Periampullary Cancer Research Articles

Management Outcome Assessment of Obstructive Jaundice and Associated Factor from Yekatit 12 Hospital Medical College Addis Ababa, Ethiopia

Background: Obstructive jaundice is common problem in daily clinical practice and among the most challenging conditions for planning current and future management. The causes are varied, but it is most commonly due to choledocholithiasis; benign strictures of the biliary tract, pancreaticobiliary malignancies, and metastatic disease. Surgery in patients with obstructive jaundice is generally considered to be associated with a higher incidence of complication and mortality. Objective: The purpose of the study was to assess outcome of obstructive jaundice and associated factors at Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia. Methods: A longitudinal study design was used to conduct the study and all patients admitted to the surgical wards for whom surgery was done for obstructive jaundice from May 1, 2022 to April 30, 2023 G.C were included. Chi square fisher’s exact test was used to see the association between obstructive jaundice outcome and independent variables, significance was determined by p-value <0.05. Results: In these study 31 patients were enrolled and the mean age was 49.03 SD±16.16 years. Of patients diagnosed to have obstructive jaundice majority are due to benign causes. Common bile duct stones are the commonest benign condition accounting 88.2% and peri-ampullary cancers are the most frequent (48.4%) cause of obstructive jaundice from malignant condition. Among patients operated 38.7% were underwent bypass procedures. Post-operative complications occurred in 9 (24.3. %) of patients, with surgical site infection being commonest (55.5%). Significant association was identified between types of post-operative complication and management outcome (P=0.034). Conclusion: The most common cause of obstructive jaundice was bile duct stone. Post-operative complications were significantly associated with management outcome of obstructive jaundice.

Modern endovascular treatment strategies in the management of postpancreatectomy haemorrhage in patients with pancreatic cancer

Objective — to determine the occurrence and management of postpancreatectomy haemorrhage in pancreatic cancer patients, as well as to identify effective treatment strategies to improve patient outcomes.
 Materials and methods. From January 2010 to December 2022, 878 patients who underwent radical pancreatic resections for malignant tumours were retrospectively analysed.
 Patients were divided into two groups. The main group consisted of 500 patients who were treated in the clinic from 2016 to 2022. In the main group, postpancreatectomy haemorrhage occurred in 31 (6.2%) patients. These patients were treated according to our diagnostic and treatment algorithm, using endovascular techniques as the first step of treatment. The comparison group consisted of 378 patients who were treated in our department from 2010 to 2015. In the comparison group, postpancreatectomy haemorrhage occurred in 20 (5.3%) patients. These patients were treated according to standard approaches. The definition of postpancreatectomy haemorrhage proposed by the International Study Group of Pancreatic Surgery was used in our research.
 Results. Out of 31 patients in the main group, 16 (51.6%) had endovascular embolisation. A total of 10 patients underwent endovascular occlusion, whereas 5 patients experienced cessation of bleeding with the use of a stent graft. Angiography did not detect the cause of bleeding in 3 (9.7%) individuals in the main group. They underwent laparotomy with subsequent haemostasis. 11 (35.5%) patients underwent open surgical interventions. In the main group, one (3.2%) patient died due to the emergence of infectious complications after laparotomy and subsequent haemostasis. 2 (10%) patients underwent endovascular haemostasis, while 15 (75%) patients underwent relaparotomy with haemostasis. In the comparison group, 6 (30%) patients died after open relaparotomies.
 Conclusions. The initial course of action for managing postpancreatectomy haemorrhage involves the implementation of endovascular techniques, wherein stent grafts are used to address bleeding originating from the main blood vessel. The application of advanced treatment strategies that optimised the use of minimally invasive endovascular techniques resulted in a notable decrease in the mortality rate associated with postpancreatectomy bleeding from 30% to 3.2% (χ2=7.3, p=0.006). Ensuring 24/7 access to endovascular treatment, which can be provided exclusively in high‑volume centres, is imperative for improving the treatment outcomes of patients with pancreatic and periampullary cancer.

Poly (Adp-Ribose) Polymerase-1 (PARP-1) Is a Good Prognostic Marker for Pancreatic/Periampullary Cancers.

Periampullary cancer (PAC) is highly aggressive with no effective adjuvant therapy or prognostic markers. Recently, poly (ADP-ribose) polymerase-1 (PARP-1) has emerged as a target in solid cancers, and its relationship with epithelial-mesenchymal transition (EMT) has been observed. However, the relationship between PARP-1 and EMT in PAC has not explored well. We assessed the prognostic significance of PARP-1 in 190 PACs patients and correlated it with EMT markers, including FGF8, FGFR4, MMP2, MMP3, Snail, and ZEB1. Immunohistochemistry for PARP-1 and EMT markers was performed using a tissue microarray. PARP-1 and FGF8 expression were associated with better survival unlike other solid cancers ( P = 0.006 and P = 0.003), and MMP3 and ZEB1 expression were associated with poor prognosis in multivariate and survival analyses ( P = 0.009 and P < 0.001). In addition, PARP-1 is related negatively to Snail but not related with other EMT markers, implying an independent mechanism between PARP-1 and EMT in PACs. PARP-1 and FGF8 are independent good survival markers in PACs unlike other solid cancers. PARP-1 and FGF8 in PACs could not be related to the EMT pathway but must be rather understood in light of similar cancer-protective roles. Further studies are required on EMT-associated immune markers in PACs.

