Discrimination of pancreato-biliary cancer and pancreatitis patients by non-invasive liquid biopsy.

BACKGROUND: Current diagnostics for the detection of pancreato-biliary cancers (PBCs) need to be optimized. We therefore propose that methylated cell-free DNA (cfDNA) derived from non-invasive liquid biopsies serves as a novel biomarker with the ability to discriminate pancreato-biliary cancers from non-cancer pancreatitis patients. METHODS: Differentially methylated regions (DMRs) from plasma cfDNA between PBCs, pancreatitis and clinical control samples conditions were identified by next-generation sequencing after enrichment using methyl-binding domains and database searches to generate a discriminatory panel for a hybridization and capture assay with subsequent targeted high throughput sequencing. RESULTS: The hybridization and capture panel, covering around 74 kb in total, was applied to sequence a cohort of 25 PBCs, 25 pancreatitis patients, 25 clinical controls, and seven cases of Intraductal Papillary Mucinous Neoplasia (IPMN). An unbiased machine learning approach identified the 50 most discriminatory methylation markers for the discrimination of PBC from pancreatitis and controls resulting in an AUROC of 0.85 and 0.88 for a training (n = 45) and a validation (n = 37) data set, respectively. The panel was also able to distinguish high grade from low grade IPMN samples. CONCLUSIONS: We present a proof of concept for a methylation biomarker panel with better performance and improved discriminatory power than the current clinical marker CA19-9 for the discrimination of pancreato-biliary cancers from non-cancerous pancreatitis patients and clinical controls. This workflow might be used in future diagnostics for the detection of precancerous lesions, e.g. the identification of high grade IPMNs vs. low grade IPMNs.

PTEN deficiency induces an extrahepatic cholangitis-cholangiocarcinoma continuum via aurora kinase A in mice.

BACKGROUND & AIMS: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease. METHODS: The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the effectiveness of an Aurka inhibitor. RESULTS: We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as 1 month after birth. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated disease progression, potentially by downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expression of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression. CONCLUSIONS: Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum that was dependent on Aurka. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA. IMPACT AND IMPLICATIONS: The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition, cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted disease progression. This model will be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.

Insights for clinical management from the real-life data of the centralized West of Scotland biliary cancer clinic.

BACKGROUND: With the increasing of novel therapeutics for the treatment of Biliary Tract Cancers (BTC), and the need to assess their socio-economic impacts for national licence approvals, it is as important as ever to have real-life data in national populations. METHODS AND RESULTS: We performed an audit of the first 2 year-activity (Sep 2019-Sep 2021) of the centralized West-of-Scotland-BTC clinic. 122 patients accessed the service, including 68% with cholangiocarcinoma (CCA), 27% with gallbladder cancer (GBC), and 5% with ampulla of Vater carcinoma with biliary phenotype (AVC). Median age at diagnosis was 66 (28-84), with 30% of newly diagnosed patients being younger than 60 years-old. Thirty-five cases (29%) underwent surgery, followed by adjuvant-chemotherapy in 66%. 60% had recurrent disease (80% with distant relapse). Sixty-four patients (58%) started first-line Systemic-AntiCancer-Treatment (SACT). Of these, 37% received second line SACT, the majority of which had iCCA and GBC. Thirty-% of those who progressed received third line SACT. CONCLUSIONS: About 30% of BTC were eligible for curative surgery. Fifty-eight and twenty% of the overall cohort of advanced BTC patients received first and second line SACT. Our data suggest that reflex genomic profiling may not be cost-effective until molecularly driven strategies are limited to second line setting.

Helicobacter hepaticus and Helicobacter bilis in liver and biliary cancers from ATBC and PLCO.

BACKGROUND: Helicobacter species (spp.) have been detected in human bile and hepatobiliary tissue Helicobacter spp. promote gallstone formation and hepatobiliary tumors in laboratory studies, though it remains unclear whether Helicobacter spp. contribute to these cancers in humans. We used a multiplex panel to assess whether seropositivity to Helicobacter (H.) hepaticus or H. bilis proteins was associated with the development of hepatobiliary cancers in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, and US-based Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). METHODS: We included 62 biliary and 121 liver cancers, and 190 age-matched controls from ATBC and 74 biliary and 105 liver cancers, and 364 age- and sex-matched controls from PLCO. Seropositivity to 14 H. hepaticus and H. bilis antigens was measured using a multiplex assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for major hepatobiliary cancer risk factors and Helicobacter pylori serostatus. RESULTS: Seropositivity to the H. bilis antigen, P167D, was associated with more than a twofold higher risk of liver cancer (OR: 2.38; 95% CI: 1.06, 5.36) and seropositivity to the H. hepaticus antigens HH0407 or HH1201, or H. bilis antigen, HRAG 01470 were associated with higher risk of biliary cancer (OR: 5.01; 95% CI: 1.53, 16.40; OR: 2.40; 95% CI: 1.00, 5.76; OR: 3.27; 95% CI: 1.14, 9.34, respectively) within PLCO. No associations for any of the H. hepaticus or H. bilis antigens were noted for liver or biliary cancers within ATBC. CONCLUSIONS: Further investigations in cohort studies should examine the role of Helicobacter spp. in the etiology of liver and biliary cancers.

