Publications by authors named "Rondell P Graham"

117 Publications

Tumor-Infiltrating Lymphocytes for Prognostic Stratification in Nonmetastatic Colon Cancer-Are We There Yet?

JAMA Oncol 2021 Apr 8. Epub 2021 Apr 8.

Department of Pathology and Laboratory Medicine, Mayo Clinic, Mayo Comprehensive Cancer Center, Rochester, Minnesota.

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http://dx.doi.org/10.1001/jamaoncol.2021.0177DOI Listing
April 2021

Outcomes on anti-VEGFR-2/paclitaxel treatment after progression on immune checkpoint inhibition in patients with metastatic gastroesophageal adenocarcinoma.

Int J Cancer 2021 Mar 19. Epub 2021 Mar 19.

Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.

Through our involvement in KEYNOTE-059, we unexpectedly observed durable responses in two patients with metastatic gastroesophageal adenocarcinoma (mGEA) who received ramucirumab (anti-VEGFR-2)/paclitaxel after immune checkpoint inhibition (ICI). To assess the reproducibility of this observation, we piloted an approach to administer ramucirumab/paclitaxel after ICI in more patients, and explored changes in the immune microenvironment. Nineteen consecutive patients with mGEA received ICI followed by ramucirumab/paclitaxel. Most (95%) did not respond to ICI, yet after irRECIST-defined progression on ICI, all patients experienced tumor size reduction on ramucirumab/paclitaxel. The objective response rate (ORR) and progression-free survival (PFS) on ramucirumab/paclitaxel after ICI were higher than on the last chemotherapy before ICI in the same group of patients (ORR, 58.8% vs 11.8%; PFS 12.2 vs 3.0 months; respectively). Paired tumor biopsies examined by imaging mass cytometry showed a median 5.5-fold (range 4-121) lower frequency of immunosuppressive forkhead box P3+ regulatory T cells with relatively preserved CD8+ T cells, post-treatment versus pre-treatment (n = 5 pairs). We then compared the outcomes of these 19 patients with a separate group who received ramucirumab/paclitaxel without preceding ICI (n = 68). Median overall survival on ramucirumab/paclitaxel was longer with (vs without) immediately preceding ICI (14.8 vs 7.4 months) including after multivariate analysis, as was PFS. In our small clinical series, outcomes appeared improved on anti-VEGFR-2/paclitaxel treatment when preceded by ICI, in association with alterations in the immune microenvironment. However, further investigation is needed to determine the generalizability of these data. Prospective clinical trials to evaluate sequential treatment with ICI followed by anti-VEGF(R)/taxane are underway.
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http://dx.doi.org/10.1002/ijc.33559DOI Listing
March 2021

Mesenteric and Retroperitoneal Mucinous Cystic Neoplasms: A Case Series.

Int J Surg Pathol 2021 Mar 18:1066896921993536. Epub 2021 Mar 18.

195112Mayo Clinic, Rochester, MN, USA.

. Mucinous cystic neoplasms (MCNs) are cystic neoplasms with mucinous epithelium surrounded by ovarian-like stroma. Extraovarian MCN occurring in the liver and pancreas have been well characterized. However, only rare case reports of MCN arising outside of these locations have been reported. MCNs arising in unusual locations should enter the differential diagnosis of mucinous intra-abdominal tumors and must be distinguished from more common mimics. Therefore, we aimed to examine a series of MCNs of the retroperitoneum and mesentery to characterize the clinicopathologic features of this entity. Seven MCNs arising in the abdominal mesentery or retroperitoneum were retrospectively identified. A clinicopathologic, histologic, and immunohistochemical (keratin 7, keratin 19, keratin 20, calretinin, inhibin-α, steroidogenic factor-1 (SF-1), estrogen receptor (ER), progesterone receptor (PR), PAX8, CDX2, and CD10) analysis was performed. All 7 MCNs were from females with a median age of 41 years old and a median size of 8 cm. All cases demonstrated mucinous with or without concomitant non-mucinous epithelium overlying spindle cell ovarian-like stroma. Luteinized cells were noted. The epithelium was positive for keratin 7 and keratin 19 in all 7 cases, while the stroma expressed ER, PR, and SF-1 in all cases stained. Calretinin was focally positive in the stroma of 3 of 7 cases, while inhibin-α was focally expressed in 5 of 6 cases. . These results highlight the clinicopathologic, histologic, and immunophenotypic similarities between MCNs of the mesentery, retroperitoneum, pancreas, and liver. Overlapping features suggest a common histogenesis for all MCNs, which could include periductal fetal mesenchyme, aberrant migration of primordial germ cells, or abnormal differentiation or metaplasia of the embryonic coelomic epithelium.
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http://dx.doi.org/10.1177/1066896921993536DOI Listing
March 2021

Predicting Metastasis Risk in Pancreatic Neuroendocrine Tumors Using Deep Learning Image Analysis.

Front Oncol 2020 25;10:593211. Epub 2021 Feb 25.

Department of Biology, Georgia State University, Atlanta, GA, United States.

