Category Archives: articles

Recent Articles on Pancreatobiliary #Pathology – 2020-10-21

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


  • Epithelial Nr5a2 heterozygosity cooperates with mutant Kras in the development of pancreatic cystic lesions

The Journal of pathology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33079429

Cystic neoplasms of the pancreas are an increasingly important public health problem. The majority of these lesions are benign but some progress to invasive pancreatic ductal adenocarcinoma (PDAC). There is a dearth of mouse models of these conditions. The orphan nuclear receptor NR5A2 regulates development, differentiation, and inflammation. Germline Nr5a2 heterozygosity sensitizes mice to the oncogenic effects of mutant Kras in the pancreas. Here, we show that – unlike constitutive Nr5a2+/- mice – conditional Nr5a2 heterozygosity in pancreatic epithelial cells, combined with mutant Kras, (KPN+/- ) leads to a dramatic replacement of the pancreatic parenchyma with cystic structures and an accelerated development of high grade PanINs and PDAC. Timed histopathological analyses indicated that in KPN+/- mice PanINs precede the formation of cystic lesions and the latter precede PDAC. A single episode of acute caerulein pancreatitis is sufficient to accelerate the development of cystic lesions in KPN+/- mice. Epithelial cells of cystic lesions of KPN+/- mice express MUC1, MUC5AC, and MUC6 but lack expression of MUC2, CDX2 and acinar markers, indicative of a pancreato-biliary/gastric phenotype. In accordance with this, in human samples we found a non-significantly decreased expression of NR5A2 in mucinous tumours, compared with conventional PDAC. These results highlight that the effects of loss of one Nr5a2 allele are time- and cell context-dependent. KPN+/- mice represent a new model to study the formation of cystic pancreatic lesions and their relationship with PanINs and classical PDAC. Our findings suggest that pancreatitis could also contribute to acceleration of cystic tumour progression in patients. This article is protected by copyright. All rights reserved.

doi: https://doi.org/10.1002/path.5570



  • Novel Technique for Single-Layer Pancreatojejunostomy is Not Inferior to Modified Blumgart Anastomosis in Robotic Pancreatoduodenectomy: Results of a Randomized Controlled Trial

Annals of surgical oncology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33079303

BACKGROUND: A novel technique of single-layer continuous suturing (SCS) for pancreaticojejunostomy (PJ) during robotic pancreaticoduodenectomy (RPD), a technically straightforward procedure, has been shown to produce promising results in a previous study. The present RCT aims to show that SCS during RPD does not increase the incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) when compared with modified Blumgart anastomosis (MBA).
PATIENTS AND METHODS: Between January 2019 and September 2019, consecutive patients (ASA score ≤ 2) who underwent RPD were enrolled and randomized to the SCS or the MBA group. The primary endpoint was the rate of CR-POPF. A noninferiority margin of 10% was chosen.
RESULTS: Of the 186 patients, 4 were excluded because PJ was not performed. The remaining 182 patients were randomized to the SCS group (n = 89) or MBA group (n = 93). CR-POPF rate was not inferior in the SCS group [SCS: 6.7%, MBA: 11.8%; 95% confidence interval (- 0.76, - 0.06), P = 0.0002]. PJ duration was significantly lower in the SCS group (P < 0.01). No significant differences were found between the two groups in operative time, estimated blood loss, postoperative hospital stay, or rates of conversion to laparotomy, morbidity, reoperation, or mortality. On subgroup analysis of patients with a soft pancreas and small main pancreatic duct, SCS significantly reduced the duration of PJ.
CONCLUSIONS: This study showed that SCS was not inferior to MBA in terms of the CR-POPF rate during RPD. Registration number: ChiCTR1800020086 ( www.Chictr.org.cn ).

doi: https://doi.org/10.1245/s10434-020-09204-z



  • Surveillance of high-risk individuals for pancreatic cancer with EUS and MRI: A meta-analysis

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33077384

BACKGROUND/OBJECTIVES: Consensus guidelines recommend surveillance of high-risk individuals (HRIs) for pancreatic cancer (PC) using endoscopic ultrasonography (EUS) and/or magnetic resonance imaging (MRI). This study aims to assess the yield of PC surveillance programs of HRIs and compare the detection of high-grade dysplasia or T1N0M0 adenocarcinoma by EUS and MRI.
METHODS: The MEDLINE and Embase (Ovid) databases were searched for prospective studies published up to April 11, 2019 using EUS and/or MRI to screen HRIs for PC. Baseline detection of focal pancreatic abnormalities, cystic lesions, solid lesions, high-grade dysplasia or T1N0M0 adenocarcinoma, and all pancreatic adenocarcinoma were recorded. Weighted pooled proportions of outcomes detected were compared between EUS and MRI using random effects modeling.
RESULTS: A total of 1097 studies were reviewed and 24 were included, representing 2112 HRIs who underwent imaging. The weighted pooled proportion of focal pancreatic abnormalities detected by baseline EUS (0.34, 95% CI 0.30-0.37) was significantly higher (p = 0.006) than by MRI (0.31, 95% CI 0.28-0.33). There were no significant differences between EUS and MRI in detection of other outcomes. The overall weighted pooled proportion of patients with high-grade dysplasia or T1N0M0 adenocarcinoma detected at baseline (regardless of imaging modality) was 0.0090 (95% CI 0.0022-0.016), corresponding to a number-needed-to-screen (NNS) of 111 patients to detect one high-grade dysplasia or T1N0M0 adenocarcinoma.
CONCLUSIONS: Surveillance programs are successful in detecting high-risk precursor lesions. No differences between EUS and MRI were noted in the detection of high-grade dysplasia or T1N0M0 adenocarcinoma, supporting the use of either imaging modality.

doi: https://doi.org/10.1016/j.pan.2020.10.025



  • Fatty acid ethyl ester (FAEE) associated acute pancreatitis: An ex-vivo study using human pancreatic acini

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33077383

BACKGROUND & AIM: Fatty acid ethyl esters (FAEEs), are produced by non-oxidative alcohol metabolism and can cause acinar cell damage and subsequent acute pancreatitis in rodent models. Even though experimental studies have elucidated the FAEE mediated early intra-acinar events, these mechanisms have not been well studied in humans. In the present study, we evaluate the early intra-acinar events and inflammatory response in human pancreatic acinar tissues and cells in an ex-vivo model.
METHODS: Experiments were conducted using normal human pancreatic tissues exposed to FAEE. Subcellular fractionation was performed on tissue homogenates and trypsin and cathepsin B activities were estimated in these fractions. Acinar cell injury was evaluated by histology and immunohistochemistry. Cytokine release from exposed acinar cells was evaluated by performing Immuno-fluorescence. Serum was collected from patients with AP within the first 72 h of symptom onset for cytokine estimation using FACS.
RESULTS: We observed significant trypsin activation and acinar cell injury in FAEE treated tissue. Cathepsin B was redistributed from lysosomal to zymogen compartment at 30 min of FAEE exposure. IHC results indicated the presence of apoptosis in pancreatic tissue at 1 & 2hrs of FAEE exposure. We also observed a time dependent increase in secretion of cytokines IL-6, IL-8, TNF-α from FAEE treated acinar tissue. There was also a significant elevation in plasma cytokines in patents with alcohol associated AP within 72 h of symptom onset.
CONCLUSION: Our data suggest that alcohol metabolites can cause acute acinar cell damage and subsequent cytokine release which could eventually culminant in SIRS.

doi: https://doi.org/10.1016/j.pan.2020.10.027



  • What should we trust to define, predict and assess pancreatic fistula after pancreatectomy?

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33077382

OBJECTIVE: The ISGPF postoperative pancreatic fistula (POPF) definition using amylase drain concentration is widely used. However, the interest of lipase drain concentration, daily drain output and absolute enzyme daily production (concentration x daily drain volume) have been poorly investigated.
MATERIAL AND METHODS: These predictive on postoperative day (POD) 1, 3, 5 and 7 were analyzed in a development cohort, and subsequently tested in an independent validation cohort.
RESULTS: Of the 227 patients of the development cohort, 17% developed a biochemical fistula and 34% a POPF (Grade B/C). Strong correlation was found between amylase/lipase drain concentration at all postoperative days (ρ = 0.90; p = 0.001). Amylase and lipase were both significantly higher in patients with a POPF (p < 0.001) presenting an equivalent under the ROC curve area (0.85 vs 0.84; p = 0.466). Combining POD1 and POD3 threefold enzyme cut-off value increased significantly POPF prediction sensibility (97.4% vs 77.8%) and NPV (97.1% vs 86.3%). These results were also confirmed in the validation cohort of 554 patients. Finally, absolute enzyme daily production and daily drain output were significantly higher in patients with a POPF (p < 0.001) but did not add clinical value when compared to drain enzyme concentration.
CONCLUSION: Lipase is as effective as amylase drain concentration to define POPF. Absolute enzyme daily production or daily drain output do not help to better predict clinically significant POPF occurrence and severity. Lipase and amylase should mainly be used for their negative predictive value to predict the absence of clinically significant POPF and could allow early drain removal and hospital discharge.

doi: https://doi.org/10.1016/j.pan.2020.10.036



  • Novel techniques for management of portal system hemorrhage in acute pancreatitis

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33077381

Current management of infected pancreatic necrosis is focused on a minimally invasive step-up approach. The step-up approach consists of initial percutaneous or endoscopic drainage of infected pancreatic necrosis, followed, if necessary, by minimally invasive surgical or endoscopic debridement. While there is reduced morbidity and mortality, vascular complications can be life-threatening. Reported vascular complications have been limited to arterial bleeding. Venous bleeding has not been previously reported. We present two cases of portal venous bleeding in patients who underwent treatment for infected pancreatic necrosis with a step-up approach. We discuss the clinical presentation, diagnosis, and initial management. Moreover, we present two different techniques that can be used to successfully manage venous bleeding in patients who have percutaneous drains in place as part of a step-up approach. These techniques involve tamponading the cavity or drain tract with topical hemostatics and direct embolization of the bleeding vein. These experiences can serve as a guide for managing portal venous bleeding in patients with infected pancreatic necrosis.

doi: https://doi.org/10.1016/j.pan.2020.09.022



  • Is Hospital Occupancy Rate Associated with Postoperative Outcomes Among Patients Undergoing Hepatopancreatic Surgery?

Annals of surgery 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33074907

OBJECTIVE: To define the association between hospital occupancy rate and postoperative outcomes among patients undergoing hepatopancreatic (HP) resection.
SUMMARY BACKGROUND DATA: Previous studies have sought to identify hospital-level characteristics associated with optimal surgical outcomes and decreased expenditures. The present study utilized a novel hospital quality metric coined “occupancy rate” based on publicly available data to assess differences in postoperative outcomes among Medicare beneficiaries undergoing HP procedures.
METHODS: Medicare beneficiaries who underwent an elective HP surgery between 2013 and 2017 were identified. Occupancy rate was calculated and hospitals were categorized into quartiles. Multivariable logistic regression was utilized to assess the association between occupancy rate and clinical outcomes.
RESULTS: Among 33,866 patients, the majority underwent a pancreatic resection (58.5%; n = 19,827), were male (88.4%; n = 7,488), or white (88.4%; n = 29,950); median age was 72 years [interquartile range (IQR): 68-77] and median Charleston Comorbidity Index was 3 (IQR 2-8). Hospitals were categorized into quartiles based on hospital occupancy rate (cutoffs: 48.1%, 59.4%, 68.2%). Most patients underwent an HP operation at a hospital with an above average occupancy rate (n = 20,865, 61.6%), whereas only a small subset of patients had an HP procedure at a low occupancy rate hospital (n = 1,218, 3.6%). On multivariable analysis, low hospital occupancy rate was associated with increased odds of a complication [(OR) 1.35, 95% confidence interval (CI) 1.18-1.55) and 30-day mortality (OR 1.58, 95% CI 1.27-1.97). Even among only high-volume HP hospitals, patients operated on at hospitals that had a low occupancy rate were at markedly higher risk of complications (OR 1.42, 95% CI 1.03-1.97), as well as 30 day morality (OR 2.20, 95% CI 1.27-3.83).
CONCLUSIONS: Among Medicare beneficiaries undergoing an elective HP resection, more than 1 in 4 hospitals performing HP surgeries utilized less than half of their beds on average. There was a monotonic relationship between hospital occupancy rate and the odds of experiencing a complication, as well as 30-day mortality, independent of other hospital level characteristics including procedural volume.

doi: https://doi.org/10.1097/SLA.0000000000004418



  • Are Volume Pledge Standards Worth the Travel Burden for Major Abdominal Cancer Operations?

Annals of surgery 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33074899

OBJECTIVE: The study objective is to determine the association between travel distance and surgical volume on outcomes after esophageal, pancreatic, and rectal cancer resections.
SUMMARY OF BACKGROUND DATA: “Take the Volume Pledge” aims to centralize esophagectomies, pancreatectomies, and proctectomies to hospitals meeting minimum volume standards. The impact of travel, and possible care fragmentation, on potential benefits of centralized surgery is not well understood.
METHODS: Using the National Cancer Database (2004-2016), patients who underwent esophageal, pancreatic, or rectal resections at far HVH meeting volume standards versus local intermediate (IVH) and low-volume (LVH) hospitals were identified. Perioperative outcomes and 5-year OS were compared.
RESULTS: Of 49,454 patients, 17,544 (34.5%) underwent surgery at far HVH, 11,739 (23.7%) at local IVH, and 20,171 (40.8%) at local LVH. The median (interquartile range) travel distances were 77.1 (51.1-125.4), 13.2 (5.8-27.3), and 7.8 (3.1-15.5) miles to HVH, IVH, and LVH, respectively. By multivariable analysis, LVH was associated with increased 30-day mortality for all resections compared to HVH, but IVH was associated with mortality only for proctectomies [odds ratio 1.90, 95% confidence interval (CI) 1.31-2.75]. Compared to HVH, both IVH (hazard ratio 1.25, 95% CI 1.19-1.31) and LVH (hazard ratio 1.35, 95% CI 1.29-1.42) were associated with decreased 5-year OS.
CONCLUSIONS: Compared to far HVH, 30-day mortality was higher for all resections at LVH, but only for proctectomies at IVH. Five-year OS was consistently worse at local LVH and IVH. Improving long-term outcomes at IVH may provide opportunities for greater access to quality cancer care.

doi: https://doi.org/10.1097/SLA.0000000000004361



  • A Critical Assessment of Postneoadjuvant Therapy Pancreatic Cancer Regression Grading Schemes With a Proposal for a Novel Approach

The American journal of surgical pathology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33074853

