Recent Articles on Pancreatobiliary #Pathology – 2020-09-07

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


  • Defining Benchmark Outcomes for Pancreatoduodenectomy With Portomesenteric Venous Resection

Annals of surgery 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32889866

OBJECTIVE: The aim of this study was to establish clinically relevant outcome benchmark values using criteria for pancreatoduodenectomy (PD) with portomesenteric venous resection (PVR) from a low-risk cohort managed in high-volume centers.
SUMMARY BACKGROUND DATA: PD with PVR is regarded as the standard of care in patients with cancer involvement of the portomesenteric venous axis. There are, however, no benchmark outcome indicators for this population which hampers comparisons of patients undergoing PD with and without PVR resection.
METHODS: This multicenter study analyzed patients undergoing PD with any type of PVR in 23 high-volume centers from 2009 to 2018. Nineteen outcome benchmarks were established in low-risk patients, defined as the 75th percentile of the median outcome values of the centers (NCT04053998).
RESULTS: Out of 1462 patients with PD and PVR, 840 (58%) formed the benchmark cohort, with a mean age was 64 (SD11) years, 413 (49%) were females. Benchmark cutoffs, among others, were calculated as follows: Clinically relevant pancreatic fistula rate (International Study Group of Pancreatic Surgery): ≤14%; in-hospital mortality rate: ≤4%; major complication rate Grade≥3 and the CCI up to 6 months postoperatively: ≤36% and ≤26, respectively; portal vein thrombosis rate: ≤14% and 5-year survival for patients with pancreatic ductal adenocarcinoma: ≥9%.
CONCLUSION: These novel benchmark cutoffs targeting surgical performance, morbidity, mortality, and oncological parameters show relatively inferior results in patients undergoing vascular resection because of involvement of the portomesenteric venous axis. These benchmark values however can be used to conclusively assess the results of different centers or surgeons operating on this high-risk group.

doi: https://doi.org/10.1097/SLA.0000000000004267



  • Pancreatic perfusion imaging method that reduces radiation dose and maintains image quality by combining volumetric perfusion CT with multiphasic contrast enhanced-CT

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32888809

OBJECTIVES: The aim of this study is to propose and evaluate a new method of volumetric perfusion computed tomography (PCT) incorporated into pancreatic multiphasic contrast enhanced (CE)-CT in the clinical setting.
METHODS: In this ethically approved study, PCT was incorporated into our existing scanning protocol in 17 patients and effective doses related to PCT were evaluated. CT values and signal-to-noise ratio (SNR) of anatomical structure were compared in diagnostic images that were acquired using 320-detector volumetric scan mode and 64-detector helical scan mode. In addition, focal lesion depiction was qualitatively assessed in the two groups. Perfusion parameters in normal pancreas were measured by two radiologists and the interobserver-reliability was assessed.
RESULTS: The effective dose of PCT was 5.1 ± 0.3 mSv. The actual effective dose (AED) including the dose used in volumetric scans for diagnostic imaging was 22.8 ± 5.3 mSv and the putative effective dose (PED) was 21.9 ± 9.1 mSv on average. There was no significant difference between AED and PED (p = 0.404). Compared with conventional helical scans, volumetric scans did not decrease CT values or SNR, but rather significantly increased those of the aorta in the arterial phase. Both groups had acceptable qualitatively assessed image quality with no significant difference in the depiction of each structure. There was almost perfect interobserver agreement in the measurement of perfusion parameters (mean ICCs > 0.9).
CONCLUSIONS: Our scanning protocol for pancreatic perfusion CT provides high-quality images while requiring lower radiation doses than conventional methods.

doi: https://doi.org/10.1016/j.pan.2020.08.010



  • Molecular profiling of neuroendocrine tumours to predict response and toxicity to peptide receptor radionuclide therapy