Background: The prognosis of patients with pancreatic neuroendocrine tumors (PanNET), the second most common type of pancreatic cancer, varies significantly, and up to 15% of patients develop metastasis. Although certain morphological characteristics of PanNETs have been associated with patient outcome, there are no available morphology-based prognostic markers. Given that current clinical histopathology markers are unable to identify high-risk PanNET patients, the development of accurate prognostic biomarkers is needed. Here, we describe a novel machine learning, multiclassification pipeline to predict the risk of metastasis using morphological information from whole tissue slides.

Methods: Digital images from surgically resected tissues from 89 PanNET patients were used. Pathologist-annotated regions were extracted to train a convolutional neural network (CNN) to identify tiles consisting of PanNET, stroma, normal pancreas parenchyma, and fat. Computationally annotated cancer or stroma tiles and patient metastasis status were used to train CNN to calculate a region based metastatic risk score. Aggregation of the metastatic probability scores across the slide was performed to predict the risk of metastasis.

Results: The ability of CNN to discriminate different tissues was high (per-tile accuracy >95%; whole slide cancer regions Jaccard index = 79%). Cancer and stromal tiles with high evaluated probability provided F1 scores of 0.82 and 0.69, respectively, when we compared tissues from patients who developed metastasis and those who did not. The final model identified low-risk (n = 76) and high-risk (n = 13) patients, as well as predicted metastasis-free survival (hazard ratio: 4.71) after adjusting for common clinicopathological variables, especially in grade I/II patients.

Conclusion: Using slides from surgically resected PanNETs, our novel, multiclassification, deep learning pipeline was able to predict the risk of metastasis in PanNET patients. Our results suggest the presence of prognostic morphological patterns in PanNET tissues, and that these patterns may help guide clinical decision making.
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http://dx.doi.org/10.3389/fonc.2020.593211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946991PMC
February 2021

Usefulness of Controlled Attenuation Parameter and Liver Stiffness Measurement for the Identification of Extended-criteria Donors and Risk-assessment in Liver Transplantation.

Transplantation 2021 Feb 23. Epub 2021 Feb 23.

Division of Gastroenterology, Hepatology and Nutrition, and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA. Liver Transplantation Program, University of Arkansas for Medical Sciences, Little Rock, AR. Division of Transplantation Surgery, Mayo Clinic, Rochester, MN. Division of Organ Transplantation, Northwestern University, Chicago, IL. College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. Department of Pathology, University of Michigan, Ann Arbor, MI. Division of Anatomic Pathology, Mayo Clinic, Rochester, MN. Division of Multiorgan Transplantation, Stanford University, Palo Alto, CA. Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA.

Background: Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) are noninvasive surrogates for hepatic steatosis and fibrosis, respectively, and could help identify extended criteria donors in liver transplantation (LT). We aimed to determine the accuracy of CAP/LSM in deceased donors along with post-LT changes.

Methods: Accuracy of preprocurement CAP/LSM to grade/stage steatosis/fibrosis was determined using liver biopsy as reference. Transplant outcomes, including primary nonfunction (PNF) and early allograft dysfunction (EAD), were recorded. Recipients underwent CAP/LSM as outpatients. Areas under the receiver operating characteristic curve (AUROC) and regression models were constructed to analyze data.

Results: We prospectively evaluated 160 allografts (138 transplanted). Same-probe paired baseline/post-LT CAP was 231 dB/m (181-277) / 225 (187-261) (p=0.61), and LSM 7.6 kPa (6.3-10.8) / 5.9 (4.6-8.7) (p=0.002), respectively. CAP reading was affected by BMI and LSM by ALT, race and bilirubin. Although CAP did not correlate with steatosis from frozen sections (rho=0.08; p=0.47), it correlated with steatosis from permanent sections (rho=0.32; p<0.001) and with oil red O histomorphometry (rho=0.35, p=0.001). CAP identified moderate-to-severe steatosis with an AUROC curve of 0.79 (0.66-0.91), for a negative predictive value of 100% at a cutoff value of 230 dB/m. LSM correlated with fibrosis staging (rho=0.22, p=0.007) and it identified discarded allografts with advanced fibrosis/cirrhosis. Patients with no to minimal fibrosis had an LSM of 7.6 (6-10.1) kPa.

Conclusions: Our results are proof-of-concept of the utility of CAP/LSM during organ procurement. Establishing the precise role of these noninvasive tools in the organ allocation process mandates confirmatory studies.
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http://dx.doi.org/10.1097/TP.0000000000003720DOI Listing
February 2021

F-FDG PET/CT of hepatocellular adenoma subtypes and review of literature.

Abdom Radiol (NY) 2021 Feb 8. Epub 2021 Feb 8.

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

Introduction: This study evaluates 18F-FDG PET/CT imaging characteristics of pathologically proven hepatocellular adenoma (HCA) subtypes.

Methods: This is a retrospective review of an institutional database (2011-2017) for subjects with a pathologic diagnosis of hepatic adenomas established within 6 months of a pre-treatment 18F-FDG PET/CT exam. An expert pathological review by a hepatopathologist was performed to confirm diagnosis and subtype HCA. A review of the 18F-FDG PET/CT exams was performed by two board-certified nuclear radiologists in consensus. Corresponding demographic and clinical data were obtained by electronic chart review.

