Recent Articles on Pancreatobiliary #Pathology – 2020-08-13

These are the recent articles on Pancreatobiliary Pathology:

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New Pancreas Articles


  • PAF1 Regulates Stem Cell Features of Pancreatic Cancer Cells, Independently of the PAF1 Complex, via Interactions with PHF5A and DDX3

Gastroenterology 2020 Aug;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32781084

BACKGROUND & AIMS: It is not clear how pancreatic cancer stem cells (CSCs) are regulated, resulting in ineffective treatments for pancreatic cancer. PAF1, a RNA polymerase II-associated factor 1 complex (PAF1C) component, maintains pluripotency of stem cells, by unclear mechanisms, and is a marker of CSCs. We investigated mechanisms by which PAF1 maintains CSCs and contributes to development of pancreatic tumors.
METHODS: Pancreatic cancer cell lines were engineered to knockdown PAF1 using inducible small hairpin RNAs. These cells were grown as orthotopic tumors in athymic nude mice and PAF1 knockdown was induced by administration of doxycycline in drinking water. Tumor growth and metastasis were monitored via IVIS imaging. CSCs were isolated from pancreatic cancer cell populations using flow cytometry and characterized by tumor sphere formation, tumor formation in nude mice, and expression of CSC markers. Isolated CSCs were depleted of PAF1 using the CRISPR/Cas9 system. PAF1-regulated genes in CSCs were identified via RNA-seq and PCR array analyses of cells with PAF1 knockdown. Proteins that interact with PAF1 in CSCs were identified by immunoprecipitations and mass spectrometry. We performed chromatin immunoprecipitation sequencing of CSCs to confirm the binding of the PAF1 sub-complex to target genes.
RESULTS: Pancreatic cancer cells depleted of PAF1 formed smaller and fewer tumor spheres in culture and orthotopic tumors and metastases in mice. Isolated CSCs depleted of PAF1 downregulated markers of self-renewal (NANOG, SOX9, and BETA-CATENIN), of CSCs (CD44v6, and ALDH1), and the metastasis-associated gene signature, compared to CSCs without knockdown of PAF1. The role of PAF1 in CSC maintenance was independent of its RNA polymerase II-associated factor 1 complex component identity. We identified DDX3 and PHF5A as proteins that interact with PAF1 in CSCs and demonstrated that the PAF1-PHF5A-DDX3 sub-complex bound to the promoter region of Nanog, whose product regulates genes that control stemness. Levels of the PAF1-DDX3 and PAF1-PHF5A were increased and co-localized in human pancreatic tumor specimens, human pancreatic tumor-derived organoids, and organoids derived from tumors of KPC mice, compared with controls. Binding of DDX3 and PAF1 to the Nanog promoter, and the self-renewal capacity of CSCs, were decreased in cells incubated with the DDX3 inhibitor RK-33. CSCs depleted of PAF1 downregulated genes that regulate stem cell features (Flot2, Taz, Epcam, Erbb2, Foxp1, Abcc5, Ddr1, Muc1, Pecam1, Notch3, Aldh1a3, Foxa2, Plat, and Lif).
CONCLUSIONS: In pancreatic CSCs, PAF1 interacts with DDX3 and PHF5A to regulate expression of NANOG and other genes that regulate stemness. Knockdown of PAF1 reduces the ability of orthotopic pancreatic tumors to develop and progress in mice and their numbers of CSCs. Strategies to target the PAF1-PHF5A-DDX3 complex might be developed to slow or inhibit progression of pancreatic cancer.

doi: https://doi.org/10.1053/j.gastro.2020.07.053



  • IgG4-Related Disease of the Ovary

Turk patoloji dergisi 2020 Aug;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32779156