Abstract 6884: Evaluating tumor-infiltrating immune cells helps predicting prognosis in biliary tract cancer

Abstract Background: The tumor microenvironment (TME) is composed of not only cancer cells but also an extracellular matrix and many types of non-cancerous cells, including fibroblasts and immune cells. In recent years, infiltrating immune cells in TME are known as a predictor of chemotherapy and immunotherapy effectiveness. The purpose of this study is to evaluate infiltrations of lymphocytes and macrophages in biliary tract cancers (BTCs). Methods: Clinical data and tissues were obtained from 130 patients who underwent surgical treatment for BTCs (intrahepatic, perihilar, and distal bile duct cancer, gallbladder cancer, and ampullary cancer) at our institution between 2001 and 2017.The immunohistochemical evaluation was performed to evaluate the number of CD8+ T cells, CD4+ T cells and FOXP3+ T cells and CD68+ Macrophages around the tumor cells. We defined Immunoscore based on the status of infiltrating immune cells. With CD8-high, CD4-high, and FOXP3-high TILs and CD68-low TAMs as one factor, the number of factors was counted in each case, and Immunoscore was assigned a score of 5 stages, from 0 to 4. It was high for the score of 3-4 and low for the score of 0-2. Also, to evaluate the correlation with TME and systemic inflammatory reaction, we examined blood inflammatory biomarker from peripheral blood samples. Results: A total of 59 cases had high Immunoscore and 71 cases had low Immunoscore. Patients with high Immunoscore showed significantly superior overall survival (OS) and recurrence free survival (RFS) than those with low Immunoscore (median OS 60.8 vs. 26.4 months, p = 0.001; median RFS not reached vs. 17.2 months, p &amp;lt; 0.001). For OS, low Immunoscore, positive lymph node metastasis, presence of distant metastasis, and high serum CA19-9 level were independent poor prognostic factors (hazards ratio 2.05, 3.48, 1.7, and 2.05; p = 0.01, p = 0.005, p = 0.05, and p = 0.01, respectively). For RFS, low Immunoscore, T classification of pT3-4, and presence of distant metastasis were independent poor prognostic factors with hazards ratio of 2.41 (p = 0.001), 2.16 (p = 0.005), and 3.58 (p = 0.005), respectively. Patients with high preoperative Neutrophil-to-lymphocyte ratio (NLR) had a significantly lower average number of CD8+ T cells as compared to patients with low NLR (p = 0.02). Preoperative NLR was associated with infiltrating CD8+ T cells in TME. Conclusions: High Immunoscore group had significantly longer OS and RFS and was an independent good prognostic factor. Also, infiltrating CD8+ T cells in TME correlated preoperative NLR. Our findings indicated that in biliary tract cancer, the evaluation of infiltrating immune cells in TME was useful to predict patient prognosis, and preoperative NLR may predict the tumor infiltrating CD8+ T cells. Citation Format: Kousuke Hatta, Ryota Tanaka, Kenjiro Kimura, Shinpei Eguchi, Go Ohira, Hiroji Shinkawa, Kohei Nishio, Masahiko Kinoshita, Shigeaki Kurihara, Shuhei Kushiyama, Takahito Kawaguchi, Naoki Tani, Koichi Nakanishi, Mizuki Yoshida, Takeaki Ishizawa. Evaluating tumor-infiltrating immune cells helps predicting prognosis in biliary tract cancer [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 6884.

Abstract 5197: Identification of novel molecular biomarkers for predicting postoperative recurrence of ampulla of Vater carcinoma

Abstract Background: Ampulla of Vater (AoV) carcinoma is a rare tumor that accounts for 20 % of periampullary cancers. Surgical resection is the only treatment that can expect cure of disease, and there is still an unmet need to predict postoperative recurrence. In this study, we investigated the novel molecular biomarkers that can predict the risk of recurrence after surgery with AoV carcinoma. Methods: In this retrospective study, we collected the surgically resected tissue and medical records of patients who were diagnosed with AoV carcinoma at Samsung Medical Center from January 2005 to December 2020. Patients were classified patients according to the initial stage and experience of tumor recurrence. Whole transcriptomic analysis using primary AOV tumor and recurred tumor tissue samples was conducted to identify the molecular biomarker for tumor recurrence. Results: A total of 40 tumor tissue from primary site in non-recurrence group, 22 tumor tissue from primary site in recurrence group, and paired 22 tumor tissue from recurrence site were analyzed. A total of 1005 genes differentially expressed between primary tumor of non-recurrence group and recurrence group were found. Gene set enrichment analysis showed that pathways related to fatty acid metabolism, adipogenesis, oxidative phosphorylation, and hypoxia were upregulated, and pathways associated with interferon gamma response, and mTOR signaling were downregulated in recurrence group. These pathways were significantly affecting the recurrence free survival which was verified with TCGA data, and we further identified some candidate genes including PIM3, IGFBP4, SLC19A1, HIF1A and CXCL11 to predict tumor recurrence . Moreover, we found candidates for single gene level biomarkers to predict early tumor recurrence in N0 stage. Low expression of UQCC3 and high expression of CLCNKB was related to early tumor recurrence. Conclusions: We found the candidates for novel molecular level biomarker to predict postoperative recurrence of AoV carcinoma. In the future, it is necessary to develop a predictive model for the risk of recurrence after surgical resection for AoV carcinoma. Citation Format: Hyemin Kim, Jin Ho Choi, Hyoung-oh Jeong, Aryoung Kim, Se-Hoon Lee, Kwang Hyuck Lee, Kyu Taek Lee, Jong Kyun Lee, Semin Lee, Joo Kyung Park. Identification of novel molecular biomarkers for predicting postoperative recurrence of ampulla of Vater carcinoma [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 5197.