The Lancet. Oncology 2020 Sep;21(9):e431-e443

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32888472

Peptide receptor radionuclide therapy (PRRT) is a type of radiotherapy that targets peptide receptors and is typically used for neuroendocrine tumours (NETs). Some of the key challenges in its use are the prediction of efficacy and toxicity, patient selection, and response optimisation. In this Review, we assess current knowledge on the molecular profile of NETs and the strategies and tools used to predict, monitor, and assess the toxicity of PRRT. The few mutations in tumour genes that can be evaluated (eg, ATM and DAXX) are limited to pancreatic NETs and are most likely not informative. Assays that are transcriptomic or based on genes are effective in the prediction of radiotherapy response in other cancers. A blood-based assay for eight genes (the PRRT prediction quotient [PPQ]) has an overall accuracy of 95% for predicting responses to PRRT in NETs. No molecular markers exist that can predict the toxicity of PRRT. Candidate molecular targets include seven single nucleotide polymorphisms (SNPs) that are susceptible to radiation. Transcriptomic evaluations of blood and a combination of gene expression and specific SNPs, assessed by machine learning with algorithms that are tumour-specific, might yield molecular tools to enhance the efficacy and safety of PRRT.

doi: https://doi.org/10.1016/S1470-2045(20)30323-5



  • Factors Influencing Exercise Following Pancreatic Tumor Resection

Annals of surgical oncology 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32886288

BACKGROUND: We previously demonstrated associations between exercise during pancreatic cancer treatment and quality of life and physical fitness prior to pancreatectomy. In this study, we quantified exercise among survivors following pancreatic tumor resection and characterized concordance with established guidelines.
METHODS: We quantified exercise frequency, duration, and intensity among survivors who underwent pancreatectomy for adenocarcinoma or a neuroendocrine tumor at our center from 2000 to 2017 and compared them with American College of Sports Medicine Guidelines for Cancer Survivors. Additional surveys measured motivation to exercise, barrier self-efficacy, quality of life, and fatigue. Multivariable models were constructed to evaluate associations between clinicodemographic and psychosocial variables and guideline concordance, and between guideline concordance and quality of life and fatigue.
RESULTS: Of 504 eligible survivors, 262 (52%) returned surveys. Only 62 participants (24%) reported meeting both aerobic and strengthening guidelines; 103 (39%) reported meeting neither. Adjusted analyses demonstrated that higher autonomous motivation was associated with higher aerobic and strengthening guideline concordance (both p < 0.01). Higher barrier self-efficacy and older age were associated with higher aerobic guideline concordance (p < 0.01). We identified no significant associations between guideline concordance and tumor type, time since surgery, or recent cancer therapy (all p > 0.05). We found favorable associations between aerobic guideline concordance and both quality of life and fatigue (both p < 0.001).
CONCLUSIONS: Less than one-quarter of participants exercised sufficiently to meet national exercise guidelines following pancreatectomy. To maximize exercise and related benefits, interventions should help survivors increase intrinsic motivation and overcome barriers to exercise.

doi: https://doi.org/10.1245/s10434-020-09062-9



  • Association of malnutrition with geriatric assessment impairments and health-related quality of life among older adults with gastrointestinal malignancies

Cancer 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32885848

BACKGROUND: A majority of older adults with cancer develop malnutrition; however, the implications of malnutrition among this vulnerable population are poorly understood. The goal of this study was to quantify the prevalence of nutrition related-symptoms and malnutrition among older adults with gastrointestinal (GI) malignancies and the association of malnutrition with geriatric assessment (GA) impairment, health-related quality of life (HRQoL), and health care utilization.
METHODS: We performed a cross-sectional study of older adults (≥60 years) who were referred to the GI Oncology clinic at the University of Alabama at Birmingham. Participants underwent the Cancer & Aging Resilience Evaluation survey that includes the abbreviated Patient-Generated Subjective Global Assessment of nutrition. Nutrition scores were dichotomized into normal (0-5) and malnourished (≥6), and multivariate analyses adjusted for demographics, cancer type, and cancer stage were used to examine associations with GA impairment, HRQoL, and health care utilization.
RESULTS: A total of 336 participants were included (men, 56.8%; women, 43.2%), with a mean age of 70 years (standard deviation, ±7.2 years) and colorectal cancer (33.6%) and pancreatic cancer (24.4%) being the most common diagnoses. Overall, 52.1% of participants were identified as malnourished. Malnutrition was associated with a higher prevalence of several GA impairments, including 1 or more falls (adjusted odds ratio [aOR], 2.1), instrumental activities of daily living impairment (aOR, 4.1), and frailty (aOR, 8.2). Malnutrition was also associated with impaired HRQoL domains; both physical (aOR, 8.7) and mental (aOR, 5.0), and prior hospitalizations (aOR, 2.2).
CONCLUSION: We found a high prevalence of malnutrition among older adults with GI malignancies that was associated with increased GA impairments, reduced HRQoL, and increased health care utilization.