Currently, there is no consensus on the optimal tumor response score (TRS) system to assess regression in pancreatic cancers resected after neoadjuvant therapy. We developed a novel TRS (Royal North Shore [RNS] system) based on estimating the percentage of tumor bed occupied by viable cancer and categorized into 3 tiers: grade 1 (≤10%), grade 2 (11% to 75%), and grade 3 (>75%). We assessed 147 resected carcinomas with this and other TRS systems (College of American Pathologists [CAP], MD Anderson Cancer Center [MDACC], and Evans). The 3-tiered RNS system predicted median survival after surgery for grades 1, 2, and 3 of 54, 23, and 9 months, respectively (P<0.05). The CAP, MDACC, and Evans systems also predicted survival (P<0.05) but less consistently. The median survival for MDACC and CAP grade 0 (complete regression) was less than MDACC grade 1 and CAP grades 1 and 2. There was no difference in survival between CAP grades 2 and 3 (P=0.960), Evans grades 1 and 2a (P=0.395), and Evans grades 2a and 2b (P=0.587). Interobserver concordance was weak for CAP (κ=0.431), moderate for MDACC (κ=0.691), minimal for Evans (κ=0.307), and moderate to strong for RNS (κ=0.632 to 0.84). Of age, sex, size, stage, grade, perineural and vascular invasion, extrapancreatic extension, margin status, and RNS score, only RNS score, vascular invasion, and extrapancreatic extension predicted survival in univariate analysis. Only extrapancreatic extension (P=0.034) and RNS score (P<0.0001) remained significant in multivariate analysis. We conclude that the RNS system is a reproducible and powerful predictor of survival after resection for pancreatic cancers treated with neoadjuvant therapy and should be investigated in larger cohorts.

doi: https://doi.org/10.1097/PAS.0000000000001601



  • CRS/HIPEC with Major Organ Resection in Peritoneal Mesothelioma Does not Impact Major Complications or Overall Survival: A Retrospective Cohort Study of the US HIPEC Collaborative

Annals of surgical oncology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33073341

INTRODUCTION: CRS/HIPEC is thought to confer a survival advantage for patients with malignant peritoneal mesothelioma (MPM). However, the impact of nonperitoneal organ resection is not clearly defined. We evaluated the impact of major organ resection (MOR) on postoperative outcomes and overall survival (OS).
PATIENTS AND METHODS: The US HIPEC collaborative database (2000-2017) was reviewed for MPM patients who underwent CRS/HIPEC. MOR was defined as total or partial resection of diaphragm, stomach, spleen, pancreas, small bowel, colon, rectum, kidney, ureter, bladder, and/or uterus. MOR was categorized as 0, 1, or 2+ organs.
RESULTS: A total of 174 patients were identified. Median PCI was 16 (3-39). The distribution of patients with MOR-0, MOR-1, and MOR-2+ was 94, 45, and 35 patients, respectively. MOR-1 and MOR-2+ groups had a higher frequency of any complication compared with MOR-0 (57.8%, 74.3%, and 48.9%, respectively, p = 0.035), but Clavien ¾ complications were similar. Median length of stay was slightly higher in the MOR-1 and MOR-2+ groups (10 and 11 days) compared with the MOR-0 cohort (9 days, p = 0.005). Incomplete cytoreduction, ASA class 4, and male gender were associated with increased mortality on unadjusted analysis; however, their impact on OS was attenuated on multivariable analysis. MOR was not associated with OS based on these data (MOR-1: HR 1.67, 95% CI 0.59-4.74; MOR-2+ : HR 0.77, 95% CI 0.22-2.69).
CONCLUSIONS: MOR was not associated with an increase in major complications or worse OS in patients undergoing CRS/HIPEC for MPM and should be considered, if necessary, to achieve complete cytoreduction for MPM patients.

doi: https://doi.org/10.1245/s10434-020-09232-9



  • Nationwide compliance with a multidisciplinary guideline on pancreatic cancer during 6-year follow-up

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33069583

BACKGROUND: Compliance with national guidelines on pancreatic cancer management could improve patient outcomes. Early compliance with the Dutch guideline was poor. The aim was to assess compliance with this guideline during six years after publication.
MATERIALS AND METHODS: Nationwide guideline compliance was investigated for three subsequent time periods (2012-2013 vs. 2014-2015 vs. 2016-2017) in patients with pancreatic cancer using five quality indicators in the Netherlands Cancer Registry: 1) discussion in multidisciplinary team meeting (MDT), 2) maximum 3-week interval from final MDT to start of treatment, 3) preoperative biliary drainage when bilirubin >250 μmol/L, 4) use of adjuvant chemotherapy, and 5) chemotherapy for inoperable disease (non-metastatic and metastatic).
RESULTS: In total, 14 491 patients were included of whom 2290 (15.8%) underwent resection and 4561 (31.5%) received chemotherapy. Most quality indicators did not change over time: overall, 88.8% of patients treated with curative intent were discussed in a MDT, 42.7% were treated with curative intent within the 3-week interval, 62.7% with a resectable head tumor and bilirubin >250 μmol/L underwent preoperative biliary drainage, 57.2% received chemotherapy after resection, and 36.6% with metastatic disease received chemotherapy. Only use of chemotherapy for non-metastatic, non-resected disease improved over time (23.4% vs. 25.6% vs. 29.7%).
CONCLUSION: Nationwide compliance to five quality indicators for the guideline on pancreatic cancer management showed little to no improvement during six years after publication. Besides critical review of the current quality indicators, these outcomes may suggest that a nationwide implementation program is required to increase compliance to guideline recommendations.

doi: https://doi.org/10.1016/j.pan.2020.10.032



  • Hyalinized stroma is a characteristic feature of pancreatic intraductal oncocytic papillary neoplasm: An immunohistochemical study

Annals of diagnostic pathology 2020 Oct;49():151639

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33069084

Hyalinized stroma (HS) is a dense, eosinophilic, and amorphous extracellular material in the stroma. HS is observed in several tumors; however, it has not been comprehensively studied in pancreatic intraductal papillary mucinous neoplasm (IPMN) or intraductal oncocytic papillary neoplasm (IOPN). Here, we aimed to evaluate the immunohistochemical and microscopic characteristics of HS in IPMN and IOPN. The prevalence of HS was determined in 168 cases of IPMN, including intestinal type (IPMN-I), gastric type (IPMN-G), and pancreatobiliary type (IPMN-PB), as well as in 11 cases of IOPN. Immunohistochemical staining for laminin and collagen (types I, II, III, IV, and V), as well as Congo red staining were performed in IPMN and IOPN cases containing HS. The prevalence of HS among the IPMN and IOPN specimens was 1.2% (2/168 cases) and 45.5% (5/11 cases), respectively. The prevalence rates of HS in each IPMN subtype were as follows: 2.2% (2/91 cases) in IPMN-G, and 0% in IPMN-PB and IPMN-I. All seven HS cases were positive for collagen I, III, IV, and V but were negative for Congo red staining. Most cases showed negative, focal, or weak expression of laminin and type II collagen. These findings indicate that HS is associated with IOPN and is primarily composed of collagen fibers.

doi: https://doi.org/10.1016/j.anndiagpath.2020.151639



  • Neoadjuvant S-1 With Concurrent Radiotherapy Followed by Surgery for Borderline Resectable Pancreatic Cancer: A Phase II Open-Label Multicenter Prospective Trial (JASPAC05)

Annals of surgery 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33065644

OBJECTIVE: This study assessed whether neoadjuvant chemoradiotherapy (CRT) with S-1 increases the R0 resection rate in borderline resectable pancreatic cancer (BRPC).
SUMMARY BACKGROUND DATA: Although a multidisciplinary approach that includes neoadjuvant treatment has been shown to be a better strategy for BRPC than upfront resection, a standard treatment for BRPC has not been established.
METHODS: A multicenter, single-arm, phase II study was performed. Patients who fulfilled the criteria for BRPC received S-1 (40 mg/m bid) and concurrent radiotherapy (50.4 Gy in 28 fractions) before surgery. The primary endpoint was the R0 resection rate. At least 40 patients were required, with a one-sided α = 0.05 and β = 0.05 and expected and threshold values for the primary endpoint of 30% and 10%, respectively.
RESULTS: Fifty-two patients were eligible, and 41 were confirmed to have definitive BRPC by a central review. CRT was completed in 50 (96%) patients and was well tolerated. The rate of grade ¾ toxicity with CRT was 43%. The R0 resection rate was 52% among the 52 eligible patients and 63% among the 41 patients who were centrally confirmed to have BRPC. Postoperative grade III/IV adverse events according to the Clavien-Dindo classification were observed in 7.5%. Among the 41 centrally confirmed BRPC patients, the 2-year overall survival rate and median overall survival duration were 58% and 30.8 months, respectively.
CONCLUSIONS: S-1 and concurrent radiotherapy appear to be feasible and effective at increasing the R0 resection rate and improving survival in patients with BRPC.
TRIAL REGISTRATION: UMIN000009172.

doi: https://doi.org/10.1097/SLA.0000000000004535



  • Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients

Cell 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33065029

KRAS mutations are among the most common genetic alterations in lung, colorectal, and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a long-standing pursuit in precision oncology, one established shortly after the discovery of RAS mutations in human cancer cells nearly 40 years ago. Recent advances in medicinal chemistry have established inhibitors targeting KRAS(G12C), a mutation found in ∼13% of lung adenocarcinomas and, at a lower frequency, in other cancers. Preclinical studies describing their discovery and mechanism of action, coupled with emerging clinical data from patients treated with these drugs, have sparked a renewed enthusiasm in the study of KRAS and its therapeutic potential. Here, we discuss how these advances are reshaping the fundamental aspects of KRAS oncoprotein biology and the strides being made toward improving patient outcomes in the clinic.

doi: https://doi.org/10.1016/j.cell.2020.09.044



  • Mural Intracholecystic Neoplasms Arising in Adenomyomatous Nodules of the Gallbladder: An Analysis of 19 Examples of a Clinicopathologically Distinct Entity

The American journal of surgical pathology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33060404

Intracholecystic neoplasms (ICNs) (pyloric gland adenomas and intracholecystic papillary neoplasms, collectively also called intracholecystic papillary/tubular neoplasms) form multifocal, extensive proliferations on the gallbladder mucosa and have a high propensity for invasion (>50%). In this study, 19 examples of a poorly characterized phenomenon, mural papillary mucinous lesions that arise in adenomyomatous nodules and form localized ICNs, were analyzed. Two of these were identified in 1750 consecutive cholecystectomies reviewed specifically for this purpose, placing its incidence at 0.1%. Median age was 68 years. Unlike other gallbladder lesions, these were slightly more common in men (female/male=0.8), and 55% had documented cholelithiasis. All were characterized by a compact multilocular, demarcated, cystic lesion with papillary proliferations and mucinous epithelial lining. The lesions' architecture, distribution, location, and typical size were suggestive of evolution from an underlying adenomyomatous nodule. All had gastric/endocervical-like mucinous epithelium, but 5 also had a focal intestinal-like epithelium. Cytologic atypia was graded as 1 to 3 and defined as 1A: mucinous, without cytoarchitectural atypia (n=3), 1B: mild (n=7), 2: moderate (n=2), and 3: severe atypia (n=7, 3 of which also had invasive carcinoma, 16%). Background gallbladder mucosal involvement was absent in all but 2 cases, both of which had multifocal papillary mucosal nodules. In conclusion, these cases highlight a distinct clinicopathologic entity, that is, mural ICNs arising in adenomyomatous nodules, which, by essentially sparing the “main” mucosa, not displaying “field-effect/defect” phenomenon, and only rarely (16%) showing carcinomatous transformation, are analogous to pancreatic branch duct intraductal papillary mucinous neoplasms.

doi: https://doi.org/10.1097/PAS.0000000000001603



  • The use of immunohistochemistry for IgG4 in the diagnosis of autoimmune pancreatitis: A systematic review and meta-analysis

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33060017

BACKGROUND: The diagnosis of autoimmune pancreatitis (AIP) remains challenging, especially when serum IgG4 is normal or imaging features are indeterminate. We performed a systematic review and meta-analysis to evaluate the performance of IgG4 immunostaining of pancreatic, biliary, and ampullary tissues as a diagnostic aid for AIP.
METHODS: A comprehensive literature search of the PubMed, EMBASE, and Ovid MEDLINE databases was conducted until February 2020. The methodological quality of each study was assessed according to the Quality Assessment of Diagnostic Accuracy Studies checklist. A random-effects model was used to summarize the diagnostic odds ratio and other measures of accuracy.
RESULTS: The meta-analysis included 20 studies comprising 346 patients with AIP and 590 patients with other pancreatobiliary diseases, including 371 pancreatobiliary malignancies. The summary estimates for tissue IgG4 in discriminating AIP and controls were as follows: diagnostic odds ratio 38.86 (95% confidence interval (CI), 18.70-80.75); sensitivity 0.64 (95% CI, 0.59-0.69); specificity 0.93 (95% CI, 0.91-0.95). The area under the curve was 0.939 for tissue IgG4 in discriminating AIP and controls. Subgroup analysis revealed no significant difference in diagnostic accuracy according to control groups (pancreatobiliary cancer versus other chronic pancreatitis) and sampling site (pancreas versus bile duct/ampulla).
CONCLUSIONS: Current data demonstrate that IgG4 immunostaining of pancreatic, biliary, and ampullary tissue has a high specificity but moderate sensitivity for diagnosing AIP. IgG4 immunostaining may be useful in supporting a diagnosis of AIP when AIP is clinically suspected, but a combination of imaging and serology does not provide a conclusive diagnosis.

doi: https://doi.org/10.1016/j.pan.2020.10.028



  • Worldwide Burden of, Risk Factors for, and Trends in Pancreatic Cancer

Gastroenterology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33058868

BACKGROUND & AIMS: We evaluated global and regional burdens of, risk factors for, and epidemiologic trends in pancreatic cancer among groups of different sexes and ages.
METHODS: We used data from the GLOBOCAN database to estimate pancreatic cancer incidence and mortality in 184 countries. We examined the association between lifestyle and metabolic risk factors, extracted from the World Health Organization Global Health Observatory database, and pancreatic cancer incidence and mortality by univariable and multivariable linear regression. We retrieved country-specific on age-standardized rates (ASRs) of incidence and mortalities from cancer registries from 48 countries through 2017 for trend analysis by joinpoint regression analysis.
RESULTS: The highest incidence and mortality of pancreatic cancer were in regions with very high (ASRs, 7.7 and 4.9) and high HDIs (ASRs, 6.9 and 4.6) in 2018. Countries with higher incidence and mortality were more likely to have higher prevalence of smoking, alcohol drinking, physical inactivity, obesity, hypertension, and high cholesterol. From 2008 to 2017, 2007 to 2016, or 2003 to 2012, depending on the availability of the data, there were increases in incidence among men and women in 14 (average annual percent changes [AAPCs], 8.85 to 0.41) and 17 (AAPCs, 6.04 to 0.87) countries, respectively. For mortality, the increase was observed in eight (AAPCs, 4.20 to 0.55) countries among men and 14 (AAPCs, 5.83 to 0.78) countries among women. While the incidence increased in 18 countries (AAPCs, 7.83 to 0.91) among individuals 50 years or older, an increasing trend in pancreatic cancer was also identified among individuals younger than 50 years and 40 years in eight (AAPCs, 8.75 to 2.82) and four (AAPCs, 11.07 to 8.31) countries, respectively.
CONCLUSIONS: In an analysis of data from 48 countries, we found increasing incidence and mortality trends in pancreatic cancer, especially among women and populations 50 years or older, but also among younger individuals. More preventive efforts are recommended for these populations.

