Biliopancreatic Cancer Research Articles

POLQ immunostaining behaves as a prognostic factor for pancreatic carcinoma.

DNA polymerase theta (POLQ) is a translesion synthesis polymerase essential for the repair of double strand breaks by the error-prone TMEJ (Theta Mediated End Joining) pathway. Although POLQ participates in maintaining genome stability, several studies have shown that its overexpression correlates with cancer progression and poor prognosis. Due to the fact that its role as a biomarker in pancreatic cancer remains unexplored, we aimed to study the usefulness of POLQ H-score as a prognostic factor in a pancreatic cancer patient cohort. We evaluated POLQ gene expression using a web-based tool to deliver gene expression profiling and interactive analyses based on TCGA and GTEx (GEPIA) and we examined the POLQ immunostaining in 152 biliopancreatic cancer surgical specimens using tissue microarrays. Association with survival was evaluated by Kaplan Meier curves and uni-multivariate Cox regression. GEPIA analysis showed statistical differences according to POLQ mRNA levels in Disease Free Survival (DFS) (log rank 0.023, HR 2.8, p=0.029) and Overall Survival (OS) (log rank 0.011, HR 3.1, p=0.016). For immunohistochemistry (IHC) evaluation, POLQ H-score was calculated, and showed statistical differences for OS in Kaplan Meier curves (log rank 0.001) and uni-multivariate analysis (HR 2.27; 95% CI 1.24-4.15, p=0.008). Our results indicate that POLQ is an independent prognostic factor in pancreatic cancer when analyzed by immunostaining, which is in agreement with the results shown by the POLQ gene expression analysis (GEPIA).

1947P Organoid establishment from multiple biological sources in biliopancreatic cancers

1947P Organoid establishment from multiple biological sources in biliopancreatic cancers

Duodenal Fluid Analysis as a Rewarding Approach to Detect Low-Abundance Mutations in Biliopancreatic Cancers.

Diagnosis of biliopancreatic cancers by the available serum tumor markers, imaging, and histopathological tissue specimen examination remains a challenge. Circulating cell-free DNA derived from matched pairs of secretin-stimulated duodenal fluid (DF) and plasma from 10 patients with biliopancreatic diseases and 8 control subjects was analyzed using AmpliSeq™ HD technology for Ion Torrent Next-Generation Sequencing to evaluate the potential of liquid biopsy with DF in biliopancreatic cancers. The median cfDNA concentration was greater in DF-derived than in plasma-derived samples. A total of 13 variants were detected: 11 vs. 1 were exclusive for DF relative to the plasma source, and 1 was shared between the two body fluids. According to the four-tier systems, 10 clinical tier-I-II (76.9%), 1 tier-III (7.7%), and 2 tier-IV (15.4%) variants were identified. Notably, the 11 tier-I-III variants were exclusively found in DF-derived cfDNA from five patients with biliopancreatic cancers, and were detected in seven genes (KRAS, TP53, BRAF, CDKN2A, RNF43, GNAS, and PIK3CA); 82% of the tier-I-III variants had a low abundance, with a VAF < 6%. The mutational profiling of DF seems to be a reliable and promising tool for identifying cancer-associated alterations in malignant cancers of the biliopancreatic tract.

370P Cardiotoxicity associated with chemotherapy used in biliopancreatic cancers

370P Cardiotoxicity associated with chemotherapy used in biliopancreatic cancers

Detection and characterization of pancreatic and biliary tract cancers using cell-free DNA fragmentomics

BackgroundPlasma cell-free DNA (cfDNA) fragmentomics has demonstrated significant differentiation power between cancer patients and healthy individuals, but little is known in pancreatic and biliary tract cancers. The aim of this study is to characterize the cfDNA fragmentomics in biliopancreatic cancers and develop an accurate method for cancer detection.MethodsOne hundred forty-seven patients with biliopancreatic cancers and 71 non-cancer volunteers were enrolled, including 55 patients with cholangiocarcinoma, 30 with gallbladder cancer, and 62 with pancreatic cancer. Low-coverage whole-genome sequencing (median coverage: 2.9 ×) was performed on plasma cfDNA. Three cfDNA fragmentomic features, including fragment size, end motif and nucleosome footprint, were subjected to construct a stacked machine learning model for cancer detection. Integration of carbohydrate antigen 19–9 (CA19-9) was explored to improve model performance.ResultsThe stacked model presented robust performance for cancer detection (area under curve (AUC) of 0.978 in the training cohort, and AUC of 0.941 in the validation cohort), and remained consistent even when using extremely low-coverage sequencing depth of 0.5 × (AUC: 0.905). Besides, our method could also help differentiate biliopancreatic cancer subtypes. By integrating the stacked model and CA19-9 to generate the final detection model, a high accuracy in distinguishing biliopancreatic cancers from non-cancer samples with an AUC of 0.995 was achieved.ConclusionsOur model demonstrated ultrasensitivity of plasma cfDNA fragementomics in detecting biliopancreatic cancers, fulfilling the unmet accuracy of widely-used serum biomarker CA19-9, and provided an affordable way for accurate noninvasive biliopancreatic cancer screening in clinical practice.