doi: https://doi.org/10.1002/cncr.33122



  • Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours

Gut 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32883872

OBJECTIVE: A comprehensive analysis of the immune landscape of pancreatic neuroendocrine tumours (PanNETs) was performed according to clinicopathological parameters and previously defined molecular subtypes to identify potential therapeutic vulnerabilities in this disease.
DESIGN: Differential expression analysis of 600 immune-related genes was performed on 207 PanNET samples, comprising a training cohort (n=72) and two validation cohorts (n=135) from multiple transcriptome profiling platforms. Different immune-related and subtype-related phenotypes, cell types and pathways were investigated using different in silico methods and were further validated using spatial multiplex immunofluorescence.
RESULTS: The study identified an immune signature of 132 genes segregating PanNETs (n=207) according to four previously defined molecular subtypes: metastasis-like primary (MLP)-1 and MLP-2, insulinoma-like and intermediate. The MLP-1 subtype (26%-31% samples across three cohorts) was strongly associated with elevated levels of immune-related genes, poor prognosis and a cascade of tumour evolutionary events: larger hypoxic and necroptotic tumours leading to increased damage-associated molecular patterns (viral mimicry), stimulator of interferon gene pathway, T cell-inflamed genes, immune checkpoint targets, and T cell-mediated and M1 macrophage-mediated immune escape mechanisms. Multiplex spatial profiling validated significantly increased macrophages in the MLP-1 subtype.
CONCLUSION: This study provides novel data on the immune microenvironment of PanNETs and identifies MLP-1 subtype as an immune-high phenotype featuring a broad and robust activation of immune-related genes. This study, with further refinement, paves the way for future precision immunotherapy studies in PanNETs to potentially select a subset of MLP-1 patients who may be more likely to respond.

doi: https://doi.org/10.1136/gutjnl-2020-321016



  • Comprehensive genomic profiling of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs)

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32883742

PURPOSE: GEP-NENs are rare malignancies with increasing incidence. Their molecular characteristics are still undefined. We explored the underlying biology of GEP-NENs and the differences between gastrointestinal (GI) and pancreatic (PNET), high grade (HG) and low grade (LG) tumors.
EXPERIMENTAL DESIGN: GEP-NENs were analyzed using next-generation sequencing (NGS; MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry, and in-situ hybridization. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci.
RESULTS: In total, 724 GEP-NENs were examined: GI (N=469), PNEN (N=255), HG (N=135), and LG (N=335). Forty-nine% were female, median age was 59. Among LG tumors, the most frequently mutated genes were ATRX (13%), ARID1A (10%) and MEN1 (10%). HG tumors showed TP53 (51%), KRAS (30%), APC (27%), ARID1A (23%). Immune-related biomarkers yielded a lower prevalence in LG tumors compared to HG: MSI-H 0% vs 4% (P=.04), PD-L1 overexpression 1% vs 6% (P=.03) TMB-high 1% vs 7% (P=.05). Compared to LG, HG NETs showed a higher mutation rate in BRAF (5.4% v 0%, P<.0001), KRAS (29.4% v 2.6%, P<.0001) and PI3KCA (7% v 0.3%, P<.0001). When compared to GI, PNEN carried higher frequency of MEN1 (25.9% v 0.0%, P<.0001), FOXO3 (8.6% v 0.8%, P=.005), ATRX (20.6% v 2.0%, P=.007), and TSC2 (6.3% vs 0.0%, P=.007), but lower frequency of mutations in APC (1.0% v 13.8%, P<.0001).
CONCLUSIONS: Significant molecular differences were observed in GEP-NENs by tumor location and grade, indicating differences in carcinogenic pathways and biology.

doi: https://doi.org/10.1158/1078-0432.CCR-20-1804



  • Surgeon-Placed Continuous Wound Infusion Pain Catheters Markedly Decrease Narcotic Use and Improve Outcomes After Pancreatic Tumor Resection