doi: https://doi.org/10.1053/j.gastro.2020.10.007



  • Race/Ethnicity and County-Level Social Vulnerability Impact Hospice Utilization Among Patients Undergoing Cancer Surgery

Annals of surgical oncology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33057860

BACKGROUND: Integration of palliative care services into the surgical treatment plan is important for holistic patient care. We sought to examine the association between patient race/ethnicity and county-level vulnerability relative to patterns of hospice utilization.
PATIENTS AND METHODS: Medicare Standard Analytic Files were used to identify patients undergoing lung, esophageal, pancreatic, colon, or rectal cancer surgery between 2013 and 2017. Data were merged with the Centers for Disease Control and Prevention's social vulnerability index (SVI). Logistic regression was utilized to identify factors associated with overall hospice utilization among deceased individuals.
RESULTS: A total of 54,256 Medicare beneficiaries underwent lung (n = 16,645, 30.7%), esophageal (n = 1427, 2.6%), pancreatic (n = 6183, 11.4%), colon (n = 26,827, 49.4%), or rectal (n = 3174, 5.9%) cancer resection. Median patient age was 76 years (IQR 71-82 years), and 28,887 patients (53.2%) were male; the majority of individuals were White (91.1%, n = 49,443), while a smaller subset was Black or Latino (racial/ethnic minority: n = 4813, 8.9%). Overall, 35,416 (65.3%) patients utilized hospice services prior to death. Median SVI was 52.8 [interquartile range (IQR) 30.3-71.2]. White patients were more likely to utilize hospice care compared with minority patients (OR 1.24, 95% CI 1.17-1.31, p < 0.001). Unlike White patients, there was reduced odds of hospice utilization (OR 0.97, 95% CI 0.96-0.99) and early hospice initiation (OR 0.94, 95% CI 0.91-0.97) as SVI increased among minority patients.
CONCLUSIONS: Patients residing in counties with high social vulnerability were less likely to be enrolled in hospice care at the time of death, as well as be less likely to initiate hospice care early. The effects of increasing social vulnerability on hospice utilization were more profound among minority patients.

doi: https://doi.org/10.1245/s10434-020-09227-6



  • An Aggressive Approach to Locally Confined Pancreatic Cancer: Defining Surgical and Oncologic Outcomes Unique to Pancreatectomy with Celiac Axis Resection (DP-CAR)

Annals of surgical oncology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33051739

BACKGROUND: Modern chemotherapeutics have led to improved systemic disease control for patients with locally advanced pancreatic cancer (LAPC). Surgical strategies such as distal pancreatectomy with celiac axis resection (DP-CAR) are increasingly entertained. Herein we review procedure-specific outcomes and assess biologic rationale for DP-CAR.
METHODS: A prospectively maintained single-institution database of all pancreatectomies was queried for patients undergoing DP-CAR. We excluded all patients for whom complete data were not available and those who were not treated with contemporary multi-agent therapy. Data were supplemented with dedicated chart review and outreach for long-term oncologic outcomes.
RESULTS: Fifty-four patients underwent DP-CAR between 2008 and 2018. The median age was 62.7 years. Ninety-eight percent received induction chemotherapy. Arterial reconstruction was performed in 17% and concomitant visceral resection in 30%. The R0 resection rate was 87%. Postoperative complications were common (43%) with chyle leak being the most frequent (17%). Length of stay was 8 days, readmission occurred in one-third, and 90-day mortality was 2%. Disease recurrence occurred in 74% during a median follow up of 17.4 months. Median recurrence-free (RFS) and overall survival (OS) were 9 and 25 months, respectively.
CONCLUSIONS: Following modern induction paradigms, DP-CAR can be performed with low mortality, manageable morbidity, and excellent rates of margin-negative resection in high-volume settings. The profile of complications of DP-CAR is distinct from pancreaticoduodenectomy and simple distal pancreatectomy. OS and RFS are similar to those undergoing resection of borderline resectable and resectable disease. Improved systemic disease control will likely lead to increasing utilization of aggressive surgical approaches to LAPC.

doi: https://doi.org/10.1245/s10434-020-09201-2



  • Subtype-discordant pancreatic ductal adenocarcinoma tumors show intermediate clinical and molecular characteristics

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33051307

Background RNA-sequencing-based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. 'Classical' and 'basal-like' PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice. Methods Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were employed on each sample, and results were tested for subtype call consistency and association with survival. Results Basal-like and classical subtype calls were concordant in 88% of patient samples, and survival outcomes were significantly different (p<0.05) between prognostic subtypes. 12% of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression (p<0.0001) and mutant KRAS allelic imbalance (p<0.001). Conclusions Nearly one in six patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed towards clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice.

doi: https://doi.org/10.1158/1078-0432.CCR-20-2831



  • Expression of the EWSR1-FLI1 fusion oncogene in pancreas cells drives pancreatic atrophy and lipomatosis

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33051146

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) harbors mutant KRAS as the most common driver mutation. Studies on mouse models have uncovered the tumorigenic characteristics of the Kras oncogene driving pancreatic carcinogenesis. Similarly, Ewing sarcoma predominantly depends on the occurrence of the EWSR1-FLI1 fusion oncogene. The expression of EWSR1-FLI1 affects pro-tumorigenic pathways and induces cell transformation. In this study, we investigated whether mutant Kras could be exchanged by another potent oncogene, such as EWSR1-FLI1, to initiate pancreatic cancer development.
METHODS: We generated two conditional mouse models expressing mutant KrasG12D (KC) or the EWSR1-FLI1 oncogene (E/F) in pancreas cells. Pancreatic tissue was collected from the mice at 4-6 weeks and 11-13 weeks of age as well as from survival cohorts to determine the development of spontaneous acinar-to-ductal metaplasia (ADM) and neoplastic lesions. Immunohistochemistry and immunofluorescence staining were performed to characterize and quantify changes in tissue morphology.
RESULTS: The expression of the EWSR1-FLI1 fusion protein in pancreas cells was confirmed by positive FLI1 immunohistochemistry staining. Notably, the EWSR1-FLI1 expression in pancreas cells resulted in a strong depletion of the acinar cell mass and an extensive lipomatosis. Although the E/F mice exhibited spontaneous ADM formation and a shorter overall survival rate compared to KC mice, no development of neoplastic lesion was observed in aging E/F mice.
CONCLUSIONS: The expression of the EWSR1-FLI1 oncogene leads to a strong pancreatic atrophy and lipomatosis. ADM formation indicates that pancreatic acinar cells are susceptible for EWSR1-FLI1-mediated oncogenic transformation to a limited extent. However, the EWSR1-FLI1 oncogene is insufficient to induce pancreatic cancer development.

doi: https://doi.org/10.1016/j.pan.2020.10.033



  • FOLFIRINOX as second-line chemotherapy for advanced pancreatic cancer: A subset analysis of data from a nationwide multicenter observational study in Japan

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Oct;20(7):1519-1525

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32972834

BACKGROUND: Data on FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer are limited. In the JASPAC06 study-a nationwide, multicenter, observational study-FOLFIRINOX for patients with unresectable or recurrent pancreatic cancer as any line of treatment showed favorable efficacy and safety in Japanese clinical practice.
METHODS: We performed exploratory analyses of patients with unresectable or recurrent pancreatic cancer who received FOLFIRINOX as the second-line chemotherapy in Japanese clinical settings.
RESULTS: Of the 399 evaluable patients, 44 were eligible for inclusion in the analysis. The patients' characteristics were as follows: median age, 62 years; men, 26 (59%); Eastern Cooperative Oncology Group-Performance status 0/1, 30 (68%)/14 (32%); disease status, recurrent/local/metastatic: 4 (9%)/8 (18%)/32 (73%). The initial dose was reduced in 28 (64%) patients. The median time to treatment failure and number of cycles were 4.5 (range, 0.2-19.1) months and 6 cycles (range, 1-13 or more), respectively. The major grade ¾ adverse events were neutropenia in 29 (66%), leucopenia in 17 (39%), anorexia in 7 (16%), febrile neutropenia in 5 (11%), and anemia in 5 (11%) patients. The median overall survival, progression-free survival, and 1-year survival rates were 10.3 (95% confidence interval [CI], 7.2-13.3), 4.1 (95% CI, 2.6-5.5) months, and 30%, respectively.
CONCLUSION: Our findings suggest that FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer was effective in patients with a good performance status. It displayed toxicity similar to that observed with its use as a first-line treatment.

doi: https://doi.org/10.1016/j.pan.2020.07.006



  • The quality of pain management in pancreatic cancer: A prospective multi-center study

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Oct;20(7):1511-1518

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32952041

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with severe pain. Given the almost inevitably fatal nature of the disease, pain control is crucial. However, data on quality of pain management in PDAC is scarce.
METHODS: This is a multi-center, prospective study to evaluate the quality of pain management in PDAC. Insufficient pain treatment (undertreatment) was prevalent if there was an incongruence between the patients level of pain and the potency of analgesic drug therapy. Determinants of pain and undertreatment were identified using multivariable logistic regression.
RESULTS: 139 patients with histologically confirmed PDAC were analyzed. The prevalence of pain was 63%, with approximately one third of the patients grading their pain as moderate to severe. Palliative stage (OR: 3.37, 95%CI: 1.23-9.21, p = 0.018) and localization of the primary tumor in the body or tail (OR: 2.57, 95%CI: 1.05-6.31, p = 0.039) were independent determinants of pain. Of those reporting pain, 60% were undertreated and in 89% pain interfered with activities and emotions. Age ≥ 70 years (OR: 3.20, 95%CI: 1.09-9.41, p = 0.035) was an independent predictor of undertreatment. Patients with longer-known PDAC ( ≥ 30 days) showed improved pain management compared to new cases (OR: 0.19, 95%CI: 0.05-0.81, p = 0.025). Treatment by gastroenterologists (OR: 0.22, 95%CI: 0.05-0.89, p = 0.034) was associated with less undertreatment.
CONCLUSIONS: The results show a high proportion of PDAC patients with pain, pain interference and undertreatment, whose characteristics could help to identify patients at risk in the future. Several changes in the management of cancer-related pain are necessary to overcome barriers to optimal treatment.

doi: https://doi.org/10.1016/j.pan.2020.08.017



  • Computerized tomography scan in pre-diagnostic pancreatic ductal adenocarcinoma: Stages of progression and potential benefits of early intervention: A retrospective study

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Oct;20(7):1495-1501

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32950386

BACKGROUND: The frequency, nature and timeline of changes on thin-slice (≤3 mm) multi-detector computerized tomography (CT) scans in the pre-diagnostic phase of pancreatic ductal adenocarcinoma (PDAC) are unknown. It is unclear if identifying imaging changes in this phase will improve PDAC survival beyond lead time.
METHODS: From a cohort of 128 subjects (Cohort A) with CT scans done 3-36 months before diagnosis of PDAC we developed a CTgram defining CT Stages (CTS) I through IV in the radiological progression of pre-diagnostic PDAC. We constructed Cohort B of PDAC resected at CTS I and II and compared survival in CTS I and II in Cohort A (n = 22 each; control natural history cohort) vs Cohort B (n = 33 and 72, respectively; early interception cohort).
RESULTS: CTs were abnormal in 16% and 85% at 24-36 and 3-6 months respectively, before PDAC diagnosis. The PDAC CTgram stages, findings and median lead times (months) to clinical diagnosis were: CTS I: Abrupt duct cut-off/duct dilatation (-12.8); CTS II: Low density mass confined to pancreas (-9.5), CTS III: Peri-pancreatic infiltration (-5.8), CTS IV: Distant metastases (only at diagnosis). PDAC survival was better in cohort B than in cohort A despite inclusion of lead time in Cohort A: CTS I (36 vs 17.2 months, p = 0.03), CTS II (35.2 vs 15.3 months, p = 0.04).
CONCLUSION: Starting 12-18 months before PDAC diagnosis, progressive and increasingly frequent changes occur on CT scans. Resection of PDAC at the time of pre-diagnostic CT changes is likely to provide survival benefit beyond lead time.

doi: https://doi.org/10.1016/j.pan.2020.07.410



  • Clinical outcomes of acute pancreatitis in elderly patients: An experience of single tertiary center

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Oct;20(7):1296-1301

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32900631

BACKGROUND: Although well understanding the course of diseases in geriatric population is of paramount importance in order to provide the optimal treatment, there is only a few studies with controversial results that have been conducted about the course and outcomes of acute pancreatitis (AP) in elderly. We aimed to compare clinical outcomes of AP disease in geriatric age group and to evaluate the risk factors affecting outcomes.
METHODS: A total of 336 patients diagnosed with AP, hospitalized and followed-up in our hospital between July/2013-February/2019 were included in this study. Patients aged 65 years and over were assessed as elderly population. Patients' demographic data, comorbidities, duration of hospitalization, local systemic complications, and mortality rates were documented.
RESULTS: 196(58.3%) of the patients were female with a mean age of 54.1 ± 17.9 years. The number of patients was 114(33.9%) in the elderly group and 222(66.1%) in the non-elderly group. Although there was no significant difference between both groups in terms of abscess, pseudocyst and necrosis, pancreatic necrosis and systemic complications were higher in the elderly group (p < 0.05). The durations of oral intake and hospitalization were longer, the mortality rate and severity of AP according to the Ranson and Atlanta criteria were significantly higher in the geriatric population (p < 0.05). In addition, age and severity of AP were found to be independent predictive factors of developing complications.
CONCLUSIONS: Early recognition of AP is important in the geriatric population. Clinical and laboratory investigations, and early diagnosis in severe patients will be largely helpful in providing close follow-up and the optimal treatment.

doi: https://doi.org/10.1016/j.pan.2020.06.006



  • Pancreatic neuroendocrine carcinoma G3 may be heterogeneous and could be classified into two distinct groups

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Oct;20(7):1421-1427

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32891532

BACKGROUND/OBJECTIVES: Pancreatic neuroendocrine carcinoma (PanNEC)-G3 often presents along with genetic abnormalities such as KRAS, RB1, and TP53 mutations. However, the association between these genetic findings and response to chemotherapy and prognosis has not been clarified. This study aimed to clarify the clinicopathological features of PanNEC-G3.
METHODS: We performed a subgroup analysis of the Japanese PanNEN-G3 study (multicenter, retrospective study), which revealed that Rb loss and KRAS mutation were predictors of the response to platinum-based regimen in PanNEN-G3. We re-classified WHO grades of PanNENs using the 2017 WHO classification and then analyzed the clinicopathological features and prognostic factors in 49 patients with PanNEC-G3.
RESULTS: The rates of Rb loss and KRAS mutation in PanNEC-G3 were 54.5% and 48.7%, respectively. Patients with Rb loss and/or KRAS mutation showed a higher response rate to first-line platinum-based regimen than those without Rb loss or KRAS mutation (object response rate 70.0% vs 33.3%, odds ratio 9.22; 95% CI 1.26-67.3, P = 0.029), but tended to have shorter overall survival rates than those without Rb loss or KRAS mutation (median 239 vs 473 days, hazard ratio 2.11; 95% CI 0.92-4.86, P = 0.077).
CONCLUSIONS: Patients with PanNEC-G3 have varied clinical outcomes for platinum-based regimen. When grouped based on Rb loss and KRAS mutation, there seemed to be two groups with distinct prognoses and responses to the platinum-based regimen. PanNEC-G3 could, therefore, be classified into two distinct groups based on immunohistochemical and genetic findings.