Immunoglobulin G4-related disease is characterized by dense fibrosis, obliterative phlebitis, and lymphoplasmacytic infiltration that contains abundant IgG4 positive plasma cells. It causes tumefactive lesions in the involved organs and is most commonly seen in the salivary glands, pancreas, and retroperitoneum. Ovarian involvement has been reported in only two cases. In our case, a 58-year-old female patient presented with abdominal distention and pain. Pelvic computed tomography revealed a soft tissue lesion compatible with the omental cake, several intraabdominal implants, and bilateral adnexal fullness. A laparotomy was performed under suspicion of peritoneal carcinomatosis secondary to bilateral adnexal mass. In the histopathologic examination, abundant lymphoplasmacytic infiltration and dense fibrosis were observed in both ovaries and the peritoneum. In the areas of greatest density, the density of IgG4-positive plasma cells was found to range from 40 to 50 per high-power field. The patient was accepted as suffering from probable IgG4-related disease because of the bilateral involvement of the ovaries and the histopathological findings. In conclusion, we present this case to draw attention to the fact that IgG4-related disease can also be seen in the ovary.

doi: https://doi.org/10.5146/tjpath.2020.01500



  • Margin-Positive Pancreatic Ductal Adenocarcinoma during Pancreaticoduodenectomy: Additional Resection Does Not Improve Survival

Annals of surgical oncology 2020 Aug;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32779052

BACKGROUND: The impact of resecting positive margins during pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDA) remains debated. Additionally, the survival benefit of resecting multiple positive margins is unknown.
METHODS: We identified patients with PDA who underwent PD from 2006 to 2015. Pancreatic neck, bile duct, and uncinate frozen section margins were assessed before and after resection of positive margins. Survival curves were compared with log-rank tests. Multivariable Cox regression assessed the effect of margin status on overall survival.
RESULTS: Of 501 patients identified, 17.3%, 5.3%, and 19.7% had an initially positive uncinate, bile duct, or neck margin, respectively. Among initially positive bile duct and neck margins, 77.8% and 67.0% were resected, respectively. Although median survival was decreased among patients with any positive margins (15.6 vs. 20.9 months; p = 0.006), it was similar among patients with positive bile duct or neck margins with or without R1 to R0 resection (17.0 vs. 15.6 months; p = 0.20). Median survival with and without positive uncinate margins was 13.8 vs. 19.7 months (p = 0.04). Uncinate margins were never resected. Resection of additional margins when the uncinate was concurrently positive was not associated with improved survival (p = 0.37). Patients with positive margins who received adjuvant therapy had improved survival, regardless of margin resection (p = 0.03). Adjuvant therapy was independently protective against death (hazard ratio 0.6, 95% CI 0.5-0.7).
CONCLUSIONS: Positive PD margins at any position are associated with reduced overall survival; however, resection of additional margins may not improve survival, particularly with concurrently positive uncinate margins. Adjuvant chemotherapy improves survival with positive margins, regardless of resection.

doi: https://doi.org/10.1245/s10434-020-09000-9



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

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32778368

BACKGROUND/OBJECTIVES: Preclinical data indicated a functional and molecular interaction between Hedgehog (HH)/GLI and PI3K-AKT-mTOR pathways promoting pancreatic ductal adenocarcinoma (PDAC). A phase I study was conducted of Vismodegib and Sirolimus combination to evaluate maximum tolerated dose (MTD) and preliminary anti-tumor efficacy.
METHODS: Cohort I included advanced solid tumors patients following a traditional 3 + 3 design. Vismodegib was orally administered at 150 mg daily with Sirolimus starting at 3 mg daily, increasing to 6 mg daily at dose level 2. Cohort II included only metastatic PDAC patients. Anti-tumor efficacy was evaluated every two cycles and target assessment at pre-treatment and after a single cycle.
RESULTS: Nine patient were enrolled in cohort I and 22 patients in cohort II. Twenty-eight patients were evaluated for dose-limiting toxicities (DLTs). One DLT was observed in each cohort, consisting of grade 2 mucositis and grade 3 thrombocytopenia. The MTD for Vismodegib and Sirolimus were 150 mg daily and 6 mg daily, respectively. The most common grade 3-4 toxicities were fatigue, thrombocytopenia, dehydration, and infections. A total of 6 patients had stable disease. No partial or complete responses were observed. Paired biopsy analysis before and after the first cycle in cohort II consistently demonstrated reduced GLI1 expression. Conversely, GLI and mTOR downstream targets were not significantly affected.
CONCLUSIONS: The combination of Vismodegib and Sirolimus was well tolerated. Clinical benefit was limited to stable disease in a subgroup of patients. Targeting efficacy demonstrated consistent partial decreases in HH/GLI signaling with limited impact on mTOR signaling. These findings conflict with pre-clinical models and warrant further investigations.

