Recent Articles on Pancreatobiliary #Pathology – 2020-07-28

These are the recent articles on Pancreatobiliary Pathology:

To see all journal watch articles please visit: http://pbpath.org/journal-watch-upcoming-issue/

New Pancreas Articles


  • Tuft Cells Inhibit Pancreatic Tumorigenesis in Mice by Producing Prostaglandin D2

Gastroenterology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32717220

BACKGROUND & AIMS: Development of pancreatic ductal adenocarcinoma (PDA) involves acinar to ductal metaplasia and genesis of tuft cells. It has been a challenge to study these rare cells due to lack of animal models. We investigated the role of tuft cells in pancreatic tumorigenesis.
METHODS: We performed studies with LSL-KrasG12D/+; Ptf1aCre/+ mice (KC, develop pancreatic tumors), KC mice crossed with mice with pancreatic disruption of Pou2f3 (KPouC mice, do not develop Tuft cells), or mice with pancreatic disruption of the hematopoietic prostaglandin D synthase gene (Hpgds, KHC mice), and wild-type mice. Mice were allowed to age or were given caerulein to induce pancreatitis; pancreata were collected and analyzed by histology, immunohistochemistry, RNA sequencing, ultrastructural microscopy, and metabolic profiling. We performed laser-capture dissection and RNA sequencing analysis of pancreatic tissues from 26 patients with pancreatic intraepithelial neoplasias (PanINs), 19 patients with intraductal papillary mucinous neoplasms (IPMN), and 197 patients with PDA.
RESULTS: Pancreata from KC mice had increased formation of tuft cells and higher levels of prostaglandin D2 than wild-type mice. Pancreas-specific deletion of POU2F3 in KC mice (KPouC mice) resulted in a loss of tuft cells and accelerated tumorigenesis. KPouC mice had increased fibrosis and activation of immune cells following administration of caerulein. Pancreata from KPouC and KHC mice had significantly lower levels of PGD2, compared with KC mice, and significantly increased numbers of PanINs and PDAs. KPouC and KHC mice had increased pancreatic injury, following administration of caerulein, significantly less normal tissue, more extracellular matrix deposition, and higher PanIN grade than KC mice. Human PanIN and IPMN had gene expression signatures associated with tuft cells and increased expression of Hpgds mRNA compared with PDA.
CONCLUSIONS: In mice with KRAS-induced pancreatic tumorigenesis, loss of tuft cells accelerates tumorigenesis and increases the severity of caerulein-induced pancreatic injury, via decreased production of PGD2. These data are consistent with the hypothesis that tuft cells are a metaplasia-induced tumor attenuating cell type.

doi: https://doi.org/10.1053/j.gastro.2020.07.037



  • Extracellular cold-inducible RNA-binding protein regulates neutrophil extracellular trap formation and tissue damage in acute pancreatitis

Laboratory investigation; a journal of technical methods and pathology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32709888