Results: Nine subjects were identified. An HCA subtype was established in seven subjects (4 HNF1A-mutated and 3 Inflammatory). The mean HCA lesion size was 2.8 cm (range 0.6-6.2, SD 2.0) with a mean SUVmax of 5.9 (range 2.1-18.9, SD 5.1). The SUV values of HNF1A-mutated HCA were significantly higher than inflammatory HCA: lesion SUVmax (5.3 ± 1.48 vs. 2.8 ± 0.59, p < 0.033), lesion-to-liver SUVmax ratio (1.4 ± 0.22 vs. 0.8 ± 0.21, p = 0.031), lesion SUVmean (3.6 ± 0.37 vs. 2.0 ± 0.46, p = 0.0086).

Conclusion: HNF1A-mutated HCA may have greater SUV values than inflammatory HCA on 18F-FDG PET/CT exams. However, there are contradictory data in the literature and further investigation is warranted.
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http://dx.doi.org/10.1007/s00261-021-02968-2DOI Listing
February 2021

RNA-Seq Reveals Differences in Expressed Tumor Mutation Burden in Colorectal and Endometrial Cancers with and without Defective DNA-Mismatch Repair.

J Mol Diagn 2021 Feb 4. Epub 2021 Feb 4.

Divisions of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Tumor mutation burden (TMB) is an emerging biomarker of immunotherapy response. RNA sequencing in FFPE tissue samples was used for determining TMB in microsatellite-stable (MSS) and microsatellite instability-high (MSI-H) tumors in patients with colorectal or endometrial cancer. Tissue from tumors and paired normal tissue from 46 MSI-H and 12 MSS cases were included. Of the MSI-H tumors, 29 had defective DNA mismatch-repair mutations, and 17 had MLH1 promoter hypermethylation. TMB was measured using the expressed somatic nucleotide variants (eTMB). A method of accurate measurement of eTMB was developed that removes FFPE-derived artifacts by leveraging mutation signatures. There was a significant difference in the median eTMB values observed between MSI-H and MSS cases: 27.3 versus 6.7 mutations/megabase (mut/Mb) (P = 3.5 × 10). Among tumors with DNA-mismatch repair, those with mismatch-repair mutations had a significantly higher median eTMB than did those with hypermethylation: 28.1 versus 17.5 mut/Mb (P = 0.037). Multivariate analysis showed that MSI status, tissue type (endometrial or colorectal), and age were significantly associated with eTMB. Additionally, using whole-exome sequencing in a subset of these patients, it was determined that DNA TMB correlated well with eTMB (Spearman correlation coefficient, 0.83). These results demonstrate that RNA sequencing can be used for measuring eTMB in FFPE tumor specimens.
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http://dx.doi.org/10.1016/j.jmoldx.2021.01.008DOI Listing
February 2021

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

Hepatic Mucinous Cystic Neoplasm Versus Simple Biliary Cyst: Assessment of Distinguishing Imaging Features Using CT and MRI.

AJR Am J Roentgenol 2021 02 23;216(2):403-411. Epub 2020 Dec 23.

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

The purpose of our study was to identify the imaging features that differentiate a hepatic mucinous cystic neoplasm (MCN) from a simple biliary cyst. Surgically resected hepatic MCNs and simple biliary cysts over a 20-year period (October 29, 1997-January 23, 2018) with preoperative CT, MRI, or both were retrospectively identified. Included cases underwent histopathologic confirmation of diagnosis based on the 2010 World Health Organization criteria and blinded imaging review. Various imaging features, including cyst shape and septal enhancement, were assessed for performance. For septate cysts, the relationship of the septation to the cyst wall-that is, arising from the wall without an indentation versus arising from an external macrolobulation-was recorded. Statistical analysis was performed for the imaging features with the chi-square test. The study group comprised 22 hepatic MCNs and 56 simple biliary cysts. A unilocular hepatic cystic lesion was highly predictive of a simple biliary cyst (positive predictive value = 95.2%). The imaging feature of septations arising only from macro-lobulations was 100% specific for a simple biliary cyst on CT ( = 0.001). The presence of septations arising from the cyst wall without indentation was 100% sensitive for hepatic MCN but was only 56.3% specific on CT. Septal enhancement reached 100% sensitivity for hepatic MCN on MRI ( = 0.018). The presence of septations, relationship of the septations to the cyst wall, and septal enhancement were sensitive imaging features in the detection of hepatic MCN. The imaging feature of septations arising only from macrolobulations in the cyst wall was specific for simple biliary cysts on CT and helped differentiate simple biliary cysts from hepatic MCNs.
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http://dx.doi.org/10.2214/AJR.20.22768DOI Listing
February 2021

Molecular Genetic Landscape of Sclerosing Pneumocytomas.

Am J Clin Pathol 2021 02;155(3):397-404

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

Objectives: Sclerosing pneumocytomas are rare pulmonary neoplasms that are typically benign. However, rare patients experience progressive disease, and therapy targeting specific genetic underpinnings could be an attractive therapeutic option. Recent studies have found recurrent AKT 1 mutations in sclerosing pneumocytoma, but little is known about whether oncogenic fusion genes may also be present.

Methods: To better understand the genetic background, 10 sclerosing pneumocytomas were subjected to next-generation sequencing cancer mutation panel testing (n = 9) and/or RNA sequencing (n = 3). The patients were all women (average age, 47 years; range, 17-74 years).

