Publications by authors named "Rondell P Graham"

153 Publications

Safety and Outcomes of Combined Pancreatic and Hepatic Resections for Metastatic Pancreatic Neuroendocrine Tumors.

Ann Surg Oncol 2022 Jun 22. Epub 2022 Jun 22.

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

Background: Approximately 40-50% of patients with pancreatic neuroendocrine tumors (pNETs) initially present with distant metastases. Little is known about the outcomes of patients undergoing combined pancreatic and hepatic resections for this indication.

Methods: Patients who underwent hepatectomy for metastatic pNETs at Mayo Clinic Rochester from 2000 to 2020 were retrospectively reviewed. Major pancreatectomy was defined as pancreaticoduodenectomy or total pancreatectomy, and major hepatectomy as right hepatectomy or trisegmentectomy. Characteristics and outcomes of patients who underwent pancreatectomy with simultaneous hepatectomy were compared with those of patients who underwent isolated hepatectomy (with or without prior history of pancreatectomy).

Results: 205 patients who underwent hepatectomy for metastatic pNETs were identified: 131 underwent pancreatectomy with simultaneous hepatectomy and 74 underwent isolated hepatectomy. Among patients undergoing simultaneous hepatectomy, 89 patients underwent minor pancreatectomy with minor hepatectomy, 11 patients underwent major pancreatectomy with minor hepatectomy, 30 patients underwent minor pancreatectomy with major hepatectomy, and 1 patient underwent major pancreatectomy with major hepatectomy. Patients undergoing simultaneous hepatectomy had more numerous liver lesions (10 or more lesions in 54% vs. 34%, p = 0.008), but the groups were otherwise similar. Rates of any major complications (31% versus 24%, p = 0.43), hepatectomy-specific complications such as bile leak, hemorrhage, and liver failure (0.8-7.6% vs. 1.4-12%, p = 0.30-0.99), and 90-day mortality (1.5% vs. 2.7%, p = 0.62) were similar between the two groups. 5-year overall survival was 64% after combined resections and 65% after isolated hepatectomy (p = 0.93).

Conclusion: For patients with metastatic pNETs, combined pancreatic and hepatic resections can be performed with acceptable morbidity and mortality in selected patients at high-volume institutions.
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http://dx.doi.org/10.1245/s10434-022-12029-7DOI Listing
June 2022

Impact of FGFR2 gene fusions on survival of patients with intrahepatic cholangiocarcinoma following curative intent resection.

HPB (Oxford) 2022 May 28. Epub 2022 May 28.

Department of Surgery, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: Intrahepatic Cholangiocarcinoma (iCCA) is an aggressive cancer with diverse mutational profiles. An important molecular subtype is fibroblast growth factor receptor 2 (FGFR2) fusion. The effect of FGFR2 fusions on prognosis is unknown. Our aim was to assess the outcomes in resected CCA patients in relation to FGFR2 status.

Methods: Surgically treated CCA patients from a single institution were retrospectively reviewed between 2008 and 2014. FGFR rearrangements were detected by fluorescence in situ hybridization (FISH). Data included patient demographics, tumor pathology, disease-free survival (DFS) and overall survival (OS).

Results: Ninety-five patients underwent surgical resection for iCCA. Twelve (13%) of these were found to have FGFR2 fusion, none of which were treated with FGFR targeted therapy. Patients with FGFR2 fusions were found to have a longer 5-year (83 vs. 32%, p = 0.01) and 10-year (46 vs. 22%, p = 0.04) OS. Five and 10-year DFS was also increased (68 vs. 33% p = 0.04) and (68 vs. 25 %, p = 0.02,). FGFR2 fusion status was the strongest independent factor associated with improved OS (HR 0.23, 0.09-0.62, p=0.003) and DFS (HR 0.18, 0.05-0.67, p=0.01).

Conclusion: Patients with CCA FGFR2 fusion have improved OS and DFS following surgical resection.
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http://dx.doi.org/10.1016/j.hpb.2022.05.1341DOI Listing
May 2022

Perianal Basal Cell Carcinoma: 35-Year Experience.

Dis Colon Rectum 2021 Dec 27. Epub 2021 Dec 27.

Division of Colon and Rectal Surgery, Mayo Clinic Rochester, Minneapolis.

Background: Basal cell carcinoma of the perianal region is a rare anorectal disease. This condition is not related to exposure to ultra-violet radiation. Due to the low prevalence and poor detection, there is a paucity of data relating to this condition in literature. Perianal basal cell carcinoma present different surgical challenges from other anatomic locations and may not share the same prevalence or natural history. Here, we describe the largest series to date on the surgical management of perianal basal cell carcinoma.

Objective: To present our 3- year experience in managing perianal basal cell carcinoma.

Design: This was a retrospective single center analysis.

Setting: The study was conducted at a large tertiary referral academic healthcare system.

Patients: All patients undergoing surgical management of pathology confirmed perianal basal cell carcinoma.

Interventions: All patients underwent surgical management of their disease.

Main Outcome Measures: The primary outcomes were disease recurrence, mortality, and wound complications.

Results: A total of 29 patients were identified with an average follow up of 5.5 years. 27.6% of patients had multiple basal cell carcinoma in other anatomic locations at index presentation. 93% of patients were adequately treated with local excision but 60% had wound dehiscence at time of first follow up visit. Ultimately there were no recurrences or disease related mortality during the follow-up period.

Limitations: Limitations to our study include its nonrandomized retrospective nature, single-institution experience, and small patient sample size.

Conclusions: Perianal basal cell carcinoma carries a high rate of synchronous presentation in other locations and should prompt a thorough evaluation. Perianal BCCs can and should be successfully treated with local excision despite the high rate of wound complications. See Video Abstract at http://links.lww.com/DCR/B883.
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http://dx.doi.org/10.1097/DCR.0000000000002234DOI Listing
December 2021

Clinical Testing for Tumor Cell-Free DNA.

Arch Pathol Lab Med 2022 Jun 10. Epub 2022 Jun 10.

From the Departments of Pathology and Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland (Xian).

Context.—: Clinical testing for tumor cell-free DNA (cfDNA) has evolved rapidly, but no practice guidelines exist.

Objective.—: To summarize cfDNA laboratory practices based on self-reporting and assess preanalytical, analytical, and postanalytical trends that may influence the quality, accuracy, and consistency of cfDNA testing.

Design.—: Data were derived from the College of American Pathologists cfDNA proficiency testing program submitted by 101 participating laboratories from 2018 to 2019.