Neutrophil extracellular traps (NETs) play a key role in the development of acute pancreatitis (AP). In the present study, we studied the role of extracellular cold-inducible RNA-binding protein (eCIRP), a novel damage-associated-molecular-pattern molecule, in severe AP. C57BL/6 mice underwent retrograde infusion of taurocholate into the pancreatic duct. C23, an eCIRP inhibitor, was given 1 h prior to induction of AP. Pancreatic, lung, and blood samples were collected and levels of citrullinated histone 3, DNA-histone complexes, eCIRP, myeloperoxidase (MPO), amylase, cytokines, matrix metalloproteinase-9 (MMP-9), and CXC chemokines were quantified after 24 h. NETs were detected by electron microscopy in the pancreas and bone marrow-derived neutrophils. Amylase secretion was analyzed in isolated acinar cells. Plasma was obtained from healthy individuals and patients with mild and moderate severe or severe AP. Taurocholate infusion induced NET formation, inflammation, and tissue injury in the pancreas. Pretreatment with C23 decreased taurocholate-induced pancreatic and plasma levels of eCIRP and tissue damage in the pancreas. Blocking eCIRP reduced levels of citrullinated histone 3 and NET formation in the pancreas as well as DNA-histone complexes in the plasma. In addition, administration of C23 attenuated MPO levels in the pancreas and lung of mice exposed to taurocholate. Inhibition of eCIRP reduced pancreatic levels of CXC chemokines and plasma levels of IL-6, HMGB-1, and MMP-9 in mice with severe AP. Moreover, eCIRP was found to be bound to NETs. Coincubation with C23 reduced NET-induced amylase secretion in isolated acinar cells. Patients with severe AP had elevated plasma levels of eCIRP compared with controls. Our novel findings suggest that eCIRP is a potent regulator of NET formation in the inflamed pancreas. Moreover, these results show that targeting eCIRP with C23 inhibits inflammation and tissue damage in AP. Thus, eCIRP could serve as an effective target to attenuate pancreatic damage in patients with AP.

doi: https://doi.org/10.1038/s41374-020-0469-5



  • Radiographic Splenic Artery Involvement Is a Poor Prognostic Factor in Upfront Surgery for Patients with Resectable Pancreatic Body and Tail Cancer

Annals of surgical oncology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32705517

PURPOSE: The prognostic impact of radiographic splenic vessel involvement in pancreatic cancer remains unclear. We evaluate its oncological significance in resectable pancreatic body/tail cancer.
PATIENTS AND METHODS: We retrospectively review 102 cases of resectable pancreatic cancer and 51 of borderline resectable pancreatic cancer (BRPC) who underwent pancreatectomy for pancreatic body/tail cancer. Resectable pancreatic body/tail cancer was classified into one of three categories based on radiographic splenic vessel involvement.
RESULTS: Among 102 cases of resectable pancreatic cancer, 37 (36.3%), 35 (34.3%), and 30 cases (29.4%) were classified as no splenic vessel involvement (Rnone), splenic vein involvement (RV), and splenic artery involvement (RA), respectively. Disease-free survival (DFS) among patients with Rnone, RV, RA, and BRPC was 58.5, 18.4, 10.8, and 9.2 months, respectively. Patients with RV and RA had significantly poorer DFS than patients with Rnone (P = 0.010, P < 0.001, respectively). Median survival among Rnone, RV, RA, and BRPC was 80.6, 23.4, 15.1, and 21.3 months, respectively. Patients with RV and RA had significantly poorer survival than patients with Rnone (P = 0.001, P < 0.001, respectively) and had short survival similar to that of those with BRPC. Multivariate Cox proportional hazard analysis detected preoperative CA19-9 ≥ 37 IU/L, radiologic splenic vein involvement, radiologic splenic artery involvement, intraoperative bleeding ≥ 500 ml, transfusion, positive washing cytology, and noncompletion of adjuvant therapy as independent prognostic factors.
CONCLUSIONS: Radiographic splenic artery involvement is a poor prognostic factor in resectable pancreatic body/tail cancer and may have a role in stratification of treatment strategy.

doi: https://doi.org/10.1245/s10434-020-08922-8



  • The genetics of ductal adenocarcinoma of the pancreas in the year 2020: dramatic progress, but far to go

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32704031

The publication of the “Pan-Cancer Atlas” by the Pan-Cancer Analysis of Whole Genomes Consortium, a partnership formed by The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC), provides a wonderful opportunity to reflect on where we stand in our understanding of the genetics of pancreatic cancer, as well as on the opportunities to translate this understanding to patient care. From germline variants that predispose to the development of pancreatic cancer, to somatic mutations that are therapeutically targetable, genetics is now providing hope, where there once was no hope, for those diagnosed with pancreatic cancer.

doi: https://doi.org/10.1038/s41379-020-0629-6



  • Peritumoral/vascular expression of PSMA as a diagnostic marker in hepatic lesions