doi: https://doi.org/10.1016/j.pan.2020.07.400



  • Serum fibrinogen as a diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Oct;20(7):1465-1471

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32873483

BACKGROUND/OBJECTIVES: Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is important as PDAC can lead to mortality; however, no specific biomarker has been identified for its early diagnosis. We previously identified fibrinogen α chain as a promising biomarker for differentiating between patients with and without PDAC using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Here, we aimed to validate the clinical usefulness of serum fibrinogen as a biomarker for PDAC.
METHODS: From 2009 to 2011, blood samples of 67 PDAC patients and 43 healthy adults (controls) were prospectively collected. Serum fibrinogen levels and their clinical significances were evaluated.
RESULTS: Mean fibrinogen levels were significantly higher in the PDAC group than in the control group (3.08 ± 0.565 vs. 2.54 ± 0.249 log10 ng/mL, P < 0.001). In the receiver operating characteristic analysis, overall sensitivity, and specificity of serum fibrinogen levels for differentiating PDAC patients from control patients were 67.4% and 83.6%, respectively, with a 427-ng/mL cutoff value. Serum fibrinogen levels were significantly higher in PDAC patients with distant metastasis than in those without distant metastasis (3.38 ± 0.581 vs. 2.93 ± 0.499 log10 ng/mL, P = 0.002). Median overall survival was significantly longer in PDAC patients with low fibrinogen levels (<1000 ng/mL) than in those with high fibrinogen levels (≥1000 ng/mL) [489 days (95% confidence interval, 248.1-729.9) vs. 172 days (58.4-285.6) (P = 0.008)]. Although serum fibrinogen levels were poorly correlated with carbohydrate antigen 19-9 levels, these two biomarkers together predicted survival better.
CONCLUSIONS: Serum fibrinogen levels may be a useful biomarker for diagnosing and predicting PDAC prognosis.

doi: https://doi.org/10.1016/j.pan.2020.06.010


New GallBladder Articles


  • Mural Intracholecystic Neoplasms Arising in Adenomyomatous Nodules of the Gallbladder: An Analysis of 19 Examples of a Clinicopathologically Distinct Entity

The American journal of surgical pathology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33060404

Intracholecystic neoplasms (ICNs) (pyloric gland adenomas and intracholecystic papillary neoplasms, collectively also called intracholecystic papillary/tubular neoplasms) form multifocal, extensive proliferations on the gallbladder mucosa and have a high propensity for invasion (>50%). In this study, 19 examples of a poorly characterized phenomenon, mural papillary mucinous lesions that arise in adenomyomatous nodules and form localized ICNs, were analyzed. Two of these were identified in 1750 consecutive cholecystectomies reviewed specifically for this purpose, placing its incidence at 0.1%. Median age was 68 years. Unlike other gallbladder lesions, these were slightly more common in men (female/male=0.8), and 55% had documented cholelithiasis. All were characterized by a compact multilocular, demarcated, cystic lesion with papillary proliferations and mucinous epithelial lining. The lesions' architecture, distribution, location, and typical size were suggestive of evolution from an underlying adenomyomatous nodule. All had gastric/endocervical-like mucinous epithelium, but 5 also had a focal intestinal-like epithelium. Cytologic atypia was graded as 1 to 3 and defined as 1A: mucinous, without cytoarchitectural atypia (n=3), 1B: mild (n=7), 2: moderate (n=2), and 3: severe atypia (n=7, 3 of which also had invasive carcinoma, 16%). Background gallbladder mucosal involvement was absent in all but 2 cases, both of which had multifocal papillary mucosal nodules. In conclusion, these cases highlight a distinct clinicopathologic entity, that is, mural ICNs arising in adenomyomatous nodules, which, by essentially sparing the “main” mucosa, not displaying “field-effect/defect” phenomenon, and only rarely (16%) showing carcinomatous transformation, are analogous to pancreatic branch duct intraductal papillary mucinous neoplasms.

doi: https://doi.org/10.1097/PAS.0000000000001603


New BileDuct Articles


  • Mantle cell lymphoma with EBV-positive Hodgkin and Reed-Sternberg-like cells in a patient after autologous PBSCT: Phenotypically distinct but genetically related tumors

Pathology international 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33079423

The case of 70-year-old man with mantle cell lymphoma (MCL) carrying t(11;14) translocation that relapsed as nodal lymphoma combining MCL and classic Hodgkin lymphoma (cHL) 9 years after autologous peripheral blood stem cell transplant (auto-PBSCT) is reported. Lymph nodes contained two separate areas of MCL and cHL-like components. Hodgkin and Reed-Sternberg (HRS)-like cells were accompanied by a prominent histiocyte background. HRS-like cells were CD5- , CD15+ , CD20- , CD30+ , PAX5+ , Bob.1- , Oct2- and EBER+ . The MCL component expressed cyclin D1 and SOX11, whereas cyclin D1 and SOX11 expressions were reduced and lost, respectively, in HRS-like cells. Polymerase chain reaction results showed a single clonal rearrangement of the IGH gene in MCL and cHL-like components. CCND1 break apart fluorescence in situ hybridization showed split signals in both MCL and HRS-like cells, suggesting that MCL and cHL-like components were clonally related. Acquisition of p53 expression and Epstein-Barr virus (EBV)-positivity was seen in HRS-like cells. The patient died of disease progression with elevated hepatobiliary enzymes. The autopsy showed both MCL and cHL-like components around the bile ducts, splenic white pulp and bone marrow. The two components were phenotypically distinct, but genetically related, suggesting that transformation of MCL to HRS-like cells during the course of MCL in association with EBV infection.

doi: https://doi.org/10.1111/pin.13038



  • The use of immunohistochemistry for IgG4 in the diagnosis of autoimmune pancreatitis: A systematic review and meta-analysis

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33060017

BACKGROUND: The diagnosis of autoimmune pancreatitis (AIP) remains challenging, especially when serum IgG4 is normal or imaging features are indeterminate. We performed a systematic review and meta-analysis to evaluate the performance of IgG4 immunostaining of pancreatic, biliary, and ampullary tissues as a diagnostic aid for AIP.
METHODS: A comprehensive literature search of the PubMed, EMBASE, and Ovid MEDLINE databases was conducted until February 2020. The methodological quality of each study was assessed according to the Quality Assessment of Diagnostic Accuracy Studies checklist. A random-effects model was used to summarize the diagnostic odds ratio and other measures of accuracy.
RESULTS: The meta-analysis included 20 studies comprising 346 patients with AIP and 590 patients with other pancreatobiliary diseases, including 371 pancreatobiliary malignancies. The summary estimates for tissue IgG4 in discriminating AIP and controls were as follows: diagnostic odds ratio 38.86 (95% confidence interval (CI), 18.70-80.75); sensitivity 0.64 (95% CI, 0.59-0.69); specificity 0.93 (95% CI, 0.91-0.95). The area under the curve was 0.939 for tissue IgG4 in discriminating AIP and controls. Subgroup analysis revealed no significant difference in diagnostic accuracy according to control groups (pancreatobiliary cancer versus other chronic pancreatitis) and sampling site (pancreas versus bile duct/ampulla).
CONCLUSIONS: Current data demonstrate that IgG4 immunostaining of pancreatic, biliary, and ampullary tissue has a high specificity but moderate sensitivity for diagnosing AIP. IgG4 immunostaining may be useful in supporting a diagnosis of AIP when AIP is clinically suspected, but a combination of imaging and serology does not provide a conclusive diagnosis.

doi: https://doi.org/10.1016/j.pan.2020.10.028


New Ampulla Articles


  • Patterns of Mycobacterium avium-intracellulare complex infection in duodenal endoscopic biopsies in HIV/AIDS patients

Annals of diagnostic pathology 2020 Oct;49():151638

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33069083

Mycobacterium avium-intracellulare complex (MAIC) is a nontuberculous opportunistic infection in immunocompromised patients. Involvement of the gastrointestinal tract (GIT) is usually part of a disseminated disease in AIDS patients with a low CD4 count, however with standard antiretroviral therapy (ART), a localized presentation is more likely. It can affect any part of the GIT, mostly the duodenum and typically as patches. Incomplete or refractory ART for HIV-strains, therapy-related side effects, noncompliant or incomplete treatment to previous MAIC infections, superimposed complications and comorbid opportunistic infections may result in atypical clinical, endoscopic and histopathologic manifestations. We performed a retrospective review study retrieving cases of MAIC in duodenal endoscopic biopsy. We found five cases of MAIC in HIV/AIDS patients. They were males with an average age of 40-years. They showed different histopathologic features, variable patterns of MAIC-histiocytic infiltrates, and varying intensity of intracellular acid-fast positive bacilli. Enterocytes vacuolization and transepithelial elimination were also observed. Three cases were associated with cytomegalovirus and cryptococcal infections. A case was complicated by lymphangiectasia-associated protein-losing enteropathy. Initially, three cases were morphologically missed. Ziehl-Neelsen stain helped reach the correct diagnosis. Pathologists have an important role in patients' management by guiding clinicians to the correct diagnosis. Pathologists should be aware of these different histopathologic manifestations, their potential pitfalls, look for certain helpful clues complemented with multiple levels and special stains. In particular, AFB stains are mandatory in all mucosal biopsy specimens from HIV/AIDS patients regardless of their appearances.

doi: https://doi.org/10.1016/j.anndiagpath.2020.151638



  • The use of immunohistochemistry for IgG4 in the diagnosis of autoimmune pancreatitis: A systematic review and meta-analysis

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33060017

BACKGROUND: The diagnosis of autoimmune pancreatitis (AIP) remains challenging, especially when serum IgG4 is normal or imaging features are indeterminate. We performed a systematic review and meta-analysis to evaluate the performance of IgG4 immunostaining of pancreatic, biliary, and ampullary tissues as a diagnostic aid for AIP.
METHODS: A comprehensive literature search of the PubMed, EMBASE, and Ovid MEDLINE databases was conducted until February 2020. The methodological quality of each study was assessed according to the Quality Assessment of Diagnostic Accuracy Studies checklist. A random-effects model was used to summarize the diagnostic odds ratio and other measures of accuracy.
RESULTS: The meta-analysis included 20 studies comprising 346 patients with AIP and 590 patients with other pancreatobiliary diseases, including 371 pancreatobiliary malignancies. The summary estimates for tissue IgG4 in discriminating AIP and controls were as follows: diagnostic odds ratio 38.86 (95% confidence interval (CI), 18.70-80.75); sensitivity 0.64 (95% CI, 0.59-0.69); specificity 0.93 (95% CI, 0.91-0.95). The area under the curve was 0.939 for tissue IgG4 in discriminating AIP and controls. Subgroup analysis revealed no significant difference in diagnostic accuracy according to control groups (pancreatobiliary cancer versus other chronic pancreatitis) and sampling site (pancreas versus bile duct/ampulla).
CONCLUSIONS: Current data demonstrate that IgG4 immunostaining of pancreatic, biliary, and ampullary tissue has a high specificity but moderate sensitivity for diagnosing AIP. IgG4 immunostaining may be useful in supporting a diagnosis of AIP when AIP is clinically suspected, but a combination of imaging and serology does not provide a conclusive diagnosis.

doi: https://doi.org/10.1016/j.pan.2020.10.028


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

Recent Articles on Pancreatobiliary #Pathology – 2020-10-15

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


  • Three distinct stroma types in human pancreatic cancer identified by image analysis of fibroblast subpopulations and collagen

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33046515

PURPOSE: Cancer-associated fibroblasts have emerged to be highly heterogenous and can play multifaced roles in dictating pancreatic ductal adenocarcinoma (PDAC) progression, immunosuppression and therapeutic response, highlighting the need for a deeper understanding of stromal heterogeneity between patients and even within a single tumor. We hypothesized that image analysis of fibroblast subpopulations and collagen in PDAC tissues might guide stroma-based patient stratification to predict clinical outcomes and tumor characteristics.
EXPERIMENTAL DESIGN: A novel multiplex immunohistochemistry-based image analysis system was established to digitally differentiate fibroblast subpopulations. Using whole-tissue slides from 215 treatment-naïve PDACs, we performed concurrent quantification of principal fibroblast subpopulations and collagen and defined three stroma types: collagen-rich stroma, fibroblast activation protein a (FAP)-dominant fibroblast-rich stroma and a smooth muscle actin (ACTA2)-dominant fibroblast-rich stroma. These stroma types were assessed for the associations with cancer-specific survival by multivariable Cox regression analyses, and with clinicopathological factors including CD8+ cell density.
RESULTS: FAP-dominant fibroblasts and ACTA2-dominant fibroblasts represented the principal distinct fibroblast subpopulations in tumor stroma. Stroma types were associated with patient survival, SMAD4 status and transcriptome signatures. Compared with FAP-dominant fibroblast-rich stroma, collagen-rich stroma correlated with prolonged survival (HR, 0.57; 95% CI, 0.33-0.99), while ACTA2-dominant fibroblast-rich stroma exhibited poorer prognosis (HR, 1.65; 95% CI, 1.06-2.58). FAP-dominant fibroblast-rich stroma was additionally characterized by restricted CD8+-cell infiltrates and intense neutrophil infiltration.
CONCLUSIONS: This study identified three distinct stroma types differentially associated with survival, immunity and molecular features, thereby underscoring the importance of stromal heterogeneity in subtyping pancreatic cancers and supporting the development of anti-stromal therapies.

doi: https://doi.org/10.1158/1078-0432.CCR-20-2298



  • Safety and Oncological Benefit of Hepatopancreatoduodenectomy for Advanced Extrahepatic Cholangiocarcinoma with Horizontal Tumor Spread: Shinshu University Experience

Annals of surgical oncology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33044629

BACKGROUND: Although hepatopancreatoduodenectomy (HPD) is the only means of achieving R0 resection of widespread extrahepatic cholangiocarcinoma, its safety and oncological benefit remain controversial because of its inherent high risk of mortality and morbidity.
OBJECTIVE: The aim of this study was to retrospectively analyze short- and long-term outcomes and evaluate the safety and oncological benefit of this advanced procedure.
METHODS: The study cohort comprised 37 consecutive patients who had undergone major HPD. Portal vein embolization was performed before surgery in 20 (54%) patients with future remnant liver volume < 35%.
RESULTS: The median operative time and blood loss were 866 min and 1000 mL, respectively. Concomitant vascular resection was performed in five patients (14%). The overall morbidity and mortality rates were 100% and 5.4% (n = 2), respectively. Nineteen patients (51%) had major (Clavien-Dindo grade III or higher) complications, the most common being intra-abdominal infection (49%) and post-hepatectomy liver failure (46%, grade B/C: 32%/5%), followed by postoperative pancreatic fistula (30%, grade B/C). R0 resection was achieved in 31 patients (84%). The 1-, 3-, and 5-year overall survival (OS) rates were 83%, 48%, and 37%, respectively. In patients with R0 resection, 5-year OS was comparable between patients who had undergone major HPD and major hepatectomy alone (41% vs. 40%, p = non-significant).
CONCLUSIONS: HPD is a valid treatment option for extensive cholangiocarcinoma, offering long-term survival benefit at the cost of relatively high but acceptable morbidity and mortality rates. HPD is advocated in selected patients provided that it is considered possible to achieve R0 resection.