Results: Eight patients had solitary sclerosing pneumocytomas, while one had two tumors, and one had many bilateral tumors. Recurrent mutations were noted in genes involved in the mTOR pathway, including AKT1, PIK3R1, and PTEN. AKT1 alterations were particularly common, present in 78%. No recurrent genetic fusions were identified. The patient in our study with multiple bilateral lesions was treated with the mammalian target of rapamycin (mTOR) inhibitor everolimus, with no objective radiographic evidence of treatment response after 4 months.

Conclusions: Our data further support that abnormal activation of the mTOR pathway is a consistent genetic event in sclerosing pneumocytoma. This warrants further exploration to determine if mTOR pathway inhibitors may be effective in patients with metastatic or recurrent disease.
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http://dx.doi.org/10.1093/ajcp/aqaa136DOI Listing
February 2021

Lipocalin-2 Expression in Pancreas Adenocarcinoma Tumor Microenvironment Via Endoscopic Ultrasound Fine Needle Biopsy Is Feasible and May Reveal a Therapeutic Target.

Pancreas 2020 Nov/Dec;49(10):e98-e99

Division of Gastroenterology & Hepatology Mayo Clinic Rochester, MN Division of Gastroenterology & Hepatology Mayo Clinic Rochester, MN Divisions of Anatomic Pathology and Laboratory Genetics Mayo Clinic Rochester, MN Center of Individualized Medicine Mayo Clinic Rochester, MN Divisions of Anatomic Pathology and Laboratory Genetics Mayo Clinic Rochester, MN Division of Anatomic Pathology Mayo Clinic Rochester, MN.

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http://dx.doi.org/10.1097/MPA.0000000000001669DOI Listing
October 2020

Liquid Chromatography-Tandem Mass Spectrometry-Based α1-Antitrypsin (AAT) Testing.

Am J Clin Pathol 2021 03;155(4):547-552

Department of Laboratory Medicine and Pathology.

Objectives: Failure to produce sufficient quantities of functional α1-antitrypsin (AAT) can result in AAT deficiency (AATD) and significant comorbidities. Laboratory testing plays a vital role in AATD, with diagnosis requiring documentation of both a low AAT level and a mutated allele. This retrospective evaluation examines the efficacy of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) (proteotyping)-based algorithm for AATD detection.

Methods: A 16-month retrospective data analysis was performed on two cohorts: 5,474 samples tested with the proteotype-based algorithm and 16,147 samples directly tested by isoelectric focusing (IEF) phenotyping.

Results: LC-MS/MS reduced the rate of IEF testing by 97%. The 3% of cases reflexed to IEF resulted in 12 (0.2%) additional phenotype findings. Retrospectively applying the proteotype-based algorithm to the IEF cohort demonstrated a 99.9% sensitivity for the detection of deficiency-associated phenotypes. Most deficiency phenotypes missed by the proteotyping algorithm would come from heterozygous patients with an F, I, or P paired to an S or Z. In all of these cases, patient AAT levels were greater than 70 mg/dL, above the threshold for AAT augmentation therapy.

Conclusions: The proteotype algorithm is a sensitive and cost-effective approach for the diagnosis of clinical AAT deficiency.
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http://dx.doi.org/10.1093/ajcp/aqaa149DOI Listing
March 2021

SMARCA4/SMARCA2-deficient Carcinoma of the Esophagus and Gastroesophageal Junction.

Am J Surg Pathol 2021 03;45(3):414-420

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

Undifferentiated carcinoma of the esophagus and gastroesophageal junction is a recently recognized entity in the fifth edition of the World Health Organization Classification of Digestive Tumors and is diagnostically challenging, particularly on small biopsies. SMARCA4 and SMARCA2 are chromatin remodeling genes with key roles in oncogenesis. We retrieved 14 cases of SMARCA4/SMARCA2-deficient undifferentiated carcinoma of the gastroesophageal junction and esophagus from the authors' institutions. The tumors showed similar histologic findings: the sheet-like proliferation of tumor cells characterized by discohesion, large nuclei, and prominent macronucleoli with many tumor cells exhibiting a rhabdoid appearance. In 8 cases, adjacent specialized intestinal metaplasia was noted and 3 cases exhibited adjacent high-grade dysplasia. Immunohistochemically, tumors variably expressed keratins and disclosed loss of expression of SMARCA4 in 12 and SMARCA2 in 7 cases. In 2 cases SMARCA2 alone was lost without SMARCA4 loss. A mutant p53 immunohistochemical pattern was seen in 4 of 4 cases, 3 of which showed diffuse, strong nuclear expression, and 1 case displayed a complete loss of nuclear expression of p53, including invasive carcinoma and associated dysplasia, when present. Limited clinical follow-up was available, but 3 patients died of disease within 0.6, 2, and 7 months of diagnosis. We present the first series of undifferentiated carcinoma of the esophagus and gastroesophageal junction with this characteristic morphology associated with loss of SMARCA4 and/or SMARCA2 expression. This tumor type likely arises from dedifferentiation of a lower grade carcinoma in some cases, and Barrett esophagus and appears to be associated with an aggressive clinical course.
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http://dx.doi.org/10.1097/PAS.0000000000001599DOI Listing
March 2021

Hepatic Venous Pressure Gradient in Fontan Physiology Has Limited Diagnostic and Prognostic Significance.

CJC Open 2020 Sep 4;2(5):360-364. Epub 2020 May 4.

