Monthly Archives: July 2020

Recent Articles on Pancreatobiliary #Pathology – 2020-07-31

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

  • Deep learning-based image analysis methods for brightfield-acquired multiplex immunohistochemistry images

Diagnostic pathology 2020 Jul;15(1):100

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32723384

BACKGROUND: Multiplex immunohistochemistry (mIHC) permits the labeling of six or more distinct cell types within a single histologic tissue section. The classification of each cell type requires detection of the unique colored chromogens localized to cells expressing biomarkers of interest. The most comprehensive and reproducible method to evaluate such slides is to employ digital pathology and image analysis pipelines to whole-slide images (WSIs). Our suite of deep learning tools quantitatively evaluates the expression of six biomarkers in mIHC WSIs. These methods address the current lack of readily available methods to evaluate more than four biomarkers and circumvent the need for specialized instrumentation to spectrally separate different colors. The use case application for our methods is a study that investigates tumor immune interactions in pancreatic ductal adenocarcinoma (PDAC) with a customized mIHC panel.
METHODS: Six different colored chromogens were utilized to label T-cells (CD3, CD4, CD8), B-cells (CD20), macrophages (CD16), and tumor cells (K17) in formalin-fixed paraffin-embedded (FFPE) PDAC tissue sections. We leveraged pathologist annotations to develop complementary deep learning-based methods: (1) ColorAE is a deep autoencoder which segments stained objects based on color; (2) U-Net is a convolutional neural network (CNN) trained to segment cells based on color, texture and shape; and ensemble methods that employ both ColorAE and U-Net, collectively referred to as (3) ColorAE:U-Net. We assessed the performance of our methods using: structural similarity and DICE score to evaluate segmentation results of ColorAE against traditional color deconvolution; F1 score, sensitivity, positive predictive value, and DICE score to evaluate the predictions from ColorAE, U-Net, and ColorAE:U-Net ensemble methods against pathologist-generated ground truth. We then used prediction results for spatial analysis (nearest neighbor).
RESULTS: We observed that (1) the performance of ColorAE is comparable to traditional color deconvolution for single-stain IHC images (note: traditional color deconvolution cannot be used for mIHC); (2) ColorAE and U-Net are complementary methods that detect 6 different classes of cells with comparable performance; (3) combinations of ColorAE and U-Net into ensemble methods outperform using either ColorAE and U-Net alone; and (4) ColorAE:U-Net ensemble methods can be employed for detailed analysis of the tumor microenvironment (TME). We developed a suite of scalable deep learning methods to analyze 6 distinctly labeled cell populations in mIHC WSIs. We evaluated our methods and found that they reliably detected and classified cells in the PDAC tumor microenvironment. We also present a use case, wherein we apply the ColorAE:U-Net ensemble method across 3 mIHC WSIs and use the predictions to quantify all stained cell populations and perform nearest neighbor spatial analysis. Thus, we provide proof of concept that these methods can be employed to quantitatively describe the spatial distribution immune cells within the tumor microenvironment. These complementary deep learning methods are readily deployable for use in clinical research studies.

doi: https://doi.org/10.1186/s13000-020-01003-0

  • Fetal & Pediatric Pathology

Fetal and pediatric pathology 2020 Jul;():1-4

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32723208

Choledochal cysts (CCs), congenital cystic dilatation of the biliary tract, are more commonly identified in females and have been associated with a myriad of other developmental abnormalities. Case Report: We present a male infant who was diagnosed with type I CC prenatally. He subsequently underwent cyst and gallbladder resection with hepaticoduodenostomy reconstruction at the age of 6 months. Pathologic examination confirmed type I CC with co-existing septate gallbladder and ectopic pancreas (Heinrich type 1). Conclusions: Although the clinical significance is unclear, this second case of CC with septate gallbladder and ectopic pancreas highlights the embryologic association of these abnormalities.

doi: https://doi.org/10.1080/15513815.2020.1797962

New GallBladder Articles

  • Fetal & Pediatric Pathology

Fetal and pediatric pathology 2020 Jul;():1-4

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32723208

Choledochal cysts (CCs), congenital cystic dilatation of the biliary tract, are more commonly identified in females and have been associated with a myriad of other developmental abnormalities. Case Report: We present a male infant who was diagnosed with type I CC prenatally. He subsequently underwent cyst and gallbladder resection with hepaticoduodenostomy reconstruction at the age of 6 months. Pathologic examination confirmed type I CC with co-existing septate gallbladder and ectopic pancreas (Heinrich type 1). Conclusions: Although the clinical significance is unclear, this second case of CC with septate gallbladder and ectopic pancreas highlights the embryologic association of these abnormalities.

