Pancreatobiliary Cancer Research Articles

Relationship of circulating tumor DNA (ctDNA) tumor fraction with prognosis in patients with metastatic pancreatobiliary cancer.

763 Background: Carcinomas of the pancreas and biliary tract are among the most lethal cancers. Currently, it is very difficult to predict individual patient outcomes with only general prognostic information available. Emerging evidence shows that baseline ctDNA tumor fraction (TF) is a prognostic factor for many tumor types, including metastatic pancreatic ductal adenocarcinoma (mPDAC). With an additional year of follow-up, we refresh our prior study of the prognostic value of ctDNA TF in mPDAC and extend the analysis to biliary tract cancers (BTC). Methods: A genomic dataset comprising patients who underwent ctDNA testing using FoundationOne Liquid or FoundationOne Liquid CDx as part of routine care was used to determine the distribution of ctDNA TF across pancreatobiliary cancer subtypes. A subset of patients was also included in the nationwide (~280 US cancer clinics, ~800 sites of care) de-identified Flatiron Health-Foundation Medicine clinico-genomic database, which was used separately for all other analyses. Clinical data were derived from the electronic health record. Real-world overall survival (rwOS) was evaluated by ctDNA TF while controlling for relevant covariates. In parallel, ctDNA TF cutoffs of ≥1% and ≥10% were evaluated. Exploratory analysis of trichotomized ctDNA TF at 1% and 10% was also performed. Results: In 8817 patients with pancreatobiliary carcinoma, 46.1% of PDAC and 41.9% of extra-hepatic cholangiocarcinoma patients had detectable levels of ctDNA TF, while patients with gallbladder carcinomas had the highest levels of ctDNA TF (median 0.8%). 470 patients with mPDAC and 89 patients with BTC were included in the outcomes analysis. High ctDNA TF was associated with clinical features linked to poor prognosis in mPDAC: Stage IV at diagnosis, pretherapy opioid prescriptions, high neutrophil-to-lymphocyte ratio and CA19-9 at baseline, and alterations in KRAS , TP53 , CDKN2A , or SMAD4 . In BTC, high ctDNA TF was associated with Stage IV at diagnosis and cholangiocarcinoma histology. Higher ctDNA TF in mPDAC was associated with significantly reduced rwOS for both cutoffs (1%: HR 1.55 [1.25-1.93], P < 0.001; 10%: HR 1.85 [1.42-2.41], P < 0.001). When ctDNA TF was trichotomized, higher ctDNA TF groups had reduced rwOS stepwise. Similar trends were observed in patients with BTC, but results were not statistically significant. Conclusions: ctDNA from pancreatobiliary carcinomas can be frequently detected and characterized in liquid biopsy while also assessing key genomic biomarkers. ctDNA TF was a prognostic biomarker for mPDAC, but not for BTC in this cohort. Detection of ctDNA associated with other clinical factors linked to poor outcomes. Cohorts given uniform treatment could possibly help further evaluate the ability of ctDNA TF to identify patients with more aggressive disease and inform future studies to personalize therapeutic decision-making.

Universal screening for mismatch repair deficiency in gastrointestinal cancers in a reference center in Mexico.