doi: https://doi.org/10.1245/s10434-020-09209-8



  • Amsterdam International Consensus Meeting: tumor response scoring in the pathology assessment of resected pancreatic cancer after neoadjuvant therapy

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33041332

Histopathologically scoring the response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant treatment can guide the selection of adjuvant therapy and improve prognostic stratification. However, several tumor response scoring (TRS) systems exist, and consensus is lacking as to which system represents best practice. An international consensus meeting on TRS took place in November 2019 in Amsterdam, The Netherlands. Here, we provide an overview of the outcomes and consensus statements that originated from this meeting. Consensus (≥80% agreement) was reached on a total of seven statements: (1) TRS is important because it provides information about the effect of neoadjuvant treatment that is not provided by other histopathology-based descriptors. (2) TRS for resected PDAC following neoadjuvant therapy should assess residual (viable) tumor burden instead of tumor regression. (3) The CAP scoring system is considered the most adequate scoring system to date because it is based on the presence and amount of residual cancer cells instead of tumor regression. (4) The defining criteria of the categories in the CAP scoring system should be improved by replacing subjective terms including “minimal” or “extensive” with objective criteria to evaluate the extent of viable tumor. (5) The improved, consensus-based system should be validated retrospectively and prospectively. (6) Prospective studies should determine the extent of tissue sampling that is required to ensure adequate assessment of the residual cancer burden, taking into account the heterogeneity of tumor response. (7) In future scientific publications, the extent of tissue sampling should be described in detail in the “Materials and methods” section.

doi: https://doi.org/10.1038/s41379-020-00683-9


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Recent Articles on Pancreatobiliary #Pathology – 2020-10-13

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  • Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Gastroenterology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33039466

BACKGROUND AND AIMS: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC.
METHODS: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids.
RESULTS: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency.
CONCLUSIONS: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy.

doi: https://doi.org/10.1053/j.gastro.2020.09.043



  • Focal parenchymal atrophy of pancreas: An important sign of underlying high-grade pancreatic intraepithelial neoplasia without invasive carcinoma, i.e., carcinoma in situ

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33039293

OBJECTIVES: Diagnosing high-grade intraepithelial neoplasia without invasion, traditionally referred to as carcinoma in situ (CIS), is essential for improving prognosis. We examined the imaging findings of patients with and without CIS to identify significant aspects for the diagnosis of CIS.
METHODS: Forty-six patients strongly suspected of early pancreatic cancer without nodule on imaging (CIS group, n = 27; non-malignant group, n = 19) were retrospectively evaluated according to ten factors of computed tomography/magnetic resonance imaging (CT/MRI), endoscopic ultrasonography (EUS), and endoscopic retrograde cholangiopancreatography (ERCP) using hierarchical cluster and univariate analyses.
RESULTS: Two clusters were formed by hierarchical cluster analysis. One cluster consisted of 83.3% CIS cases with similar image findings such as focal pancreatic parenchymal atrophy (FPPA) on CT/MRI, main pancreatic duct (MPD) stricture surrounded by hypoechoic areas on EUS, and MPD stricture with upstream MPD dilation on ERCP. On univariate analysis, the CIS and non-malignant groups had FPPA on CT/MRI in 15 (55.6%) and 3 (15.8%) cases (p = 0.013), and MPD stricture surrounded by hypoechoic areas on EUS in 20 (74.1%) and 4 (21.1%) cases (p = 0.001), respectively. MPD stricture surrounded by hypoechoic areas was observed in 80% (12/15) of CIS cases with FPPA on CT/MRI and correlated with FPPA. Moreover, FPPA and MPD stricture surrounded by hypoechoic areas had histopathologically observed fibrosis or fat replacement due to pancreatic parenchymal atrophy.
CONCLUSIONS: FPPA and MPD stricture surrounded by hypoechoic areas are significant findings for the diagnosis of CIS.

doi: https://doi.org/10.1016/j.pan.2020.09.020



  • Par-4 activation restrains EMT-induced chemoresistance in PDAC by attenuating MDM-2

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33039292

BACKGROUND: We recently reported prostate apoptosis response 4 (Par-4), a potential tumor suppressor protein restrains epithelial-mesenchymal transition (EMT) properties and promotes mesenchymal-epithelial transition (MET) in invasive cancer cells by repressing Twist-1 promoter activity. Here, we demonstrate that genetic as well as pharmacological modulation of Par-4 by NGD16 (a small molecule antimetastatic agent), limits EMT-induced chemoresistance in aggressive cancer cells by suppressing MDM-2, a downstream effector of Twist-1.
METHODS: Matrigel invasion assay, gelatin degradation assay, cell scattering assay, MTT assay and colony formation assay were used to study the proliferation and migration abilities of invasive cancer cells. Immunoblotting, immunocytochemistry, and immunoprecipitation analysis were utilized for determining protein expression and protein-protein interaction. 4T1 aggressive mouse carcinoma model was employed to evaluate tumor growth and lung metastasis.
RESULTS: Treatment of gemcitabine (nucleoside analogue anticancer agent) to pancreatic cancer (Panc-1, MiaPaca-2) and breast cancer (MDA-MB-231) cells amplified MDM-2 expression along with increase in EMT properties. Conversely, NGD16 boosted expression of tumor suppressor Par-4 and inhibited invasion and migration abilities of these cells. Moreover, induction of Par-4 effectively diminished MDM-2 along with pro-EMT markers, whereas, augmented the expression of epithelial markers. Furthermore, siRNA-mediated silencing of Par-4 divulged that NGD16 exerts its EMT inhibitory effects in a Par-4-dependent manner. Mechanistically, Par-4 activation provokes p53 by disrupting MDM-2-p53 interaction, which restored epithelial characteristics in cancer cells. Additionally, partial knockdown of MDM-2 through siRNA pronounced the anti-proliferative and anti-invasive effects of NGD16. Finally, NGD16 efficiently inhibited tumor growth and lung metastasis in mouse mammary carcinoma model without showing any undesirable effects.
CONCLUSION: Our findings unveil Par-4 as a key therapeutic target and NGD16 (the pharmacological modulator of Par-4) are potential tools to suppress EMT and associated chemoresistance, which could be exploited clinically for the treatment of aggressive cancers.

doi: https://doi.org/10.1016/j.pan.2020.09.021


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  • Stratification of Postoperative Prognosis by Invasive Tumor Thickness in Perihilar Cholangiocarcinoma

Annals of surgical oncology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33040247

BACKGROUND: The pathological tumor classification of distal cholangiocarcinoma in the American Joint Committee on Cancer (AJCC) Cancer Staging Manual 8th edition is based on invasive depth, whereas that of perihilar cholangiocarcinoma (PHCC) continues to be layer-based. We aimed to clarify whether invasive depth measurement based on invasive tumor thickness (ITT) could help determine postoperative prognosis in patients with PHCC.
METHODS: We enrolled 184 patients with PHCC who underwent hepatectomy plus extrahepatic bile duct resection or hepatopancreatoduodenectomy with curative intent. ITT was measured using simple definitions according to the sectioning direction or gross tumor pattern.
RESULTS: The median ITT was 5.8 mm (range 0.7-15.5). Using the recursive partitioning technique, ITT was classified into grades A (ITT < 2 mm, n = 9), B (2 mm ≤ ITT < 5 mm, n = 68), C (5 mm ≤ ITT < 11 mm, n = 81), and D (11 mm < ITT, n = 26). The median survival times (MSTs) in patients with grade B, C, or D were 90.8, 44.6, and 21.1 months, respectively (patients with grade A did not reach the MST). There were significant differences in postoperative prognosis between ITT grades (A vs. B, p = 0.027; B vs. C, p < 0.001; C vs. D, p = 0.004). Through multivariate analysis, regional node metastasis, invasive carcinoma at the resected margin, and ITT grade were determined as independent prognostic factors.
CONCLUSION: ITT could be measured using simple methods and may be used to stratify postoperative prognosis in patients with PHCC.

doi: https://doi.org/10.1245/s10434-020-09135-9


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Recent Articles on Pancreatobiliary #Pathology – 2020-10-12

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  • Establishing a living biobank of patient-derived organoids of intraductal papillary mucinous neoplasms of the pancreas

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33037322

Pancreatic cancer (PaCa) is the third leading cause of cancer-related deaths in the United States. There is an unmet need to develop strategies to detect PaCa at an early, operable stage and prevent its progression. Intraductal papillary mucinous neoplasms (IPMNs) are cystic PaCa precursors that comprise nearly 50% of pancreatic cysts detected incidentally via cross-sectional imaging. Since IPMNs can progress from low- and moderate-grade dysplasia to high-grade dysplasia and invasion, the study of these lesions offers a prime opportunity to develop early detection and prevention strategies. Organoids are an ideal preclinical platform to study IPMNs, and the objective of the current investigation was to establish a living biobank of patient-derived organoids (PDO) from IPMNs. IPMN tumors and adjacent normal pancreatic tissues were successfully harvested from 15 patients with IPMNs undergoing pancreatic surgical resection at Moffitt Cancer Center & Research Institute (Tampa, FL) between May of 2017 and March of 2019. Organoid cultures were also generated from cryopreserved tissues. Organoid count and size were determined over time by both Image-Pro Premier 3D Version 9.1 digital platform and Matlab application of a Circular Hough Transform algorithm, and histologic and genomic characterization of a subset of the organoids was performed using immunohistochemistry and targeted sequencing, respectively. The success rates for organoid generation from IPMN tumor and adjacent normal pancreatic tissues were 81% and 87%, respectively. IPMN organoids derived from different epithelial subtypes showed different morphologies in vitro, and organoids recapitulated histologic and genomic characteristics of the parental IPMN tumor. In summary, this preclinical model has the potential to provide new opportunities to unveil mechanisms of IPMN progression to invasion and to shed insight into novel biomarkers for early detection and targets for chemoprevention.

doi: https://doi.org/10.1038/s41374-020-00494-1



  • A single center randomized double blind controlled trial of pentoxifylline in acute pancreatitis: Challenges and opportunities

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33036921

OBJECTIVES: Despite substantial morbidity and mortality associated with acute pancreatitis (AP), only one small randomized controlled drug trial (RCT) is available in the past few decades from the United States. Hence, we conducted a single-center, double-blind, placebo-controlled RCT of pentoxifylline in AP.
METHODS: A total of 9 doses of oral pentoxifylline 400 mg or placebo tablet, three times daily, was administered within 72 h of diagnosis, using randomization blocks by pharmacy. Primary outcome was a composite outcome including any of the following: death, peripancreatic and/or pancreatic necrosis, infected pancreatic necrosis, persistent organ failure, persistent systemic inflammatory response syndrome, hospital stay longer than 4 days, need for intensive care, and need for intervention for necrosis.
RESULTS: Between July 7, 2015, and April 4, 2017, we identified 685 patients with AP, 233 met eligibility criteria and 176 were approached for the study. Of these, 91 (51.7%) declined and finally 45 in pentoxifylline group and 38 in placebo group (83 total) were compared. There were no significant differences in primary outcome (27 [60.0%] vs 15 [39.5%]; P = .06). Pentoxifylline group was not associated with any benefit, but withlonger stay (42% vs. 21%; P = .04) and higher readmission rates (16 %vs 3%; P = .047).
CONCLUSIONS: We could not demonstrate superiority of pentoxifylline over placebo. Smaller sample size and inclusion of all types of severity might be the reasons for lack of efficacy. The challenges observed in the present study indicate that, in order to conduct a successful drug trial in AP, a multi center collaboration is essential.

doi: https://doi.org/10.1016/j.pan.2020.09.023


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  • A retrospective study on the association of gastrointestinal symptoms in children with low lactase activity and low activity of other disaccharidases

BMC gastroenterology 2020 Oct;20(1):331

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33036568

BACKGROUND: Disaccharides such as lactose and sucrose are sugars commonly found in human diet. They are broken down by mucosal disaccharidases in the duodenum. Previous small studies found no associations between gastrointestinal (GI) symptoms and combined low disaccharidase activity. We aim to explore the associations of low activity of disaccharidase and combinations of low activity of different disaccharidases with general GI symptom presentations in a large cohort of pediatric patients.
METHODS: We examined a cohort (0-21 yrs.) who have undergone esophagogastroduodenoscopy and received disaccharidase activity assay from duodenal biopsy in the time period 2010 to 2012. Disaccharidase assays tested for activity of lactase, sucrase, maltase, and palatinase. GI symptoms were grouped into four categories, abdominal pain, diarrhea, weight loss, and gastroesophageal reflux.
RESULTS: Of the 347 subjects, we found an association between low lactase activity and abdominal pain (OR = 1.78; 95% CI = 1.07-2.97; p < 0.05). Subjects with a lactase/sucrase ratio < 0.2 were found to be associated with abdominal pain (OR = 2.25; 95% CI = 1.25-4.04; p < 0.05), Subjects with low pandisaccharidase may be correlated with abdominal pain and have a unique frequency of GI symptoms due to low frequency of diarrhea and weight loss, but they were not statistically significant.
CONCLUSIONS: Low activities of certain disaccharidase combinations may be associated with GI symptoms in subjects; a prospective study may be needed to investigate further.

doi: https://doi.org/10.1186/s12876-020-01443-4


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Recent Articles on Pancreatobiliary #Pathology – 2020-10-11

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  • O-positive blood type is associated with prolonged recurrence-free survival following curative resection of pancreatic neuroendocrine tumors

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33032924

BACKGROUND: The ABO blood group may influence the development and progression of cancer. In particular, the prognosis of patients with blood type O is better for pancreatic adenocarcinoma, although this has not been extensively explored in pancreatic neuroendocrine tumors (PanNET).
OBJECTIVE: To assess the influence of the ABO and Rhesus blood types on the risk of recurrence in patients who underwent curative intent PanNET surgical resection.
METHODS: All consecutive patients operated on for well-differentiated panNET in an expert center from 2003 to 2018 were retrospectively included. Blood group, Rhesus system, demographic and clinical data were collected. The primary endpoint was recurrence free survival (RFS). Factors associated with RFS were explored using Cox proportional hazard models.
RESULTS: Overall, 300 patients (male 43%) were included, median age 54 years old (IQR 45-64). The ABO blood group distribution was similar to that of the French population. There was no association between blood group and tumor features. The median postoperative follow-up was 43.9 months (17.0-77.8). The 5- and 10-year RFS rates were 85 ± 4% and 71 ± 13% in O RhD + patients, versus 72 ± 4% and 63 ± 6% otherwise, respectively (p = 0.035). The O RhD + blood group was associated with a decreased risk of recurrence (HR 0.34, 95% CI [0.15-0.75]), p = 0.007 in multivariable analysis adjusted for age, ki67, functioning syndrome, resection margins, tumor size, lymph node status, oncogenetic syndrome.
CONCLUSIONS: After curative-intent surgical resection for PanNET, patients with a non-O RhD + blood group may have an increased risk of recurrence and could benefit from closer follow-up.