Abstract 5150: An immunohistochemical survey of predictive biomarkers for immunotherapy in ampullary carcinoma identifies strata with unique prognostic signatures

Abstract Introduction: Carcinomas located in the ampulla of Vater are a low incidence malignancy. Therapeutic options for early stage disease largely consist of pancreaticoduodenectomy followed by adjuvant chemotherapy with or without radiation. We explored the localization of CD8 and CD3 positive cells in addition to PDL-1 staining and mismatch repair deficiency markers to gain insight into the potential applicability of immunotherapy for patients with this disease. Methods: Excess material from clinically diagnosed cases collected between 1997 - 2013 were used to construct a duplicate 0.6mm core tissue microarray (TMA). All cases were derived from the Vancouver Coastal Health Region. Immunohistochemical staining was performed with the following markers: CD8, CD3, PD-L1, and the mismatch repair (MMR) markers: MSH2, MSH6, MLH1 and PMS2. CD3 and CD8 were quantified using localization within the tissue. PD-L1 was considered positive with &amp;gt;1% of cells stating positive. MMR markers were confirmed using full section and cases with convincing loss of any MMR marker were considered MMR deficient. Univariable disease specific survival analysis was performed to identify unique prognostic signatures and contingency analysis was performed to identify co-expression of the aforementioned biomarkers. Results: Ninety-eight cases were evaluable for all markers. The median age of the cohort was 69 [41 - 84] years. Forty-two percent were female. Adjuvant chemotherapy was provided to 15% of patients with the remainder undergoing post-surgical observation. Almost 90% were pT3 or pT4 and 48% had regional lymph node metastasis. CD3+ T-cells were either localized in the tumor stroma only (59%) or in both the stroma and epithelial compartments (41%). CD8+ T-cells were principally located in the stroma (66%) and both the epithelial and stroma (24%). Ten percent of cases had no CD8+ T-cells. PD-L1 staining was found in 10% of cases. MMR deficiency was found in 5% of cases. Improved prognostic signatures were found for cases with CD3+ and CD8+ T-cells in both the epithelial and stromal compartments (p &amp;lt;= 0.02). A trend towards a negative prognostic signature was observed for MMR deficient cases and for PD-L1 positive cases. The only significant positive association between biomarkers was found for CD3+ and CD8+ in both the epithelial and stromal compartments. Conclusions: The results of this analysis suggest that enhancement of an immune response yielding an increase CD3+ and CD8+ T-cells in the epithelial compartment may have a beneficial effect on prognosis. The relative scarcity of MMR deficiency in this disease is within the expected prevalence supported by other studies. Further exploration of the potential role of immunotherapy in immune enhanced subgroups of ampullary cancers is warranted. Citation Format: Steve E. Kalloger, Joanna Karasinska, James Topham, Daniel J. Renouf, David F. Schaeffer. An immunohistochemical survey of predictive biomarkers for immunotherapy in ampullary carcinoma identifies strata with unique prognostic signatures [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 5150.

Periampullary cancer and neurological interactions: current understanding and future research directions.

Periampullary cancer is a malignant tumor occurring around the ampullary region of the liver and pancreas, encompassing a variety of tissue types and sharing numerous biological characteristics, including interactions with the nervous system. The nervous system plays a crucial role in regulating organ development, maintaining physiological equilibrium, and ensuring life process plasticity, a role that is equally pivotal in oncology. Investigations into nerve-tumor interactions have unveiled their key part in controlling cancer progression, inhibiting anti-tumor immune responses, facilitating invasion and metastasis, and triggering neuropathic pain. Despite many mechanisms by which nerve fibers contribute to cancer advancement still being incompletely understood, the growing emphasis on the significance of nerves within the tumor microenvironment in recent years has set the stage for the development of groundbreaking therapies. This includes combining current neuroactive medications with established therapeutic protocols. This review centers on the mechanisms of Periampullary cancer's interactions with nerves, the influence of various types of nerve innervation on cancer evolution, and outlines the horizons for ongoing and forthcoming research.