840 Background: Gastrointestinal (GI) cancers have a poor prognosis. With the availability of immunotherapy for tumors with deficient mismatch repair (dMMR), identifying these patients has become increasingly important. Universal dMMR screening across all GI cancers is uncommon, and its prevalence has not been well studied prospectively. In Mexico, the prevalence of dMMR is unknown, even though GI cancers account for a large portion of new cancer cases and cancer-related deaths. Our objective was to prospectively determine the prevalence of dMMR in GI cancers at a referral center in Mexico. Methods: Prospective universal screening for dMMR began in March 2024. Primary tumor sites included were esophagus, stomach, pancreas, biliary tract, small intestine, colon, and rectum. Histologies included were adenocarcinoma, squamous cell, or mixed. All consecutive patients were included regardless of age, clinical stage or medical history. MMR status was determined by immunohistochemistry, analyzing expression of MLH1, PMS2, MSH2, and MSH6. This abstract presents the results from the first six months of this universal screening. Results: A total of 161 GI cancers were included (see Table). Prevalence of dMMR was 9.3% (n=15). The highest prevalence was in gastric cancer (13.3%, 2/15), followed by colon (12.1%, 7/58), pancreatic (11.1%, 4/36), and bile duct (8.3%, 2/24) cancer. MMR status was not performed in 9.3% (n=15) of cases. Combined deficiency was found in 60% (9/15) for MLH1/PMS2 and 20% (3/15) for MSH2/MSH6. Isolated deficiency occurred in 20% (3/15) for PMS2 and 13.3% (2/15) for MSH2. No difference in age or clinical stage was observed between MMR status groups. Conclusions: The high prevalence of dMMR, along with the poor prognosis and availability of immunotherapy based treatments, supports the need for universal screening. The high prevalence of dMMR in pancreatobiliary cancers was notable. Implementation efforts in our institution are essential to obtain MMR status in all cases. Characteristics of population. pMMRn=131 (%) dMMRn=15 (%) Not performedn=15 (%) Totaln=161 p value Gender Male 63 (48.1) 10 (66.7) 7 (46.7) 80 (49.7) 0.38 Female 68 (51.9) 5 (33.3) 8 (53.3) 81 (50.3) Age Median (IQR) 65 (54 -72) 52 (43 -80) 65 (57 -71) 65 (53 -72) 0.52 Histology Adenocarcinoma 130 (99.2) 15 (100.0) 14 (93.3) 159 (98.8) N/A Mixed 1 (0.8) 0 (0.0) 0 (0.0) 1 (0.6) Squamous Cell 0 (0.0) 0 (0.0) 1 (6.7) 1 (0.6) Clinical Stage Unknown 12 (9.2) 1 (6.7) 1 (6.7) 14 (8.7) 0.49 Localized 24 (18.3) 2 (13.3) 2 (13.3) 28 (17.4) Locally advanced 40 (30.5) 8 (53.3) 3 (20.0) 51 (31.7) Metastatic 55 (42.0) 4 (26.7) 9 (60.0) 68 (42.2) Tumor site Esophageal 9 (6.9) 0 (0.0) 1 (6.7) 10 (6.2) N/A Gastric 13 (9.9) 2 (13.3) 0 (0.0) 15 (9.3) Small B. 1 (0.8) 0 (0.0) 0 (0.0) 1 (0.6) Bile duct 14 (10.7) 2 (13.3) 8 (53.3) 24 (14.9) Pancreas 29 (22.1) 4 (26.7) 3 (20.0) 36 (22.4) Colon 50 (38.2) 7 (46.7) 1 (6.7) 58 (36.0) Rectal 15 (11.5) 0 (0.0) 2 (13.3) 17 (10.6)

Robust circulating microRNA signature for the diagnosis and early detection of pancreatobiliary cancer

BackgroundA new circulating biomarker superior to carbohydrate antigen 19–9 (CA19-9) is needed for diagnosing pancreatobiliary cancer (PBca). The aim of this study was to identify serum microRNA (miRNA) signatures comprising reproducible and disease-related miRNAs.MethodsThis multicenter study involved patients with treatment-naïve PBca and healthy participants. The optimized serum processing conditions were evaluated using t-distributed stochastic neighbor embedding (t-SNE) visualization. Serum miRNA candidates for disease association were selected using weighted gene coexpression network analysis (WGCNA). A miRNA signature combining multiple serum miRNAs was tested in exploratory, validation, and independent validation sets. The synthesis and secretion of diagnostic miRNAs were evaluated using human pancreatic cancer cells.ResultsIn total, 284 (150 healthy and 134 PBca) of 827 serum samples were processed within 2 h of blood collection before freezing, distributed in the same area as that in the t-SNE map, and assigned to an exploratory set. The 193 optimized samples were assigned to either the validation (50 healthy, 47 PBca) or independent validation (50 healthy, 46 PBca) set. Index-1, a combination of five serum miRNAs (hsa-miR-1343-5p, hsa-miR-4632-5p, hsa-miR-4665-5p, hsa-miR-665, and hsa-miR-6803-5p) with disease association in WGCNA, showed a sensitivity and specificity of > 80% and an AUC outperforming that of CA19-9 in the exploratory, validation, and independent validation sets. The AUC of Index-1 was superior to that of CA19-9 (0.856 vs. 0.649, p = 0.038) for detecting T1 tumors. miR-665, a component of Index-1, was expressed in human pancreatic cancer cells, and its transfection inhibited cell growth.ConclusionsThe serum miRNA signature Index-1 is useful for detecting PBca and could facilitate the early diagnosis of PBca. These findings can help improve clinical PBca detection by providing an optimized biomarker that overcomes the limitations of the current standard.

The origin of patient-derived cancer organoids from pathologically undiagnosed specimen in patients with pancreatobiliary cancers.