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

Background: Hepatic venous pressure gradient (HVPG) is measure of portal pressure and a prognostic tool in patients with viral and alcoholic cirrhosis; its utility is unknown in patients with Fontan-associated liver disease (FALD). Limited data suggest that patients with FALD have normal HVPG. On the basis of the available data, we hypothesized that there would be no association between HVPG, liver disease severity, and transplant-free survival in FALD.

Methods: A retrospective study of Fontan patients who had liver biopsy and HVPG assessment at Mayo Clinic was performed. HVPG was calculated as wedged HVP minus free HVP; liver disease severity was measured by histologic assessment of fibrosis and standard clinical liver disease risk scores.

Results: Of 56 patients (aged 28 ± 7 years), the mean Fontan pressure was 16 ± 4 and the mean HVPG was 1.4 ± 0.3 mm Hg (range, 0-3). Perisinusoidal fibrosis and periportal fibrosis were present in 56 (100%) and 54 (94%) patients, respectively; 18 (32%) met criteria for cirrhosis. There was no correlation between HVPG and degree of hepatic fibrosis. Similarly, there was no correlation between HVPG and any clinical liver disease risk score. Six (11%) patients died and 2 (4%) underwent heart transplantation during follow-up; HVPG was not associated with transplant-free survival.

Conclusions: HVPG is not elevated in FALD even in the setting of cirrhosis and does not correlate with liver disease severity or clinical outcomes. These results suggest the limited diagnostic and prognostic role of HVPG in the management of FALD and highlight the potential pitfalls of using HVPG in this population.
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http://dx.doi.org/10.1016/j.cjco.2020.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499375PMC
September 2020

Transcriptomic and Proteomic Analysis of Steatohepatitic Hepatocellular Carcinoma Reveals Novel Distinct Biologic Features.

Am J Clin Pathol 2021 01;155(1):87-96

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

Objectives: Steatohepatitic hepatocellular carcinoma is a distinct variant of hepatocellular carcinoma strongly associated with underlying nonalcoholic steatohepatitis. The molecular biology of steatohepatitic hepatocellular carcinoma is not fully elucidated, and thus we aimed to investigate the molecular underpinnings of this entity.

Methods: Transcriptomic analysis using RNAseq was performed on eight tumor-nonneoplastic pairs of steatohepatitic hepatocellular carcinoma with comparison to conventional hepatocellular carcinoma transcriptomes curated in The Cancer Genome Atlas. Immunohistochemistry was used to validate key RNA-level findings.

Results: Steatohepatitic hepatocellular carcinoma demonstrated a distinctive differential gene expression profile compared with The Cancer Genome Atlas curated conventional hepatocellular carcinomas (n = 360 cases), indicating the distinctive steatohepatitic hepatocellular carcinoma morphology is associated with a unique gene expression profile. Pathway analysis comparing tumor-nonneoplastic pairs revealed significant upregulation of the hedgehog pathway based on GLI1 overexpression and significant downregulation of carnitine palmitoyltransferase 2 transcript. Glutamine synthetase transcript was significantly upregulated, and fatty acid binding protein 1 transcript was significantly downregulated and immunohistochemically confirmed, indicating steatohepatitic hepatocellular carcinoma tumor cells display a zone 3 phenotype.

Conclusions: Steatohepatitic hepatocellular carcinoma demonstrates a distinctive morphology and gene expression profile, phenotype of zone 3 hepatocytes, and activation of the hedgehog pathway and repression of carnitine palmitoyltransferase 2, which may be important in tumorigenesis.
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http://dx.doi.org/10.1093/ajcp/aqaa114DOI Listing
January 2021

Molecular and Immunohistochemical Analysis of Mucinous Cystic Neoplasm of the Liver.

Am J Clin Pathol 2020 11;154(6):837-847

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

Objectives: Mucinous cystic neoplasm of the liver is characterized by neoplastic mucinous and/or biliary epithelium surrounded by ovarian-type stroma. Immunohistochemical studies have shown that the ovarian-type stroma expresses estrogen receptor, suggesting potential hormonal responsiveness. The molecular biology of mucinous cystic neoplasm of the liver remains poorly studied.

Methods: Transcriptome sequencing and immunohistochemistry were performed on a series of mucinous cystic neoplasms.

Results: Mucinous cystic neoplasm of the liver exhibited significantly increased RNA expression of ovarian stromal markers WT1, PR, and ER2 and sex cord stromal markers SF-1, inhibin-α, and calretinin compared with nonneoplastic liver. Immunohistochemistry confirmed the RNA-level data. Evidence for sex hormone biosynthesis was identified by significant overexpression of multiple estrogen biosynthetic enzymes. Expression of 17β-hydroxysteroid dehydrogenase 1 was confirmed immunohistochemically. Pathway analysis also identified significant upregulation of the hedgehog and Wnt pathways and significant downregulation of T-helper 1 and T-helper 2 pathways.

Conclusions: Mucinous cystic neoplasm of the liver recapitulates ovarian stroma at the morphologic, DNA, RNA, and protein levels. These data support the concept that this tumor likely arises from ectopic primitive gonadal tissue and/or stromal cells with capacity to transdifferentiate to ovarian cortical cells.
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http://dx.doi.org/10.1093/ajcp/aqaa115DOI Listing
November 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

GLI1/GLI2 functional interplay is required to control Hedgehog/GLI targets gene expression.