Assessment of quality of life in patients after surgery for pancreatic and periampullary malignancies. Systematic review

Aim. To analyze the current methods of life quality assessment in patients undergoing surgical treatment for pancreatic and periampullary cancer, to study the influence of surgical treatment and postoperative complications on the quality of life. Materials and methods. The study involves a systematic review of the literature available in MEDLINE, Embase and e-Library electronic databases for 2015–2022. The methodology of the systematic review is reflected in the study protocol, designed according to PRISMA guidelines. Results. The systematic review embraces 26 studies including 4937 patients met the inclusion criteria. The present study examines design and objectives, survey forms, methods of surgical interventions and drug treatment, survey frequency and data collection methodology, risk of systematic error, etc. Conclusion. When choosing a survey form, most authors favored EORTC QLQ-C30 and EORTC QLQ-PAN26. Even the most complex surgeries such as pancreaticoduodenal resection and pancreatectomy can provide a satisfactory quality of life. Many current studies appear methodologically-challenged thereby increasing the risk of systematic error and reducing the reliability of the data. The quality of life of patients in this category is to be further investigated, the optimal principles and methodology of such studies are to be standardized, in particular, in Russian healthcare system.

Association between Cholecystectomy and the Incidence of Pancreaticobiliary Cancer after Endoscopic Choledocholithiasis Management.

(1) Background: Previous studies have raised concerns about a potential increase in pancreaticobiliary cancer risk after cholecystectomy, but few studies have focused on patients who undergo cholecystectomy after receiving endoscopic retrograde cholangiopancreatography (ERCP) for choledocholithiasis. This study aims to clarify cancer risks in these patients, who usually require cholecystectomy, to reduce recurrent biliary events. (2) Methods: We conducted a nationwide cohort study linked to the National Health Insurance Research Database, the Cancer Registry Database, and the Death Registry Records to evaluate the risk of pancreaticobiliary cancers. All patients who underwent first-time therapeutic ERCP for choledocholithiasis from 2011 to 2017 in Taiwan were included. We collected the data of 13,413 patients who received cholecystectomy after endoscopic retrograde cholangiopancreatography and used propensity score matching to obtain the data of 13,330 patients in both the cholecystectomy and non-cholecystectomy groups with similar age, gender, and known pancreaticobiliary cancer risk factors. Pancreaticobiliary cancer incidences were further compared. (3) Results: In the cholecystectomy group, 60 patients had cholangiocarcinoma, 61 patients had pancreatic cancer, and 15 patients had ampullary cancer. In the non-cholecystectomy group, 168 cases had cholangiocarcinoma, 101 patients had pancreatic cancer, and 49 patients had ampullary cancer. The incidence rates of cholangiocarcinoma, pancreatic cancer, and ampullary cancer were 1.19, 1.21, and 0.3 per 1000 person-years in the cholecystectomy group, all significantly lower than 3.52 (p < 0.0001), 2.11 (p = 0.0007), and 1.02 (p < 0.0001) per 1000 person-years, respectively, in the non-cholecystectomy group. (4) Conclusions: In patients receiving ERCP for choledocholithiasis, cholecystectomy is associated with a significantly lower risk of developing pancreaticobiliary cancer.

"Five steps four quadrants" modularized en bloc dissection technique for accessing hepatic hilum lymph nodes in laparoscopic pancreaticoduodenectomy.

Although en bloc dissection of hepatic hilum lymph nodes has many advantages in radical tumor treatment, the feasibility and safety of this approach for laparoscopic pancreaticoduodenectomy (LPD) require further clinical evaluation and investigation. To explore the application value of the "five steps four quadrants" modularized en bloc dissection technique for accessing hepatic hilum lymph nodes in LPD patients. A total of 52 patients who underwent LPD via the "five steps four quadrants" modularized en bloc dissection technique for hepatic hilum lymph nodes from April 2021 to July 2023 in our department were analyzed retrospectively. The patients' body mass index (BMI), preoperative laboratory indices, intraoperative variables and postoperative complications were recorded. The relationships between preoperative data and intraoperative lymph node dissection time and blood loss were also analyzed. Among the 52 patients, 36 were males and 16 were females, and the average age was 62.2 ± 11.0 years. There were 26 patients with pancreatic head cancer, 16 patients with periampullary cancer, and 10 patients with distal bile duct cancer. The BMI was 22.3 ± 3.3 kg/m², and the median total bilirubin (TBIL) concentration was 57.7 (16.0-155.7) µmol/L. All patients successfully underwent the "five steps four quadrants" modularized en bloc dissection technique without lymph node clearance-related complications such as postoperative bleeding or lymphatic leakage. Correlation analysis revealed significant associations between preoperative BMI (r = 0.3581, P = 0.0091), TBIL level (r = 0.2988, P = 0.0341), prothrombin time (r = 0.3018, P = 0.0297) and lymph node dissection time. Moreover, dissection time was significantly correlated with intraoperative blood loss (r = 0.7744, P < 0.0001). Further stratified analysis demonstrated that patients with a preoperative BMI ≥ 21.9 kg/m² and a TIBL concentration ≥ 57.7 μmol/L had significantly longer lymph node dissection times (both P < 0.05). The "five steps four quadrants" modularized en bloc dissection technique for accessing the hepatic hilum lymph node is safe and feasible for LPD. This technique is expected to improve the efficiency of hepatic hilum lymph node dissection and shorten the learning curve; thus, it is worthy of further clinical promotion and application.