Tissue confirmation of pancreatobiliary cancer is often difficult because of the location of the tumor and structure of the surrounding blood vessels. Patient-derived cancer organoids (PDCOs) reflect the genomic characteristics of individual cancers. Although diverse attempts to construct PDCOs for various pancreatobiliary cancer models are ongoing, no research results have yet confirmed the possibility of performing a precise diagnosis on PDCOs derived from pathologically negative patient samples. We obtained a total of nine samples, including pathologically negative samples, from four patients (three patients with pancreatic cancer and one patient with gallbladder cancer) using different tissue acquisition methods to establish PDCOs (success rate 75%). We successfully verified whether the constructed PDCOs could represent the tissues of patients with pancreatobiliary cancer at each multi-omics level using tumor panel sequencing, single-cell RNA sequencing, hematoxylin and eosin, and immunohistochemical staining. PDCOs from pathologically negative samples showed expression patterns of malignant ductal cell-related biomarkers similar to those of other pathologically positive samples. Furthermore, the expression patterns at the single-cell level in PDCO from patients ultimately diagnosed with gallbladder cancer after surgery were different from those in patients with pancreatic cancer. Therefore, our study implicated the potential of PDCOs as diagnostic and research tools, including for case involving limited tissue samples. Based on these results, we anticipate that this could be extended to more advanced studies, such as drug sensitivity testing, through large-scale trials in the near future.

Association between Gamma-Glutamyl Transferase Levels and Pancreatobiliary Cancer Risk in Patients with Diabetes: Evidence from the National Health Insurance Cooperation Health Checkup 2009 to 2012.

Elevated gamma-glutamyl transferase (GGT) levels indicate hepatic dysfunction and have been linked to an increased risk of pancreatobiliary cancers. However, this association, particularly in individuals with diabetes mellitus (DM), requires elucidation. We aimed to examine the association between elevated serum GGT levels and pancreatobiliary cancer risk in patients with diabetes. Our study included data from the National Health Insurance Service (NHIS) database for 2,459,966 adults aged >20 years diagnosed with DM between 2009 and 2012. We examined the association between serum GGT levels and pancreatobiliary cancer risk, considering DM-related factors. Serum GGT levels were categorized into quartiles, and Cox proportional hazards analysis was performed to evaluate the association between serum GGT levels and pancreatobiliary cancer risk. Over a median follow-up period of 7.2 years, 21,795 patients (0.89%) were newly diagnosed with pancreatobiliary cancer. The adjusted hazard ratio for pancreatobiliary cancer in quartiles 2-4 compared with that in quartile 1 was 1.091, 1.223, and 1.554, respectively, demonstrating a significant upward trend (p<0.001). This association remained consistent across all cancer types and was independent of the DM duration or treatment regimen. Elevated serum GGT levels were independently associated with an increased risk of pancreatobiliary cancer, regardless of the duration of DM or the use of oral hypoglycemic agents and insulin. While these findings suggest the potential utility of serum GGT as a biomarker for identifying individuals at higher risk of pancreatobiliary cancer within the diabetic population, further research is needed to validate its clinical applicability.

Efficacy of hemostasis by gastroduodenal covered metal stent placement for hemorrhagic duodenal stenosis due to pancreatobiliary cancer invasion: a retrospective study.

Advanced pancreatic and biliary tract cancers can invade the duodenum and cause duodenal hemorrhagic stenosis. This study aimed to evaluate the efficacy of covered self-expandable metal stents in the treatment of cancer-related duodenal hemorrhage with stenosis. Between January 2014 and December 2016, metal stents were placed in 51 patients with duodenal stenosis. Among these patients, a self-expandable covered metal stent was endoscopically placed in 10 patients with hemorrhagic duodenal stenosis caused by pancreatobiliary cancer progression. We retrospectively analyzed the therapeutic efficacy of the stents by evaluating the technical and clinical success rates based on successful stent placement, degree of oral intake, hemostasis, stent patency, and overall survival. The technical and clinical success rates were 100%. All 10 patients achieved a gastric outlet obstruction scoring system score of three within two weeks after the procedure and had no recurrence of melena. The median stent patency duration and overall survival after stent placement were 52 days (range, 20-220 days) and 66.5 days (range, 31-220 days), respectively. Endoscopic placement of a covered metal stent for hemorrhagic duodenal stenosis associated with pancreatic or biliary tract cancer resulted in duodenal hemostasis, recanalization, and improved quality of life.

Prognostic value of immuno-nutritional status in patients with cancer treated by immune checkpoint inhibitors.