Biochem J 2020 09;477(17):3131-3145

Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A.

The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.
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http://dx.doi.org/10.1042/BCJ20200335DOI Listing
September 2020

Epidermoid Metaplasia of the Esophagus.

Mayo Clin Proc 2020 08;95(8):1796

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. Electronic address: https://twitter.com/AmritKambojMD.

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http://dx.doi.org/10.1016/j.mayocp.2020.04.041DOI Listing
August 2020

Carboxypeptidase A1 and regenerating islet-derived 1α as new markers for pancreatic acinar cell carcinoma.

Hum Pathol 2020 09 21;103:120-126. Epub 2020 Jul 21.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, United States.

Acinar cell carcinoma (ACC) is a rare tumor that differentiates toward pancreatic acinar cells and shows evidence of pancreatic enzyme production. Mixed acinar-neuroendocrine carcinoma (MANC) is defined as having more than 30% of both acinar and neuroendocrine cell types as per immunohistochemistry analysis. Trypsin is currently the most commonly used stain for acinar differentiation. In this study, we investigate the utility of two novel markers, carboxypeptidase A1 (CPA1) and regenerating islet-derived 1α (REG1a), in diagnosing ACC/MANC. Immunohistochemical staining for CPA1 and REG1a was performed on 14 cases of ACC and 5 cases of MANC as well as on 80 other pancreatic tumors including 20 cases each of ductal adenocarcinoma, well-differentiated neuroendocrine tumor, mucinous cystic neoplasm, and solid pseudopapillary tumor. All ACCs and MANCs were positive for CPA1 (all diffuse) and REG1a (12 diffuse, 4 patchy, and 3 focal). A diffuse or patchy staining pattern was significantly more common in ACC/MANC cases (100% diffuse/patchy for CPA1 and 84% for REG1a) than in other pancreatic tumors (5% diffuse/patchy for CPA1 and 7.5% for REG1a), with a P-value of <0.0001 for both CPA1 and REG1a. The sensitivity and specificity of diffuse/patchy staining for CPA1 and REG1a in diagnosing pancreatic ACC/MANC were 100% and 95% for CPA1 and 84% and 93% for REG1a, respectively. In conclusion, CPA1 and REG1a are sensitive markers for ACC that can be used as additional acinar cell differentiation markers to help in the diagnosis of pancreatic ACC and MANC. A negative result for CPA1 virtually excludes ACC/MANC.
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http://dx.doi.org/10.1016/j.humpath.2020.07.019DOI Listing
September 2020

Human Cancers Express TRAILshort, a Dominant Negative TRAIL Splice Variant, Which Impairs Immune Effector Cell Killing of Tumor Cells.

Clin Cancer Res 2020 Nov 15;26(21):5759-5771. Epub 2020 Jul 15.

Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota.

Purpose: TNF-related apoptosis inducing ligand (TRAIL) expression by immune cells contributes to antitumor immunity. A naturally occurring splice variant of TRAIL, called TRAILshort, antagonizes TRAIL-dependent cell killing. It is unknown whether tumor cells express TRAILshort and if it impacts antitumor immunity.

Experimental Design: We used an unbiased informatics approach to identify TRAILshort expression in primary human cancers, and validated those results with IHC and ISH. TRAILshort-specific mAbs were used to determine the effect of TRAILshort on tumor cell sensitivity to TRAIL, and to immune effector cell dependent killing of autologous primary tumors.

Results: As many as 40% of primary human tumors express TRAILshort by both RNA sequencing and IHC analysis. By ISH, TRAILshort expression is present in tumor cells and not bystander cells. TRAILshort inhibition enhances cancer cell lines sensitivity to TRAIL-dependent killing both and in immunodeficient xenograft mouse models. Immune effector cells isolated from patients with B-cell malignancies killed more autologous tumor cells in the presence compared with the absence of TRAILshort antibody ( < 0.05).

Conclusions: These results identify TRAILshort in primary human malignancies, and suggest that TRAILshort blockade can augment the effector function of autologous immune effector cells..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642027PMC
November 2020

Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma.

J Clin Invest 2020 10;130(10):5380-5396

Division of Gastroenterology and Hepatology.

Immune checkpoint blockade (ICB) has revolutionized cancer therapeutics. Desmoplastic malignancies, such as cholangiocarcinoma (CCA), have an abundant tumor immune microenvironment (TIME). However, to date, ICB monotherapy in such malignancies has been ineffective. Herein, we identify tumor-associated macrophages (TAMs) as the primary source of programmed death-ligand 1 (PD-L1) in human and murine CCA. In a murine model of CCA, recruited PD-L1+ TAMs facilitated CCA progression. However, TAM blockade failed to decrease tumor progression due to a compensatory emergence of granulocytic myeloid-derived suppressor cells (G-MDSCs) that mediated immune escape by impairing T cell response. Single-cell RNA sequencing (scRNA-Seq) of murine tumor G-MDSCs highlighted a unique ApoE G-MDSC subset enriched with TAM blockade; further analysis of a human scRNA-Seq data set demonstrated the presence of a similar G-MDSC subset in human CCA. Finally, dual inhibition of TAMs and G-MDSCs potentiated ICB. In summary, our findings highlight the therapeutic potential of coupling ICB with immunotherapies targeting immunosuppressive myeloid cells in CCA.
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http://dx.doi.org/10.1172/JCI137110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524481PMC
October 2020

Liver metastases from pituitary carcinomas mimicking visceral well-differentiated neuroendocrine tumors: a series of four cases.