Annals of surgical oncology 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32880771

BACKGROUND: Pancreatectomy results in significant postoperative pain and typically requires opioid analgesia for adequate pain control. Local anesthetics may decrease postoperative pain and opioid requirements but can be limited by onset of action, duration of effect, and inability to titrate dosing after administration. This can be overcome by surgeon placement of tunneled peri-incisional catheters with continuous wound infusion (CWI).
METHODS: This retrospective cohort study analyzed patients undergoing open pancreatic tumor resection. All the patients received patient-controlled analgesia (PCA), enabling an objective comparison of opioid requirements, and underwent the same recovery pathway. The patients received CWI (n = 45), PCA alone (n = 11), or epidural analgesia (EA) (n = 9). The primary outcome was total opioid use in terms of intravenous morphine milligram equivalents (MMEs) and patient-reported pain scores on a numeric rating scale (NRS) of 0 to 10.
RESULTS: No differences in baseline patient or tumor characteristics were observed. In both the uni- and multivariate analyses, CWI was associated with lower opioid use than PCA (MME, 83 vs 207 mg; p = 0.004) or EA (MME, 83 vs 156 mg; p < 0.001) without having a negative impact on pain scores. Furthermore, CWI was associated with a greater percentage of time that patients experienced optimal pain control (NRS, ≤ 4: 63% vs 50%; p = 0.033) and a shorter time to PCA independence (4.0 vs 4.9 days; p = 0.004) than PCA alone. In addition, CWI was associated with earlier ambulation [EA vs CWI: odds ratio (OR), 0.05; p = 0.021], improved spirometry performance (CWI vs PCA: regression coefficient (coef), 267; p = 0.013), and earlier urinary catheter removal (EA vs CWI: coef, 1.30; p = 0.013). The findings showed no differences in time to return of bowel function, antiemetic use, or hospital length of stay.
CONCLUSIONS: After open pancreatic tumor resection, CWI is safe and associated with decreased opioid requirements and improved functional outcomes without a negative impact on pain scores, supporting its potential for preferred use over PCA or EA alone.

doi: https://doi.org/10.1245/s10434-020-09067-4



  • Drug-induced acute pancreatitis: Prevalence, Causative agents, and Outcomes

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32878711

BACKGROUND: We sought to study the causative drugs, prevalence and outcomes of drug-induced acute pancreatitis (DIAP).
METHODS: Retrospective study of DIAP patients at a tertiary teaching hospital. The diagnosis and severity of pancreatitis were determined based on the Revised Atlanta Classification. The cases were further subclassified using the Badalov et al., 2008 classification, and Naranjo score to evaluate and determine the odds of drug-related adverse reaction as a causative factor for AP.
RESULTS: Out of 841 AP patients, a total of 31 patients (3.6%) with DIAP were included. The mean age was 52.9 years, 51.6% were male. The most common causative drugs are listed in Table 3. Most cases were mild in severity (87%), moderate AP occurred in 2 patients (6.5%) and severe AP in 2 patients (6.5%). 19.3% had systemic inflammatory response syndrome at presentation, but it persisted beyond 48 h in only 9.6%. 9.6% developed acute kidney injury. One patient with valproate induced DIAP had pancreatic necrosis, splenic vein thrombus, and sub occlusive superior mesenteric vein thrombus on abdominal imaging. Three patients had recurrent AP, and two (6.5%) of them eventually developed chronic pancreatitis. Notably, none of our patients developed complications such as shock, acute respiratory distress syndrome, bacteremia, or death. 1 patient had an acute peripancreatic fluid collection on initial imaging and another patient developed a pseudocyst on follow up imaging. None of them required drainage.
CONCLUSION: Our study showed a prevalence of DIAP of (3.6%) and hydrochlorothiazide, azathioprine, and doxycycline were the most common culprit drugs.

doi: https://doi.org/10.1016/j.pan.2020.07.401



  • Peritoneal Lavage Tumor DNA as a Novel Biomarker for Predicting Peritoneal Recurrence in Pancreatic Ductal Adenocarcinoma

Annals of surgical oncology 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32875467