Advanced Adenosquamous Carcinoma of the Ampulla of Vater Treated with Adjuvant Chemotherapy after Pancreaticoduodenectomy.

Introduction: Adenosquamous carcinoma (ASC) of the ampulla of Vater (AmV) is rare. The prognosis is generally worse in patients undergoing resection of ASC of the AmV than in those undergoing resection of adenocarcinoma of the AmV because the former shows early recurrence after surgery. A treatment strategy for ASC of the AmV has not been established, and the efficacy of adjuvant chemotherapy after curative resection is unclear. Given the paucity of data, we report a case of ASC of the AmV that was curatively resected and treated with adjuvant chemotherapy. Case Presentation: A 66-year-old man presented with pruritus and anorexia. Contrast-enhanced computed tomography revealed a tumor measuring 1.6 cm in diameter located at the AmV and distal bile duct. Biopsy revealed adenocarcinoma of the AmV. The patient underwent subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination contradictorily revealed ASC of the AmV and lymph node metastases. The postoperative course of the patient was uneventful, and he was discharged on day 25. The patient underwent S-1 adjuvant chemotherapy for 6 months and did not exhibit any postoperative recurrence for a follow-up duration of 28 months. Conclusion: Although treatment strategy for ASC of the AmV has not been established, our case shows that surgery followed by S-1 adjuvant chemotherapy could improve prognosis of patients with such tumors. However, further research is required to determine the efficacy of adjuvant chemotherapy and treatment strategies for resectable ASC of the AmV.

HER-2 directed therapies across gastrointestinal tract cancers - A new frontier.

Gastrointestinal (GI) cancers are common and in the metastatic setting they have a poor prognosis. The current mainstay of treatment of GI cancers is chemotherapy; however, the biomarker-directed treatment landscape is evolving. HER-2 is overexpressed in a portion of GI cancers and is an emerging target for therapy, with recent FDA tumor agnostic approval for trastuzumab deruxtecan. Testing for HER-2 expression is not standardized across GI cancers, methodology requires further optimization and standardization as HER-2 targeted therapy emerges into the treatment landscape. There is established rationale for use of HER-2 targeted therapy in first line treatment of metastatic gastric cancer, and emerging evidence with variable benefit in bile duct, pancreatic and colorectal cancers.

Mahamana Technique of Pancreaticogastrostomy: A Safe and Reliable Technique for a Difficult Pancreatic Stump.

Pancreatoduodenectomy is a complex surgical procedure involving three anastomoses. Anastomosis of the pancreatic stump with the gastrointestinal tract is associated with most complications described in the postoperative period. So, there have been multiple attempts to discover safe and sound steps for this particular anastomosis. Pancreaticogastrostomy involves anastomosis between the remaining pancreas and stomach. Since it was first performed, its surgical steps have been modified multiple times, but there is no gold standard method to perform it. In this paper, we describe the surgical steps of pancreaticogastrostomy in difficult pancreatic stumps in eight patients using two transpancreatic sutures, one purse string suture, and the incorporation of transpancreatic sutures in the third layer of the gastrojejunostomy anastomosis. Postoperative outcomes of this series have provided encouraging short-term results.

Laparoscopic Conversion to Open Cholecystectomy: Is Incidental Gallbladder Cancer Any Different?

