thresholds. Thirty EMR scans were obtained - 15 T1a specimens from 9 patients and 15 T1b specimens from 11 patients. T1b specimen VLE scans exhibited higher signal intensity (  < 0.0001) and higher signal attenuation compared to T1a specimens (  = 0.03). A combination of signal attenuation and signal intensity at 150 µm depth yielded optimal diagnostic thresholds and an area under the curve (AUC) of 0.77. VLE signal attenuation was significantly associated with grade of differentiation, irrespective of EAC stage. VLE signal intensity and signal attenuation are quantitatively distinct in T1a and T1b EAC and associated with grade of differentiation. This is the first study examining the role of VLE for staging of T1 EAC and demonstrates promising diagnostic performance. With further in vivo validation, VLE may serve a role in staging superficial EAC.
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http://dx.doi.org/10.1055/a-0838-5326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428686PMC
April 2019

A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma: North Central Cancer Treatment Group Trial N064B (Alliance).

Oncologist 2019 05 24;24(5):589-e160. Epub 2019 Jan 24.

Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.

Lessons Learned: Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy.A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy.The dual EGFR-directed therapy resulted in increased toxicity.

Background: Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab.

Methods: Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported values are two-sided.

Results: A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530-1.260; = .1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555-1.280; = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B ( = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; = .0018).

Conclusion: Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.
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http://dx.doi.org/10.1634/theoncologist.2018-0878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516109PMC
May 2019

Variation in Endoscopic Activity Assessment and Endoscopy Score Validation in Adults With Eosinophilic Esophagitis.

Clin Gastroenterol Hepatol 2019 07 23;17(8):1477-1488.e10. Epub 2018 Nov 23.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Background & Aims: Eosinophilic esophagitis (EoE) is assessed endoscopically (endoscopic activity), based on grades of edema, rings, exudates, furrows, and strictures (EREFS). We examined variations in endoscopic assessments of severity, developed and validated 3 EREFS-based scoring systems, and assessed responsiveness of these systems using data from a randomized placebo-controlled trial of patients with EoE.

Methods: For the development set, 5 gastroenterologists reviewed EREFS findings from 266 adults with EoE and provided endoscopist global assessment scores (EndoGA, scale of 0 to 10); variation (ΔEndoGA) was assessed using linear regression. We evaluated simple scores (features given arbitrary values from 0 to 3) and developed 2 scoring systems (adjusted score range, 0-100). We then fitted our linear regression model with mean EndoGA to data from 146 adults recruited in centers in Switzerland and the United States between April 2011 and December 2012. For the validation set, we collected data from 120 separate adults (recruited in centers in Switzerland and the United States between May 2013 and July 2014), assessing regression coefficient-based scores using Bland-Altman method. We assessed the responsiveness of our scoring systems using data from a randomized trial of patients with EoE given fluticasone (n=16) or placebo (n=8).

Results: The distribution of EndoGA values differed among endoscopists (mean ΔEndoGA, 2.6±1.8; range 0-6.6). We developed 2 regression-based scoring systems to assess overall and proximal and distal esophageal findings; variation in endoscopic features accounted for more than 90% of the mean EndoGA variation. In the validation group, differences between mean EndoGA and regression-based scores were small (ranging from -4.70 to 2.03), indicating good agreement. In analyses of data from the randomized trial, the baseline to end of study change in patients given fluticasone was a reduction of 24.3 in simple score (reduction of 4.6 in patients given placebo, P=.052); a reduction of 23.5 in regression-based overall score (reduction of 6.56 in patients given placebo, P=.12), and a reduction of 23.8 (reduction of 8.44 in patients given placebo, P=.11).

Conclusion: Assessments of endoscopic activity in patients with EoE vary among endoscopists. In an analysis of data from a randomized controlled trial, we found that newly developed scoring systems are no better than simple scoring system in detecting changes in endoscopic activity. These results support the use of a simple scoring system in evaluation of endoscopic activity in patients with EoE. clinicaltrials.gov no: NCT00939263 and NCT01386112.
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http://dx.doi.org/10.1016/j.cgh.2018.11.032DOI Listing
July 2019

High-Grade Dysplasia in Resected Main-Duct Intraductal Papillary Mucinous Neoplasm (MD-IPMN) is Associated with an Increased Risk of Subsequent Pancreatic Cancer.