doi: https://doi.org/10.1080/15513815.2020.1797962

New BileDuct Articles

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New Ampulla Articles

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Recent Articles on Pancreatobiliary #Pathology – 2020-07-30

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

  • Systematic Review and Metaanalysis of Lymph Node Metastases of Resected Pancreatic Neuroendocrine Tumors

Annals of surgical oncology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32720049

BACKGROUND: The optimal surgical strategy for pancreatic neuroendocrine tumors (PNETs) is unknown. However, current guidelines recommend a watch-and-wait strategy for small nonfunctional PNETs (NF-PNETs). The aim of this study is to investigate the risk stratification and prognostic significance of lymph node metastasis (LNM) of PNETs to guide decision-making for lymphadenectomy.
PATIENTS AND METHODS: The MEDLINE and Web of Science databases were systematically searched for studies reporting either risk factors of LNM in resected PNETs or survival of patients with LNM. The weighted average incidence of LNM was calculated according to tumor characteristics. Random-effects metaanalyses were performed, and pooled hazard ratios (HR) and their 95% confidence intervals (CI) were calculated to determine the impact of LNM on overall survival (OS). In subgroup analyses, NF-PNETs were assessed.
RESULTS: From a total of 5883 articles, 98 retrospective studies with 13,374 patients undergoing resection for PNET were included. In all PNETs, the weighted median rates of LNM were 11.5% for small (≤ 2 cm) PNETs and 15.8% for G1 PNETs. In NF-PNETs, the rates were 11.2% for small PNETs and 10.3% for G1 PNETs. LNM of all PNETs (HR 3.87, 95% CI 3.00-4.99, P < 0.001) and NF-PNETs (HR 4.98, 95% CI 2.81-8.83, P < 0.001) was associated with worse OS.
CONCLUSIONS: LNM is potentially prevalent even in small and well-differentiated PNETs and is associated with worse prognosis. A watch-and-wait strategy for small NF-PNETs should be reappraised, and oncologic resection with lymphadenectomy can be considered. Prospective and controlled studies are needed in the future.

doi: https://doi.org/10.1245/s10434-020-08850-7

  • Low dose Hsp90 inhibitor selectively radiosensitizes HNSCC and Pancreatic xenografts

Clinical cancer research : an official journal of the American Association for Cancer Research 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32718999

PURPOSE: Treatment approaches using Hsp90 inhibitors at their maximum tolerated doses have not produced selective tumor toxicity. Inhibition of Hsp90 activity causes degradation of client proteins including those involved in recognizing and repairing DNA lesions. We hypothesized that if DNA repair proteins were degraded by concentrations of an Hsp90 inhibitor below those required to cause non-specific cytotoxicity, significant tumor-selective radiosensitization might be achieved.
EXPERIMENTAL DESIGN: Tandem Mass Tagged (TMT)-mass spectrometry (MS) was performed to determine the effect of a sub-cytotoxic concentration of the Hsp90 inhibitor, AT13387 (Onalespib) on global protein abundance. The effect of AT13387 on in vitro radio-sensitization was assessed using a clonogenic assay. Pharmacokinetic (PK) profiling was performed in mice bearing xenografts. Finally, the effect of low-dose AT13387 on the radiosensitization of three tumor models was assessed.
RESULTS: A sub-cytotoxic concentration of AT13387 reduced levels of DNA repair proteins, without affecting the majority of Hsp90 clients. The PK study using one-third of the maximum tolerated dose (MTD) showed 40-fold higher levels of AT13387 in tumors compared to plasma. This low dose enhanced Hsp70 expression in peripheral blood mononuclear cells (PBMC), which is a biomarker of Hsp90 inhibition. Low dose monotherapy was ineffective but, when combined with radiotherapy (RT), produced significant tumor growth inhibition.
CONCLUSIONS: The current study shows that a significant therapeutic ratio can be achieved by a low dose of Hsp90 inhibitor in combination with radiotherapy. Hsp90 inhibition, even at a low dose, can be monitored by measuring Hsp70 expression in PBMC in human studies.