226 Background: The treatment efficacy of immune checkpoint inhibitors (ICIs) may relate to tumor factors or host factors, such as systemic inflammation status or nutritional status. In this study, we investigated the prognostic value of immuno-nutritional status in cancer patients treated by ICIs, and develop nomogram models for predicting overall survival (OS). Methods: We used Chang Gung Research Database to retrospectively evaluate cancer patients who received ICIs during January 2015 to December 2021. Patients had double cancer or received only one cycle of ICI were excluded. All patients were divided into a training cohort and a validation cohort. The training cohort was used to analyze the risk factors and develop nomogram models. The models were validated by the validation cohort. The univariate analysis, stepwise multivariate analysis, receiver operator characteristics (ROC) analysis were used to find out the independent risk factors. The calibration plot were used to evaluate the reliability of the models. Results: All patients (3219 cases) could be categorized into lung cancer (22.1%), genitourinary cancer (14.9%), upper gastrointestinal tract cancer (8.1%), colorectal cancer (3.1%), hepatocellular carcinoma (24.6%), pancreatobiliary cancer (3.8%), head and neck cancer (12.9%), melanoma (4.0%), breast cancer (1.9%) and lymphoma (0.5%). 80.2% of patients received anti-PD1, 19.8% of patients received anti-PD-L1. In training cohort, the cut-off value was set for neutrophil-to-lymphocyte ratio (NLR), total lymphocyte count (TLC), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), prognostic nutrition index (PNI) and hemoglobin-albumin-lymphocyte-platelet (HALP) score. The above risk factors showed significant difference in median OS in validation cohort respectively (Table). The multivariate analysis demonstrated that NLR, PNI and HALP score were independent risk factors in predicting OS. The hazard ratio were 1,439 (95% CI 1.149-1.801), 0.689 (95% CI 0.549-0.865) and 0.784 (95% CI 0.626-0.982) respectively. Conclusions: We developed nomogram models to investigate the immuno-nutritional status and predict the OS of cancer patients who received ICIs therapy. High NLR, low PNI and low HALP score were associated with worse OS. [Table: see text]

Postoperative distress and influencing factors in patients with pancreatobiliary cancer

This study aimed to investigate distress levels, using the distress thermometer (DT), and the factors associated with distress in postoperative patients with pancreatobiliary cancer. This study retrospectively investigated 155 patients who underwent surgery for pancreatobiliary cancer between December 1, 2019 and September 30, 2021. The DT and problem list were used to measure distress. Descriptive statistics, t-test, and multivariate logistic regression analysis were used to analyze the data. Of the 155 patients, 16.8% (n = 26) and 83.2% (n = 129) were in the mild-distress and moderate-to-severe distress groups, respectively. The average DT score was 6.21; that for the mild-distress and moderate-to-severe distress groups was 2.46 and 6.97, respectively. More patients in the moderate-to-severe distress group reported having problems of “sadness” (χ2 = 4.538, P < 0.05), “indigestion” (χ2 = 10.128, P < 0.001), “eating” (χ2 = 6.147, P < 0.013), and “getting around” (χ2 = 4.275, P < 0.039) than in the mild-distress group. In addition, occupation status (odds ratio [OR] = 0.342, 95% confidence interval [CI] = 0.133–0.879, P = 0.026) and indigestion (OR = 5.897, 95% CI = 1.647–21.111, P = 0.006) were independent risk factors for the presence of severe distress. Patients with pancreatobiliary cancer demonstrated elevated levels of psychological distress. Healthcare providers should therefore be vigilant when evaluating patients for distress and providing appropriate referrals, particularly those who are unemployed or have indigestion.

Implications of Serum IgG4 Levels for Pancreatobiliary Disorders and Cancer.

Background/Objectives: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated disorder presenting as mass-like lesions with obstructions. An elevated serum IgG4 level is identified in more than half of affected patients and is considered a diagnostic criterion. IgG4-RD is still easily misdiagnosed as neoplastic or infectious disease. We aimed to conduct a hospital-based study to illuminate the association between serum IgG4 levels and pancreatobiliary disorders and cancer. Methods: In this study, serum IgG4 levels were assessed at our hospital's immunology laboratory, utilizing data from the hospital's computer center, and the diagnostic codes used were based on ICD-9-CM. We analyzed IgG4 level data collected between April 2013 and April 2020, including patients' age, gender, and diseases, but excluding the rationale for IgG4 level assessment. Employing propensity score matching (PSM) at a 1:1 ratio to mitigate age and gender confounding, we analyzed 759 patients divided into groups by IgG4 levels (≤140 and >140 mg/dL; and ≤140, 141-280, >280 mg/dL). We explored associations between IgG4 levels and conditions such as pancreatobiliary cancer (the group included cholangiocarcinoma, pancreatic cancer, and ampullary cancer), cholangitis, cholangiocarcinoma, pancreatitis, pancreatic cancer, and ampullary cancer. Results: Our study analyzed the demographics, characteristics, and serum IgG4 levels of participants and found no significant differences in serum IgG4 levels across various pancreatobiliary conditions. Nevertheless, the crude odds ratios (ORs) suggested a nuanced association between a higher IgG4 level > 280 mg/dL and increased risks of cancer and pancreatitis, with crude ORs of 1.52 (p = 0.03) and 1.49 (p = 0.008), respectively. After PSM matching, the further analysis of 759 matched patients showed no significant differences in IgG4 levels > 140 mg/dL between cancerous and non-cancerous groups, nor across other pancreatobiliary conditions. A higher serum IgG4 level > 280 mg/dL was significantly associated with pancreatobiliary cancer and cholangiocarcinoma, with crude ORs of 1.61 (p = 0.026) and 1.62 (p = 0.044), respectively. In addition, IgG4 > 280 mg/dL showed a greater association with pancreatic cancer compared with 141-280 mg/dL, with crude OR of 2.18 (p = 0.038). Conclusions: Our study did not find a clear association between serum IgG4 levels (>140 mg/dL) and pancreatobiliary cancer. We observed that higher IgG4 levels (>280 mg/dL) may be associated with cholangiocarcinoma and pancreatic cancer, as indicated by crude ORs. However, the adjusted analysis did not demonstrate the significant association between IgG4 level > 280 mg/dL and cancer. Considering IgG4-RD as a chronic and persistent inflammatory status, it is more closely associated with inflammatory diseases than with cancer. Therefore, further long-term cohort studies are necessary to evaluate the potential role of IgG4 levels in cancer risk among these patients.