Am J Gastroenterol 2019 03;114(3):524-529

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

Background: There is lack of consensus on post-operative surveillance for resected non-invasive intraductal papillary neoplasms (IPMNs). In this study we explored risk factors for subsequent PC in patients with MD-IPMN undergoing partial pancreatectomy.

Methods: We searched the Mayo Clinic surgical pathology database for all cases of resected MD-IPMN between 1997 and 2014. Cases with histologically confirmed main pancreatic duct involvement either isolated or in a mixed pattern with branch-duct involvement were included. Outcomes of PC in the remnant pancreas, and death related to MD-IPMN were assessed with survival analyses (Kaplan-Meier and Cox regression).

Results: Among the 179 patients with resected MD-IPMN the incidence of concomitant PC and high-grade dysplasia (HGD) in the resected specimen was 23 and 14%, respectively. The mean duration of follow-up was 4.31 years (range 0.12-13.5 years). Excluding 28 subjects who either underwent initial total pancreatectomy or partial pancreatectomy with surgical margins positive for PC/HGD, the 5-year incidence of subsequent PC was 12%, including 60.6% and 15.6% in those with initial PC and HGD, respectively. The 10-year incidence of PC was 21.2% overall, 60.6% for PC, 38.3% for HGD, and 3.0% for LGD. Risk of subsequent PC was significantly higher for those with initial PC compared with HGD (HR = 4.95, 95% CI: 1.63-15.03, p = 0.005 and for HGD compared with LGD (HR = 11.30, 95% CI: 1.55-82.26, p = 0.017).

Conclusions: Patients with MD-IPMN with PC or HGD undergoing segmental pancreatectomy are at higher risk of subsequent PC and may benefit from post-operative surveillance. The post-operative surveillance intervals in resected MD-IPMNs need to be tailored based on dysplasia grade.
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http://dx.doi.org/10.1038/s41395-018-0403-2DOI Listing
March 2019

uses amino acids associated with gut microbial dysbiosis in a subset of patients with diarrhea.

Sci Transl Med 2018 10;10(464)

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

The gut microbiota plays a critical role in pathogen defense. Studies using antibiotic-treated mice reveal mechanisms that increase susceptibility to infection (CDI), but risk factors associated with CDI in humans extend beyond antibiotic use. Here, we studied the dysbiotic gut microbiota of a subset of patients with diarrhea and modeled the gut microbiota of these patients by fecal transplantation into germ-free mice. When challenged with , the germ-free mice transplanted with fecal samples from patients with dysbiotic microbial communities showed increased gut amino acid concentrations and greater susceptibility to CDI. A mutant that was unable to use proline as an energy source was unable to robustly infect germ-free mice transplanted with a dysbiotic or healthy human gut microbiota. Prophylactic dietary intervention using a low-proline or low-protein diet in germ-free mice colonized by a dysbiotic human gut microbiota resulted in decreased expansion of wild-type after challenge, suggesting that amino acid availability might be important for CDI. Furthermore, a prophylactic fecal microbiota transplant in mice with dysbiosis reduced proline availability and protected the mice from CDI. Last, we identified clinical risk factors that could potentially predict gut microbial dysbiosis and thus greater susceptibility to CDI in a retrospective cohort of patients with diarrhea. Identifying at-risk individuals and reducing their susceptibility to CDI through gut microbiota-targeted therapies could be a new approach to preventing infection in susceptible patients.
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http://dx.doi.org/10.1126/scitranslmed.aam7019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537101PMC
October 2018

Hepatocellular Carcinoma Detection by Plasma Methylated DNA: Discovery, Phase I Pilot, and Phase II Clinical Validation.

Hepatology 2019 03 5;69(3):1180-1192. Epub 2019 Feb 5.

Mayo Clinic, Rochester, MN.