Diagnostic pathology 2020 Jul;15(1):92

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32703222

BACKGROUND: The differential diagnosis between primary cholangiocarcinoma and metastatic pancreatobiliary adenocarcinoma is histologically challenging due to lack of distinct morphological features and reliable molecular markers. Prostate-specific membrane antigen (PSMA) is expressed in prostate epithelium and upregulated on the surface of prostatic adenocarcinoma cells. Studies have shown PSMA enzymatic activity is involved in malignancy-driven neoangiogenesis in the endothelium of tumor-associated neovasculature in breast, lung, thyroid, hepatocellular carcinoma (HCC) and urothelial cancer. Recently, PSMA-targeted imaging technology (PSMA PET-CT) detected the presence of PSMA in primary cholangiocarcinoma. However histological correlation with PSMA expression other mass lesions in the liver has not yet been studied.
METHODS: 72 cases of liver mass resection were collected at a tertiary hospital from 2011 to 2019. Immunohistochemical stains for PSMA and CD34 were performed. The expression of PSMA in tumor cells and associated neovascular endothelium were analyzed separately and the locations of vascular structures were confirmed by CD34 expression.
RESULTS: Among 72 cases, 28 cases (22/72, 38.9%) showed PSMA peritumoral/vascular expression only, 3 cases (3/72, 4.2%) showed tumor cell expression only, and 2 cases (2/72, 2.8%) showed both tumor cell and peritumoral/vascular expression. The remainder (39/72, 54.2%) showed no expression. Particularly, most of primary cholangiocarcinoma showed PSMA vascular expression (13/15, 86.7%), while none of the 18 cases of metastatic pancreatobiliary adenocarcinoma were positive for PSMA (0/18, 0%) (p < 0.01). Outside of pancreatobiliary adenocarcinoma, none of the metastatic tumors, including colon and lung cancers, expressed PSMA. In 8 cases of metastatic prostate carcinoma, 3 showed PSMA expressions in tumor cells only (3/8, 37.5%) and 2 expressed PMSA in both tumor cells and neovasculature (2/8, 25.0%). Out of 22 HCC cases, 15 (15/22, 68.2%) were positive for PSMA in tumor vasculature. None of the 5 hepatic adenoma expressed PSMA (0/5, 0%).
CONCLUSION: Significantly enhanced tumor-associated neovascular PSMA expression was identified in primary cholangiocarcinoma, compared to metastatic pancreatobiliary adenocarcinoma. Our findings potentially provide a sensitive marker in differential diagnosis between otherwise morphologically indistinguishable cases.

doi: https://doi.org/10.1186/s13000-020-00982-4


New GallBladder Articles


  • Effect of diabetes mellitus on survival in patients with gallbladder Cancer: a systematic review and meta-analysis

BMC cancer 2020 Jul;20(1):689

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32709224

BACKGROUND: Increasing evidences indicated that diabetes might increase the incidence of gallbladder cancer. However, no sufficient data has ever clarified the impact of diabetes on the survival of patients with gallbladder cancer.
METHODS: We comprehensively searched PubMed, Embase, and the Cochrane Library databases through July 2019 in order to find sufficient eligible researches. The pooled hazard risks (HRs) and relative risks (RRs) with 95% confidence intervals (CIs) were calculated with either fix-effects or random-effects model. Due to the low gallbladder cancer mortality in general population, the RRs and standard mortality ratios (SMRs) were considered the similar estimates of the HRs.
RESULTS: Ten eligible studies were included in this meta-analysis. Analysis of eight cohorts found that diabetes was closely associated with the mortality of gallbladder cancer (HR = 1.10; 95% CI: 1.06-1.14; P < 0.00001). However, the mortality in male diabetes patients was not higher than female patients (RR = 1.08, 95%CI = 0.57-2.04, P = 0.80).
CONCLUSIONS: These findings indicated that diabetes patients had a higher mortality of gallbladder cancer compared with non-diabetes.