doi: https://doi.org/10.1016/j.pan.2020.06.015



  • Precision medicine phase II study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment

BMC cancer 2020 Aug;20(1):748

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32778095

BACKGROUND: Tumors with deficient homologous repair are sensitive to PARP inhibitors such as olaparib which is known to have immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) which inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate the efficacy of combination of olaparib, durvalumab and tremelimumab in patients with a solid tumors with a mutation in homologous gene repair.
METHODS: This phase II study will assess the efficacy and safety of olaparib/D/T association in patients (n = 213) with several types of solid cancers (breast cancer, ovarian cancer, pancreatic cancer, endometrial cancer, prostate cancer and others) with at least one mutation in homologous repair genes (BRCA1, BRCA2, PALB2, ATM, FANCA, FANCB, FANCC, FANCE, FANCF, CHEK2, RAD51, BARD1, MRE11, RAD50, NBS1, HDAC2), LKB1/STK11, INPP4B, STAG2, ERG, CHEK1, BLM, LIG4, ATR, ATRX, CDK12). Good performance status patients and corresponding to specific inclusion criteria of each cohort will be eligible. STEP1: Patients will receive olaparib 300 mg BID. In absence of progression after 6 weeks of olaparib, they will follow STEP 2 with olaparib and immunotherapy by durvalumab (1500 mg Q4W) + tremelimumab (75 mg IV Q4W) during 4 months and will further pursue durvalumab alone until disease progression, death, intolerable toxicity, or patient/investigator decision to stop (for a maximum duration of 24 months, and 36 months for ovarian cohort). Primary endpoint is safety and efficacy according to progression-free survival (PFS) of olaparib + immunotherapy (durvalumab + tremelimumab) during 4 months followed by durvalumab alone as maintenance in patients with solid cancers and in response or stable, after prior molecular target therapy by olaparib; secondary endpoints include overall survival (OS), disease control rate (DCR), response rate after 6 weeks of olaparib, safety of olaparib/durvalumab/tremelimumab association. Blood, plasma and tumor tissue will be collected for potential prognostic and predictive biomarkers.
DISCUSSION: This study is the first trial to test the combination of olaparib and double immunotherapy based on molecular screening.
TRIAL REGISTRATION: NCT04169841 , date of registration November 20, 2019.

doi: https://doi.org/10.1186/s12885-020-07253-x



  • Diagnostic accuracy of contrast-enhanced diffusion-weighted MRI for liver metastases of pancreatic cancer: towards adequate staging and follow-up of pancreatic cancer – DIA-PANC study: study protocol for an international, multicenter, diagnostic trial