Results.—: Most laboratories performing clinical circulating tumor DNA testing are commercial/nonhospital (71.2%; 72 of 101) and international (77.2%; 78 of 101) laboratories. Commercial laboratories had higher monthly test volumes than hospital-based laboratories (median, 36 versus 7-8) and tended to have larger gene panels (median, 50 versus 11 genes) when panel-based testing was offered. The main clinical indications include therapy selection and treatment/disease monitoring. Plasma is the most commonly accepted specimen, which is predominantly collected in cell-stabilizing tubes. Equal proportions of laboratories use next-generation sequencing (NGS) and non-NGS methods to assess key genes, including EGFR, BRAF, KRAS, NRAS, and IDH1. Most laboratories reported a lower limit of detection (LLOD) of 0.5%, variant allele frequency or less, which did not differ by method, NGS or non-NGS, except for EGFR. Sixty-five percent (17 of 26) of laboratories using the FDA-approved non-NGS EGFR assay report analytical sensitivities higher than 0.5%, as compared to 15% (16 of 104) of laboratories using an alternative NGS or non-NGS method. There is also a wider range in LLODs obtained for the FDA-approved EGFR assay than nonapproved assays.

Conclusions.—: These results highlight emerging practice trends and serve as a foundation to initiate future practice recommendations.
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http://dx.doi.org/10.5858/arpa.2021-0585-CPDOI Listing
June 2022

Gut microbial β-glucuronidases regulate host luminal proteases and are depleted in irritable bowel syndrome.

Nat Microbiol 2022 May 28;7(5):680-694. Epub 2022 Apr 28.

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

Intestinal proteases mediate digestion and immune signalling, while increased gut proteolytic activity disrupts the intestinal barrier and generates visceral hypersensitivity, which is common in irritable bowel syndrome (IBS). However, the mechanisms controlling protease function are unclear. Here we show that members of the gut microbiota suppress intestinal proteolytic activity through production of unconjugated bilirubin. This occurs via microbial β-glucuronidase-mediated conversion of bilirubin conjugates. Metagenomic analysis of faecal samples from patients with post-infection IBS (n = 52) revealed an altered gut microbiota composition, in particular a reduction in Alistipes taxa, and high gut proteolytic activity driven by specific host serine proteases compared with controls. Germ-free mice showed 10-fold higher proteolytic activity compared with conventional mice. Colonization with microbiota samples from high proteolytic activity IBS patients failed to suppress proteolytic activity in germ-free mice, but suppression of proteolytic activity was achieved with colonization using microbiota from healthy donors. High proteolytic activity mice had higher intestinal permeability, a higher relative abundance of Bacteroides and a reduction in Alistipes taxa compared with low proteolytic activity mice. High proteolytic activity IBS patients had lower fecal β-glucuronidase activity and end-products of bilirubin deconjugation. Mice treated with unconjugated bilirubin and β-glucuronidase-overexpressing E. coli significantly reduced proteolytic activity, while inhibitors of microbial β-glucuronidases increased proteolytic activity. Together, these data define a disease-relevant mechanism of host-microbial interaction that maintains protease homoeostasis in the gut.
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http://dx.doi.org/10.1038/s41564-022-01103-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081267PMC
May 2022

Safety and activity of PolyPEPI1018 combined with maintenance therapy in metastatic colorectal cancer: an open-label, multicenter, phase 1b study.

Clin Cancer Res 2022 Apr 26. Epub 2022 Apr 26.

Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori and University of Pisa, Pisa, Italy.

Purpose: Although chemotherapy is standard-of-care for metastatic colorectal cancer (mCRC), immunotherapy has no role in microsatellite stable (MSS) mCRC, a "cold" tumor. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine derived from 7 tumor-associated antigens (TAAs) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in MSS mCRC patients.

Experimental Design: 11 patients with MSS mCRC received PolyPEPI1018 and Montanide ISA51VG adjuvant subcutaneously, combined with fluoropyrimidine/biologic following first-line induction with chemotherapy and a biologic (NCT03391232). In Part A of the study five patients received a single dose, in Part B six patients received up to three doses of PolyPEPI1018 every 12 weeks. The primary objective was safety, secondary objectives were preliminary efficacy, immunogenicity at peripheral and tumor-level, and immune correlates.

Results: PolyPEPI1018 vaccination was safe and well tolerated. No vaccine-related serious adverse event occurred. 80% of patients had CD8+ T-cell responses against {greater than or equal to}3 TAAs. Increased density of tumor-infiltrating lymphocytes were detected post-treatment for 3 of 4 patients' liver biopsies, combined with increased expression of immune-related gene-signatures. Three patients had objective response according to RECISTv1.1, and two patients qualified for curative surgery. Longer median progression-free survival for patients receiving multiple doses compared with a single dose (12.5 vs 4.6 months; p=0.017) suggested a dose-efficacy correlation. The host HLA genotype predicted multi-antigen-specific T-cell responses (p=0.01) indicative of clinical outcome.

Conclusions: PolyPEPI1018 added to maintenance chemotherapy for patients with unresectable, MSS mCRC was safe and associated with specific immune responses and antitumor activity warranting further confirmation in a randomized, controlled setting.
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http://dx.doi.org/10.1158/1078-0432.CCR-22-0112DOI Listing
April 2022

Neuropilin-1 deficiency in vascular smooth muscle cells is associated with hereditary hemorrhagic telangiectasia arteriovenous malformations.

JCI Insight 2022 May 9;7(9). Epub 2022 May 9.

Vascular and Interventional Radiology Translational laboratory, Division of Vascular and Interventional Radiology, Department of Radiology.

Patients with hereditary hemorrhagic telangiectasia (HHT) have arteriovenous malformations (AVMs) with genetic mutations involving the activin-A receptor like type 1 (ACVRL1 or ALK1) and endoglin (ENG). Recent studies have shown that Neuropilin-1 (NRP-1) inhibits ALK1. We investigated the expression of NRP-1 in livers of patients with HHT and found that there was a significant reduction in NRP-1 in perivascular smooth muscle cells (SMCs). We used Nrp1SM22KO mice (Nrp1 was ablated in SMCs) and found hemorrhage, increased immune cell infiltration with a decrease in SMCs, and pericyte lining in lungs and liver in adult mice. Histologic examination revealed lung arteriovenous fistulas (AVFs) with enlarged liver vessels. Evaluation of the retina vessels at P5 from Nrp1SM22KO mice demonstrated dilated capillaries with a reduction of pericytes. In inflow artery of surgical AVFs from the Nrp1SM22KO versus WT mice, there was a significant decrease in Tgfb1, Eng, and Alk1 expression and phosphorylated SMAD1/5/8 (pSMAD1/5/8), with an increase in apoptosis. TGF-β1-stimulated aortic SMCs from Nrp1SM22KO versus WT mice have decreased pSMAD1/5/8 and increased apoptosis. Coimmunoprecipitation experiments revealed that NRP-1 interacts with ALK1 and ENG in SMCs. In summary, NRP-1 deletion in SMCs leads to reduced ALK1, ENG, and pSMAD1/5/8 signaling and reduced cell death associated with AVM formation.
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http://dx.doi.org/10.1172/jci.insight.155565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090252PMC
May 2022

Gene fusions in gastrointestinal tract cancers.