BACKGROUND: The clinical role of peritoneal lavage cytology (CY) in pancreatic ductal adenocarcinoma (PDAC) remains controversial, partly due to its low sensitivity. This study aimed to develop a new biomarker, defined as peritoneal lavage tumor DNA (ptDNA), using DNAs extracted from peritoneal lavage samples from patients with PDAC.
METHODS: Samples were collected intraoperatively from 89 PDAC patients who underwent pancreatectomy between 2012 and 2017. Droplet digital polymerase chain reaction (PCR) was used to measure ptDNA for detection of KRAS mutations. The ptDNA status and clinical characteristics were retrospectively evaluated.
RESULTS: Positive ptDNA was found in 41 patients, including all 9 patients positive for CY (CY+) and 32 patients negative for CY (CY-). The mutant allele frequency was significantly higher in the CY+ patients than in the CY- patients. The disease-free survival (DFS) and overall survival (OS) were significantly poorer in the high-ptDNA group than in the low-ptDNA group (median DFS, 11.0 vs. 18.8 months; p = 0.007; median OS, 28.7 vs not reached; p = 0.001). The survival curves of DFS and OS in the CY+ group were almost equal to those in the CY- and high-ptDNA group. In a multivariable analysis, ptDNA was an independent predictive factor for DFS (p = 0.025) and OS (p = 0.047). The estimated cumulative incidence of peritoneal recurrence was 45.5% in the high-ptDNA group. The ptDNA biomarker had a much higher sensitivity for peritoneal recurrence than CY, whereas CY had higher specificity.
CONCLUSIONS: As a promising biomarker, ptDNA may predict poor prognosis and peritoneal recurrence in PDAC, resolving the controversy surrounding CY.

doi: https://doi.org/10.1245/s10434-020-08990-w



  • Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer

Gut 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32873698

OBJECTIVE: ATM serine/threonine kinase (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC).
DESIGN: Combinational synergy screening was performed to endeavour a genotype-tailored targeted therapy.
RESULTS: Synergy was found on inhibition of PARP, ATR and DNA-PKcs (PAD) leading to synthetic lethality in ATM-deficient murine and human PDAC. Mechanistically, PAD-induced PARP trapping, replication fork stalling and mitosis defects leading to P53-mediated apoptosis. Most importantly, chemical inhibition of ATM sensitises human PDAC cells toward PAD with long-term tumour control in vivo. Finally, we anticipated and elucidated PARP inhibitor resistance within the ATM-null background via whole exome sequencing. Arising cells were aneuploid, underwent epithelial-mesenchymal-transition and acquired multidrug resistance (MDR) due to upregulation of drug transporters and a bypass within the DNA repair machinery. These functional observations were mirrored in copy number variations affecting a region on chromosome 5 comprising several of the upregulated MDR genes. Using these findings, we ultimately propose alternative strategies to overcome the resistance.
CONCLUSION: Analysis of the molecular susceptibilities triggered by ATM deficiency in PDAC allow elaboration of an efficient mutation-specific combinational therapeutic approach that can be also implemented in a genotype-independent manner by ATM inhibition.

doi: https://doi.org/10.1136/gutjnl-2019-319970



  • Western-type diet influences mortality from necrotising pancreatitis and demonstrates a central role for butyrate

Gut 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32873697

OBJECTIVE: The gut microbiota are the main source of infections in necrotising pancreatitis. We investigated the effect of disruption of the intestinal microbiota by a Western-type diet on mortality and bacterial dissemination in necrotising pancreatitis and its reversal by butyrate supplementation.
DESIGN: C57BL/6 mice were fed either standard chow or a Western-type diet for 4 weeks and were then subjected to taurocholate-induced necrotising pancreatitis. Blood and pancreas were collected for bacteriology and immune analysis. The cecum microbiota composition of mice was analysed using 16S rRNA gene amplicon sequencing and cecal content metabolites were analysed by targeted (ie, butyrate) and untargeted metabolomics. Prevention of necrotising pancreatitis in this model was compared between faecal microbiota transplantation (FMT) from healthy mice, antibiotic decontamination against Gram-negative bacteria and oral or systemic butyrate administration. Additionally, the faecal microbiota of patients with pancreatitis and healthy subjects were analysed.
RESULTS: Mortality, systemic inflammation and bacterial dissemination were increased in mice fed Western diet and their gut microbiota were characterised by a loss of diversity, a bloom of Escherichia coli and an altered metabolic profile with butyrate depletion. While antibiotic decontamination decreased mortality, Gram-positive dissemination was increased. Both oral and systemic butyrate supplementation decreased mortality, bacterial dissemination, and reversed the microbiota alterations. Paradoxically, mortality and bacterial dissemination were increased with FMT administration. Finally, patients with acute pancreatitis demonstrated an increase in Proteobacteria and a decrease of butyrate producers compared with healthy subjects.
CONCLUSION: Butyrate depletion and its repletion appear to play a central role in disease progression towards necrotising pancreatitis.