BMC cancer 2020 Aug;20(1):744

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32778061

BACKGROUND: At the time of surgery, approximately 10-20% of the patients with pancreatic cancer are considered unresectable because of unexpected liver metastasis, peritoneal carcinomatosis or locally advanced disease. This leads to futile surgical treatment with all the associated morbidity, mortality and costs. More than 50% of all liver metastases develop in the first six months postoperatively. These (subcentimeter) liver metastases are most likely already present at the time of diagnosis and have not been identified pre-operatively, due to the poor sensitivity of routine preoperative contrast-enhanced CT (CECT).
METHODS: The DIA-PANC study is a prospective, international, multicenter, diagnostic cohort study investigating diffusion-weighted, contrast-enhanced MRI for the detection of liver metastases in patients with all stages of pancreatic cancer. Indeterminate or malignant liver lesions on MRI will be further investigated histopathologically. For patients with suspected liver lesions without histopathological proof, follow up imaging with paired CT and MRI at 3-, 6- and 12-months will serve as an alternative reference standard.
DISCUSSION: The DIA-PANC trial is expected to report high-level evidence of the diagnostic accuracy of MRI for the detection of liver metastases, resulting in significant value for clinical decision making, guideline development and improved stratification for treatment strategies and future trials. Furthermore, DIA-PANC will contribute to our knowledge of liver metastases regarding incidence, imaging characteristics, their number and extent, and their change in time with or without treatment. It will enhance the worldwide implementation of MRI and consequently improve personalized treatment of patients with suspected pancreatic ductal adenocarcinoma.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03469726 . Registered on March 19th 2018 – Retrospectively registered.

doi: https://doi.org/10.1186/s12885-020-07226-0



  • Preoperative anthropomorphic and nutritious status and fistula risk score for predicting clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy

BMC gastroenterology 2020 Aug;20(1):264

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32770952

BACKGROUND: Postoperative pancreatic fistula (POPF) is a life-threatening postoperative complication. The aim of this study was to evaluate the efficacy of the fistula risk score (FRS) and preoperative body composition factors for predicting the occurrence of clinically relevant POPF (CR-POPF) after pancreaticoduodenectomy (PD).
METHODS: In this study, 136 consecutive patients who underwent PD between 2006 and 2018 were enrolled. The risk factors of CR-POPF (grades B and C) were analyzed. Preoperative visceral adipose tissue area (VATA), skeletal mass index (SMI), and subcutaneous adipose tissue area (SATA) were calculated from computed tomography data.
RESULTS: The overall 30-day mortality and morbidity rates were 0.7 and 38%, respectively. The incidence rates of grade B and C CR-POPF were 27 and 4%, respectively. A univariate analysis revealed that male sex, habitual smoking, prognostic nutritional index (PNI) < 45, VATA ≥90, VATA/SATA ≥0.9, VATA/SMI ≥ 1.4, and FRS > 4 were significantly associated with the incidence of CR-POPF. A multivariate analysis revealed that PNI < 45, VATA/SMI ≥ 1.4 and FRS > 4 were the independent risk factors of CR-POPF.
CONCLUSIONS: Preoperative anthropomorphic imbalance, PNI, and FRS were independent risk factors for CR-POPF. Patients with high-risk factors should be closely monitored during the postoperative period.

doi: https://doi.org/10.1186/s12876-020-01397-7


New GallBladder Articles

Today there is no new Gallbladder Article.

New BileDuct Articles


  • Margin-Positive Pancreatic Ductal Adenocarcinoma during Pancreaticoduodenectomy: Additional Resection Does Not Improve Survival

Annals of surgical oncology 2020 Aug;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32779052

BACKGROUND: The impact of resecting positive margins during pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDA) remains debated. Additionally, the survival benefit of resecting multiple positive margins is unknown.
METHODS: We identified patients with PDA who underwent PD from 2006 to 2015. Pancreatic neck, bile duct, and uncinate frozen section margins were assessed before and after resection of positive margins. Survival curves were compared with log-rank tests. Multivariable Cox regression assessed the effect of margin status on overall survival.
RESULTS: Of 501 patients identified, 17.3%, 5.3%, and 19.7% had an initially positive uncinate, bile duct, or neck margin, respectively. Among initially positive bile duct and neck margins, 77.8% and 67.0% were resected, respectively. Although median survival was decreased among patients with any positive margins (15.6 vs. 20.9 months; p = 0.006), it was similar among patients with positive bile duct or neck margins with or without R1 to R0 resection (17.0 vs. 15.6 months; p = 0.20). Median survival with and without positive uncinate margins was 13.8 vs. 19.7 months (p = 0.04). Uncinate margins were never resected. Resection of additional margins when the uncinate was concurrently positive was not associated with improved survival (p = 0.37). Patients with positive margins who received adjuvant therapy had improved survival, regardless of margin resection (p = 0.03). Adjuvant therapy was independently protective against death (hazard ratio 0.6, 95% CI 0.5-0.7).
CONCLUSIONS: Positive PD margins at any position are associated with reduced overall survival; however, resection of additional margins may not improve survival, particularly with concurrently positive uncinate margins. Adjuvant chemotherapy improves survival with positive margins, regardless of resection.