Genes Chromosomes Cancer 2022 05;61(5):285-297

Division of Laboratory of Genetics and Genomics, Mayo Clinic, Rochester, Minnesota, USA.

Fusion genes have been identified in a wide array of human neoplasms including hematologic and solid tumors, including gastrointestinal tract neoplasia. A fusion gene is the product of parts of two genes that are joined together following a deletion, translocation, or chromosomal inversion. Together with single nucleotide variants, insertions, deletions, and amplification, fusion genes represent one of the key genomic mechanisms for tumor development. Detecting fusions in the clinic is accomplished by a variety of techniques including break-apart fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and next-generation sequencing. Some recurrent gene fusions have been successfully targeted by small molecule or monoclonal antibody therapies (ie targeted therapies), while others are used as biomarkers for diagnostic and prognostic purposes. The purpose of this review article is to discuss the clinical utility of detection of gene fusions in carcinomas and neoplasms arising primarily in the digestive system.
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http://dx.doi.org/10.1002/gcc.23035DOI Listing
May 2022

Diagnosis and Treatment of ERBB2-Positive Metastatic Colorectal Cancer: A Review.

JAMA Oncol 2022 05;8(5):760-769

Division of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona.

Importance: Amplification of ERBB2 (formerly referred to as HER2) is present in nearly 3% of patients with metastatic colorectal cancer overall and 5% of patients with KRAS and NRAS wild-type tumors. Despite the availability of several ERBB2-targeted therapeutic options for patients with ERBB2-positive breast and gastric/gastroesophageal tumors, to date, there are currently no approved therapies for patients with ERBB2-positive metastatic colorectal cancer, although ERBB2-targeted therapies are recommended in National Comprehensive Cancer Network guidelines. Recent evidence indicates that anti-ERBB2 therapeutic strategies are active in patients with ERBB2-positive metastatic colorectal cancer and could potentially represent a new standard-of-care.

Observations: The protein ERBB2 is a member of a family of epidermal growth factor receptors that also includes epidermal growth factor receptor (ERBB1), ERBB3, and ERBB4. Amplification of ERBB2 leads to overexpression of the ERBB2 tyrosine kinase receptor, resulting in aberrant signaling and cell migration, growth, adhesion, and differentiation. Colorectal tumors that harbor ERBB2 amplification are more likely to originate on the left side of the colon, are associated with primary and acquired resistance to anti-epidermal growth factor receptor therapies, and have increased incidence of central nervous system metastases. Using immunohistochemistry, fluorescence in situ hybridization, next-generation sequencing, and liquid biopsy techniques, several randomized clinical trials have evaluated the efficacy of ERBB2-targeted therapies in patients with ERBB2-positive metastatic colorectal cancer. These therapies include monoclonal antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors, many of which were associated with favorable efficacy and safety profiles when treating patients with ERBB2-positive metastatic colorectal cancer.

Conclusions And Relevance: The results of this review suggest the ERBB2 receptor is a promising target for patients with metastatic colorectal cancer; however, to date, no therapies are approved for use in this patient population. Therefore, it is imperative to continue to work to address this unmet need so that patients with ERBB2-positive metastatic colorectal cancer have therapeutic options should they become refractory to treatment with standard therapies.
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http://dx.doi.org/10.1001/jamaoncol.2021.8196DOI Listing
May 2022

Outcomes of idiopathic versus secondary nodular regenerative hyperplasia of the liver: A longitudinal study of 167 cases.

Liver Int 2022 06 28;42(6):1379-1385. Epub 2022 Feb 28.

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

Background: Nodular regenerative hyperplasia (NRH) is a rare condition characterized clinically by the development of non-cirrhotic portal hypertension. NRH is the histopathological result in the liver of various systemic disease processes including autoimmune disorders, haematological malignancies and medications. However, natural history of this condition has been limited to small case series while patient outcomes pertaining to different aetiologies of NRH are largely unknown.

Methods: A retrospective cohort of consecutive patients diagnosed with pathology-confirmed NRH at Mayo Clinic between 2002 and 2017 was identified. The histological diagnosis of NRH was determined by expert liver pathologists. Patients with metastatic liver disease, history of liver transplantation or younger than 18 were excluded. Potential aetiologies of NRH were classified as haematological, rheumatological, drug-associated, miscellaneous or idiopathic. Long-term mortality was analysed using Kaplan-Meier estimation and Cox regression models.

Results: One hundred and sixty-seven consecutive patients with pathology-confirmed NRH were analysed over a 15-year period and followed for a median time of 50 months (1-306 months). The mean age at diagnosis was 53 years. No aetiology or risk factor for NRH was identified in the majority of patients (94, 56.3%), whereas an associated, possibly causal, condition was found in 73 patients (secondary NRH). The most common presenting feature was elevated liver tests (80%), but no significant differences in laboratory tests were seen based on aetiology of NRH. Compared to idiopathic NRH, those with an identified cause had a higher rate of splenomegaly at presentation (54% vs. 27%, p = 0.002). Portal hypertension-related complications at diagnosis were common, with ascites present in one-third of patients. Overall transplant-free survival was 63% at 5 years. Median survival in idiopathic NRH was 9.4 years compared to 7.3 years in secondary NRH. Age, renal function and volume status at presentation were significantly associated with survival; however, MELD score was not.

Conclusions: The rates of liver-related complications and mortality in NRH are low, and only a small number of patients ultimately require liver transplantation. Most patients do not have an identified risk factor or aetiology for NRH, and liver-related outcomes do not appear to differ based on associated, possibly causal, conditions.
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http://dx.doi.org/10.1111/liv.15202DOI Listing
June 2022

Calm before the Storm.