Diagn Pathol 2020 Jul 4;15(1):81. Epub 2020 Jul 4.

Division of Anatomic Pathology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Background: Pathologists frequently encounter neuroendocrine tumors (NETs) presenting as multiple liver masses in routine practice. Most often, these are well-differentiated tumors with characteristic histologic features. In contrast, pituitary carcinoma is very rare, and there is limited data on its natural history and pathologic characterization.

Methods: The aim of this study was to describe clinical characteristics, histomorphology, immunophenotype and follow-up of pituitary carcinoma involving the liver and mimicking well-differentiated NETs of visceral origin. We selected a group of well-differentiated NETs of the pancreas to use as immunophenotypic controls. We identified 4 patients (age range, 51 to 73) with pituitary corticotroph carcinoma with liver metastases. Three patients presented with Cushing syndrome.

Results: All cases histologically resembled well-differentiated NETs of visceral origin with Ki-67 proliferation indices of 5-42% and expression of T-PIT; metastatic tumors were not immunoreactive with CDX2, Islet 1 or TTF-1.

Conclusions: Frequently, these cases display adrenocorticotropic hormone (ACTH) secretion and pituitary-specific transcription factor immunohistochemistry may be used as a reliable marker to distinguish metastatic pituitary carcinoma from NETs of visceral origin in addition to delineating a corticotroph carcinoma from somatotroph, lactotroph, thyrotroph, and gonadotroph lineage. Although rare, the differential diagnosis of pituitary carcinoma should be considered in metastatic well-differentiated NETs in which the site of origin is uncertain. In summary, pituitary corticotroph carcinoma can metastasize to the liver and mimic well-differentiated NET.
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http://dx.doi.org/10.1186/s13000-020-00997-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335443PMC
July 2020

Clinical and histological features of secondary carcinomas in gastrointestinal tract biopsies.

Histopathology 2020 Oct 12;77(4):622-630. Epub 2020 Sep 12.

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

Background: Secondary carcinoma involving the gastrointestinal (GI) tract is an uncommon finding in biopsy specimens. The diagnosis can be challenging for tumours mimicking a primary carcinoma and when the clinical context is unknown.

Methods And Results: A multicentre retrospective study was performed to evaluate the clinical and histological features of a series of secondary carcinoma in GI biopsies. A total of 197 cases from 190 patients (median age = 67 years; 57% females) were reviewed. In 16% of patients, the primary carcinoma was unknown. Most lesions presented endoscopically as mucosal or submucosal masses (58%). In 13%, the endoscopy was non-suspicious for malignancy. The most common tumours were carcinomas of the breast (38%), kidney (13%), lung (12%), prostate (8%) and ovary (7%). The sites of involvement were the stomach (34%), colon (27%), rectum (18%), duodenum (13%), oesophagus (5%), jejunum (3%) and anus (0.5%). Histological patterns of infiltration were mucosal (76%), submucosal (41%), lymphatic (14%), and epithelial colonisation (8%). Submucosal infiltration was found significantly more frequently in carcinomas of the prostate (67%) and lung (62%), compared with carcinomas of the ovary (27%) and breast (23%). Histological obstructive changes were observed in 36% of all cases, with the highest rate in prostate carcinoma (53%) and the lowest rate in kidney carcinoma (8%).

Conclusion: Awareness of the main clinical and histological patterns of secondary carcinomas in GI tract biopsies may help pathologists to raise the possibility of this uncommon diagnosis and confirm it with the judicious use of immunohistochemistry.
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http://dx.doi.org/10.1111/his.14195DOI Listing
October 2020

Ki-67 "hot spot" digital analysis is useful in the distinction of hepatic adenomas and well-differentiated hepatocellular carcinomas.

Virchows Arch 2021 Feb 25;478(2):201-207. Epub 2020 Jun 25.

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

This study aims to investigate the utility of digital protocols for Ki-67 immunohistochemistry quantitative analysis ("hot spot" method) in the setting of well-differentiated hepatocellular neoplasms. Resection cases of typical hepatic adenomas (HAs) (n = 40), atypical HAs (n = 9), and well-differentiated hepatocellular carcinomas (WD HCCs) (n = 56) were selected. HAs were further classified by immunohistochemistry using antibodies against liver fatty acid binding protein, glutamine synthetase, B-catenin, hepatic serum amyloid A, and C-reactive protein. Ki-67 proliferative index by immunohistochemistry was evaluated in all cases by digital analysis using a modified neuroendocrine tumor "hot spot" protocol. The proliferative rate of HAs (typical, median 1.2% (range 0-7.4%) and atypical, median 1.0% (range 0.3-3%)) was significantly lower than that of WD HCCs (median 4.5%, range 0-49.8%) (P < 0.0001). Only a few (7.5%) of the adenomas (all inflammatory/telangiectatic type) had proliferative rates higher than 4%, compared to most (51%) of HCCs. Ki-67 is a potentially useful adjunct marker in the evaluation of WD hepatocellular neoplasms, as "hot spot" proliferative rates are consistently very low in HAs but vary significantly in WD HCCs.
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http://dx.doi.org/10.1007/s00428-020-02868-8DOI Listing
February 2021

Colonic Angiosarcoma Arising in Association with Amyloid Deposits.