Different Periampullary Types and Subtypes Leading to Different Perioperative Outcomes of Pancreatoduodenectomy: Reality and Not a Myth; An International Multicenter Cohort Study.

This international multicenter cohort study included 30 centers. Patients with duodenal adenocarcinoma (DAC), intestinal-type (AmpIT) and pancreatobiliary-type (AmpPB) ampullary adenocarcinoma, distal cholangiocarcinoma (dCCA), and pancreatic ductal adenocarcinoma (PDAC) were included. The primary outcome was 30-day or in-hospital mortality, and secondary outcomes were major morbidity (Clavien-Dindo 3b≥), clinically relevant post-operative pancreatic fistula (CR-POPF), and length of hospital stay (LOS). Results: Overall, 3622 patients were included in the study (370 DAC, 811 AmpIT, 895 AmpPB, 1083 dCCA, and 463 PDAC). Mortality rates were comparable between DAC, AmpIT, AmpPB, and dCCA (ranging from 3.7% to 5.9%), while lower for PDAC (1.5%, p = 0.013). Major morbidity rate was the lowest in PDAC (4.4%) and the highest for DAC (19.9%, p < 0.001). The highest rates of CR-POPF were observed in DAC (27.3%), AmpIT (25.5%), and dCCA (27.6%), which were significantly higher compared to AmpPB (18.5%, p = 0.001) and PDAC (8.3%, p < 0.001). The shortest LOS was found in PDAC (11 d vs. 14-15 d, p < 0.001). Discussion: In conclusion, this study shows significant variations in perioperative mortality, post-operative complications, and hospital stay among different periampullary cancers, and between the ampullary subtypes. Further research should assess the biological characteristics and tissue reactions associated with each type of periampullary cancer, including subtypes, in order to improve patient management and personalized treatment.

Anomalies of the right hepatic artery in periampullary cancer treatment: are pathological and clinical outcomes different? A single tertiary referral center retrospective analysis.

Anomalies of the right hepatic artery (RHA) may represent an additional challenge in pancreatoduodenectomy (PD). The aim of this study is to assess the potential impact of variations in hepatic arterial anatomy on perioperative outcomes. PDs performed for periampullary malignancies between 2017 and 2022 were retrospectively enrolled and subdivided in two groups: modal pattern of vascularization (MPV) and anomalous pattern of vascularization (APV). A propensity score matching (PSM) analysis was conducted to homogenize the two study populations. The two groups were then compared in terms of perioperative outcomes and pathological findings. Thirty-eight patients (16.3%) out of 232 presented a vascular anomaly: an accessory RHA in 7 cases (3%), a replaced RHA in 26 cases (11.2%), and a replaced HA in 5 cases (2.1%). After PSM, 76 MPV patients were compared to the 38 APV patients. The incidence rate of postoperative complications was comparable between the two study populations (p=0.2). Similarly, no difference was detected in terms of histopathological data, including margin status. No difference was noted in terms of intraoperative hemorrhage and vascular resection. When PDs are performed in high-volume centers, the presence of an APV of the RHA does not relate to a significant impact on perioperative complications. Moreover, no influence was noted on histopathological findings.

Feasibility of new-generation endocytoscopy for the real-time diagnosis of ampullary lesions: A pilot study (with video).

An early and accurate diagnosis of ampullary neoplasia is crucial; however, sampling bias is still a major concern. New-generation endocytoscopy enables real-time visualization of cellular structures and enables an accurate pathological prediction; however, its feasibility for small ampullary lesions has never been investigated. We developed a novel endocytoscopic (EC) classification system for ampullary lesions after an expert review and agreement from five experienced endoscopists and one pathologist. We then consecutively enrolled a total of 43 patients with an enlarged ampulla (<3cm), all of whom received an endocytoscopic examination. The feasibility of endocytoscopy was evaluated, and the performance of the EC classification system was then correlated with the final histopathology. In five cases (11.6%), the endocytoscope could not approach the ampulla, and these cases were defined as technical failure. Among the remaining 38 patients, 8 had histopathology-confirmed adenocarcinoma, 15 had adenoma, and 15 had non-neoplastic lesions. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the EC classification system to diagnose ampullary neoplasias were 95.7%, 86.7%, 91.7%, 92.9%, and 92.1%, respectively. Moreover, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the EC classification to diagnose ampullary cancer were 62.5%, 100%, 100%, 90.9%, and 92.1%, respectively. One case with intra-ampullary papillary-tubular carcinoma was classified as having a non-neoplastic lesion by endocytoscopy. Endocytoscopy and the novel EC classification system demonstrated good feasibility to discriminate ampullary neoplasias from non-neoplastic lesions and may be useful for optical biopsies of clinically suspicious ampullary lesions.

Projected Incidence of Hepatobiliary Cancers and Trends Based on Age, Race, and Gender in the United States.