doi: https://doi.org/10.1016/j.pan.2020.09.014


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Recent Articles on Pancreatobiliary #Pathology – 2020-10-10

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  • 2-year remission of type 2 diabetes and pancreas morphology: a post-hoc analysis of the DiRECT open-label, cluster-randomised trial

The lancet. Diabetes & endocrinology 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33031736

BACKGROUND: The pancreas is small and irregular in shape in people with type 2 diabetes. If these abnormalities are caused by the disease state itself rather than being a predisposing factor, remission of type 2 diabetes should restore normal pancreas morphology. The objective of this study was to determine whether changes in pancreas volume and shape occurred during 2 years of remission.
METHODS: For this post-hoc analysis, we included a subset of adult participants of the Diabetes Remission Clinical Trial (DiRECT), who had type 2 diabetes and were randomly assigned to a weight management intervention or routine diabetes management. Intervention group participants were categorised as responders (HbA1c <6·5% [48 mmol/mol] and fasting blood glucose <7·0 mmol/L, off all anti-diabetes medication) and non-responders, who were classified as remaining diabetic. Data on pancreas volume and irregularity of pancreas border at baseline, 5 months, 12 months, and 24 months after intervention were compared between responders and non-responders; additional comparisons were made between control group participants with type 2 diabetes and a non-diabetic comparator (NDC) group, who were matched to the intervention group by age, sex, and post-weight-loss weight, to determine the extent of any normalisation. We used a mixed-effects regression model based on repeated measures ANOVA with correction for potential confounding. Magnetic resonance techniques were employed to quantify pancreas volume, the irregularity of the pancreas borders, and intrapancreatic fat content. β-cell function and biomarkers of tissue growth were also measured.
FINDINGS: Between July 25, 2015, and Aug 5, 2016, 90 participants with type 2 diabetes in the DiRECT subset were randomly assigned to intervention (n=64) or control (n=26) and were assessed at baseline; a further 25 non-diabetic participants were enrolled into the NDC group. At baseline, mean pancreas volume was 61·7 cm3 (SD 16·0) in all participants with type 2 diabetes and 79·8 cm3 (14·3) in the NDC group (p<0·0001). At 24 months, pancreas volume had increased by 9·4 cm3 (95% CI 6·1 to 12·8) in responders compared with 6·4 cm3 (2·5 to 10·3) in non-responders (p=0·0008). Pancreas borders at baseline were more irregular in participants with type 2 diabetes than in the NDC group (fractal dimension 1·138 [SD 0·027] vs 1·097 [0·025]; p<0·0001) and had normalised by 24 months in responders only (1·099 [0·028]). Intrapancreatic fat declined by 1·02 percentage points (95% CI 0·53 to 1·51) in 32 responders and 0·51% (-0·17 to 1·19) in 13 non-responders (p=0·23).
INTERPRETATION: These data show for the first time, to our knowledge, reversibility of the abnormal pancreas morphology of type 2 diabetes by weight loss-induced remission.
FUNDING: Diabetes UK.

doi: https://doi.org/10.1016/S2213-8587(20)30303-X



  • Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions

Gut 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33028669

OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression.
DESIGN: We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples.
RESULTS: Our multiregion whole exome sequencing identified KLF4, a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs.
CONCLUSION: Hotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.

doi: https://doi.org/10.1136/gutjnl-2020-321217



  • Utilisation of artificial intelligence for the development of an EUS-convolutional neural network model trained to enhance the diagnosis of autoimmune pancreatitis

Gut 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33028668

OBJECTIVE: The diagnosis of autoimmune pancreatitis (AIP) is challenging. Sonographic and cross-sectional imaging findings of AIP closely mimic pancreatic ductal adenocarcinoma (PDAC) and techniques for tissue sampling of AIP are suboptimal. These limitations often result in delayed or failed diagnosis, which negatively impact patient management and outcomes. This study aimed to create an endoscopic ultrasound (EUS)-based convolutional neural network (CNN) model trained to differentiate AIP from PDAC, chronic pancreatitis (CP) and normal pancreas (NP), with sufficient performance to analyse EUS video in real time.
DESIGN: A database of still image and video data obtained from EUS examinations of cases of AIP, PDAC, CP and NP was used to develop a CNN. Occlusion heatmap analysis was used to identify sonographic features the CNN valued when differentiating AIP from PDAC.
RESULTS: From 583 patients (146 AIP, 292 PDAC, 72 CP and 73 NP), a total of 1 174 461 unique EUS images were extracted. For video data, the CNN processed 955 EUS frames per second and was: 99% sensitive, 98% specific for distinguishing AIP from NP; 94% sensitive, 71% specific for distinguishing AIP from CP; 90% sensitive, 93% specific for distinguishing AIP from PDAC; and 90% sensitive, 85% specific for distinguishing AIP from all studied conditions (ie, PDAC, CP and NP).
CONCLUSION: The developed EUS-CNN model accurately differentiated AIP from PDAC and benign pancreatic conditions, thereby offering the capability of earlier and more accurate diagnosis. Use of this model offers the potential for more timely and appropriate patient care and improved outcome.

doi: https://doi.org/10.1136/gutjnl-2020-322821



  • Effect of germline mutations in homologous recombination repair genes on overall survival of patients with pancreatic adenocarcinoma

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33028596

PURPOSE: To compare the clinical characteristics and overall survival (OS) of germline mutation carriers in homologous recombination repair (HRR) genes and non-carriers with pancreatic ductal adenocarcinoma (PDAC).
METHODS: Germline DNA from 3,078 patients with PDAC enrolled in a prospective registry at Mayo Clinic between 2000 and 2017 was analyzed for mutations in 37 cancer predisposition genes. Characteristics and OS of patients with mutations in 8 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, and RAD51D) involved in HRR were compared to patients testing negative for mutations in all 37 genes.
RESULTS: The 175 HRR mutation carriers and 2,730 non-carriers in the study had a median duration of follow-up of 9.9 years. HRR mutation carriers were younger (Median age at diagnosis: 63 vs. 66 years, p<0.001) and more likely to have metastatic disease at diagnosis (46% vs. 36%, p=0.004). In a multivariable model adjusting for sex, age at diagnosis, and tumor staging, patients with germline HRR mutations had a significantly longer OS compared to non-carriers (HR: 0.83, 95% CI: 0.70 to 0.97, p= 0.02). Further gene-level analysis demonstrated that germline ATM mutation carriers had longer OS compared to patients without germline mutations in any of the 37 HRR genes (HR: 0.72, 95% CI: 0.55 – 0.94, p=0.01).
CONCLUSIONS: This study demonstrates that germline mutation carrier status in PDAC is associated with longer OS compared to non-carriers. Further research into tumor biology and response to platinum-based chemotherapy in germline mutation carriers with PDAC are needed to better understand the association with longer OS.

doi: https://doi.org/10.1158/1078-0432.CCR-20-1788


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  • A unique type of fully covered metal stent for the management of post liver transplant biliary anastomotic strictures

BMC gastroenterology 2020 Oct;20(1):329

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33028218

BACKGROUND: We report our experience of treating anastomotic strictures using a novel type of fully covered metal stent (FCSEMS). This stent, known as the Kaffes Stent, is short-length with an antimigration waist and is easily removable due to long retrieval wires deployed within the duodenum.
METHODS: Sixty-two patients underwent ERCP and Kaffes stent insertion for post-transplant anastomotic strictures following confirmation of a stricture on MRCP. These patients were retrospectively analysed for immediate and long-term stricture resolution, improvement in symptoms and liver function tests (LFTs), stricture recurrence and complication rates.
RESULTS: Of the 56 patients who had their stent removed at the time of analysis, 54 (96%) had immediate stricture resolution and 42 continued to have long-term resolution (mean follow-up period was 548 days). Of the 16 patients with symptoms of biliary obstruction, 13 had resolution of their symptoms. Overall, there was a significant improvement in LFTs after stent removal compared to before stent insertion. Complication rates were 15% with only one patient requiring biliary reconstruction.
CONCLUSIONS: The Kaffes stent is effective and safe at resolving post liver transplant biliary anastomotic strictures.

doi: https://doi.org/10.1186/s12876-020-01479-6


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Recent Articles on Pancreatobiliary #Pathology – 2020-10-09

These are the recent articles on Pancreatobiliary Pathology:

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New Pancreas Articles


  • Comparison of prognostic impact of anatomic location of the pancreas on postoperative pancreatic fistula in laparoscopic and open gastrectomy

BMC gastroenterology 2020 Oct;20(1):325

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33023478

BACKGROUND: Postoperative pancreatic fistula (POPF) is a serious complication after gastric cancer surgery. The current study aimed to investigate the significance of the anatomic location of the pancreas as a predictor for POPF in both laparoscopic gastrectomy (LG) and open gastrectomy (OG).
METHODS: In total, 233 patients with gastric cancer were assessed retrospectively. We measured the maximum vertical (P-L height; PLH) and horizontal length (P-L depth; PLD) between the upper border of pancreas and the root of left gastric artery on a preoperative CT in the sagittal direction. The maximum length of the vertical line between the surface of the pancreas and the aorta (P-A length), previously reported as prognostic factor of POPF, was also measured. We investigated the correlations between these parameters and the incidence of POPF in LG and OG groups.
RESULTS: Among the patients in this study, 118 underwent OG and 115 underwent LG. In LG, the median PLH and P-A length in patients with POPF were significantly longer compared with those without POPF (p = 0.026, 0.034, respectively), but not in OG. There was no significant difference in the median PLD between the patients with or without POPF in both LG and OG. The multivariate analysis demonstrated that PLH (odds ratio [OR] 4.19, 95% confidence interval [CI] 1.57-11.3, P = 0.004) and P-A length (OR 4.06, 95%CI 1.05-15.7, P = 0.042] were independent factors for predicting POPF in LG. However, intraoperative blood loss (OR 2.55, 95%CI 1.05-6.18, P = 0.038) was extracted as an independent factor in OG. The median amylase level in the drained fluid (D-Amy) were significantly higher in patients with high PLH(≥12.4 mm) or high P-A length (≥45 mm) compared with those with low PLH or low P-A length in LG. However, there were no differences in the D-Amy levels by PLH or P-A length in OG patients.
CONCLUSIONS: The anatomic location of the pancreas is a specific and independent predictor of POPF in LG but not in OG. PLH is a simple parameter that can evaluate the anatomic position of the pancreas, and it may be useful for preventing POPF after LG.

doi: https://doi.org/10.1186/s12876-020-01476-9


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Recent Articles on Pancreatobiliary #Pathology – 2020-10-08

These are the recent articles on Pancreatobiliary Pathology:

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  • Identification of new enterosynes using prebiotics: roles of bioactive lipids and mu-opioid receptor signalling in humans and mice

Gut 2020 Oct;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33020209

OBJECTIVE: The enteric nervous system (ENS) plays a key role in controlling the gut-brain axis under normal and pathological conditions, such as type 2 diabetes. The discovery of intestinal actors, such as enterosynes, able to modulate the ENS-induced duodenal contraction is considered an innovative approach. Among all the intestinal factors, the understanding of the role of gut microbes in controlling glycaemia is still developed. We studied whether the modulation of gut microbiota by prebiotics could permit the identification of novel enterosynes.
DESIGN: We measured the effects of prebiotics on the production of bioactive lipids in the intestine and tested the identified lipid on ENS-induced contraction and glucose metabolism. Then, we studied the signalling pathways involved and compared the results obtained in mice to human.
RESULTS: We found that modulating the gut microbiota with prebiotics modifies the actions of enteric neurons, thereby controlling duodenal contraction and subsequently attenuating hyperglycaemia in diabetic mice. We discovered that the signalling pathway involved in these effects depends on the synthesis of a bioactive lipid 12-hydroxyeicosatetraenoic acid (12-HETE) and the presence of mu-opioid receptors (MOR) on enteric neurons. Using pharmacological approaches, we demonstrated the key role of the MOR receptors and proliferator-activated receptor γ for the effects of 12-HETE. These findings are supported by human data showing a decreased expression of the proenkephalin and MOR messanger RNAs in the duodenum of patients with diabetic.
CONCLUSIONS: Using a prebiotic approach, we identified enkephalin and 12-HETE as new enterosynes with potential real beneficial and safety impact in diabetic human.

doi: https://doi.org/10.1136/gutjnl-2019-320230


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Recent Articles on Pancreatobiliary #Pathology – 2020-10-07

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  • TRPS1: a highly sensitive and specific marker for breast carcinoma, especially for triple-negative breast cancer

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33011748

Currently there is no highly specific and sensitive marker to identify breast cancer-the most common malignancy in women. Breast cancer can be categorized as estrogen receptor (ER)/progesterone receptor (PR)-positive luminal, human epidermal growth factor receptor 2 (HER2)-positive, or triple-negative breast cancer (TNBC) types based on the expression of ER, PR, and HER2. Although GATA3 is the most widely used tumor marker at present to determine the breast origin, which has been shown to be an excellent marker for ER-positive and low-grade breast cancer, but it does not work well for TNBC with sensitivity as low as <20% in metaplastic breast carcinoma. In the current study, through TCGA data mining we identified trichorhinophalangeal syndrome type 1 (TRPS1) as a specific gene for breast carcinoma across 31 solid tumor types. Moreover, high mRNA level of TRPS1 was found in all four subtypes of breast carcinoma including ER/PR-positive luminal A and B types, HER2-positive type, and basal-type/TNBC. We then analyzed TRPS1 expression in 479 cases of various types of breast cancer using immunochemistry staining, and found that TRPS1 and GATA3 had comparable positive expression in ER-positive (98% vs. 95%) and HER2-positive (87% vs. 88%) breast carcinomas. However, TRPS1 which was highly expressed in TNBC, was significantly higher than GATA3 expression in metaplastic (86% vs. 21%) and nonmetaplastic (86% vs. 51%) TNBC. In addition, TRPS1 expression was evaluated in 1234 cases of solid tumor from different organs. In contrast to the high expression of GATA3 in urothelial carcinoma, TRPS1 showed no or little expression in urothelial carcinomas or in other tumor types including lung adenocarcinoma, pancreatic adenocarcinoma, colon and gastric adenocarcinoma, renal cell carcinoma, melanoma, and ovarian carcinoma. These findings suggest that TRPS1 is a highly sensitive and specific marker for breast carcinoma and can be used as a great diagnostic tool, especially for TNBC.

doi: https://doi.org/10.1038/s41379-020-00692-8


New GallBladder Articles


  • Pitfalls in Morphologic Diagnosis of Pathogens: Lessons Learned From the Pseudo-Cystoisospora Epidemic