N Engl J Med 2022 Feb;386(5):479-485

From the Division of Gastroenterology and Hepatology (M.B.B.N., P.S.K.), the Division of Infectious Diseases (A.D.B.), and the Division of Hematology (S.A.P.), Department of Medicine, and the Department of Laboratory Medicine and Pathology (R.P.G.), Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1056/NEJMcps2111163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8830531PMC
February 2022

Neoplastic Cellularity Assessment in Molecular Testing.

Arch Pathol Lab Med 2022 Jan 28. Epub 2022 Jan 28.

The Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Moncur).

Context.—: Neoplastic cellularity assessment has become an essential component of molecular oncology testing; however, there are currently no best practice recommendations or guidelines for this potentially variable step in the testing process.

Objective.—: To describe the domestic and international practices of neoplastic cellularity assessment and to determine how variations in laboratory practices affect neoplastic cellularity assessment accuracy.

Design.—: Data were derived from 57 US and international laboratories that participated in the 2019 College of American Pathologists Neoplastic Cellularity Proficiency Testing Survey (NEO-B 2019). NEO-B 2019 included 29 laboratory practice questions and 5 images exhibiting challenging histologic features. Participants assessed the neoplastic cellularity of hematoxylin-eosin-stained digital images, and results were compared to a criterion standard derived from a manual cell count.

Results.—: The survey responses showed variations in the laboratory practices for the assessment of neoplastic cellularity, including the definition of neoplastic cellularity, assessment methodology, counting practices, and quality assurance practices. In some instances, variation in laboratory practice affected neoplastic cellularity assessment performance.

Conclusions.—: The results highlight the need for a consensus definition and improved standardization of the assessment of neoplastic cellularity. We put forth an initial set of best practice recommendations to begin the process of standardizing neoplastic cellularity assessment.
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http://dx.doi.org/10.5858/arpa.2021-0166-CPDOI Listing
January 2022

Outcomes of pancreatectomy with portomesenteric venous resection and reconstruction for locally advanced pancreatic neuroendocrine neoplasms.

HPB (Oxford) 2021 Dec 31. Epub 2021 Dec 31.

Department of Surgery, Mayo Clinic, Rochester, MN, USA.

Background: While pancreatectomy with portomesenteric venous resection and reconstruction is commonly performed for locally advanced pancreatic adenocarcinoma, little is known regarding outcomes for pancreatic neuroendocrine neoplasms (panNENs).

Methods: Patients who underwent non-parenchyma-sparing pancreatectomy for panNENs at Mayo Clinic from 2000 to 2020 were retrospectively reviewed. Propensity score matching was performed and patient characteristics and outcomes compared.

Results: Of 867 eligible patients, 41 (4.7%) required vascular resection, including 38 patients who underwent portomesenteric venous resection only. Of these, 23 underwent pancreaticoduodenectomy or total pancreatectomy and 15 distal pancreatectomy. Patients who required portomesenteric venous resection had larger tumors, higher tumor grade, and higher disease stage. After propensity score matching to patients undergoing standard resection, the portomesenteric venous resection group had longer operative times, greater blood loss, and higher transfusion rates. While portomesenteric venous thrombosis was more common after venous resection, major complication rates and perioperative mortality were similar between the two groups, as were 5-year overall and progression-free survival.

Conclusion: For patients with locally advanced panNENs, pancreatectomy with portomesenteric venous resection and reconstruction can be performed in selected patients at high-volume centers with acceptable perioperative morbidity and short- and long-term survival.
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http://dx.doi.org/10.1016/j.hpb.2021.12.016DOI Listing
December 2021

Metallothionein immunohistochemistry has high sensitivity and specificity for detection of Wilson disease.

Mod Pathol 2021 Dec 21. Epub 2021 Dec 21.

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

Diagnosis of Wilson disease (WD) can be difficult because of its protean clinical presentations, but early diagnosis is important because effective treatment is available and can prevent disease progression. Similarly, diagnosis of WD on liver biopsy specimens is difficult due to the wide range of histologic appearances. A stain that could help identify WD patients would be of great value. The goal of this study was to use mass spectrometry-based proteomics to identify potential proteins that are differentially expressed in WD compared to controls, and could serve as potential immunohistochemical markers for screening. Several proteins were differentially expressed in WD and immunohistochemical stains for two (metallothionein (MT) and cytochrome C oxidase copper chaperone (COX17)) were tested and compared to other methods of diagnosis in WD including copper staining and quantitative copper assays. We found diffuse metallothionein immunoreactivity in all liver specimens from patients with WD (n = 20); the intensity of the staining was moderate to strong. This staining pattern was distinct from that seen in specimens from the control groups (none of which showed strong, diffuse staining), which included diseases that may be in the clinical or histologic differential of WD (steatohepatitis (n = 51), chronic viral hepatitis (n = 40), autoimmune hepatitis (n = 50), chronic biliary tract disease (n = 42), and normal liver (n = 20)). COX17 immunostain showed no significant difference in expression between the WD and control groups. MT had higher sensitivity than rhodanine for diagnosis of WD. While the quantitative liver copper assays also had high sensitivity, they require more tissue, have a higher cost, longer turnaround time, and are less widely available than an immunohistochemical stain. We conclude that MT IHC is a sensitive immunohistochemical stain for the diagnosis of WD that could be widely deployed as a screening tool for liver biopsies in which WD is in the clinical or histologic differential diagnosis.
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http://dx.doi.org/10.1038/s41379-021-01001-7DOI Listing
December 2021

Pathologic Examination of Pancreatic Specimens Resected for Treated Pancreatic Ductal Adenocarcinoma: Recommendations From the Pancreatobiliary Pathology Society.

Am J Surg Pathol 2022 06 15;46(6):754-764. Epub 2021 Dec 15.

Department of Pathology, Koc University Hospital and KUTTAM Research Center, Istanbul, Turkey.