The Role of Endoscopy in the Palliation of Pancreatico-Biliary Cancers: Biliary Drainage, Management of Gastrointestinal Obstruction, and Role in Relief of Oncologic Pain.

Therapeutic endoscopy permits many and various treatments for cancer palliation in patients with bilio-pancreatic cancers, enabling different options, supporting patients during their route to oncologic treatments, and trying to improve their quality of life. Therefore, both endoscopic and endoscopic ultrasound (EUS)-guided techniques are performed in this scenario. We performed a literature review focusing on the role of endoscopy in the palliation of those advanced pancreatic and biliary cancers developing malignant biliary obstruction (MBO), gastric outlet obstruction (GOO), and pain unresponsive to medical therapies. Therefore, we explored and focused on the clinical outcomes of endoscopic procedures in this scenario. In fact, the endoscopic treatment is based on achieving biliary drainage in the case of MBO through endoscopic retrograde cholangiopancreatography (ERCP) or EUS-guided biliary drainage (EUS-BD), while GOO is endoscopically treated through the deployment of an enteral stent or the creation of EUS-guided gastro-entero-anastomosis (EUS-GEA). Furthermore, untreatable chronic abdominal pain is a major issue in patients unresponsive to high doses of painkillers, so EUS-guided celiac plexus neurolysis (CPN) or celiac ganglia neurolysis (CGN) helps to reduce dosage and have better pain control. Therefore, therapeutic endoscopy in the palliative setting is an effective and safe approach for managing most of the clinical manifestations of advanced biliopancreatic tumors.

A Two-Step Diagnostic Approach for NTRK Gene Fusion Detection in Biliary Tract and Pancreatic Adenocarcinomas.

It is of interest to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers, because of possible treatment with TRK inhibitors for advanced tumors. The aim of the present study was to apply the guidelines for NTRK testing algorithm to a series of patients with bilio-pancreatic cancers. Immunohistochemistry screening was applied on formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies, or cytological samples of biliary tract and pancreatic adenocarcinomas. The presence of at least a weak staining in rare tumor cells led to testing by 2 RNA-based NGS panels. For biliary tract tumors, 153 samples have been selected. A total of 140 samples were suitable to perform IHC, and 17 samples were IHC positive. RNA NGS testing of the 17 IHC-positive samples revealed a single NTRK3 gene fusion (ETV6(4)-NTRK3(14)) that was detected by both NGS panels. In this perihilar cholangiocarcinoma, IHC performed on a biopsy showed a weak focal cytoplasmic and nuclear staining. No other NTRK fusion was detected on the 16 other samples with both panels. Overall in the patients screened by IHC and confirmed by NGS, the percentage of NTRK fusions was 0.7%. For pancreatic cancers, 319 samples have been selected and 297 were suitable to perform IHC. Nineteen samples were IHC positive. No fusion was detected by NGS. NTRK gene fusions are rare in bilio-pancreatic cancers but testing is of high interest due to possible treatment with specific TRK inhibitors.

ARID1A in cancer: Friend or foe?

ARID1A belongs to a class of chromatin regulatory proteins that function by maintaining accessibility at most promoters and enhancers, thereby regulating gene expression. The high frequency of ARID1A alterations in human cancers has highlighted its significance in tumorigenesis. The precise role of ARID1A in cancer is highly variable since ARID1A alterations can have a tumor suppressive or oncogenic role, depending on the tumor type and context. ARID1A is mutated in about 10% of all tumor types including endometrial, bladder, gastric, liver, biliopancreatic cancer, some ovarian cancer subtypes, and the extremely aggressive cancers of unknown primary. Its loss is generally associated with disease progression more often than onset. In some cancers, ARID1A loss is associated with worse prognostic features, thus supporting a major tumor suppressive role. However, some exceptions have been reported. Thus, the association of ARID1A genetic alterations with patient prognosis is controversial. However, ARID1A loss of function is considered conducive for the use of inhibitory drugs which are based on synthetic lethality mechanisms. In this review we summarize the current knowledge on the role of ARID1A as tumor suppressor or oncogene in different tumor types and discuss the strategies for treating ARID1A mutated cancers.