Incorporating Molecular Data Into Treatment Decision Making in Gastroesophageal and Pancreaticobiliary Cancers: Timing and Strategies.

Gastroesophageal (GE) and pancreatobiliary (PB) cancers represent a significant clinical challenge. In this context, it is critical to understand the key molecular targets within these malignancies including how they are assayed for as well as the clinical actionability of these targets. Integrating biomarkers into the standard of care presents a critical avenue for refining treatment paradigms. This review aims to explore these complexities, offering insights into the optimal sequencing of chemotherapy and targeted therapies and their utility in the management of GE and PB cancers. The timely integration of promising investigational therapies into clinical practice has broader implications around strategies for future clinical trial designs, which would pave the way for advancements in the management of GE and PB cancers. This review provides guidance in navigating the evolving landscape of GE and PB cancer care, which ultimately will drive forward progress in the field and lead to improved patient outcomes.

CAR-T Cell Therapy in Pancreatic and Biliary Tract Cancers: An Updated Review of Clinical Trials.

Pancreatic and biliary tract cancers are digestive system tumors with dismal prognosis and limited treatment options. The effectiveness of conventional surgical interventions, radiation therapy, and systemic therapy is restricted in these cases. Furthermore, clinical trials have shown that immunotherapy using immune checkpoint inhibitors has only demonstrated modest clinical results when applied to patients with pancreatobiliary tumors. This highlights the importance of implementing combination immunotherapy approaches or exploring alternative therapeutic strategies to improve treatment outcomes. We reviewed the relevant literature on chimeric antigen receptor (CAR)-T cell therapy for pancreatobiliary cancers from PubMed/Medline and ClinicalTrials.gov and retrieved the relevant data accordingly. Attention was additionally given to the examination of grey literature with the aim of obtaining additional details regarding ongoing clinical trials. We mainly focused on abstracts and presentations and e-posters and slides of recent important annual meetings (namely ESMO Immuno-Oncology Congress, ESMO Congress, ASCO Virtual Scientific Program, ASCO Gastrointestinal Cancers Symposium). CAR-T cell therapy has emerged as a promising and evolving treatment approach for pancreatic and biliary tract cancer. This form of adoptive cell therapy utilizes genetic engineering to modify the expression of specific antibodies on the surface of T cells enabling them to target specific cancer-associated antigens and to induce potent anti-tumor activity. The aim of this review is to provide an updated summary of the available evidence from clinical trials that have explored the application of CAR-T cell therapy in treating pancreatobiliary cancers. While the utilization of CAR-T cell therapy in pancreatobiliary cancers is still in its initial phases with only a limited amount of clinical data available, the field is advancing rapidly, incorporating novel technologies to mitigate potential toxicities and enhance antigen-directed tumor eradication.

Feasibility of comprehensive genomic profiling using endoscopic ultrasound-guided tissue acquisition with a 22-gauge Franseen needle.