doi: https://doi.org/10.1158/1078-0432.CCR-19-3102

New GallBladder Articles

  • Early pathogenesis of cystic fibrosis gallbladder disease in a porcine model

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32719544

Hepatobiliary disease causes significant morbidity in people with cystic fibrosis (CF), yet this problem remains understudied. We previously found that newborn CF pigs have microgallbladders with significant luminal obstruction in the absence of infection and consistent inflammation. In this study, we sought to better understand the early pathogenesis of CF pig gallbladder disease. We hypothesized that loss of CFTR would impair gallbladder epithelium anion/liquid secretion and increase mucin production. CFTR was expressed apically in non-CF pig gallbladder epithelium but was absent in CF. CF pig gallbladders lacked cAMP-stimulated anion transport. Using a novel gallbladder epithelial organoid model, we found that Cl- or HCO3- was sufficient for non-CF organoid swelling. This response was absent for non-CF organoids in Cl-/HCO3–free conditions and in CF. Single-cell RNA-sequencing revealed a single epithelial cell type in non-CF gallbladders that coexpressed CFTR, MUC5AC, and MUC5B. Despite CF gallbladders having increased luminal MUC5AC and MUC5B accumulation, there was no significant difference in the epithelial expression of gel-forming mucins between non-CF and CF pig gallbladders. In conclusion, these data suggest that loss of CFTR-mediated anion transport and fluid secretion contribute to microgallbladder development and luminal mucus accumulation in CF.

doi: https://doi.org/10.1038/s41374-020-0474-8

New BileDuct Articles

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New Ampulla Articles

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#pathology Tweet Collection: #SurgPath group 1

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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

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#pathology Tweet Collection: #PathEdu group 1

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Recent Articles on Pancreatobiliary #Pathology – 2020-07-24

These are the recent articles on Pancreatobiliary Pathology:

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New Pancreas Articles

  • CPA1 and REG1a as New Markers for Pancreatic Acinar Cell Carcinoma

Human pathology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32702400

Acinar cell carcinoma (ACC) is a rare tumor that differentiates towards 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 by immunohistochemistry. 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 ACC and 5 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 ACC and MANC were positive for CPA1 (all diffuse) and REG1a (12 diffuse, 4 patchy, 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) compared to 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. 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.

doi: https://doi.org/10.1016/j.humpath.2020.07.019

  • Invasion inhibition in pancreatic cancer using the oral iron chelating agent deferasirox

BMC cancer 2020 Jul;20(1):681

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32698792

BACKGROUND: Iron is required for cellular metabolism, and rapidly proliferating cancer cells require more of this essential nutrient. Therefore, iron regulation may well represent a new avenue for cancer therapy. We have reported, through in vitro and in vivo research involving pancreatic cancer cell lines, that the internal-use, next-generation iron chelator deferasirox (DFX) exhibits concentration-dependent tumour-suppressive effects, among other effects. After performing a microarray analysis on the tumour grafts used in that research, we found that DFX may be able to suppress the cellular movement pathways of pancreatic cancer cells. In this study, we conducted in vitro analyses to evaluate the effects of DFX on the invasive and migratory abilities of pancreatic cancer cells.
METHODS: We used pancreatic cancer cell lines (BxPC-3, Panc-1, and HPAF II) to examine the efficacy of DFX in preventing invasion in vitro, evaluated using scratch assays and Boyden chamber assays. In an effort to understand the mechanism of action whereby DFX suppresses tumour invasion and migration, we performed G-LISA to examine the activation of Cdc42 and Rac1 which are known for their involvement in cellular movement pathways.
RESULTS: In our scratch assays, we observed that DFX-treated cells had significantly reduced invasive ability compared with that of control cells. Similarly, in our Boyden chamber assays, we observed that DFX-treated cells had significantly reduced migratory ability. After analysis of the Rho family of proteins, we observed a significant reduction in the activation of Cdc42 and Rac1 in DFX-treated cells.
CONCLUSIONS: DFX can suppress the motility of cancer cells by reducing Cdc42 and Rac1 activation. Pancreatic cancers often have metastatic lesions, which means that use of DFX will suppress not only tumour proliferation but also tumour invasion, and we expect that this will lead to improved prognoses.

doi: https://doi.org/10.1186/s12885-020-07167-8

  • Molecular characterization of organoids derived from pancreatic intraductal papillary mucinous neoplasms

The Journal of pathology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32696980