BACKGROUND: A majority of gallbladder cancers present incidentally. Operative risk factors and outcomes for laparoscopic converted to open cholecystectomy in incidental gallbladder cancer are not well characterized. METHODS: Patients with incidental gallbladder cancer and acute cholecystitis undergoing laparoscopic cholecystectomy and conversion to open cholecystectomy in the National Surgical Quality Improvement Program (NSQIP) database of the American College of Surgeons (ACS) from 2010-2019 were reviewed. The primary endpoint was risk factors for conversion to open cholecystectomy in incidental gallbladder cancer. Chi-squared test or Fisher's exact test was used for categorical variables. Continuous variables were compared using the Mann-Whitney U test. RESULTS: A total of 5,789 patients undergoing laparoscopic cholecystectomy were identified, of which, 50 (0.9%) had incidental gallbladder cancer. For incidental gallbladder cancer patients, there were no differences in preoperative profile and risk factors between laparoscopic and converted to open cholecystectomy groups. Incidental carcinoma patients undergoing conversion to open cholecystectomy had lower preoperative sodium levels than the laparoscopic cholecystectomy group (P=0.007). Hospital length of stay (days) was longer for those with a conversion to open cholecystectomy for incidental carcinoma compared to non-conversion, 14 (10.8, 18.8) vs 2 (0.3, 5) (P=0.004). The patients converted to open cholecystectomy also had higher rates of postoperative sepsis (50% vs 0%, P<0.001) and reoperation than the laparoscopic cohort (50% vs 2.2%, P<0.001). Readmission and mortality rates, among other complications, were not significantly different between both surgical approaches in incidental gallbladder cancer patients. CONCLUSIONS:  Patients with conversion to open cholecystectomy had worse outcomes including longer hospital stays and higher rates of sepsis and reoperation. It remains difficult to predict which incidental gallbladder patients will require a conversion to open surgery. Further study examining whether more complicated recovery results in worse oncologic outcomes is warranted.

Exercise and Nutrition Interventions for Prehabilitation in Hepato-Pancreato-Biliary Cancers: A Narrative Review.

Gastrointestinal (GI) cancers constitute over 25% of global cancer cases annually, with hepato-pancreato-biliary (HPB) cancers presenting particularly poor prognosis and challenging surgical treatments. While advancements in clinical care have improved post-operative outcomes over time, surgery for HPB cancers remains associated with high morbidity and mortality rates. Patients with HPB cancer are often older, diagnosed at later stages, and have a higher prevalence of co-morbid conditions, leading to reduced life expectancy, suboptimal post-operative recovery, and increased recurrence risk. Exercise and nutrition interventions have emerged as safe non-pharmacological strategies to enhance clinical outcomes among cancer survivors, but their potential in the pre-operative period for patients with HPB cancer remains underexplored. This narrative review evaluates existing evidence on exercise and nutritional interventions during pre-operative prehabilitation for HPB cancer populations, focusing on clinically relevant post-operative outcomes related to frailty and malnutrition. We conducted a literature search in PubMed and Google Scholar databases to identify studies utilizing a prehabilitation intervention in HPB cancer populations with exercise and nutritional components. The currently available evidence suggests that incorporating exercise and nutrition into prehabilitation programs offers a critical opportunity to enhance post-operative outcomes, mitigate the risk of comorbidities, and support overall survivorship among HPB cancer populations. This review underscores the need for further research to optimize the timing, duration, and components of pre-operative prehabilitation programs, emphasizing patient-centered, multidisciplinary approaches in this evolving field.

Valoración de la linfadenectomía en una serie consecutiva de pacientes tratados por cáncer biliar / Evaluation of lymphadenectomy in a consecutive series of patients treated for biliary cancer

Resumen Introducción: Si bien actualmente la 8a edición de la clasificación del AJCC para cáncer biliar, recomienda una linfadenectomía con 6 o más GL, su aplicación es escasa. Objetivo: Analizar la aplicabilidad y los resultados de la linfadenectomía en pacientes resecados con fines curativos por cáncer biliar. Materiales y Método: Análisis retrospectivo de pacientes operados por cáncer biliar de 2001 a 2018. Se analizaron variables perioperatorias referidas a la linfadenectomía (número de GL, GL+, morbilidad), comparando supervivencia en pacientes con < 6 y ≥ 6 GL resecados. Resultados: en 72 pacientes resecados por cáncer biliar (46 CaV, 26 CC), se realizaron 66 (91.7%) linfadenectomías N1. En 62.1% (n = 41) se obtuvieron < 6 GL y en el 37.9% (n = 25) ≥ 6 GL. El promedio de GL resecados fue de 5. En 16 (24,2%) linfadenectomías se hallaron GL+ sin diferencias entre ambos grupos. La morbimortalidad global fue de 30,3%, con una mortalidad del 4.5% sin diferencias. Con un seguimiento de 36.9 meses, la supervivencia a 5 años fue 43,7% (n = 17), 7 pacientes con ≥ 6 GL, y 10 pacientes con < 6 GL (p = NS). La supervivencia media en pacientes con GL+ fue 15 meses (6-34 meses). Conclusión: la linfadenectomía ocupa un rol primordial en la cirugía curativa del cáncer biliar, tanto para definir una estadificación y un pronóstico adecuados como para optimizar los resultados de la resección curativa en esta entidad. Su indicación debe ser sistemática con la obtención de un número adecuado de GL acorde a las recomendaciones actuales.