Currently, there are no internationally accepted consensus guidelines for pathologic evaluation of posttherapy pancreatectomy specimens. The Neoadjuvant Therapy Working Group of Pancreatobiliary Pathology Society was formed in 2018 to review grossing protocols, literature, and major issues and to develop recommendations for pathologic evaluation of posttherapy pancreatectomy specimens. The working group generated the following recommendations: (1) Systematic and standardized grossing and sampling protocols should be adopted for pancreatectomy specimens for treated pancreatic ductal adenocarcinoma (PDAC). (2) Consecutive mapping sections along the largest gross tumor dimension are recommended to validate tumor size by histology as required by the College of American Pathologists (CAP) cancer protocol. (3) Tumor size of treated PDACs should be measured microscopically as the largest dimension of tumor outer limits that is bound by viable tumor cells, including intervening stroma. (4) The MD Anderson grading system for tumor response has a better correlation with prognosis and better interobserver concordance among pathologists than does the CAP system. (5) A case should not be classified as a complete response unless the entire pancreas, peripancreatic tissues, ampulla of Vater, common bile duct, and duodenum adjacent to the pancreas are submitted for microscopic examination. (6) Future studies on tumor response of lymph node metastases, molecular and/or immunohistochemical markers, as well as application of artificial intelligence in grading tumor response of treated PDAC are needed. In summary, systematic, standardized pathologic evaluation, accurate tumor size measurement, and reproducible tumor response grading to neoadjuvant therapy are needed for optimal patient care. The criteria and discussions provided here may provide guidance towards these goals.
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http://dx.doi.org/10.1097/PAS.0000000000001853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106848PMC
June 2022

Mismatch repair deficiency: The what, how and why it is important.

Genes Chromosomes Cancer 2022 06 9;61(6):314-321. Epub 2021 Dec 9.

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

The mismatch repair system is a major pathway that functions in the maintenance of genomic integrity. It is involved in mitotic and meiotic recombination, apoptosis, immunoglobulin gene rearrangement, somatic hypermutation, and other processes. Deficiencies in mismatch repair give rise to hypermutability and the phenomenon called microsatellite instability. Detection of deficient mismatch repair function or microsatellite instability is used diagnostically, predictively, and prognostically. Specifically, deficient mismatch repair function is used for screening of Lynch syndrome, determining patients who are likely to respond to immune checkpoint inhibition, and to contributes to an understanding of which cancer patients may pursue a more aggressive clinical course. Microsatellite instability can be evaluated directly by polymerase chain reaction (PCR) or indirectly by assessment of mismatch repair protein expression using immunohistochemistry (IHC), and mismatch repair function using next-generation sequencing assays which evaluates homopolymer indels. In this article, we provide a concise practical review on mismatch repair deficiency (MMR-d)/microsatellite instability (MSI), focusing on clinical testing, different testing methods, interpretation of findings, the predictive, and prognostic utility of MSI.
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http://dx.doi.org/10.1002/gcc.23015DOI Listing
June 2022

Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy.

J Gastrointest Oncol 2021 Oct;12(5):2275-2286

Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.

Background: Previous reports suggest that intact SMAD4 expression is associated with a locally aggressive pancreas cancer phenotype. The objectives of this work were to determine the frequency of intact SMAD4 and its association with patterns of recurrence in patients with upfront resected pancreas cancer receiving adjuvant therapy.

Methods: A tissue microarray was constructed using resected specimens from patients who underwent upfront surgery and adjuvant gemcitabine with no neoadjuvant treatment for pancreas cancer. SMAD4 expression was determined by immunohistochemical staining. Associations of SMAD4 expression and clinicopathologic parameters with clinical outcomes were evaluated using Cox proportional hazard models.

Results: One hundred twenty-seven patients were included with a median follow up of 5.7 years. Most patients had stage ≥ pT3 tumors (75%) and pN1 (68%). All patients received adjuvant gemcitabine, and 79% of patients received adjuvant chemoradiotherapy. Ten (8%) patients had intact SMAD4 expression. Grade was the only clinicopathologic parameter statistically associated with SMAD4 expression (P=0.05). Median overall survival was 2.1 years. On univariate analysis, SMAD4 expression was associated with increased locoregional recurrence (hazard ratio 7.0, P<0.01, 95% confidence interval: 2.8-18.0) but not distant recurrence (P=0.06) or overall survival (P=0.73). On multivariable analysis, SMAD4 expression (hazard ratio 9.6, P<0.01, 95% confidence interval: 3.7-24.8) and adjuvant chemoradiotherapy (hazard ratio 0.3, P=0.01, 95% confidence interval: 0.1-0.8) were associated with higher and lower locoregional recurrence, respectively.

Conclusions: In patients with upfront resected pancreas cancer, SMAD4 expression was associated with an increased risk of locoregional recurrence. Prospective evaluation of the frequency of SMAD4 expression and validation of its predictive utility is warranted.
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http://dx.doi.org/10.21037/jgo-21-55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576222PMC
October 2021

Neoadjuvant Chemotherapy Switch in Borderline Resectable/Locally Advanced Pancreatic Cancer.

Ann Surg Oncol 2022 Mar 1;29(3):1579-1591. Epub 2021 Nov 1.

Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN, USA.

Background: Neoadjuvant chemotherapy (NAC) is an integral part of preoperative treatment for patients with borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). The identification of a chemotherapeutic regimen that is both effective and tolerable is critical for NAC to be of oncologic benefit. After initial first-line (FL) NAC, some patients have lack of response or therapeutic toxicities precluding further treatment with the same regimen; optimal decision making regarding this patient population is unclear. Chemotherapy switch (CS) may allow for a larger proportion of patients to undergo curative-intent resection after NAC.

Methods: We reviewed our surgical database for patients undergoing combinatorial NAC for BR/LA PDAC. Variant histologic exocrine carcinomas, intraductal papillary mucinous neoplasm-associated PDAC, and patients without research consent were excluded.

Results: Overall, 468 patients with BR/LA PDAC receiving FL chemotherapy were reviewed, of whom 70% (329/468) continued with FL chemotherapy followed by surgical resection. The remaining 30% (139/468) underwent CS, with 72% (100/139) of CS patients going on to curative-intent surgical resection. Recurrence-free survival (RFS) and overall survival (OS) were not significantly different between the resected FL and CS cohorts (30.0 vs. 19.1 months, p = 0.13, and 41.4 vs. 36.4 months, p = 0.94, respectively) and OS was significantly worse in those undergoing CS without subsequent resection (19 months, p < 0.0001). On multivariable analysis, carbohydrate antigen (CA) 19-9 and pathologic treatment responses were predictors of RFS and OS.

Conclusion: CS in patients undergoing NAC for BR/LA pancreatic cancer does not incur oncologic detriment. The incorporation of CS into NAC treatment sequencing may allow a greater proportion of patients to proceed to curative-intent surgery.
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http://dx.doi.org/10.1245/s10434-021-10991-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810469PMC
March 2022

BRAF Rearrangements and BRAF V600E Mutations Are Seen in a Subset of Pancreatic Carcinomas With Acinar Differentiation.

Arch Pathol Lab Med 2021 10 6. Epub 2021 Oct 6.