Intraductal papillary mucinous neoplasms (IPMNs) are a commonly identified non-invasive cyst-forming pancreatic neoplasms with the potential to progress into invasive pancreatic adenocarcinoma. There are few in vitro models with which to study the biology of IPMNs and their progression to invasive carcinoma. Therefore, we generated a living biobank of organoids from 7 normal pancreatic ducts and 10 IPMNs. We characterized 8 IPMN organoid samples using whole genome sequencing and characterized 5 IPMN organoids and 7 normal pancreatic duct organoids using transcriptome sequencing. We identified an average of 11 344 somatic mutations in the genomes of organoids derived from IPMNs, with one sample harboring 61 537 somatic mutations enriched for T- > C transitions and T- > A transversions. Recurrent coding somatic mutations were identified in 15 genes, including KRAS, GNAS, RNF43, PHF3, and RBM10. The most frequently mutated genes were KRAS, GNAS, and RNF43, with somatic mutations identified in 6 (75%), 4 (50%), and 3 (37.5%) IPMN organoid samples respectively. On average, we identified 36 structural variants in IPMN derived organoids, and none had an unstable phenotype (>200 structural variants). Transcriptome sequencing identified 28 genes differentially expressed between normal pancreatic duct organoid and IPMN organoid samples. The most significantly upregulated and downregulated genes were CLDN18 and FOXA1. Immunohistochemical analysis of FOXA1 expression in 112 IPMNs, 113 mucinous cystic neoplasms, and 145 pancreatic ductal adenocarcinomas demonstrated statistically significant loss of expression in low-grade IPMNs (p < 0.0016), mucinous cystic neoplasms (p < 0.0001), and pancreatic ductal adenocarcinoma of any histologic grade (p < 0.0001) compared to normal pancreatic ducts. These data indicate that FOXA1 loss of expression occurs early in pancreatic tumorigenesis. Our study highlights the utility of organoid culture to study the genetics and biology normal pancreatic duct and IPMNs. This article is protected by copyright. All rights reserved.

doi: https://doi.org/10.1002/path.5515

  • Phase 1b study of Wnt inhibitor ipafricept (IPA) with gemcitabine and nab-paclitaxel in patients with previously untreated stage IV pancreatic cancer (mPDAC)

Clinical cancer research : an official journal of the American Association for Cancer Research 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32694153

BACKGROUND: The recombinant fusion protein ipafricept (IPA) blocks Wnt signaling, and in combination with gemcitabine (G) and nab-paclitaxel (Nab-P) caused tumor regression in xenografts. This phase 1b study evaluated the combination of IPA with Nab-P+G in untreated metastatic PDAC (mPDAC) patients.
METHODS: Dose escalation started with standard dose Nab-P+G and IPA (3.5 mg/kg days 1, 15). Due to fragility fractures seen with different anti-Wnt agents, following cohorts had >=6 patients treated with IPA 3 – 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. Based on pre-clinical data sequential dosing was evaluated in cohort 4 (IPA day 1 followed Nab-P+G day 3). Objectives included safety, MTD, RP2D, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy.
RESULTS: 26 patients were enrolled, 5 in the cohort 1 and 7 each in cohorts 2-4. IPA-related AEs of any grade included fatigue, nausea, vomiting, anorexia and pyrexia. IPA-related AEs >=grade3 included 2 events of AST elevation, and 1 each of nausea, rash, vomiting and leucopenia. No DLTs or fragility fractures were observed. Nine patients (34.6%) had PR, 12 (46.2%) SD as best response, with clinical benefit rate of 81%. Median PFS was 5.9m (95%CI 3.4-18.4), median OS was 9.7m (95%CI: 7.0-14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use.
CONCLUSIONS: IPA can be administered with Nab-P+G with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.

doi: https://doi.org/10.1158/1078-0432.CCR-20-0489

New GallBladder Articles

  • Extended Resections for Advanced Gallbladder Cancer: Results from a Nationwide Cohort Study

Annals of surgical oncology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32696306

BACKGROUND: Extended resections (i.e., major hepatectomy and/or pancreatoduodenectomy) are rarely performed for gallbladder cancer (GBC) because outcomes remain inconclusive. Data regarding extended resections from Western centers are sparse. This Dutch, multicenter cohort study analyzed the outcomes of patients who underwent extended resections for locally advanced GBC.
METHODS: Patients with GBC who underwent extended resection with curative intent between January 2000 and September 2018 were identified from the Netherlands Cancer Registry. Extended resection was defined as a major hepatectomy (resection of ≥ 3 liver segments), a pancreatoduodenectomy, or both. Treatment and survival data were obtained. Postoperative morbidity, mortality, survival, and characteristics of short- and long-term survivors were assessed.
RESULTS: The study included 33 patients. For 16 of the patients, R0 resection margins were achieved. Major postoperative complications (Clavien Dindo ≥ 3A) occurred for 19 patients, and 4 patients experienced postoperative mortality within 90 days. Recurrence occurred for 24 patients. The median overall survival (OS) was 12.8 months (95% confidence interval, 6.5-19.0 months). A 2-year survival period was achieved for 10 patients (30%) and a 5-year survival period for 5 patients (15%). Common bile duct, liver, perineural and perivascular invasion and jaundice were associated with reduced survival. All three recurrence-free patients had R0 resection margins and no liver invasion.
CONCLUSION: The median OS after extended resections for advanced GBC was 12.8 months in this cohort. Although postoperative morbidity and mortality were significant, long-term survival (≥ 2 years) was achieved in a subset of patients. Therefore, GBC requiring major surgery does not preclude long-term survival, and a subgroup of patients benefit from surgery.