Comprehensive genomic profiling (CGP) test for solid tumors is now increasingly utilized in clinical practice, especially in pancreatobiliary cancer, and specimens obtained by endoscopic ultrasound-guided tissue acquisition (EUS-TA) are often submitted for tissue-based CGP test. In this study, we evaluated the feasibility of EUS-TA using a 22-gauge Franseen needle for the CGP test. Consecutive patients with solid tumors who underwent EUS-TA using a 22-gauge Franseen needle, and whose tissue samples were pre-checked for suitability for CGP test, were included in this single-center, retrospective analysis. The success rates of appropriate sample collection for CGP evaluated by pathologists (1st quality control) and CGP test (2nd quality control) were evaluated. In addition, The EUS-TA slides were evaluated for the tissue area and tumor area content, using the image software. A total of 50 cases, with 78% of pancreatic cancer, were included in the analysis. A median of 3 passes of EUS-TA were performed with an adverse event rate of 4%. The success rates for 1st and 2nd quality control for CGP tests were 86% and 76%, respectively. The image analyses suggested EUS-TA specimen did not always fulfill CGP test criteria, with 18% of tissue area ≥16 mm2 and 38% of tumor area content ≥20%, even in cases with successful CGP tests. The suction method yielded a significantly larger amount of DNA but without a significant difference in the multivariate analysis. The present study demonstrated the feasibility of EUS-TA using a 22-gauge Franseen needle for CGP test.

Abstract 4980: Genomic and clinical characteristics of advanced pancreatobiliary cancer, stratified by KRAS mutation status

Abstract Mutations in KRAS are common in pancreatobiliary cancer, occurring in 90% of advanced pancreatic ductal adenocarcinomas (PDAC) and 20% of advanced cholangiocarcinomas (CCA). We analyzed clinico-genomic databases to evaluate the hypothesis that KRAS mutation status defines subsets of PDAC and CCA with similar genomic characteristics and clinical behavior. Using the genomic data of PDAC and CCA from AACR Project GENIE Cohort version 14.0-public, we analyzed the genomic landscape of four cohorts of pancreatobiliary cancer: KRAS mutated PDAC, KRAS wild-type PDAC, KRAS mutated CCA, and KRAS wild-type CCA. Excluding KRAS mutations, there were 53 gene alterations observed in &amp;gt;2.5% of cases in at least one of the four cohorts. The three most common gene alterations in each cohort were; TP53, SMAD4, and CDKN2A mutations (KRAS mutated PDAC), TP53, ARID1A, and SMAD4 mutations (KRAS wild-type PDAC), TP53 mutation, CDKN2A deletion and SMAD4 mutation (KRAS mutated CCA), and TP53, ARID1D and IDH1 mutations. (KRAS wild-type CCA) The similarity of gene alteration patterns was evaluated by principal component analysis (PCA) 3D plot and calculation of average Euclidean distance. The PCA plot suggested heterogeneous genomic profiles in KRAS wild-type CCA in contrast to relatively monotonous profiles in KRAS mutated PDAC. The average Euclidean distance between KRAS mutated CCA and KRAS wild-type CCA was significantly longer than that between KRAS mutated CCA and KRAS mutated PDAC (2.00 vs. 1.89, p &amp;lt; 0.001), suggesting that KRAS mutated CCA is more genomically related to KRAS mutated PDAC than KRAS wild-type CCA. The average Euclidean distance between KRAS mutated PDAC and KRAS wild-type PDAC was significantly shorter than that between KRAS wild-type CCA and KRAS wild-type PDAC. To compare the clinical characteristics of the four cohorts, we evaluated the data of patients with stage IV pancreatobiliary cancer, using cBioPortal. The number of cases in each cohort was 1544 (KRAS mutated PDAC), 121 (KRAS wild-type PDAC), 91 (KRAS mutated CCA), and 459 (KRAS wild-type CCA). Median overall survival (OS) was 14.7, 21.5, 10.7, and 15.4 months, respectively. Compared to KRAS wild-type CCA, KRAS mutated CCA had a significantly shorter OS (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.12 - 1.89). The OS of KRAS mutated CCA was shorter than KRAS mutated PDAC (HR 1.32, 95% CI 1.03 - 1.68). KRAS wild-type PDAC had a significantly longer OS compared to KRAS mutated PDAC. (HR 0.72, 95% CI 0.57 - 0.92) In conclusion, KRAS mutated CCA has a poor OS and a genomic landscape distinct from KRAS wild-type CCA; it is genomically more similar to KRAS mutated PDAC. KRAS wild-type PDAC has a better OS than KRAS mutated PDAC, though it was not genomically similar to KRAS wild-type CCA. Therapeutic approaches stratified by KRAS mutation status should be considered for pancreaticobiliary cancers. Citation Format: Hirotaka Miyashita, Parth S. Shah, Gabriel A. Brooks. Genomic and clinical characteristics of advanced pancreatobiliary cancer, stratified by KRAS mutation status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4980.