Early detection improves hepatocellular carcinoma (HCC) outcomes, but better noninvasive surveillance tools are needed. We aimed to identify and validate methylated DNA markers (MDMs) for HCC detection. Reduced representation bisulfite sequencing was performed on DNA extracted from 18 HCC and 35 control tissues. Candidate MDMs were confirmed by quantitative methylation-specific PCR in DNA from independent tissues (74 HCC, 29 controls). A phase I plasma pilot incorporated quantitative allele-specific real-time target and signal amplification assays on independent plasma-extracted DNA from 21 HCC cases and 30 controls with cirrhosis. A phase II plasma study was then performed in 95 HCC cases, 51 controls with cirrhosis, and 98 healthy controls using target enrichment long-probe quantitative amplified signal (TELQAS) assays. Recursive partitioning identified best MDM combinations. The entire MDM panel was statistically cross-validated by randomly splitting the data 2:1 for training and testing. Random forest (rForest) regression models performed on the training set predicted disease status in the testing set; median areas under the receiver operating characteristics curve (AUCs; and 95% confidence interval [CI]) were reported after 500 iterations. In phase II, a six-marker MDM panel (homeobox A1 [HOXA1], empty spiracles homeobox 1 [EMX1], AK055957, endothelin-converting enzyme 1 [ECE1], phosphofructokinase [PFKP], and C-type lectin domain containing 11A [CLEC11A]) normalized by beta-1,3-galactosyltransferase 6 (B3GALT6) level yielded a best-fit AUC of 0.96 (95% CI, 0.93-0.99) with HCC sensitivity of 95% (88%-98%) at specificity of 92% (86%-96%). The panel detected 3 of 4 (75%) stage 0, 39 of 42 (93%) stage A, 13 of 14 (93%) stage B, 28 of 28 (100%) stage C, and 7 of 7 (100%) stage D HCCs. The AUC value for alpha-fetoprotein (AFP) was 0.80 (0.74-0.87) compared to 0.94 (0.9-0.97) for the cross-validated MDM panel (P < 0.0001). Conclusion: MDMs identified in this study proved to accurately detect HCC by plasma testing. Further optimization and clinical testing of this promising approach are indicated.
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http://dx.doi.org/10.1002/hep.30244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429916PMC
March 2019

Identification of Prognostic Phenotypes of Esophageal Adenocarcinoma in 2 Independent Cohorts.

Gastroenterology 2018 12 27;155(6):1720-1728.e4. Epub 2018 Aug 27.

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

Background & Aims: Most patients with esophageal adenocarcinoma (EAC) present with de novo tumors. Although this could be due to inadequate screening strategies, the precise reason for this observation is not clear. We compared survival of patients with prevalent EAC with and without synchronous Barrett esophagus (BE) with intestinal metaplasia (IM) at the time of EAC diagnosis.

Methods: Clinical data were studied using Cox proportional hazards regression to evaluate the effect of synchronous BE-IM on EAC survival independent of age, sex, TNM stage, and tumor location. We analyzed data from a cohort of patients with EAC from the Mayo Clinic (n=411; 203 with BE and IM) and a multicenter cohort from the United Kingdom (n=1417; 638 with BE and IM).

Results: In the Mayo cohort, BE with IM had a reduced risk of death compared to patients without BE and IM (hazard ratio [HR] 0.44; 95% CI, 0.34-0.57; P<.001). In a multivariable analysis, BE with IM was associated with longer survival independent of patient age or sex, tumor stage or location, and BE length (adjusted HR, 0.66; 95% CI, 0.5-0.88; P=.005). In the United Kingdom cohort, patients BE and IM had a reduced risk of death compared with those without (HR, 0.59; 95% CI, 0.5-0.69; P<.001), with continued significance in multivariable analysis that included patient age and sex and tumor stage and tumor location (adjusted HR, 0.77; 95% CI, 0.64-0.93; P=.006).

Conclusion: Two types of EAC can be characterized based on the presence or absence of BE. These findings could increase our understanding the etiology of EAC, and be used in management and prognosis of patients.
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http://dx.doi.org/10.1053/j.gastro.2018.08.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298575PMC
December 2018

A Tale of Three Tails and a Cystic Lesion: A Rare Cause of Recurrent Acute Pancreatitis.

Am J Gastroenterol 2018 Sep 2;113(9):1398-1399. Epub 2018 Jul 2.

Division of Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA. Division of Diagnostic Radiology, Mayo Clinic, Rochester, MN 55905, USA. Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN 55905, USA. Division of Anatomic Pathology, Mayo Clinic, Rochester, MN 55905, USA.

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http://dx.doi.org/10.1038/s41395-018-0178-5DOI Listing
September 2018