A case of bullous pemphigoid associated with metastatic bilio-pancreatic cancer

A case of bullous pemphigoid associated with metastatic bilio-pancreatic cancer

Contribution of Endoscopic Ultrasound (EUS) in Biliopancreatic Pathology: Experience of the Hepato Gastroenterology Moroccan Department

Introduction: Endoscopic ultrasound (EUS) is a method of exploration in gastroenterology, it combines ultrasound and endoscopy for the examination of the digestive tract and nearby structures. It is an ultrasound technique that allows the use of high-definition ultrasound transducers. Materials and methods: It is a descriptive retrospective study covering a period of 34 months, from 01/2019 to 10/2021. It concerned 100 patients who had endoscopic ultrasound for biliopancreatic pathology, in the and the university hospital Sheikh Khalifa. We noted the demographic, clinical and morphological data, such as transcutaneous ultrasound, abdominal CT scan and MRI as well as the EUS. The results of the EUS were compared with the imaging and histology data when performed. We were therefore able to evaluate the reliability of each examination and thus its strong and weak points. Results: The average age of our patients was 58 years, with a sex ratio: 1.05. The symptomatology was dominated by abdominal pain and jaundice, the biology by cytolysis and biological cholestasis syndrome. We noted a predominance of tumor pathology with 42% followed by inflammatory pathology: acute pancreatitis as part of the etiological assessment. The reliability of EUS in the diagnosis of pancreatic cancer is 88% with a reliability of abdominal CT of 68%. Our study also allowed us to evaluate with precision the reliability of detection of lymph node and vascular invasion of biliopancreatic cancers, which was 88%. We also noted other pathologies for which EUS was a good diagnostic tool, main bile duct stones but also cystic lesions of the pancreas. Conclusion: In view of the comparative study of these results with the other types of explorations, of which the EUS, proved to be more effective in the exploration of the pancreatic region especially in for the assessment of tumor extension and diagnosis of choledocholithiasis and characterization of cystic lesions. The EUS has a therapeutic interest ....

Biliary Diseases from the Microbiome Perspective: How Microorganisms Could Change the Approach to Benign and Malignant Diseases.

Recent evidence regarding microbiota is modifying the cornerstones on pathogenesis and the approaches to several gastrointestinal diseases, including biliary diseases. The burden of biliary diseases, indeed, is progressively increasing, considering that gallstone disease affects up to 20% of the European population. At the same time, neoplasms of the biliary system have an increasing incidence and poor prognosis. Framing the specific state of biliary eubiosis or dysbiosis is made difficult by the use of heterogeneous techniques and the sometimes unwarranted invasive sampling in healthy subjects. The influence of the microbial balance on the health status of the biliary tract could also account for some of the complications surrounding the post-liver-transplant phase. The aim of this extensive narrative review is to summarize the current evidence on this topic, to highlight gaps in the available evidence in order to guide further clinical research in these settings, and, eventually, to provide new tools to treat biliary lithiasis, biliopancreatic cancers, and even cholestatic disease.

Obesity and Biliopancreatic Cancers: Exploring Current Evidence

Background: Pancreatic cancer (PC) is among foremost causes of cancer related deaths worldwide due to generic symptoms and lack of screening. The risk of developing pancreatic cancer in obese or overweight individuals is 1.5 times higher than individuals with a normal BMI. Bariatric Surgery has been associated with a reduction of obesity- related cancer, however, the number of cases that developed pancreatic cancer post Bariatric surgery is not known. Aim: Examine the relationship between Bariatric Surgery and Pancreatic cancer and identify reported cases of pancreatic cancer after bariatric surgery. Materials and Methods: A narrative review of the literature was conducted. A MEDLINE database search was performed using the following Medical Subject Headings (MeSH) terms: pancreatic cancer, bariatric surgery, weight reduction surgery, pancreatic adenocarcinoma. These were combined with the following: postoperative, after surgery, and during surgery. A WebScience search was then performed using similar terms. Additional references were then identified by manual search of the articles obtained from the MEDLINE and Web of Science. Cancer cases that were identified at the pre-operative period or intra-operatively were excluded. The searches covered the period from January 2000 to November 2020. Results/Review: Epidemiological evidence has shown that obesity as a risk factor for the development of PC is a dose dependent risk. The review found that the risk of developing pancreatic cancer in obese or overweight individuals is 1.5 times higher than individuals with a normal BMI. At the same time, evidence from literature demonstrated that weight reduction by dietary restriction, physical activities, pharmacotherapy or weight reduction surgery reduces risk of PDAC. A total of 24 cases of pancreatic cancer were identified and reported post Bariatric Surgery in the literature. The average age at diagnosis was 57.2 years and onset from surgery to diagnosis ranged from 2 months to 25 years. Of the identified cases, 23 cases were post Roux-en-Y Gastric Bypass and one case post Duodenal Switch. The review found that PDAC was the commonest reported pancreatic cancer post bariatric surgery accounting for 58.3%, followed by Neuroendocrine Tumours (NET) 16.7%. Conclusions: Along with weight reduction and improving comorbidities, Bariatric surgery reduces risk of obesity-related carcinogenesis. Given the variation in onset of diagnosis, bariatric surgery did not increase cancer risk but rather accelerated the diagnosis of pancreatic cancer.