Single-cell transcriptome profiling of primary tumors and paired organoids of pancreatobiliary cancer

Single-cell RNA-seq (scRNA-seq) and cancer organoid model have shown promise in investigating tumor microenvironment heterogeneity and facilitating chemotherapeutic drug testing to inform treatment selection. It is still unknown whether the scRNA-seq results based on organoid can faithfully reflect the heterogeneity of primary pancreatobiliary cancer. To reveal the similarities and differences between primary tumors and their matched organoids at transcriptome level, we conducted scRNA-seq for paired primary tumors and organoids from one cholangiocarcinoma (CCA) and two pancreatic ductal adenocarcinoma (PDAC) patients. We identified inter-patient and intra-tumor heterogeneity and found that the organoids retained copy number variation (CNV) patterns of primary tumors. There was no significant difference in cancer stem cell (CSC) properties between the primary tumors and the organoids, whereas organoid from one PDAC case had increased mesenchymal-score and decreased epithelial-score compared with the primary tumors. All organoids showed a transition tendency from the classical subtype to the basal-like subtype in the transcriptional level. Organoids and primary tumors differed in metabolic and unfolded protein response (UPR) signatures. In addition, we revealed the heterogeneity of cancer associated fibroblasts (CAFs) and T cells, and explored the developmental trajectory of T cells. Our findings facilitate further understanding of organoid model and confirm its application prospects in pancreatobiliary cancer.

Failure of peritoneal lavage to prevent operative site infection and peritoneal tumor recurrence in pancreatic surgery.

Although intraoperative peritoneal lavage often is performed routinely with the aim of reducing peritoneal contamination, evidence of lavage benefit in elective pancreatic surgery is limited. We retrospectively classified patients who had undergone pancreatic surgery to groups given or not given peritoneal lavage, then comparing clinical results. This saline lavage was performed at the end of the operation. The primary endpoint was rate of surgical site infection. Frequency of peritoneal recurrence also was evaluated. Among all 104 patients in the study, incidence of infectious complications in the lavage group (n = 65) was significantly higher than in the non-lavage group (n = 39; 35% vs. 15%, P = 0.041), while incidences of postoperative complications overall and surgical site infection did not differ between lavage (80% and 26%) and non-lavage groups (67% and 10%, P = 0.162 and 0.076, respectively). Among 63 patients undergoing pancratoduodenectomy, frequencies of positive bacterial cultures of drainage fluids on postoperative days 1 and 3 were greater in the non-lavage group (P < 0.001 and P = 0.012), but surgical site infection was significantly more frequent in the lavage group (P = 0.043). Among patients with pancreatic and biliary cancers, lavage did not affect frequency of peritoneal recurrence. Intraoperative lavage did not prevent surgical site infection or peritoneal recurrence of pancreatobiliary cancer.

Intraductal neoplasms of the pancreatobiliary tract: navigating the alphabet.

Cancers of the pancreatobiliary tract are diseases with unfavourable prognoses. In the last couple of decades, two types of lesions have been described as precursors that precede pancreatobiliary cancers. These include incidental microscopic (flat) lesions known as pancreatic intra-epithelial neoplasia and biliary intra-epithelial neoplasia, and grossly visible, mass-forming lesions (tumoral intra-epithelial neoplasia) including intraductal papillary mucinous neoplasms, intraductal oncocytic papillary neoplasms, intraductal tubulopapillary neoplasms, intraductal papillary neoplasms of the bile duct and intracholecystic papillary neoplasms. Early detection and adequate treatment of these precursor lesions, especially the second group, have the potential to prevent pancreatobiliary cancer or at least improve its prognosis. In this review, we discuss their histopathology and recent updates on molecular profiling of these intraductal neoplasms of the pancreatobiliary tract.

DNA methylation-based classifier differentiates intrahepatic pancreato-biliary tumours.

Differentiating intrahepatic cholangiocarcinomas (iCCA) from hepatic metastases of pancreatic ductal adenocarcinoma (PAAD) is challenging. Both tumours have similar morphological and immunohistochemical pattern and share multiple driver mutations. We hypothesised that DNA methylation-based machine-learning algorithms may help perform this task. We assembled genome-wide DNA methylation data for iCCA (n=259), PAAD (n=431), and normal bile duct (n=70) from publicly available sources. We split this cohort into a reference (n=399) and a validation set (n=361). Using the reference cohort, we trained three machine learning models to differentiate between these entities. Furthermore, we validated the classifiers on the technical validation set and used an internal cohort (n=72) to test our classifier. On the validation cohort, the neural network, support vector machine, and the random forest classifiers reached accuracies of 97.68%, 95.62%, and 96.5%, respectively. Filtering by anomaly detection and thresholds improved the accuracy to 99.07% (37 samples excluded by filtering), 96.22% (17 samples excluded), and 100% (44 samples excluded) for the neural network, support vector machine and random forest, respectively. Because of best balance between accuracy and number of predictable cases we tested the neural network with applied filters on the in-house cohort, obtaining an accuracy of 95.45%. We developed a classifier that can differentiate between iCCAs, intrahepatic metastases of a PAAD, and normal bile duct tissue with high accuracy. This tool can be used for improving the diagnosis of pancreato-biliary cancers of the liver. This work was supported by Berlin Institute of Health (JCS Program), DKTK Berlin (Young Investigator Grant 2022), German Research Foundation (493697503 and 314905040 - SFB/TRR 209 Liver Cancer B01), and German Cancer Aid (70113922).