doi: https://doi.org/10.1186/s12885-020-07139-y



  • A prospective feasibility study of one-year administration of adjuvant S-1 therapy for resected biliary tract cancer in a multi-institutional trial (Tokyo Study Group for Biliary Cancer: TOSBIC01)

BMC cancer 2020 Jul;20(1):688

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32703191

BACKGROUND: Although surgery is the definitive curative treatment for biliary tract cancer (BTC), outcomes after surgery alone have not been satisfactory. Adjuvant therapy with S-1 may improve survival in patients with BTC. This study examined the safety and efficacy of 1 year adjuvant S-1 therapy for BTC in a multi-institutional trial.
METHODS: The inclusion criteria were as follows: histologically proven BTC, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, R0 or R1 surgery performed, cancer classified as Stage IB to III. Within 10 weeks post-surgery, a 42-day cycle of treatment with S-1 (80 mg/m2/day orally twice daily on days 1-28 of each cycle) was initiated and continued up to 1 year post surgery. The primary endpoint was adjuvant therapy completion rate. The secondary endpoints were toxicities, disease-free survival (DFS), and overall survival (OS).
RESULTS: Forty-six patients met the inclusion criteria of whom 19 had extrahepatic cholangiocarcinoma, 10 had gallbladder carcinoma, 9 had ampullary carcinoma, and 8 had intrahepatic cholangiocarcinoma. Overall, 25 patients completed adjuvant chemotherapy, with a 54.3% completion rate while the completion rate without recurrence during the 1 year administration was 62.5%. Seven patients (15%) experienced adverse events (grade ¾). The median number of courses administered was 7.5. Thirteen patients needed dose reduction or temporary therapy withdrawal. OS and DFS rates at 1/2 years were 91.2/80.0% and 84.3/77.2%, respectively. Among patients who were administered more than 3 courses of S-1, only one patient discontinued because of adverse events.
CONCLUSIONS: One-year administration of adjuvant S-1 therapy for resected BTC was feasible and may be a promising treatment for those with resected BTC. Now, a randomized trial to determine the optimal duration of S-1 is ongoing.
TRIAL REGISTRATION: UMIN-CTR, UMIN000009029. Registered 5 October 2012-Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009347.

doi: https://doi.org/10.1186/s12885-020-07185-6


New BileDuct Articles


  • Knockout of the tachykinin receptor 1 in the Mdr2-/- mouse model of primary sclerosing cholangitis reduces biliary damage and liver fibrosis

The American journal of pathology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32712019

Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated (BDL) and Mdr2-/- mice through enhanced transforming growth factor-β1 (TGF-β1) biliary secretion. Recent evidence indicates a role for microRNA (miR)-31 in TGF-β1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-β1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with double knockout of Mdr2-/- and NK1R to further address the role of the SP/NK1R axis during chronic cholestasis. In vivo studies were performed in the following 12 wk male mice: (i) NK1R-/-; (ii) Mdr2-/-; (iii) NK1R-/-/Mdr2-/- and their corresponding wild-type (WT) controls. Liver tissues and cholangiocytes were collected and we evaluated for liver damage, changes in biliary mass/senescence and inflammation as well as liver fibrosis by both immunohistochemistry in liver sections and qPCR. miR-31 expression was measured by qPCR in isolated cholangiocytes. Decreased ductular reaction, liver fibrosis, biliary senescence and biliary inflammation were observed in NK1R-/-/Mdr2-/- compared to Mdr2-/- mice. Elevated expression of miR-31 was observed in Mdr2-/- mice, which was reduced in NK1R-/-/Mdr2-/- mice. Targeting the SP/NK1R and/or miR-31 may be a potential approach in treating human cholangiopathies including PSC.

doi: https://doi.org/10.1016/j.ajpath.2020.07.007


New Ampulla Articles

Today there is no new Ampulla Article.

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