Case Rep Gastrointest Med 2020 16;2020:3780763. Epub 2020 May 16.

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

Angiosarcoma of the colon is rare, as is colonic amyloidosis. To our knowledge, there have been no reported cases of angiosarcoma arising in association with amyloid deposition. Herein, we described a case of 77-year-old man who presented with hematochezia, and a sigmoid mass was found on colonoscopy. Histologic examination of the resected specimen showed extensive nodular deposition of AL-lambda amyloid material in the colonic wall, as well as high-grade angiosarcoma which was closely intermingled with the amyloid deposits. While the occurrence of both colonic amyloidosis and angiosarcoma in this patient may represent pure coincidence, given the intimate association of the angiosarcoma and the amyloid deposition and the rarity of both of these lesions, we hypothesize that angiosarcoma could be secondary to amyloid deposition.
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http://dx.doi.org/10.1155/2020/3780763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246417PMC
May 2020

Comparison of Tissue-Based Molecular Markers in Younger versus Older Patients with Colorectal Neoplasia.

Cancer Epidemiol Biomarkers Prev 2020 Aug 28;29(8):1570-1576. Epub 2020 May 28.

Department of Medicine, Mayo Clinic, Rochester, Minnesota.

Background: Emerging colorectal cancer trends demonstrate increased incidence and mortality in younger populations, prompting consideration of average-risk colorectal cancer screening initiation at age 45 versus 50 years. However, screening test performance characteristics in adults 45-49 years have been minimally described. To inform the biologic rationale for multi-target stool DNA (mt-sDNA) screening in younger patients, we analyzed and compared tissue levels of methylation () and mutation () markers included in the FDA-approved, mt-sDNA assay (Cologuard; Exact Sciences Corporation).

Methods: Within 40-44, 45-49, and 50-64 year age groups, archived colorectal tissue specimens were identified for 211 sporadic colorectal cancer cases, 123 advanced precancerous lesions (APLs; adenomas >1 cm, high-grade dysplasia, ≥25% villous morphology, or sessile serrated polyp; 45-49 and 50-64 age groups only), and 204 histologically normal controls. Following DNA extraction, , and were quantified using QuARTS assays, relative to (reference gene).

Results: None of the molecular marker concentrations were significantly associated with age ( > 0.05 for all comparisons), with the exception of concentration in APL samples (higher in older vs. younger cases; = 0.008). However, levels were also statistically higher in APL case versus normal control samples in both the 45-49 ( < 0.0001) and 50-64 ( < 0.0001) year age groups.

Conclusions: Overall, these findings support the potential for earlier onset of average-risk colorectal cancer screening with the mt-sDNA assay.

Impact: These novel data address an identified knowledge gap and strengthen the biologic basis for earlier-onset, average-risk screening with the mt-sDNA assay.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1598DOI Listing
August 2020

Well-Differentiated/Dedifferentiated Liposarcoma Arising in the Upper Aerodigestive Tract: 8 Cases Mimicking Non-adipocytic Lesions.

Head Neck Pathol 2020 Dec 14;14(4):974-981. Epub 2020 May 14.

Anatomic Pathology - Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA.

Well-differentiated (WDL) and dedifferentiated liposarcomas (DL) of the pharynx, larynx and oral cavity are rare, often mimicking benign lipomatous neoplasms or non-lipogenic mesenchymal tumors. Cases of WDL/DL arising in the upper aerodigestive tract, exclusive of the cervical esophagus, were reviewed. Morphologic features, ancillary studies, including fluorescence in situ hybridization (FISH) studies for CPM/MDM2, and clinical data was catalogued. Eight WDL/DL (4 WDL, 4 DL); were identified in patients ranging from 32 to 77 years (median 52.5 years; 6 males, 2 females) with sites of origin including hypopharynx (5 cases), larynx (2 cases) and oral cavity (1 case). Six of the 8 cases were received for expert consultation, and the remaining 2 cases were initially misdiagnosed as benign lymphangiomatous or fibroepithelial polyps. Morphologically, 4 tumors had areas mimicking various non-lipomatous soft tissue tumors including nodular fasciitis, mammary-type myofibroblastoma, low-grade myofibroblastic sarcoma and undifferentiated pleomorphic sarcoma, 2 cases simulated benign hypopharyngeal polyps, and 1 lesion was notable for a dense lymphoplasmacytic infiltrate suggestive of hematolymphoid neoplasm or IgG4-related sclerosing disease. FISH showed amplification of CPM/MDM2 (8/8 cases). All cases (4/4) with longer than 1-year of follow-up recurred (45-118 months) with 1 tumor showing progression to DL. WDL/DL presenting in the upper aerodigestive tract are rare and diagnostically challenging. Awareness of the morphologic spectrum of WDL/DL coupled with appropriate use of MDM2 FISH is essential for accurate classification and management, as these tumors appear to have a high risk for local recurrence and eventual dedifferentiation in these anatomical locations.
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http://dx.doi.org/10.1007/s12105-020-01171-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669978PMC
December 2020