Using Endoscopy in the Diagnosis of Pancreato-Biliary Cancers

Pancreatic cancer and cholangiocarcinoma are life threatening oncological conditions with poor prognosis and outcome. Pancreatic cystic lesions are considered precursors of pancreatic cancer as some of them have the potential to progress to malignancy. Therefore, accurate identification and classification of these lesions is important to prevent the development of invasive cancer. In the biliary tract, the accurate characterization of biliary strictures is essential for providing appropriate management and avoiding unnecessary surgery. Techniques have been developed to improve the diagnosis, risk stratification, and management of pancreato-biliary lesions. Endoscopic ultrasound (EUS) and associated techniques, such as elastography, contrasted-enhanced EUS, and EUS-guided needle confocal laser endomicroscopy, may improve diagnostic accuracy. In addition, intraductal techniques applied during endoscopic retrograde cholangiopancreatography (ERCP), such as new generation cholangioscopy and in vivo cellular evaluation through probe-based confocal laser endomicroscopy, can increase the diagnostic yield in characterizing indeterminate biliary strictures. Both EUS-guided and intraductal approaches can provide the possibility for tissue sampling with new tools, such as needles, biopsies forceps, and brushes. At the molecular level, novel biomarkers have been explored that provide new insights into diagnosis, risk stratification, and management of these lesions.

Distress and influencing factors in pancreatobiliary cancer surgery patients

Distress and influencing factors in pancreatobiliary cancer surgery patients

Comparing per-pass performance of 2 types of needles for EUS-guided fine-needle biopsy sampling of pancreatobiliary masses in a randomized trial

EUS-guided fine-needle biopsy sampling (EUS-FNB) has largely replaced FNA for tissue diagnosis of pancreatobiliary mass lesions. However, the optimal number of passes required for the diagnosis of malignancy is not clear. We aimed to compare the per-pass performance of 2 types of fine-needle biopsy (FNB) needles for the detection of malignancy. One hundred fourteen patients referred for EUS evaluation of solid pancreatobiliary mass lesions underwent randomization between biopsy sampling with a Franseen needle and a 3-prong tip needle with an asymmetric cutting surfaces. Four passes of EUS-FNB were taken from each mass lesion. Two pathologists blinded to needle type analyzed the specimens. The final diagnosis of malignancy was made based on FNB specimen pathology, surgery, or a follow-up of at least 6 months after EUS-FNB. The sensitivity of EUS-FNB to diagnose malignancy was compared between the 2 groups. The cumulative sensitivity of detection of malignancy by EUS-FNB was calculated after each pass in each arm. Other characteristics of the specimens including cellularity and blood contents were also compared between the 2 groups. In the primary analysis, lesions categorized as suspicious on EUS-FNB were considered nondiagnostic for malignancy. Ninety-eight patients (86%) had a final diagnosis of malignancy, and 16 patients (14%) had benign disease. Four passes of EUS-FNB with the Franseen needle detected malignancy in 44 of 47 patients (sensitivity, 93.6%; 95% confidence interval [CI], 82.5-98.7) and with the 3-prong asymmetric-tip needle in 50 of 51 patients (sensitivity, 98%; 95% CI, 89.6-99.9; P= .35). Two passes of EUS-FNB detected malignancy with a sensitivity of 91.5% (95% CI, 79.6-97.6) with the Franseen needle and 90.2% (95% CI, 78.6-96.7) with the 3-prong asymmetric-tip needle. The cumulative sensitivities at pass 3 were 93.6% (95% CI, 82.5-98.6) and 96.1% (95% CI, 86.5-99.5), respectively. Samples collected with the Franseen needle had significantly higher cellularity than samples collected with the 3-prong asymmetric-tip needle (P< .01). However, no difference as found between the 2 types of needles in term of specimen bloodiness. No significant differences were found in the diagnostic performance of the Franseen needle versus the 3-prong asymmetric-tip needle in patients with suspected pancreatobiliary cancer. However, the Franseen needle yielded higher cellularity of the specimen. Two passes of EUS-FNB are required to detect malignancy with at least 90% sensitivity with either type of needle. (Clinical trial registration number: NCT04975620.).