Identifying the projected incidence of hepatobiliary cancers and recognizing patient cohorts at increased risk can help develop targeted interventions and resource allocation. The expected incidence of subtypes of hepatobiliary cancers in different age groups, races, and genders remains unknown. Historical epidemiological data from the Surveillance, Epidemiology, and End Results (SEER) database was used to project future incidence of hepatobiliary malignancies in the United States and identify trends by age, race, and gender. Patients ≥18 years of age diagnosed with a hepatobiliary malignancy between 2001 and 2017 were included. US Census Bureau 2017 National Population projects provided the projected population from 2017 to 2029. Age-Period-Cohort forecasting model was used to estimate future births cohort-specific incidence. All analyses were completed using R Statistical Software. We included 110381 historical patients diagnosed with a hepatobiliary malignancy between 2001 and 2017 with the following subtypes: hepatocellular cancer (HCC) (68%), intrahepatic cholangiocarcinoma (iCCA) (11.5%), gallbladder cancer (GC) (8%), extrahepatic cholangiocarcinoma (eCCA) (7.6%), and ampullary cancer (AC) (4%). Our models predict the incidence of HCC to double (2001 to 2029) from 4.5 to 9.03 per 100,000, with the most significant increase anticipated in patients 70-79 years of age. In contrast, incidence is expected to continue to decline among the Asian population. Incidence of iCCA is projected to increase, especially in the white population, with rates in 2029 double those in 2001 (2.13 vs. 0.88 per 100,000, respectively; p < 0.001). The incidence of GC among the black population is expected to increase. The incidence of eCCA is expected to significantly increase, especially among the Hispanic population, while that of AC will remain stable. The overall incidence of hepatobiliary malignancies is expected to increase in the coming years, with certain groups at increased risk. These findings may help with resource allocation when considering screening, treatment, and research in the coming years.

Establishment and characterization of DPC-X4: a novel mixed-type ampullary cancer cell line.

Mixed-type ampullary cancer is a distinct subtype of ampullary cancer that manifests a merging of the biological characteristics of both intestinal and pancreaticobiliary subtypes. The absence of established cell lines specific to this subtype has resulted in a concomitant scarcity of research on its tumorigenic mechanisms and the development of novel therapeutic modalities. The present study achieved the successful establishment of a novel mixed-type ampullary cancer cell line, designated DPC-X4 through primary culture techniques. Subsequent analyses pertaining to phenotypic characteristics, molecular profiling, biomarker identification, and histological features validated the DPC-X4 cell line as a potent model for delineating the pathogenesis of mixed-type ampullary cancer and facilitating the development of new pharmacological agents. This newly established cell line was subjected to continuous cultivation for 1year, with stable passaging for over 50 generations. Notably, the DPC-X4 cell line manifested typical morphological features associated with epithelial tumors. Furthermore, the population doubling time for the DPC-X4 cell line was determined at 70h. Short tandem repeat (STR) analysis confirmed that the DPC-X4 cell line exhibited a high genetic concordance with the primary tumor from the patient. Karyotypic profiling indicated an abnormal sub-triploid karyotype, with representative karyotypes of 57, XXY inv (9), 14p + , 15p + , der (17), + mar. The DPC-X4 cell line demonstrated a high capacity for efficient organoid formation under suspension culture conditions. In addition, the subcutaneous inoculation of DPC-X4 cells into NXG mice led to the formation of xenografted tumors. The results of drug sensitivity testing indicated that DPC-X4 cells were sensitive to paclitaxel and resistant to oxaliplatin, 5-fluorouracil, and gemcitabine. Immunohistochemistry revealed positive expression of CK7, CK19, and CK20 in DPC-X4 cells, while CDX2 demonstrated negative expression. In addition, positive expression of E-cadherin and vimentin was identified in DPC-X4 cells, with a proliferation index indicated by Ki-67 at 70%. The findings of our study establish DPC-X4 as a novel mixed-type ampullary cancer cell line, which can serve as a potential experimental model for exploring the pathogenesis of ampullary cancer and the development of therapeutic drugs.

Outcomes in patients with pancreatic and ampullary cancer whose tumors harbor pathogenic APC mutations.