doi: https://doi.org/10.1245/s10434-020-09000-9


New Ampulla Articles


  • Approaches to Biopsy and Resection Specimens from the Ampulla

Surgical pathology clinics 2020 Sep;13(3):453-467

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32773194

The ampulla of Vater gives rise to a versatile group of cancers of mixed/hybrid histologic phenotype. Ampullary carcinomas (ACs) are most frequently intestinal or pancreatobiliary adenocarcinomas but other subtypes, such as medullary, mucinous, or signet ring/poorly cohesive cell carcinoma, may be encountered. Ampullary cancer can also be subclassified based on immunohistochemical features, however these classification systems fail to show robust prognostic reliability. More recently, the molecular landscape of AC has been uncovered, and has been shown to have prognostic and predictive significance. In this article, the site-specific, histologic, and genetic characteristics of ampullary carcinoma and its precursor lesions are discussed.

doi: https://doi.org/10.1016/j.path.2020.05.005



  • Upper Gastrointestinal Manifestations of Inflammatory Bowel Disease

Surgical pathology clinics 2020 Sep;13(3):413-430

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32773192

Although the features of lower gastrointestinal tract inflammation associated with ulcerative colitis and Crohn disease are generally familiar to pathologists, there is less awareness of and familiarity with the manifestations of inflammatory bowel disease in the esophagus, stomach, and duodenum. Nonetheless, their diagnosis has therapeutic and possibly prognostic implications, potentially foretelling severe complications. The recognition that ulcerative colitis can affect gastrointestinal organs proximal to the large intestine and terminal ileum represents a revision of concepts ingrained among generations of physicians. This article reviews the pathologic features and clinical significance of esophagitis, gastritis, and duodenitis associated with inflammatory bowel disease.

doi: https://doi.org/10.1016/j.path.2020.05.003



  • Giardia Is Often Overlooked on Histopathologic Examination: A High-Volume, Single-Institution Experience

International journal of surgical pathology 2020 Aug;():1066896920947795

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32772760

AIMS. GIARDIA: is sometimes missed by the pathologist, and we sought to determine how often this occurs at our institution-a large tertiary care center with a subspecialty gastrointestinal pathology service and what certain clinical and histologic clues can be used to flag cases with a higher likelihood of infection, targeting them for greater scrutiny.
METHODS AND RESULTS: We identified a set of patients who tested positive for Giardia with a stool-based test, and who also received a small bowel biopsy at a similar time-point. These biopsies were retrospectively reviewed for Giardia, finding 8 positive cases. The organism was prospectively detected in 4 cases (50%) but overlooked in the remaining 4 cases (50%). Three of the 4 cases missed cases showed only rare organisms. The detected cases tended to more frequently have prominent lymphoid aggregates (3 detected cases, 0 overlooked cases) and intraepithelial lymphocytosis (3 detected cases, 0 overlooked cases). Certain clinical and histologic clues can be used to flag cases with a higher likelihood of infection. Specifically, we found abnormalities of the mucosa (active inflammation, intraepithelial lymphocytosis, villous expansion, prominent lymphoid aggregates) in each case, and 4 of 8 cases were from immunocompromised patients. Finally, 2 of 8 cases were terminal ileum biopsies.
CONCLUSIONS: Biopsies with a histologic abnormality or those from immunocompromised patients should receive greater attention. Routinely looking for Giardia at that terminal ileum is necessary.

doi: https://doi.org/10.1177/1066896920947795


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