International journal of surgical pathology 2020 Oct;():1066896920960813

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33016162

Multiple groups have recently reported involvement of the gallbladder mucosa of immunocompetent patients by cystoisospora organisms. However, this has recently been disproved with the support of molecular and ultrastructural studies. Here we present a summary of these events, recounting how this pseudo-Cystoisospora epidemic began and ended. This review also highlights the important role played by ancillary techniques in supplementing the morphologic diagnosis of pathogens.

doi: https://doi.org/10.1177/1066896920960813


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Recent Articles on Pancreatobiliary #Pathology – 2020-10-04

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New Pancreas Articles


  • Kras mutation rate precisely orchestrates ductal derived pancreatic intraepithelial neoplasia and pancreatic cancer

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33009500

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Despite the high prevalence of Kras mutations in pancreatic cancer patients, murine models expressing the oncogenic mutant Kras (Krasmut) in mature pancreatic cells develop PDAC at a low frequency. Independent of cell of origin, a second genetic hit (loss of tumor suppressor TP53 or PTEN) is important for development of PDAC in mice. We hypothesized ectopic expression and elevated levels of oncogenic mutant Kras would promote PanIN arising in pancreatic ducts. To test our hypothesis, the significance of elevating levels of K-Ras and Ras activity has been explored by expression of a CAG driven LGSL-KrasG12V allele (cKras) in pancreatic ducts, which promotes ectopic Kras expression. We predicted expression of cKras in pancreatic ducts would generate neoplasia and PDAC. To test our hypothesis, we employed tamoxifen dependent CreERT2 mediated recombination. Hnf1b:CreERT2;KrasG12V (cKrasHnf1b/+) mice received 1 (Low), 5 (Mod) or 10 (High) mg per 20 g body weight to recombine cKras in low (cKrasLow), moderate (cKrasMod), and high (cKrasHigh) percentages of pancreatic ducts. Our histologic analysis revealed poorly differentiated aggressive tumors in cKrasHigh mice. cKrasMod mice had grades of Pancreatic Intraepithelial Neoplasia (PanIN), recapitulating early and advanced PanIN observed in human PDAC. Proteomics analysis revealed significant differences in PTEN/AKT and MAPK pathways between wild type, cKrasLow, cKrasMod, and cKrasHigh mice. In conclusion, in this study, we provide evidence that ectopic expression of oncogenic mutant K-Ras in pancreatic ducts generates early and late PanIN as well as PDAC. This Ras rheostat model provides evidence that AKT signaling is an important early driver of invasive ductal derived PDAC.

doi: https://doi.org/10.1038/s41374-020-00490-5



  • Changing trends in the clinicopathological features, practices and outcomes in the surgical management for cystic lesions of the pancreas and impact of the international guidelines: Single institution experience with 462 cases between 1995-2018

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33008749

INTRODUCTION: The impact on clinical practice of the international guidelines including the Sendai Guidelines (SG06) and Fukuoka Guidelines (FG12) on the management of cystic lesions of the pancreas (CLP) has not been well-studied. The primary aim was to examine the changing trends and outcomes in the surgical management of CLP in our institution over time and to determine the impact of these guidelines on our institution practice.
METHODS: 462 patients with surgically-treated CLP were retrospectively reviewed and classified under the 2 guidelines. The cohort was divided into 3 time periods: 1998-2006, 2007-2012 and 2013 to 2018.
RESULTS: Comparison across the 3 time periods demonstrated significantly increasing frequency of older patients, asymptomatic CLP, male gender, smaller tumor size, elevated Ca 19-9, use of magnetic resonance imaging (MRI) and use of endoscopic ultrasound (EUS) prior to surgery. There was also significantly increasing frequency of adherence to the international guidelines as evidenced by the increasing proportion of HRSG06 and HRFG12 CLP with a corresponding lower proportion of LRSG06 and LRFG12 being resected. This resulted in a significantly higher proportion of resected CLP whereby the final pathology confirmed that a surgery was actually indicated.
CONCLUSIONS: Over time, there was increasing adherence to the international guidelines for the selection of patients for surgical resection as evidenced by the significantly increasing proportion of HRSG06 and HRFG06 CLPs undergoing surgery. This was associated with a significantly higher proportion of patients with a definitive indication for surgery. These suggested that over time, there was a continuous improvement in our selection of appropriate CLP for surgical treatment.

doi: https://doi.org/10.1016/j.pan.2020.09.019



  • Integrated analysis identifies a pathway-related competing endogenous RNA network in the progression of pancreatic cancer

BMC cancer 2020 Oct;20(1):958

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33008376

BACKGROUND: It is well acknowledged that cancer-related pathways play pivotal roles in the progression of pancreatic cancer (PC). Employing Integrated analysis, we aim to identify the pathway-related ceRNA network associated with PC progression.
METHODS: We divided eight GEO datasets into three groups according to their platform, and combined TCGA and GTEx databases as a group. Additionally, we screened out the differentially expressed genes (DEGs) and performed functional enrichment analysis in each group, and recognized the top hub genes in the most enriched pathway. Furthermore, the upstream of miRNAs and lncRNAs were predicted and validated according to their expression and prognostic roles. Finally, the co-expression analysis was applied to identify a pathway-related ceRNA network in the progression of PC.
RESULTS: A total of 51 significant pathways that common enriched in all groups were spotted. Enrichment analysis indicated that pathway in cancer was greatly linked with tumor formation and progression. Next, the top 20 hug genes in this pathway were recognized, and stepwise prediction and validation from mRNA to lncRNA, including 11 hub genes, 4 key miRNAs, and 2 key lncRNAs, were applied to identify a meaningful ceRNA network according to ceRNA rules. Ultimately, we identified the PVT1/miR-20b/CCND1 axis as a promising pathway-related ceRNA axis in the progression of PC.
CONCLUSION: Overall, we elucidate the pathway-related ceRNA regulatory network of PVT1/miR-20b/CCND1 in the progression of PC, which can be considered as therapeutic targets and encouraging prognostic biomarkers for PC.

doi: https://doi.org/10.1186/s12885-020-07470-4



  • Clinical characteristics and blood/serum bound prognostic biomarkers in advanced pancreatic cancer treated with gemcitabine and nab-paclitaxel

BMC cancer 2020 Oct;20(1):950

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33008332

BACKGROUND: In recent years treatment options for advanced pancreatic cancer have markedly improved, and a combination regimen of gemcitabine and nab-paclitaxel is now considered standard of care in Sweden and elsewhere. Nevertheless, a majority of patients do not respond to treatment. In order to guide the individual patient to the most beneficial therapeutic strategy, simple and easily available prognostic and predictive markers are needed.
METHODS: The potential prognostic value of a range of blood/serum parameters, patient-, and tumour characteristics was explored in a retrospective cohort of 75 patients treated with gemcitabine/nab-paclitaxel (Gem/NabP) for advanced pancreatic ductal adenocarcinoma (PDAC) in the South Eastern Region of Sweden. Primary outcome was overall survival (OS) while progression free survival (PFS) was the key secondary outcome.
RESULT: Univariable Cox regression analysis revealed that high baseline serum albumin (> 37 g/L) and older age (> 65) were positive prognostic markers for OS, and in multivariable regression analysis both parameters were confirmed to be independent prognostic variables (HR 0.48, p = 0.023 and HR = 0.47, p = 0.039,). Thrombocytopenia at any time during the treatment was an independent predictor for improved progression free survival (PFS) but not for OS (HR 0.49, p = 0.029, 0.54, p = 0.073), whereas thrombocytopenia developed under cycle 1 was neither related with OS nor PFS (HR 0.87, p = 0.384, HR 1.04, p = 0.771). Other parameters assessed (gender, tumour stage, ECOG performance status, myelosuppression, baseline serum CA19-9, and baseline serum bilirubin levels) were not significantly associated with survival.
CONCLUSION: Serum albumin at baseline is a prognostic factor with palliative Gem/NabP in advanced PDAC, and should be further assessed as a tool for risk stratification. Older age was associated with improved survival, which encourages further studies on the use of Gem/NabP in the elderly.

doi: https://doi.org/10.1186/s12885-020-07426-8



  • Peptide receptor radionuclide therapy controls inappropriate calcitriol secretion in a pancreatic neuro-endocrine tumor: a case report

BMC gastroenterology 2020 Oct;20(1):324

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33008295

BACKGROUND: Hypercalcemia of malignancy is not uncommon in patients with advanced stage cancer. In rare cases the cause of the hypercalcemia is excessive production of calcitriol, the active form of vitamin D. Although inappropriate tumoral secretion of calcitriol is typically associated with lymphomas and some ovarian germ cell tumors, we present a case of calcitriol overproduction-induced hypercalcemia due to a pancreatic neuroendocrine tumor. The high expression of somatostatin receptors on this neuroendocrine neoplasm opened up the opportunity to treat the patient with radiolabelled somatostatin analogs, which successfully controlled the refractory hypercalcaemia and calcitriol levels. This case documents a rare finding of refractory hypercalcaemia of underlying malignancy due to a calcitriol-producing pancreatic neuroendocrine tumor, responding to peptide receptor radionuclide therapy (PRRT).
CASE PRESENTATION: A 57 years-old patient presented with back pain, general discomfort, polydipsia, polyuria, fatigue and recent weight loss of 10 kg. Clinical examination was normal and there was no relevant medical history. Biochemical evaluation showed hypercalcemia with markedly increased calcitriol levels. CT-thorax-abdomen and ultrasound guided biopsy revealed a pancreatic neuroendocrine tumor with multifocal liver metastases, suggesting that excessive overproduction of calcitriol by this neuroendocrine tumor was the cause of the refractory hypercalcemia. The patient was eligible for PRRT. Four cycles of 177Lu-DOTATATE PRRT resulted in a morphological response and a normalization of serum calcium levels, confirming the hypothesis of a calcitriol producing pancreatic neuroendocrine tumor. Progression of liver metastases warranted further therapy and temozolomide-capecitabine was started with morphological and biochemical (serum calcium, calcitriol) stabilization.
CONCLUSION: Although up to 30-40% of gastroenteropancreatic neuroendocrine tumors are known to be functional (i.e. producing symptoms associated with the predominant hormone/peptide secreted), calcitriol secreting pancreatic neuroendocrine tumors are very rare. However, treatment with PRRT resulted in normalization of calcium and calcitriol levels, strongly supporting the hypothesis of a calcitriol-producing pancreatic neuroendocrine tumor.

doi: https://doi.org/10.1186/s12876-020-01470-1



  • Mesenchymal plasticity regulated by Prrx1 drives aggressive pancreatic cancer biology

Gastroenterology 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33007300

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibroblast-rich desmoplastic stroma. Cancer-associated fibroblasts (CAFs) have been shown to display a high degree of interconvertible states including quiescent, inflammatory and myofibroblastic phenotypes, however, the mechanisms by which this plasticity is achieved are poorly understood. Here, we aim to elucidate the role of CAF plasticity and its impact on PDAC biology.
METHODS: To investigate the role of mesenchymal plasticity in PDAC progression, we generated a PDAC mouse model in which CAF plasticity is modulated by genetical depletion of the transcription factor Prrx1. Primary pancreatic fibroblasts from this mouse model were further characterized by functional in vitro assays. To characterize the impact of CAFs on tumor differentiation and response to chemotherapy various co-culture experiments were performed. In vivo, tumors were characterized by morphology, extracellular matrix composition as well as tumor dissemination and metastasis.
RESULTS: Our in vivo findings demonstrated that Prrx1-deficient CAFs remain constitutively activated. Importantly, this CAF phenotype determines tumor differentiation and disrupts systemic tumor dissemination. Mechanistically, co-culture experiments of tumor organoids and CAFs revealed that CAFs shape the epithelial-to-mesenchymal phenotype and confer gemcitabine resistance of PDAC cells induced by CAF-derived hepatocyte growth factor. Furthermore, gene expression analysis revealed that pancreatic cancer patients with high stromal expression of Prrx1 display the squamous, most aggressive, subtype of PDAC.
CONCLUSION: Here, we define that the Prrx1 transcription factor is critical for tuning CAF activation, allowing a dynamic switch between a dormant and an activated state. This work demonstrates that Prrx1-mediated CAF plasticity has significant impact on PDAC biology and therapeutic resistance.

doi: https://doi.org/10.1053/j.gastro.2020.09.010



  • Evidence of a common cell origin in a case of pancreatic mixed intraductal papillary mucinous neoplasm-neuroendocrine tumor

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33005981

Recently, the term mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) has been proposed as an umbrella definition covering different possible combinations of mixed neuroendocrine-exocrine neoplasms. Among these, the adenoma plus neuroendocrine tumor (NET) combination is among the rarest and not formally recognized by the 2019 WHO Classification. In this setting, the debate between either collision tumors or true mixed neoplasms is still unsolved. In this report, a pancreatic intraductal papillary mucinous neoplasm (IPMN) plus a NET is described, and the molecular investigations showed the presence in both populations of the same KRAS, GNAS, and CDKN2A mutations and the amplification of the CCND1 gene. These data prove clonality and support a common origin of both components, therefore confirming the true mixed nature. For this reason, mixed neuroendocrine-exocrine neoplasms, in which the exocrine component is represented by a glandular precursor lesion (adenoma/IPMN) only, should be included into the MiNEN family.

doi: https://doi.org/10.1007/s00428-020-02942-1



  • Carbon ion radiotherapy as definitive treatment in non-metastasized pancreatic cancer: study protocol of the prospective phase II PACK-study

BMC cancer 2020 Oct;20(1):947

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33004046

BACKGROUND: Radiotherapy is known to improve local tumor control in locally advanced pancreatic cancer (LAPC), although there is a lack of convincing data on a potential overall survival benefit of chemoradiotherapy over chemotherapy alone. To improve efficacy of radiotherapy, new approaches need to be evolved. Carbon ion radiotherapy is supposed to be more effective than photon radiotherapy due to a higher relative biological effectiveness (RBE) and due to a steep dose-gradient making dose delivery highly conformal.
METHODS: The present Phase II PACK-study investigates carbon ion radiotherapy as definitive treatment in LAPC as well as in locally recurrent pancreatic cancer. A total irradiation dose of 48 Gy (RBE) will be delivered in twelve fractions. Concurrent chemotherapy is accepted, if indicated. The primary endpoint is the overall survival rate after 12 months. Secondary endpoints are progression free survival, safety, quality of life and impact on tumor markers CA 19-9 and CEA. A total of twenty-five patients are planned for recruitment over 2 years.
DISCUSSION: Recently, Japanese researches could show promising results in a Phase I/II-study evaluating chemoradiotherapy of carbon ion radiotherapy and gemcitabine in LAPC. The present prospective PACK-study investigates the efficacy of carbon ion radiotherapy in pancreatic cancer at Heidelberg Ion Beam Therapy Center (HIT) in Germany.
TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov: NCT04194268 (Retrospectively registered on December, 11th 2019).