doi: https://doi.org/10.1136/gutjnl-2019-320430



  • CXCR3 and Cognate Ligands Are Associated with Immune Cell Alteration and Aggressiveness of Pancreatic Ductal Adenocarcinoma

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32873571

PURPOSE: The cytokine milieu in pancreatic ductal adenocarcinoma (PDAC) promotes tumor progression and immune suppression, contributing to the dismal prognosis of patients with PDAC. The roles of many of these cytokines, however, have not been thoroughly investigated in PDAC.
EXPERIMENTAL DESIGN: PDAC microarray and TCGA datasets were analyzed to identify cytokines and cognate receptors overexpressed in PDAC and associated with survival. Pathway and CIBERSORT analyses were used to elucidate potential mechanisms of altered patient survival. Comparative analysis of cytokine expression in KPC (K-rasG12D; TP53R172H; Pdx-1cre) and KC (K-rasG12D; Pdx-1cre) PDAC models and multicolor immunofluorescence (IF) staining of human PDAC-resected samples were used to validate these findings.
RESULTS: CXCL9 and CXCL10 were among the most highly overexpressed cytokines by bioinformatics analyses while their receptor, CXCR3, was significantly overexpressed by bioinformatics and IHC analysis. Higher CXCR3-ligand expression was associated with shorter overall survival, while high CXCR3 expression was associated with better survival. The CXCR3-ligands, CXCL4, 9, and 10 were overexpressed in KPC compared to KC mice. Pathway analysis of CXCR3- and CXCR3-ligand-associated genes showed that CXCR3 is a marker of anti-tumor immunity, while its ligands may promote immunosuppression. CIBERSORT and IF studies of PDAC tissues demonstrated that high CXCR3 expression was associated with increased CD8+ T-cell and naïve B-cell signatures and loss of plasma cell signatures. CXCR3-ligand expression was associated with increased CD8+ T-cell signatures and loss of NK-cell signatures.
CONCLUSION: CXCR3-ligands are overexpressed in PDAC and are associated with poor survival likely related to alterations in tumor immune infiltrate/activity.

doi: https://doi.org/10.1158/1078-0432.CCR-20-1359



  • Can the location of the mural nodule indicate benign or malignant in branch duct-type intraductal papillary mucinous neoplasm of the pancreas?

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32873485

BACKGROUND/OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are classified into main duct (MD)-type IPMNs, branch duct (BD)-type IPMNs, and mixed type IPMNs. While MD-type IPMN has a high risk of malignancy and should therefore be considered for resection if the patient is fit, BD-type IPMN needs to be carefully judged for surgical indication. The decision to resect BD-type IPMN is often based on international consensus Fukuoka guidelines 2017, but further investigation is required. In this study, we focused on whether the location of the mural nodule (MN) could be an indicator of malignancy.
METHODS: We enrolled 17 cases who had been diagnosed BD-type IPMNs which were surgically resected from January 2016 to December 2019. These cases were classified into benign and malignant group. Subsequently, a clinicopathological study was conducted based on the localization of MN (MN-central type or MN-peripheral type).
RESULTS: Although MN was found in 57% (4/11) in the benign group, 88% (7/8) was noted in the malignant group, indicating the presence of MN to be more common in the malignant group. Those with MN consisted of 6 cases of MN-central type and 5 cases of MN-peripheral type. All cases of central type were malignant compared to only one case of the peripheral group being confirmed on histology as cancer.
CONCLUSION: BD-IPMN with central mural nodule should be considered high risk for malignancy.