Introduction: Currently the 8th edition of the AJCC classification recommends the resection of 6 or more lymph nodes (LN) in gallbladder cancer and cholangiocarcinoma. However, its implementation is universally scarce. Aim: The goal is to analyze the applicability and results of lymphadenectomy in patients resected with curative purposes in biliary cancer. Materials and Method: a retrospective analysis of patients with biliary cancer (gallbladder carcinoma, intrahepatic and hilar cholangiocarcinoma) treated by curative resection from 2001 to 2018 was performed. Perioperative variables related to lymphadenectomy (LN number, LN positive, related morbidity) were analyzed, comparing survival in patients with < 6 and ≥ 6 resected LN. Results: 72 patients resected for biliary cancer (46 gallbladder cancer, 26 cholangiocarcinoma) were included with 66 (91.7%) N1 lymphadenectomies corresponding to the hepatoduodenal ligament nodes performed. In 62.1% (n = 41) < 6 LN and in 37.9% (n = 25) ≥ 6 LN were resected. Average LN count was 5. In 16 (24.2%) patients positive LN were found, 7 in the group with ≥ 6 LN (28%) vs. 9 in the group with < 6 LN (22%) (p = NS). Overall morbimortality was 30.3% (n = 20). Average follow-up was 36.9 months. Survival at 5 years was 43.7% (n = 17), 7 patients with lymphadenectomy ≥ 6 LN, and 10 patients with < 6 LN (p = NS). Survival mean in patients who had positive LN was 15 months. Conclusión: Lymphadenectomy has a primary role in the radical resection with curative intention for biliary cancer. Systematic indication of lymphadenectomy should be prioritized, with the achievement of an adequately number of LN according to the actual recommendations. Lymphadenectomy is crucial for an adequate staging and prognosis, as well as to optimize the results of curative resection in this entity.

EUS-guided biliary drainage in distal malignant biliary obstruction: a new tool when ERCP fails / Drenagem biliar ecoguiada no câncer biliar distal: uma nova ferramenta na falha da CPRE

Introduction: most of patients with biliary tract cancer are diagnosed at an advanced stage. EUS-guided biliary drainage (EBD) is an alternative to percutaneous transhepatic or surgical drainage techniques after failure at conventional access by endoscopic retrograde cholangiopancreatography (ERCP). Objectives: to evaluate EBD efficacy and safety in patients with malignant biliary obstruction at the Gastrointestinal Endoscopy Department from Hospital das Clínicas of São Paulo University. Methods: there were included in our study patients that had a clinical history of obstructive jaundice and failure at biliary drainage by ERCP. EBD was performed under radioscopic control. The efficacy was analyzed according to clinical outcome and improvement in quality of life after the procedure, which was assessed by the application of a quality of life measurement test, and an evaluation of laboratory tests, signs, symptoms and procedure-related complications. Results: from April 2010 to September 2011, 32 patients with advanced biliary tract cancer were included in our study. Three (9.4%) patients had technical failure at EBD procedure. Technical success was achieved in 90.6% (29/32) and clinical improvement occurred in 100% (29/29). EUS-guided choledochoduodenostomy was the most common drainage procedure (58.62%). Duodenal self-expandable metallic stents were placed in 7 (21.85%) cases. There were a significant ecrease in bilirubin levels (p <0.001) and patients had improvement in quality of life after the procedure (p < 0.05). Complications occurred in 6 (18.75%) patients and the median survival was 90 days. Conclusion: EBD was an effective and safe procedure with acceptable complication rates, providing significant improvement in quality of life.

Introdução: a maioria dos pacientes com câncer biliar é diagnosticada em estágio avançado. A drenagem biliar ecoguiada é uma alternativa à drenagem percutânea e à cirurgia derivativa. Objetivos: avaliar a eficácia e a segurança do método em pacientes com necessidade de drenagem biliar e falha da CPRE prévia. Método: foram incluídos pacientes com obstrução biliar maligna e falha do acesso por CPRE convencional. A eficácia foi avaliada pelo sucesso clínico e pela avaliação da qualidade de vida. Avaliação laboratorial e clínica foram estudadas e computadas por teste estatístico. Resultados: entre abril e setembro, 32 pacientes foram incluídos no protocolo. Em três verificou-se insucesso do acesso ecoguiado. O sucesso técnico ocorreu em 90,6% (29/32) e o sucesso clínico em 100% dos casos. Coledocoduodenostomia ocorreu em 58,6% e foi o acesso mais frequente da casuística apresentada. A melhora da bilirrubina em 7 dias foi significante (p <0,001) e a qualidade de vida foi melhor no seguimento de 30 dias (p <0,05). Complicações ocorreram em 6 (18,75%) e sobrevida média foi de 90 dias. Conclusões: a drenagem biliar ecoguiada é uma ferramenta importante na falha da CPRE prévia e com índices de complicações aceitáveis.