doi: https://doi.org/10.1186/s12885-020-07434-8



  • Clinical outcomes of chemotherapy in patients with undifferentiated carcinoma of the pancreas: a retrospective multicenter cohort study

BMC cancer 2020 Oct;20(1):946

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33004032

BACKGROUND: Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer. Although UC has been considered a highly aggressive malignancy, no clinical studies have addressed the efficacy of chemotherapy for unresectable UC. Therefore, we conducted multicenter retrospective study to investigate the efficacy of chemotherapy in patients with UC of the pancreas.
METHODS: This multicenter retrospective cohort study was conducted at 17 institutions in Japan between January 2007 and December 2017. A total of 50 patients treated with chemotherapy were analyzed.
RESULTS: The median overall survival (OS) in UC patients treated with chemotherapy was 4.08 months. The details of first-line chemotherapy were as follows: gemcitabine (n = 24), S-1 (n = 12), gemcitabine plus nab-paclitaxel (n = 6), and other treatment (n = 8). The median progression-free survival (PFS) was 1.61 months in the gemcitabine group, 2.96 months in the S-1 group, and 4.60 months in the gemcitabine plus nab-paclitaxel group. Gemcitabine plus nab-paclitaxel significantly improved PFS compared with gemcitabine (p = 0.014). The objective response rate (ORR) was 4.2% in the gemcitabine group, 0.0% in the S-1 group, and 33.3% in the gemcitabine plus nab-paclitaxel group. Gemcitabine plus nab-paclitaxel also showed a significantly higher ORR compared with both gemcitabine and S-1 (gemcitabine plus nab-paclitaxel vs. gemcitabine: p = 0.033; gemcitabine plus nab-paclitaxel vs. S-1: p = 0.034). A paclitaxel-containing first-line regimen significantly improved OS compared with a non-paclitaxel-containing regimen (6.94 months vs. 3.75 months, respectively; p = 0.041). After adjustment, use of a paclitaxel-containing regimen in any line was still an independent predictor of OS (hazard ratio for OS, 0.221; 95% confidence interval, 0.076-0.647; p = 0.006) in multiple imputation by chained equation.
CONCLUSIONS: The results of the present study indicate that a paclitaxel-containing regimen would offer relatively longer survival, and it is considered a reasonable option for treating patients with unresectable UC.

doi: https://doi.org/10.1186/s12885-020-07462-4



  • Efficacy of Early Percutaneous Catheter Drainage in Acute Pancreatitis of Varying Severity Associated With Sterile Acute Inflammatory Pancreatic Fluid Collection

Pancreas 2020 Oct;49(9):1246-1254

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33003087

OBJECTIVE: The aim of the study was to evaluate the efficacy of early percutaneous catheter drainage (PCD) for sterile acute inflammatory pancreatic fluid collection (AIPFC) in acute pancreatitis (AP) of varying severity.
METHODS: Retrospective analyses were performed based on the presence of sterile AIPFC and different AP severities according to 2012 Revised Atlanta Classification.
RESULTS: Early PCD contributed to obvious decreases in operation rate (OR, P = 0.006), infection rate (IR, P = 0.020), and mortality (P = 0.009) in severe AP (SAP). In moderate SAP with sterile AIPFCs, however, early PCD was associated with increased OR (P = 0.009) and IR (P = 0.040). Subgroup analysis revealed that early PCD led to remarkable decreases in OR for patients with persistent organ failure (OF) within 3 days (P = 0.024 for single OF, P = 0.039 for multiple OF) and in mortality for patients with multiple OF (P = 0.041 for OF within 3 days and P = 0.055 for 3-14 days). Moreover, lower mortality was found in SAP patients with early PCD-induced infections than with spontaneous infections (P = 0.027).
CONCLUSIONS: Early PCD may improve the prognosis of SAP with drainable sterile AIPFCs by reducing the OR, IR, and mortality.

doi: https://doi.org/10.1097/MPA.0000000000001666



  • Pancreatic Angiopathy Associated With Islet Amyloid and Type 2 Diabetes Mellitus

Pancreas 2020 Oct;49(9):1232-1239

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33003086

OBJECTIVES: Type 2 diabetes (T2D) is histopathologically characterized by islet amyloid and is closely connected with vascular complications. Here, we explore the presence of pancreatic angiopathy (PA) associated with islet amyloid and T2D.
METHODS: From a total of 172 autopsy cases who had a history of T2D diagnosis, we randomly selected 30 T2D autopsy cases with islet amyloid (DA+) in comparison with islet amyloid-free (DA-) 30 T2D cases and 60 nondiabetic (ND) controls. Amyloid deposits and PA including atherosclerosis of pancreatic interlobar arteries, arterial calcification, atheroembolism, hyaline arteriosclerosis of small arterioles, and islet capillary density were detected in all groups.
RESULTS: Pancreatic angiopathy was found in 91.7% of patients with T2D and in 68.3% of ND controls (P < 0.01). Furthermore, 100% of DA+ patients and 83.3% of DA- subjects showed PA. The intraislet capillary density was significantly lower in DA+ subjects than DA- subjects (mean [standard deviation], DA+: 205 [82] count/mm; DA-: 344 [76] count/mm; ND: 291 [94] count/mm; P < 0.01). Finally, interlobar arteriosclerosis (R = 0.603, P < 0.01) was linearly correlated with the severity of islet amyloid deposits.
CONCLUSIONS: Pancreatic angiopathy might be both a cause and a consequence of islet amyloid and T2D.

doi: https://doi.org/10.1097/MPA.0000000000001664



  • Reviews on Current Liquid Biopsy for Detection and Management of Pancreatic Cancers

Pancreas 2020 Oct;49(9):1141-1152

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33003085

Pancreatic cancer is the fourth leading cause of cancer death in the United States. Pancreatic cancer presents dismal clinical outcomes in patients, and the incidence of pancreatic cancer has continuously increased to likely become the second most common cause of cancer-related deaths by as early as 2030. One of main reasons for the high mortality rate of pancreatic cancer is the lack of tools for early-stage detection. Current practice in detecting and monitoring therapeutic response in pancreatic cancer relies on imaging analysis and invasive endoscopic examination. Liquid biopsy-based analysis of genetic alterations in biofluids has become a fundamental component in the diagnosis and management of cancers. There is an urgent need for scientific and technological advancement to detect pancreatic cancer early and to develop effective therapies. The development of a highly sensitive and specific liquid biopsy tool will require extensive understanding on the characteristics of circulating tumor DNA in biofluids. Here, we have reviewed the current status of liquid biopsy in detecting and monitoring pancreatic cancers and our understanding of circulating tumor DNA that should be considered for the development of a liquid biopsy tool, which will greatly aid in the diagnosis and healthcare of people at risk.

doi: https://doi.org/10.1097/MPA.0000000000001662



  • Total Neoadjuvant Therapy for Operable Pancreatic Cancer

Annals of surgical oncology 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33000372

BACKGROUND: Overall survival (OS) for operable pancreatic cancer (PC) is optimized when 4-6 months of nonsurgical therapy is combined with pancreatectomy. Because surgery renders the delivery of postoperative therapy uncertain, total neoadjuvant therapy (TNT) is gaining popularity.
METHODS: We performed a retrospective cohort study of patients with operable PC and compared TNT with shorter course neoadjuvant therapy (SNT). Primary outcomes of interest included completion of neoadjuvant therapy (NT) and resection of the primary tumor, receipt of 5 months of nonsurgical therapy, and median OS.
RESULTS: We reviewed 541 consecutive patients from 2009 to 2019 including 226 (42%) with resectable PC and 315 (58%) with borderline resectable (BLR) PC. The median age was 66 years (IQR [59, 72]), and 260 (48%) patients were female. TNT was administered to 89 (16%) patients and SNT was administered to 452 (84%). Both groups were equally likely to complete intended NT and surgery (p = 0.90). Patients who received TNT and surgical resection were more likely to have a complete pathologic response (8% vs 4%, p < 0.01) and were more likely to receive at least 5 months of nonsurgical therapy (67% vs 45%, p < 0.01). The median OS was 26 months [IQR (15, 57)]; not reached among patients treated with TNT, and 25 months [IQR (15, 56)] among patients treated with SNT (p = 0.19).
CONCLUSIONS: TNT ensures the delivery of intended systemic therapy prior to a complicated operation without decreasing the chance of successful surgery; a window of operability was not lost. Patients who can tolerate SNT will likely benefit from TNT.

doi: https://doi.org/10.1245/s10434-020-09149-3



  • Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth

BMC cancer 2020 Oct;20(1):941

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32998722

BACKGROUND: Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent. Specifically, SOX2 levels in tumor cells are optimized to promote tumor growth: knocking down or elevating SOX2 inhibits proliferation. Furthermore, recent studies have shown that quiescent tumor cells express higher levels of SOX2 compared to adjacent proliferating cells. Currently, the mechanisms through which elevated levels of SOX2 restrict tumor cell proliferation have not been characterized.
METHODS: To understand how elevated levels of SOX2 restrict the proliferation of tumor cells, we engineered diverse types of tumor cells for inducible overexpression of SOX2. Using these cells, we examined the effects of elevating SOX2 on their proliferation, both in vitro and in vivo. In addition, we examined how elevating SOX2 influences their expression of cyclins, cyclin-dependent kinases (CDKs), and p27Kip1.
RESULTS: Elevating SOX2 in diverse tumor cell types led to growth inhibition in vitro. Significantly, elevating SOX2 in vivo in pancreatic ductal adenocarcinoma, medulloblastoma, and prostate cancer cells induced a reversible state of tumor growth arrest. In all three tumor types, elevation of SOX2 in vivo quickly halted tumor growth. Remarkably, tumor growth resumed rapidly when SOX2 returned to endogenous levels. We also determined that elevation of SOX2 in six tumor cell lines decreased the levels of cyclins and CDKs that control each phase of the cell cycle, while upregulating p27Kip1.
CONCLUSIONS: Our findings indicate that elevating SOX2 above endogenous levels in a diverse set of tumor cell types leads to growth inhibition both in vitro and in vivo. Moreover, our findings indicate that SOX2 can function as a master regulator by controlling the expression of a broad spectrum of cell cycle machinery. Importantly, our SOX2-inducible tumor studies provide a novel model system for investigating the molecular mechanisms by which elevated levels of SOX2 restrict cell proliferation and tumor growth.

doi: https://doi.org/10.1186/s12885-020-07370-7


New GallBladder Articles

Today there is no new Gallbladder Article.

New BileDuct Articles


  • Peritumoral ductular reaction can be a prognostic factor for intrahepatic cholangiocarcinoma

BMC gastroenterology 2020 Oct;20(1):322

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33008300

BACKGROUND: Peritumoral ductular reaction (DR) was reported to be related to the prognosis of combined hepatocellular-cholangiocarcinoma and hepatocellular carcinoma. Non-mucin-producing intrahepatic cholangiocarcinoma (ICC) which may be derived from small bile duct cells or liver progenitor cells (LPCs) was known to us. However, whether peritumoral DR is also related to non-mucin-producing ICCs remains to be investigated.
METHODS: Forty-seven patients with non-mucin-producing ICC were eventually included in the study and clinicopathological variables were collected. Immunohistochemical analysis and immunofluorescence staining for cytokeratin 19, proliferating cell nuclear antigen, and α-smooth muscle actin were performed in tumor and peritumor liver tissues.
RESULTS: A significant correlation existed between peritumoral DR and local inflammation and fibrosis. (r = 0.357, 95% CI, 0.037-0.557; P = 0.008 and r = 0.742, 95% CI, 0.580-0.849; P < 0.001, respectively). Patients with obvious peritumoral DR had high recurrence rate (81.8% vs 56.0%, P = 0.058) and poor overall and disease-free survival time (P = 0.01 and P = 0.03, respectively) comparing with mild peritumoral DR. Compared with the mild peritumoral DR group, the proliferation activity of LPCs/ cholangiocytes was higher in obvious peritumoral DR, which, however, was not statistically significant. (0.43 ± 0.29 vs 0.28 ± 0.31, P = 0.172). Furthermore, the correlation analysis showed that the DR grade was positively related to the portal/septalα-SMA level (r = 0.359, P = 0.001).
CONCLUSIONS: Peritumoral DR was associated with local inflammation and fibrosis. Patients with non-mucin-producing ICC having obvious peritumoral DR had a poor prognosis. Peritumoral DR could be a prognostic factor for ICC. However, the mechanism should be further investigated.

doi: https://doi.org/10.1186/s12876-020-01471-0



  • Fishbone foreign body ingestion in duodenal papilla: a cause of abdominal pain resembling gastric ulcer

BMC gastroenterology 2020 Oct;20(1):323

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33008291

BACKGROUND: Foreign body ingestion is a common clinical problem. The upper esophagus is the most common site of foreign body, accounting for more than 75% of all cases, but cases with a foreign body in the duodenal papilla or common bile duct are rarely reported.
CASE PRESENTATION: Herein, we report a rare case that a patient's abdominal pain resembling gastric ulcer was caused by a 3 cm long fishbone inserted into the duodenal papilla.
CONCLUSION: Fishbone inserted into the duodenal papilla can cause an abdominal pain resembling gastric ulcer. Endoscopy is useful for the diagnosis and treatment of fishbone ingestion in clinical.

doi: https://doi.org/10.1186/s12876-020-01475-w


New Ampulla Articles


  • Combinatorial transcriptional profiling of mouse and human enteric neurons identifies shared and disparate subtypes in situ

Gastroenterology 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=33010250

BACKGROUND & AIMS: The enteric nervous system (ENS) coordinates essential intestinal functions through the concerted action of diverse enteric neurons (EN). However, integrated molecular knowledge of EN subtypes is lacking. To compare human and mouse ENs, we transcriptionally profiled healthy ENS from adult humans and mice. We aimed to identify transcripts marking discrete neuron subtypes and visualize conserved EN subtypes for humans and mice in multiple bowel regions.
METHODS: Human myenteric ganglia and adjacent smooth muscle were isolated by laser-capture microdissection for RNA-Seq. Ganglia-specific transcriptional profiles were identified by computationally subtracting muscle gene signatures. Nuclei from mouse myenteric neurons were isolated and subjected to single-nucleus RNA-Seq (snRNA-Seq), totaling over four billion reads and 25,208 neurons. Neuronal subtypes were defined using mouse snRNA-Seq data. Comparative informatics between human and mouse datasets identified shared EN subtype markers, which were visualized in situ using hybridization chain reaction (HCR).
RESULTS: Several EN subtypes in the duodenum, ileum, and colon are conserved between humans and mice based on orthologous gene expression. However, some EN subtype-specific genes from mice are expressed in completely distinct morphologically defined subtypes in humans. In mice, we identified several neuronal subtypes that stably express gene modules across all intestinal segments, with graded, regional expression of one or more marker genes.
CONCLUSIONS: Our combined transcriptional profiling of human myenteric ganglia and mouse EN provides a rich foundation for developing novel intestinal therapeutics. There is congruency among some EN subtypes, but we note multiple species differences that should be carefully considered when relating findings from mouse ENS research to human GI studies.

doi: https://doi.org/10.1053/j.gastro.2020.09.032


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