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


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