Changes in natural killer cell activity after surgery and predictors of its recovery–failure

We evaluated the changes in natural killer cell activity (NKA) during the entire treatment period of patients with resectable biliopancreatic cancers and investigated the predictors of the failure of recovery of NKA after surgery. A total of 202 patients who underwent curative resection for biliopancreatic cancer were enrolled in the study. NKA levels were measured six times during the treatment period. We investigated whether there was any difference in postoperative NKA recovery according to the period-by-time NKA value. NKA decreased after surgery (mean, 40 pg/ml) compared to the NKA value at admission (200.2 pg/ml), then began to increase from 3 weeks after surgery (139.7 pg/ml) and rose to normal NKA levels at 5 weeks (217.1 pg/ml). The pattern of NKA changes was distinct according to the NKA values at admission. In multivariate analysis, NKA values of less than 250 pg/ml at admission (odds ratio = 5.898, p = 0.044) were a predictor of NKA recovery failure 5 weeks after surgery. NKA rapidly decreased after curative surgery for biliopancreatic cancer and recovered to normal levels about 5 weeks later. Clinicians should be aware and cautious that patients with low NKA at admission may fail to recover NKA postoperatively.

ID: 3526418 COMBINED ENDOSCOPIC STENTING FOR CONCOMITANT MALIGNANT BILIARY AND DUODENAL OBSTRUCTION: DATA FROM A SINGLE REFERRAL CENTER

Gastric Outlet Obstruction (GOO) due to advanced gastro-duodenal and bilio-pancreatic cancer is frequently associated to Malignant Biliary Obstruction (MBO). In this setting, double biliary and duodenal stenting is needed. This endoscopic approach is a valid alternative to surgical by-pass.

Patients With Unexplained Dilated Pancreatic Duct Have High Risk of Biliopancreatic Malignancy Detected by EUS.

Patients with unexplained dilated common bile duct (CBD) and/or dilated main pancreatic duct (MPD) on noninvasive abdominal imaging tests are often referred for endoscopic ultrasound (EUS) in order to rule out biliopancreatic cancer. The aim of the study was to evaluate the diagnostic yield of EUS in this patient group. A prospective study was conducted. Patients with unexplained dilated CBD and/or MPD on abdominal imaging, who underwent EUS, were enrolled. Fifty-four patients underwent EUS (CBD dilation n=38, MPD dilation n=5 or both n=11). In 31/54 patients (57.4%), EUS revealed pathologic findings. Sixteen patients (29.6%) had EUS evidence of biliopancreatic cancer and 15 patients (27.7%) had benign pathology. Ten (62.5%) of the patients with biliopancreatic cancer had MPD dilation. MPD dilation was significantly associated with malignancy (P=0.017). Patients with unexplained dilated MPD on noninvasive image have a high risk of biliopancreatic malignancy detected by EUS.

Fecal elastase-1 testing and serum nutritional markers in biliopancreatic cancer patients

Fecal elastase-1 testing and serum nutritional markers in biliopancreatic cancer patients

71P NTRK gene fusions in bilio-pancreatic cancers

71P NTRK gene fusions in bilio-pancreatic cancers

O-4 NTRK gene fusions in bilio-pancreatic cancers

Gene fusions involving one of the 3 neurotrophic tyrosine receptor kinases (NTRK) have been identified in approximately 1% of solid tumors and inhibitors of TRK (e.g. larotrectinib) have been shown to have anti-tumor activity regardless of tumor type. NTRK gene fusions have been previously reported in bilio-pancreatic cancers. It is of interest therefore to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers.