693 Background: APC (adenomatous polyposis coli) is master regulator of the WNT signaling and beta-catenin pathway. Pathogenic (path) mutations in APC are well known for their connection to familial adenomatous polyposis, but germline (G) mutations in APC can give rise to other cancers, and somatic (S) mutations in APC can be found in multiple cancer subtypes. The clinical relevance for tumors that harbor path APC mutations is unknown. Methods: An established database of patients whose tumors have undergone genetic testing (Next-generation DNA sequencing, NGS) was queried for the presence of an APC mutation. Each APC mutation identified was assessed using the NCI Clinvar data base for determination of a path/likely path APC mutation. Patient/disease characteristics and treatment (tx) information were captured from electronic medical record review. Median overall survival (OS) was defined from the time of diagnosis of advanced/metastatic disease until death. Median time to progression (TTP) for each tx regimen was defined from the initiation of tx until documented disease progression. Results: A database of over 13000 patients entered from 2018 to present included 133 patients (1%) with G- or S-APC mutations, of which 41 were identified as path/likely path. Of the 41 patients, 56% were male, 73% were Caucasian and 24% African Americans, with a median age of 67 (range 34-90). Only 32% of patients had known G-APC mutations, but 34% had a second primary cancer, and 37% had a family history of known G-APC mutation-associated cancers. Only one patient had clinical manifestations of a polyposis syndrome. Of the 13 patients with known G-APC mutations, clinical characteristics were similar to the larger group, except that 100% of the G-APC-mutated patients were Caucasian, and the rate of family history of APC-associated cancers was 54%. Fifty-four percent of the overall group of 41 patients had a pathological diagnosis of pancreatic cancer, while the remaining 46% were ampullary or duodenal cancers. (Only 2 patients [5%] had tail of the pancreas cancers). Of the 37 patients who had somatic tumor NGS, only 70% harbored a KRAS gene mutation. For the OS analysis (n=24), the mOS was 11.7 months (range 5.2 – 56.9). Of the 22 patients evaluable for TTP, the mTTP for 5FU-based tx was 5.8 months, and 6.4 months for gemcitabine-based tx. Conclusions: APC-mutated pancreatic and ampullary cancers are uncommon, but exhibit survival rates, as well as TTP on both 5FU and gemcitabine-based txs that are similar to that seen with most pancreatic adenocarcinomas. However, 30% of APC-mutated cancers are KRAS wild type, and may harbor other driving mutations. As the loss of APC function triggers an accumulation of beta-catenin, targeted therapies that inhibit beta-catenin-regulated transcription and downregulate WNT-related signaling could be a promising tx approach for patients whose tumors harbor path/likely path APC mutations.

Role of adjuvant chemotherapy in patients with stage II-III ampullary cancer.

508 Background: Survival benefits for patients (pts) with ampullary cancer (AC) on adjuvant chemotherapy (ACT) remain unknown. Some studies support post-operative treatment, while others state the opposite. Also, there are no clear evidence indicating that histopathological types (pancreaticobiliary (PB-type) and intestinal (IN-type)) can be used to guide the adjuvant setting. The aim of this study is to assess the ACT efficacy in different histopathological types of ampullary adenocarcinoma (pathological stages II-III). Methods: 81 pts were enrolled in the study in total, 45.7% were males, median age was 66.0 (range 43.9-83.8) years. 36.9% were IN-type, 50.8% – PB-type, and 12.3% – mixed. Almost all (97.5%) pts underwent Whipple procedure. 50 pts (61.7%) received ACT: 78.0% – 5-FU-based regimen and 22.0% – gemcitabine-based. Results: There was no clinical benefit in pts administered with ACT in terms of overall survival (OS): median OS was 55.5 months versus 43.6 month in observation arm; p=0.93. The ACT (FU-based or gemcitabine-based) did not correlate to improve OS in patients with IN-type: 38.0 months in patients who received ACT versus 30.5 months in those who did not; p=0.75. The ACT has shown better survival benefit in patients with PB-type compared to observation, however there was no statistical difference: 21.1 and 43.6 months, respectively; p=0.52. 5-FU-based ACT did not show any benefits compared to gemcitabine-based therapy in this subgroup. Conclusions: The use of adjuvant chemotherapy (FU-based or gemcitabine-based) in patients with II-III stage ampullary cancer was not associated with improved overall survival in our trial. There was no clinical benefit from addition of ACT either despite the heterogeneity of the tumor tissue origin (IN-type or PB-type).

Clinical characteristics and the course of hepatobiliary and pancreatic malignant tumors with high microsatellite instability after pembrolizumab administration: A multicenter observational study.

459 Background: The Keynote-158 trial have resulted in an expanded approval for pembrolizumab (Pem) in solid tumors with high microsatellite instability (MSI-H). In the trial, Pem was administered to patients with MSI-H solid tumors, excluding colorectal cancer, and the overall response rate (ORR) was 34%. However, the ORR for pancreatic (PANC) and biliary tract (BT) cancer were 19% (4/22 cases) and 41% (9/22 cases), respectively, suggesting the possibility of varying treatment efficacy by the primary tumor site. In this study, we aimed to clarify the clinical characteristics of patients with MSI-H and the efficacy of Pem administration in hepatobiliary and pancreatic (HBP) cancers. Methods: A multicenter observational study of patients with HBP cancer with MSI-H was conducted from March 2020 to March 2023. This study consists of prospective and retrospective cohorts. We evaluated the efficacy of PEM administration in patients with PANC and BT, respectively. Results: We enrolled 51 patients, including 32 in the prospective cohort; males comprised 51% of the patients. The BT, PANC, and liver were the primary sites in 26, 24, and 1 patients, respectively. MSI-H diagnostic methods were the MSI kit (FALCO) and comprehensive genome profile in 43 (84%) and 8 (16%) patients, respectively. Intrahepatic cholangiocarcinoma (ICC) was the most common cancer in BT tumor; ICC was observed 13 (50%) patients, followed by perihilar, gallbladder, and distal bile duct (including ampullary cancer) cancers in 6, 4, and 3 patients, respectively. Some rare histological types were observed, two patients had neuroendocrine carcinoma and one had hepatoid carcinoma in PANC. One had an undifferentiated carcinoma in BT. Five and six patients with PANC and BT tumors, respectively, had one or more first-degree relatives with lynch syndrome-related disease. Pem was administered to 96% and 88% of the patients with PANC and BT tumors, respectively. The ORR was 30% in PANC and 73% in BT tumors (p=0.003). In BT tumor, three patients demonstrated complete response as follows: two with ICC and one with perihilar cholangiocarcinoma. The median progression-free survival was 3.2 months (95% confidence interval [CI], 1.3–14.4) and 16.3 months (95% CI, 8.7 to not reached) in patients PANC and BT tumors (p=0.08), respectively. Grade 3/4 immune-related adverse events occurred in 13% and 29% of the patients with PANC and BT tumors, respectively. Conclusions: ICC was the most common BT cancer with MSI-H. Pem was significantly more effective in BT tumors than in PANC tumors, with higher ORR. Clinical trial information: UMIN000040591 .