doi: https://doi.org/10.1245/s10434-020-08858-z

  • Lymph node involvement by enteropathy-like indolent NK-cell proliferation

Virchows Archiv : an international journal of pathology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32696224

Natural killer (NK)-cell enteropathy (NKCE) and lymphomatoid gastropathy (LG) are closely related lymphoproliferative disorders (LPDs) composed of mature and Epstein-Barr virus (EBV)-negative NK-cells. Although these uncommon and indolent lymphoid proliferations mostly arise within the gastrointestinal (GI) tract as their designations implies, a few cases have been reported outside the GI tract. We hereby describe a unique case of lymph node infiltration by such EBV-negative NK-cell proliferation fortuitously found during routine examination of a gallbladder resected for biliary lithiasis. The histologic, phenotypic, and molecular features of this NK-cell proliferation, which were very similar if not identical to those previously reported in NKCE or LG, suggest that similar indolent EBV-negative NK-cell LPDs may also occasionally involve lymph nodes.

doi: https://doi.org/10.1007/s00428-020-02892-8

New BileDuct Articles

  • Extended Resections for Advanced Gallbladder Cancer: Results from a Nationwide Cohort Study

Annals of surgical oncology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32696306

BACKGROUND: Extended resections (i.e., major hepatectomy and/or pancreatoduodenectomy) are rarely performed for gallbladder cancer (GBC) because outcomes remain inconclusive. Data regarding extended resections from Western centers are sparse. This Dutch, multicenter cohort study analyzed the outcomes of patients who underwent extended resections for locally advanced GBC.
METHODS: Patients with GBC who underwent extended resection with curative intent between January 2000 and September 2018 were identified from the Netherlands Cancer Registry. Extended resection was defined as a major hepatectomy (resection of ≥ 3 liver segments), a pancreatoduodenectomy, or both. Treatment and survival data were obtained. Postoperative morbidity, mortality, survival, and characteristics of short- and long-term survivors were assessed.
RESULTS: The study included 33 patients. For 16 of the patients, R0 resection margins were achieved. Major postoperative complications (Clavien Dindo ≥ 3A) occurred for 19 patients, and 4 patients experienced postoperative mortality within 90 days. Recurrence occurred for 24 patients. The median overall survival (OS) was 12.8 months (95% confidence interval, 6.5-19.0 months). A 2-year survival period was achieved for 10 patients (30%) and a 5-year survival period for 5 patients (15%). Common bile duct, liver, perineural and perivascular invasion and jaundice were associated with reduced survival. All three recurrence-free patients had R0 resection margins and no liver invasion.
CONCLUSION: The median OS after extended resections for advanced GBC was 12.8 months in this cohort. Although postoperative morbidity and mortality were significant, long-term survival (≥ 2 years) was achieved in a subset of patients. Therefore, GBC requiring major surgery does not preclude long-term survival, and a subgroup of patients benefit from surgery.

doi: https://doi.org/10.1245/s10434-020-08858-z

New Ampulla Articles

  • Acute duodenal obstruction secondary to intussusception caused by the duodenal diverticulum: a case report

BMC gastroenterology 2020 Jul;20(1):234

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32698796

BACKGROUND: The duodenal intussusception is rarely reported and usually occurs secondary to organic diseases of the duodenum such as polyps, tumors and duplication cysts. Herein we report a case of duodenal intussusception caused by duodenal diverticulum.
CASE PRESENTATION: A 21-year old male patient presented with abdominal pain and vomiting for one day. A contrast enhanced computed tomography of the abdomen revealed duodenal intussusception. On emergency laparotomy, the intussusception had reduced spontaneously while an invaginated diverticulum was seen at the junction of the descending and horizontal segments of the duodenum. The diverticulum was resected and the patient had uneventful recovery.
CONCLUSION: Duodenal intussusception is a rare complication of duodenal diverticulum. Being aware of this complication of diverticulum can help in timely diagnosis and treatment.

doi: https://doi.org/10.1186/s12876-020-01379-9

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