From the Department of Laboratory Medicine and Pathology (Ghosh, Greipp, Knutson, Kloft-Nelson, Mounajjed, Said, Zhang, Kerr, Graham), Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Context.—: Comprehensive genomic profiling has demonstrated that approximately 20% of pancreatic carcinomas with acinar differentiation harbor potentially targetable BRAF fusions that activate the MAPK pathway.

Objectives.—: To validate the above finding by BRAF break-apart fluorescence in situ hybridization (FISH) in a large series of pure acinar cell carcinomas (ACCs), evaluate tumors for the presence of BRAF V600E mutations, and compare clinicopathologic features of tumors with BRAF rearrangements with those without.

Design.—: Thirty cases of pure ACC and 6 cases of mixed acinar-neuroendocrine carcinoma (ACC-NEC) were retrieved. A break-apart FISH probe was used to detect BRAF rearrangements. Immunohistochemistry for BRAF V600E was performed.

Results.—: BRAF rearrangements by FISH were found in 6 of 36 cases (17%), 5 of which were pure ACC and 1 was a mixed ACC-NEC. Follow-up was available in 29 of 36 (81%). The median survival was 22 months for BRAF-rearranged cases and 16 months for BRAF-intact cases; the 2-year overall survival was 50% for BRAF-rearranged cases and 35% for BRAF-intact cases. No significant clinicopathologic differences were identified in cases with BRAF rearrangement compared with those without BRAF rearrangement. BRAF V600E mutation was identified in 2 of 34 cases (6%), both of which were pure ACC and were BRAF-intact by FISH.

Conclusions.—: This study supports the finding that BRAF rearrangements are present in approximately 20% of cases and identified BRAF V600E mutations in approximately 5% of cases. These cases may benefit from targeted therapy.
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http://dx.doi.org/10.5858/arpa.2020-0739-OADOI Listing
October 2021

Duodenal Mucosal Barrier in Functional Dyspepsia.

Clin Gastroenterol Hepatol 2022 05 2;20(5):1019-1028.e3. Epub 2021 Oct 2.

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

Background & Aims: In addition to gastric sensorimotor dysfunctions, functional dyspepsia (FD) is also variably associated with duodenal micro-inflammation and epithelial barrier dysfunction, the pathogenesis and clinical significance of which are unknown. Our hypothesis was that miRNAs and/or inflammation degrade epithelial barrier proteins, resulting in increased duodenal mucosal permeability in FD.

Methods: We compared the duodenal mucosal gene expression and miRNAs, in vivo permeability (lactulose-mannitol excretion between 0 and 60 and 60 and 120 minutes after saccharide ingestion), ex vivo assessments (transmucosal resistance, fluorescein isothiocyanate [FITC]-dextran flux, and basal ion transport), and duodenal histology (light and electron microscopy) in 40 patients with FD and 24 controls.

Results: Compared with controls, the mRNA expression of several barrier proteins (zonula occludens-1, occludin, claudin-12, and E-cadherin) was modestly reduced (ie, a fold change of 0.8-0.85) in FD with increased expression of several miRNAs (eg, miR-142-3p and miR-144-3-p), which suppress these genes. The urinary lactulose excretion and the lactulose:mannitol ratio between 60 and 120 minutes were greater in FD than in controls (P < .05). The FITC-dextran flux, which reflects paracellular permeability, was inversely correlated (r = -0.32, P = .03) with transmucosal resistance and directly correlated (r = 0.4, P = .02) with lactulose:mannitol ratio. Other parameters (mucosal eosinophils, intraepithelial lymphocytes, and mast cells, transmucosal resistance, FITC-dextran flux, average intercellular distance, and proportion of dilated junctions) were not significantly different between groups.

Conclusions: In FD, there is a modest reduction in the expression of several duodenal epithelial barrier proteins, which may be secondary to up-regulation of regulatory miRNAs, and increased small intestinal permeability measured in vivo.
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http://dx.doi.org/10.1016/j.cgh.2021.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8975906PMC
May 2022

Somatostatin-derived amyloidosis: a novel type of amyloidosis associated with well-differentiated somatostatin-producing neuroendocrine tumours.

Amyloid 2022 Mar 20;29(1):58-63. Epub 2021 Sep 20.

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

Objective: To report the clinicopathologic and proteomic characteristics of a novel form of amyloidosis derived from the precursor protein somatostatin.

Materials And Methods: Cases were identified by searching the Mayo Clinic amyloid liquid chromatography and tandem mass spectrometry (LC-MS/MS) typing database from 1 January 2008 to 1 September 2020 for specimens with the amyloid signature proteins and abundant somatostatin, in the absence of other amyloid precursor proteins. All available medical records and pathologic materials were examined.

Results: Somatostatin-derived amyloid deposits were found in four patients, two females and two males, with a median age of 61.5 years (range 47-73 years). One patient also had neurofibromatosis-1. The amyloid in each case was associated with a well-differentiated, somatostatin-producing neuroendocrine tumour arising in the small bowel or pancreas. The amyloid deposits were Congo Red-positive and were readily identified by LC- MS/MS analysis. Somatostatin was present exclusively in somatostatin-associated amyloid cases ( < .001), compared to small bowel and pancreas amyloidosis cases of other types. Long-term follow-up is available for one patient who is alive 6 years after initial presentation.

Conclusion: We propose that somatostatin-related amyloidosis is a novel localised human amyloid type that arises in association with well-differentiated somatostatin-producing enteropancreatic neuroendocrine tumours. Treatment of the associated neuroendocrine tumour may be adequate therapy for these patients.
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http://dx.doi.org/10.1080/13506129.2021.1979512DOI Listing
March 2022

The spectrum of histopathological findings after SVR to DAA for recurrent HCV infection in liver transplant recipients.

Virchows Arch 2022 Feb 8;480(2):335-347. Epub 2021 Sep 8.

Department of Gastrointestinal and Hepatobiliary Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA.