NTRK gene fusions in bilio-pancreatic cancers.

e16664 Background: Gene fusions involving one of the 3 neurotrophic tyrosine receptor kinases ( NTRK) have been identified in approximately 1% of solid tumors and inhibitors of TRK have been shown to have anti-tumor activity regardless of tumor type. NTRK gene fusions have been previously reported in bilio-pancreatic tumors. It is of interest therefore to determine incidence and molecular characteristics of NTRK gene fusions in these patients. Methods: Formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies or cytological samples of biliary tract tumors (BTC) including intra-hepatic (IH), extra-hepatic (EH), perihilar cholangiocarcinoma (PH) and gallbladder tumors (G), and pancreatic adenocarcinoma (PA) were retrieved from the tumor bank of CUB Hôpital Erasme between JAN 2010 and OCT 2019. A two-step diagnostic method incorporating immunohistochemistry (IHC) screening followed by NGS analysis was used. Pan–TRK IHC (monoclonal antibody clone EPR17341 [AbCam, Cambridge, MA]) was used for the screening method. Staining intensity (negative, weak, moderate or strong) pattern (diffuse, focal or rare positive cells), and localization (cytoplasmic or nuclear) were evaluated. The presence of at least weak staining tumor cells led to testing by a RNA-based NGS panel (Oncomine Focus Assay ThermoFisher Scientific). Results: For BTC, 162 archival tumors samples have been selected. 149 samples were suitable to perform IHC.17 samples were IHC positive including 9 IH, 3 PH, 2 EH and 3 G tumor samples. Intensity of staining was weak in 16 samples and moderate in one. Staining location was cytoplasmic (14/17), nuclear (2/17), and nuclear+cytoplasmic (1/17). Pattern of staining was rare positive cells (2/17), focal (4/17) and diffuse (11/17). NGS testing of the 17 IHC positive samples revealed a single NTRK3 gene fusion ( ETV6(4)- NTRK3(14)). In this PH tumor, IHC had a weak focal cytoplasmic and nuclear staining. Overall in the patients screened by IHC and confirmed by NGS, percentage of NTRK fusions was 0.67 %. For PA, 319 archival tumor samples have been selected and 297 were suitable for IHC. 19 samples were IHC positive. Intensity of staining was weak in 18 samples and moderate in one. Staining location was cytoplasmic (18/19) and nuclear (1/19). Pattern of staining was focal in 2 cases and diffuse in 17 cases. No fusion was detected by NGS. Conclusions: NTRK gene fusions are rare in bilio-pancreatic cancers but testing is of high interest due to the emergence of possible treatment with specific TRK inhibitors. These results support the use of NGS to confirm positive IHC results during diagnostic screening.

NTRK gene fusions in biliary tract cancers.

574 Background: Gene fusions involving one of the 3 neurotrophic tyrosine receptor kinases ( NTRK) have been identified in approximately 1% of solid tumors and inhibitors of TRK (e.g. larotrectinib) have been shown to have anti-tumor activity regardless of tumor type. NTRK gene fusions have been previously reported in bilio-pancreatic cancers. It is of interest therefore to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers. Methods: Formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies or cytological samples of biliary tract tumors including intra-hepatic cholangiocarcinoma (IH), extra-hepatic cholangiocarcinoma (EH), perihilar cholangiocarcinoma (PH) and gallbladder tumors (G) were selected/retrieved from the tumor bank of the CUB Hôpital Erasme between January 2010 and July 2019. A two-step diagnostic method incorporating immunohistochemistry (IHC) screening followed by NGS analysis was used. Pan–TRK IHC (monoclonal antibody clone EPR17341 [AbCam, Cambridge, MA]) was used for the screening method. Staining intensity (negative, weak, moderate or strong) and localization (cytoplasmic or nuclear) were evaluated. The presence of at least weak staining tumor cells led to testing by a RNA-based NGS panel (Oncomine Focus Assay, ThermoFisher scientific). Results: 145 archival tumors samples (81 surgical resections, 48 biopsies and 16 cytology) have been selected, including 61 IH, 32 PH, 26 EH and 26 G (67 female and 78 male). 134 samples were suitable to perform IHC. 17 samples were IHC positive. Intensity of staining was weak in 16 samples and moderate in one. Staining location was cytoplasmic (14/17), nuclear (2/17), and nuclear+cytoplasmic (1/17). NGS testing of the 17 IHC positive samples revealed a single NTRK3 gene fusion ( ETV6(4)- NTRK3(14)). In this case (female patient with a poorly differentiated PH, deceased), IHC had a weak focal cytoplasmic and nuclear staining. Overall in the patients screened by IHC and confirmed by NGS, the percentage of NTRK fusions was 0.75%. Conclusions: NTRK gene fusions are rare in biliary cancers but testing is of high interest due to the emergence of possible treatment with specific TRK inhibitors.