doi: https://doi.org/10.1016/j.pan.2020.08.006


New GallBladder Articles


  • Phase 1 and Biomarker Study of the Wnt Pathway Modulator DKN-01 in Combination with Gemcitabine/Cisplatin in Advanced Biliary Tract Cancer

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32878766

PURPOSE: Dickkopf‑1 (DKK1) modulates Wnt signaling, promoting tumor growth, metastasis, and immunosuppression. High DKK1 expression has been detected in various tumor types-including biliary tract cancer (BTC)-and is associated with poor prognosis. DKN-01-a humanized monoclonal antibody targeting DKK1-was evaluated in a phase I multicenter study in combination with gemcitabine and cisplatin in patients with unresectable or metastatic BTC with no prior systemic therapy for advanced disease.
METHODS: This study included a dose-escalation phase assessing DKN-01 at two dose levels (150mg and 300mg) combined with gemcitabine (1,000mg/m2) and cisplatin (25mg/m2) followed by dose-expansion. Primary endpoints evaluated safety and tolerability; secondary endpoints evaluated efficacy, pharmacokinetics, and circulating biomarkers.
RESULTS: Fifty-one patients with intrahepatic cholangiocarcinoma (63%), extrahepatic cholangiocarcinoma (8%), and gallbladder cancer (29%) were enrolled. No dose-limiting toxicities were seen, and the expansion phase proceeded with DKN-01 300mg (N=47). The most frequent grade ¾ treatment-emergent adverse events included neutropenia (60%), thrombocytopenia (34%), and anemia (23%). The objective response rate was 21.3% and median progression-free survival was 8.7months (95%CI: 5.4, 10.3months). Better outcomes were associated with biomarkers of angiogenesis inhibition (increased sVEGFR1 and lower VEGF-C) and reduced inflammation (lower IL-6 and decreased TNF-α).
CONCLUSIONS: DKN-01 300mg was well tolerated in this combination but did not appear to have additional activity beyond historically reported efficacy with gemcitabine/cisplatin alone. Exploratory pharmacokinetic and biomarker data indicate potential antiangiogenic and immunomodulatory activity of DKN-01/chemotherapy and the need for increased dose/intensity. A study with DKN-01 600mg in combination with a PD-1 inhibitor in BTC is ongoing.

doi: https://doi.org/10.1158/1078-0432.CCR-20-1310


New BileDuct Articles


  • Liver biopsy findings in patients on immune checkpoint inhibitors

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32884128

Immune checkpoint inhibitors (ICI) can induce a durable response against a wide range of malignancies but cause immune related adverse events. The purpose of this study was to evaluate whether the pattern of inflammation in a liver biopsy in patients on ICIs is likely to be related to ICIs or other causes, and whether the pattern correlates with LFT abnormalities, imaging findings, and responsiveness to steroids. Cancer patients on ICIs who underwent liver biopsy were identified. Clinical data were obtained from electronic records. Liver biopsies were recorded as hepatitic, cholangitic, mixed, steatotic, or as mild nonspecific changes. In total, 28 liver biopsies had a predominantly hepatitic pattern of inflammation, including 11 biopsies with granulomas and 10 with endothelialitis. Eight biopsies had a mixed hepatocytic and cholangitic pattern of injury, including 6 with granulomas and 4 with endothelialitis. Sixteen patients had a predominantly cholangitic pattern, with portal-based inflammation. Three patients had a pattern resembling fatty liver, and five had mild nonspecific changes. The three most common histologic patterns correlated with the pattern of LFT abnormalities. The majority of patients with a cholangitic pattern had competing causes for elevated LFTs, including disease progression or concomitant chemotherapy. The cholangitic pattern was more likely to have bile duct dilatation or narrowing on liver imaging. The pattern of inflammation, degree of lobular injury, or presence of granulomas or endothelialitis did not predict response to steroids or the need for secondary immunosuppression. In this retrospective study, the pattern of inflammation did not predict the need for steroids, the length of time that steroids is required, or the need for secondary immunosuppression. A cholangitic pattern was seen when the pattern of LFTs was cholestatic, and was associated with imaging abnormalities of the bile duct, but a similar pattern was seen in bile duct obstruction and other drug reactions.

doi: https://doi.org/10.1038/s41379-020-00653-1


New Ampulla Articles

Today there is no new Ampulla Article.

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