Sustained virological response (SVR) to the treatment of recurrent HCV in liver transplant recipients has excellent clinical outcomes; however, little is known about the effects on allograft histology. The study aimed to assess the histology of the allograft liver. In this single-center, retrospective cohort study, patients with recurrent hepatitis C (HCV) in allograft liver who were cured with antiviral therapy between 2010 and 2016 were identified. Biopsies were reviewed by two liver pathologists blinded to the treatment and SVR status. Paired analysis was performed to compare pre- and post-treatment histological features. Of the 62 patients analyzed, 22 patients received PEGylated interferon/ribavirin (IFN) therapy, while 40 patients received direct-acting antiviral agents (DAA). The mean age was 57 years, 24% were female, and 79% were Caucasian. RNA in situ hybridization testing for HCV and HEV was negative in all the tested patients. Significant reduction in the inflammatory grade of post-treatment biopsy specimens was noted in all subjects (n = 57; p < 0.001) and in the IFN group (n = 21; p = 0.001) but not in the DAA group (p = 0.093). Of all subjects, 21% had worsening stage, 31% had improvement, and 48% had no change in stage. Of the treatment groups, 27% in the IFN and 17% in the DAA groups had worsening stage; however, the results were not statistically significant in all subjects or by treatment modality. Persistent inflammatory infiltrates and fibrosis was noted in allograft tissue of patients cured with DAA. Significant improvement in grade was noted in the IFN group, without a significant change in stage.
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http://dx.doi.org/10.1007/s00428-021-03191-6DOI Listing
February 2022

Adenomatoid tumours of the gastrointestinal tract - a case-series and review of the literature.

Histopathology 2022 Jan 7;80(2):348-359. Epub 2021 Oct 7.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Aims: Adenomatoid tumours are mesothelial-derived benign neoplasms with a predilection for the genital tract. Extragenital sites are rare and can cause significant diagnostic challenges. Herein, we describe the clinicopathological features of a cohort of adenomatoid tumours involving the gastrointestinal tract and liver in order to more clearly characterise their histological findings and aid in diagnosis.

Methods And Results: The pathology databases at four institutions were searched for adenomatoid tumours involving the gastrointestinal tract or liver, yielding eight cases. Available clinicoradiological and follow-up data were collected from the medical records. Six tumours were incidentally discovered during imaging studies or at the time of surgical exploration for unrelated conditions; presenting symptoms were unknown in two patients. Histologically, the tumours were well-circumscribed, although focal ill-defined borders were present in four cases. No infiltration of adjacent structures was identified. Architectural heterogeneity was noted in five (63%) tumours; an adenoid pattern often predominated. The neoplastic cells were flattened to cuboidal with eosinophilic cytoplasm. Cytoplasmic vacuoles mimicking signet ring-like cells were present in five (63%) cases. Three (38%) cases showed involvement of the mesothelium with reactive mesothelial hyperplasia. Cytological atypia or increased mitotic activity was not identified. The surrounding stroma ranged from oedematous/myxoid to densely hyalinised. Immunohistochemistry confirmed mesothelial origin in all cases evaluated. No patients developed recurrence of disease.

Conclusions: The current study evaluates the clinicopathological findings in a collective series of gastrointestinal and hepatic adenomatoid tumours, correlating with those described in individually reported cases. We highlight common histological features and emphasise variable findings that could mimic a malignant neoplasm.
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http://dx.doi.org/10.1111/his.14553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712375PMC
January 2022

A rare case of vulvar extraskeletal myxoid chondrosarcoma: mimics and diagnostic clues.

Autops Case Rep 2021 20;11:e2021322. Epub 2021 Aug 20.

University of California Los Angeles (UCLA), David Geffen School of Medicine, Department of Pathology and Laboratory Medicine, Los Angeles, CA, USA.

Only 14 cases of extraskeletal myxoid chondrosarcoma (EMC) of the vulva have been documented in the literature. We report a case of a 63-year-old woman with EMC of the vulva confirmed by both and fluorescence in situ hybridization, the latter of which is a more specific probe for this entity. The unusual location of this tumor of prominent myxoid morphology gave rise to a wide differential diagnosis, which necessitated thorough histologic evaluation and confirmatory ancillary testing in the form of immunohistochemistry and cytogenetic studies. This article aims to review extraskeletal myxoid chondrosarcoma of the vulva and various diagnostic clues to help differentiate it from its histologic mimics. This is the fifth case of vulvar EMC in the literature with confirmation of a gene rearrangement.
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http://dx.doi.org/10.4322/acr.2021.322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387072PMC
August 2021

Acute Kidney Injury in Severe COVID-19 Has Similarities to Sepsis-Associated Kidney Injury: A Multi-Omics Study.

Mayo Clin Proc 2021 10 15;96(10):2561-2575. Epub 2021 Jul 15.

STTARR Innovation Core Facility, University Health Network, Toronto, Ontario, Canada.

Objective: To compare coronavirus disease 2019 (COVID-19) acute kidney injury (AKI) to sepsis-AKI (S-AKI). The morphology and transcriptomic and proteomic characteristics of autopsy kidneys were analyzed.

Patients And Methods: Individuals 18 years of age and older who died from COVID-19 and had an autopsy performed at Mayo Clinic between April 2020 to October 2020 were included. Morphological evaluation of the kidneys of 17 individuals with COVID-19 was performed. In a subset of seven COVID-19 cases with postmortem interval of less than or equal to 20 hours, ultrastructural and molecular characteristics (targeted transcriptome and proteomics analyses of tubulointerstitium) were evaluated. Molecular characteristics were compared with archived cases of S-AKI and nonsepsis causes of AKI.

Results: The spectrum of COVID-19 renal pathology included macrophage-dominant microvascular inflammation (glomerulitis and peritubular capillaritis), vascular dysfunction (peritubular capillary congestion and endothelial injury), and tubular injury with ultrastructural evidence of mitochondrial damage. Investigation of the spatial architecture using a novel imaging mass cytometry revealed enrichment of CD3CD4 T cells in close proximity to antigen-presenting cells, and macrophage-enriched glomerular and interstitial infiltrates, suggesting an innate and adaptive immune tissue response. Coronavirus disease 2019 AKI and S-AKI, as compared to nonseptic AKI, had an enrichment of transcriptional pathways involved in inflammation (apoptosis, autophagy, major histocompatibility complex class I and II, and type 1 T helper cell differentiation). Proteomic pathway analysis showed that COVID-19 AKI and to a lesser extent S-AKI were enriched in necroptosis and sirtuin-signaling pathways, both involved in regulatory response to inflammation. Upregulation of the ceramide-signaling pathway and downregulation of oxidative phosphorylation in COVID-19 AKI were noted.

Conclusion: This data highlights the similarities between S-AKI and COVID-19 AKI and suggests that mitochondrial dysfunction may play a pivotal role in COVID-19 AKI. This data may allow the development of novel diagnostic and therapeutic targets.
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http://dx.doi.org/10.1016/j.mayocp.2021.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279954PMC
October 2021

MRI-detected extramural venous invasion of rectal cancer: Multimodality performance and implications at baseline imaging and after neoadjuvant therapy.