Abstract C030: Serum levels and tumor tissue organization of decorin in pancreatic cancer: Links to chemoresistance and disease aggressiveness

Abstract Pancreatic cancer has nearly paralleling incidence and mortality rates. Only 15-20% of the tumors are resectable at presentation, and for the majority of patients the situation is palliative. Treatment options are limited to standard chemotherapy, and tumor response is often transient. The longitudinal observational clinical study Chemotherapy, Host response And Molecular dynamics in Periampullary cancer (CHAMP) aims to contribute with new insights on this devastating disease through longitudinal blood sampling during adjuvant and palliative chemotherapy and comprehensive analysis of tissue from resected as well as postmortem sampled tumor tissue. In the present study, encompassing the first 100 patients enrolled in the CHAMP study, 92 serum proteins related to inflammation and cancer were analyzed by proximity extension assay in on-treatment blood samples from baseline to six months. The results revealed that the small leucin-rich proteoglycan decorin was among the top up-regulated proteins during chemotherapy. After three months of treatment, high levels of serum decorin were significantly associated with a shorter overall survival (log rank p = 0.005). Decorin expression was also assessed by immunohistochemistry in resected tumors from 25 patients and in postmortem sampled primary tumors and metastases from 9 patients. In the latter, particularly strong expression of decorin, both in the tumor cells and in the stroma, was denoted in cases with a short overall survival. While there was no significant correlation between decorin in the tumors and in serum at baseline, strong correlations were seen at one and three months (Spearman’s rho = 0.70 and 0.85, respectively). To further validate the potential prognostic value of decorin, immunohistochemical analysis was performed on tumors from a retrospective cohort of 104 resected tumors with long-term follow-up. Survival analysis showed that high decorin expression in both the stromal compartment and in tumor cells was associated with shorter overall survival (log rank p = 0.036 and 0.001, respectively). Multivariable cox regression analysis, adjusted for conventional prognostic factors, further confirmed that decorin was an independent factor of shorter overall survival (hazard ratio: 1.74, 95% confidence interval 1.10-2.75 for stromal decorin, and hazard ratio: 1.83, 95% confidence interval 1.04-3.21 for tumor-cell specific decorin). In conclusion, these findings suggest that decorin may be associated with chemotherapy resistance in pancreatic cancer. Future studies are encouraged to further explore the mechanistic basis for these observations, and to validate the potential utility of serum-decorin as a biomarker to monitor treatment response. Citation Format: Maja Svensson, Johan Ohlsson, Sofie Olsson Hau, Alexandra Petersson, Karin Jirström. Serum levels and tumor tissue organization of decorin in pancreatic cancer: Links to chemoresistance and disease aggressiveness [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C030.

Improved method of hemostasis for the middle rectal artery

Objective. To obtain data on the comparative characteristics of traditional and improved methods of hemostasis for the middle rectal artery (MRA).Materials and methods. The material for the sectional study was 206 corpses of men (the age of the deceased was from 22 to 82 years, the average age was 57 years) and 113 corpses of women (the age of the deceased was from 32 to 93 years, the average age was 63 years). To achieve the purpose of the study, the following methods were used: vascular injection, dissection, statistical processing. 85 patients of both sexes aged from 57 to 75 years were selected to conduct the clinical part of the study at Gomel Regional Specialized Clinical Hospital. Among them, 50 people were in the comparison group and 35 people were in the main group. All patients were diagnosed with stage I or II rectal cancer. The operative technique for performing hemostasis on the MRA during anterior rectal resection in the comparison group included sequential ligation and stitching between the clamps first of the distal third of the length of this artery, and then its proximal third. In the main group, the method of hemostasis for MRA was supplemented by ligation and stitching of this vessel in the middle third of its length. Statistical data processing included parametric and nonparametric methods of comparative analysis.Results. On cadaveric material, it was found that most of the extraorgan anastomoses of the MRA both in men and women have been localized in the middle third of this artery. The results obtained during the clinical study demonstrate the superiority of the improved hemostasis method for MRA over the traditional method. The proposed method includes additional ligation and stitching of the middle third of the MRA.Conclusion. The improved hemostasis method for MRA in anterior rectal resection is highly effective, which makes it possible to recommend it as the method of choice in the surgical treatment of upper ampullary rectal cancer of stage I or II.