Insights Imaging 2021 Aug 9;12(1):110. Epub 2021 Aug 9.

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

MRI is routinely used for rectal cancer staging to evaluate tumor extent and to inform decision-making regarding surgical planning and the need for neoadjuvant and adjuvant therapy. Extramural venous invasion (EMVI), which is intravenous tumor extension beyond the rectal wall on histopathology, is a predictor for worse prognosis. T2-weighted images (T2WI) demonstrate EMVI as a nodular-, bead-, or worm-shaped structure of intermediate T2 signal with irregular margins that arises from the primary tumor. Correlative diffusion-weighted images demonstrate intermediate to high signal corresponding to EMVI, and contrast enhanced T1-weighted images demonstrate tumor signal intensity in or around vessels. Diffusion-weighted and post contrast images may increase diagnostic performance but decrease inter-observer agreement. CT may also demonstrate obvious EMVI and is potentially useful in patients with a contraindication for MRI. This article aims to review the spectrum of imaging findings of EMVI of rectal cancer on MRI and CT, to summarize the diagnostic accuracy and inter-observer agreement of imaging modalities for its presence, to review other rectal neoplasms that may cause EMVI, and to discuss the clinical significance and role of MRI-detected EMVI in staging and restaging clinical scenarios.
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http://dx.doi.org/10.1186/s13244-021-01023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353019PMC
August 2021

Osteoclast-Like Giant Cell Tumors of the Pancreas: Clinical Characteristics, Genetic Testing, and Treatment Modalities.

Pancreas 2021 08;50(7):952-956

Department of Oncology, Mayo Clinic, Rochester, MN.

Objectives: This study sought to better characterize patient characteristics, treatment options, and outcomes for osteoclast-like giant cell carcinoma of the pancreas, a rare subtype of pancreatic adenocarcinoma.

Methods: This is a retrospective study of all patients with osteoclast-like giant cell carcinoma of pancreatic origin treated at Mayo Clinic from 2000 to present. Baseline patient characteristics, treatment modalities utilized, and outcomes were compiled. Overall survival (OS) and progression-free survival were assessed using Kaplan-Meier analysis with a significance level of P ≤ 0.05.

Results: Fifteen patients met criteria for inclusion. Four patients had distant metastases at diagnosis, the remaining 11 with locoregional disease. Median OS for the entire cohort was 11 months. Metastatic disease was associated with significantly shorter OS (3.5 vs 14.1 months; P = 0.005). Three patients had no evidence of disease at time of analysis; all 3 were treated with complete resection followed by adjuvant chemotherapy.

Conclusions: Osteoclast-like giant cell carcinoma of the pancreas is an aggressive malignancy with poor prognosis. For patients with locoregional disease, surgical resection followed by adjuvant chemoradiation may play a role in extended disease-free survival. Metastatic disease presents a challenging entity to treat with little data to support any effective chemotherapy regimens.
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http://dx.doi.org/10.1097/MPA.0000000000001858DOI Listing
August 2021

Multifocality is not associated with worse survival in sporadic pancreatic neuroendocrine tumors.

J Surg Oncol 2021 Dec 26;124(7):1077-1084. Epub 2021 Jul 26.

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

Background And Objectives: Pancreatic neuroendocrine tumors (pNETs) in patients with hereditary cancer syndromes are typically multifocal. In contrast, sporadic pNETs are usually unifocal and the incidence of multifocal sporadic pNETs is unknown. The primary aim of this study was to investigate the incidence of multifocality in sporadic pNETs and any associated effect on recurrence risk and survival.

Methods: Patients who underwent resection of pNETs at Mayo Clinic from 2000 to 2019 were identified and clinical data were obtained from medical records. Syndromic disease was defined as pNETs arising in the setting of a hereditary cancer syndrome. Statistical comparisons were made using χ , Fisher's exact, and Kruskal-Wallis tests and survival was assessed using the Kaplan-Meier method.

Results: Six hundred and sixty-one patients with sporadic pNETs and fifty-nine with syndromic pNETs were identified. Multifocal disease was present in 4.8% of sporadic patients and 84.7% of syndromic patients (p < .001). Within patients with sporadic pNETs, clinicopathologic features and recurrence-free and overall survival were similar between patients with unifocal and multifocal disease.

Conclusions: Multifocal sporadic pNETs are rare and multifocality is not associated with worse survival or increased recurrence risk. Patients with multifocal sporadic pNETs can likely be safely managed with a combination of resection and observation as indicated for each tumor.
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http://dx.doi.org/10.1002/jso.26618DOI Listing
December 2021

Tyrosine Phosphoproteomics of Patient-Derived Xenografts Reveals Ephrin Type-B Receptor 4 Tyrosine Kinase as a Therapeutic Target in Pancreatic Cancer.

Cancers (Basel) 2021 Jul 7;13(14). Epub 2021 Jul 7.

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

Pancreatic ductal adenocarcinoma is a recalcitrant tumor with minimal response to conventional chemotherapeutic approaches. Oncogenic signaling by activated tyrosine kinases has been implicated in cancers resulting in activation of diverse effector signaling pathways. Thus, the discovery of aberrantly activated tyrosine kinases is of great interest in developing novel therapeutic strategies in the treatment and management of pancreatic cancer. Patient-derived tumor xenografts (PDXs) in mice serve as potentially valuable preclinical models as they maintain the histological and molecular heterogeneity of the original human tumor. Here, we employed high-resolution mass spectrometry combined with immunoaffinity purification using anti-phosphotyrosine antibodies to profile tyrosine phosphoproteome across 13 pancreatic ductal adenocarcinoma PDX models. This analysis resulted in the identification of 1199 tyrosine-phosphorylated sites mapping to 704 proteins. The mass spectrometric analysis revealed widespread and heterogeneous activation of both receptor and non-receptor tyrosine kinases. Preclinical studies confirmed ephrin type-B receptor 4 (EphB4) as a potential therapeutic target based on the efficacy of human serum albumin-conjugated soluble EphB4 in mice bearing orthotopic xenografts. Immunohistochemistry-based validation using tissue microarrays from 346 patients with PDAC showed significant expression of EphB4 in >70% of patients. In summary, we present a comprehensive landscape of tyrosine phosphoproteome with EphB4 as a promising therapeutic target in pancreatic ductal adenocarcinoma.
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http://dx.doi.org/10.3390/cancers13143404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303779PMC
July 2021
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