Project description:ContextThe optimal analgesic method for patients undergoing major open hepato-pancreatic-biliary surgery remains controversial. Continuous epidural infusion at the thoracic level remains the standard choice, however concerns have been raised due to associated complications. Single shot intrathecal morphine has emerged as a promising alternative offering similar analgesia with an enhanced safety profile.Evidence acquisitionThis review aimed to evaluate the literature comparing intrathecal morphine analgesia to other analgesic modalities following major open hepato-pancreatic-biliary surgery. The primary outcome was pain scores at rest and on movement 24 h after surgery. Secondary outcomes were postoperative opioid consumption within 72 postoperative hours, length of stay (LOS), intra-operative fluid administration and post-operative fluid administration within 72 postoperative hours, and overall systemic complication rate within 30 postoperative days.ResultsEleven trials matching the inclusion criteria were analysed. Intrathecal morphine resulted in equivalent or lower pain scores when contrasted to alternative techniques, but required higher amounts of postoperative opioid. Intrathecal morphine also offered reduced LOS and reduced fluid administration requirements to epidural analgesia, and there was no difference observed in major complication rate between analgesic modalities.ConclusionsIn summary the evidence suggests that intrathecal morphine may be a better first-line analgesic modality than epidural analgesia in the context of major open hepato-pancreatic-biliary surgery, but high-quality evidence supporting this is limited.
Project description:ObjectivesThis report describes a survey undertaken with the aim of assessing the current status of available fellowships in hepatopancreatobiliary (HPB) surgery in order to identify steps to be taken to ensure the provision of successful training in this specialty.MethodsAn online survey was conducted among members of the International Hepato-Pancreato-Biliary Association (IHPBA) targeting registered and non-registered HPB surgery fellowships. A total of 71 programmes are registered on the IHPBA website and 40 fellowship directors completed the survey. Only 18 completed surveys referred to programmes previously listed on the website.ResultsResponses showed great diversity among centres regarding their requirements for application, the duration of training and exposure to HPB cases during the fellowship. Factors associated with higher levels of training included the country of fellowship, a third year of training and the presence of a well-structured HPB curriculum. Over 90% of responders seek official accreditation from their regional association (i.e. the European, American and Asian-Pacific HPB Associations). Most programmes would welcome official IHPBA or regional association monitoring of their fellowship.ConclusionsThis survey discloses important information which will allow the IHPBA Education and Training Committee to move forward. The next steps should include close monitoring of the performance of fellows by creating a fellows' registry, as well as a blog or forum which can be used to further enhance communication among fellows. The availability of registration to both programme directors and fellows may eventually lead to an official fellowship accreditation process.
Project description:Human organoids are emerging as a valuable resource to investigate human organ development and disease. The applicability of human organoids has been limited, partly due to the oversimplified architecture of the current technology, which generates single-tissue organoids that lack inter-organ structural connections. Thus, engineering organoid systems that incorporate connectivity between neighboring organs is a critical unmet challenge in an evolving organoid field. Here, we describe a protocol for the continuous patterning of hepatic, biliary and pancreatic (HBP) structures from a 3D culture of human pluripotent stem cells (PSCs). After differentiating PSCs into anterior and posterior gut spheroids, the two spheroids are fused together in one well. Subsequently, self-patterning of multi-organ (i.e., HBP) domains occurs within the boundary region of the two spheroids, even in the absence of any extrinsic factors. Long-term culture of HBP structures induces differentiation of the domains into segregated organs complete with developmentally relevant invagination and epithelial branching. This in-a-dish model of human hepato-biliary-pancreatic organogenesis provides a unique platform for studying human development, congenital disorders, drug development and therapeutic transplantation. More broadly, our approach could potentially be used to establish inter-organ connectivity models for other organ systems derived from stem cell cultures.
Project description:Organogenesis is a complex and interconnected process that is orchestrated by multiple boundary tissue interactions1-7. However, it remains unclear how individual, neighbouring components coordinate to establish an integral multi-organ structure. Here we report the continuous patterning and dynamic morphogenesis of hepatic, biliary and pancreatic structures, invaginating from a three-dimensional culture of human pluripotent stem cells. The boundary interactions between anterior and posterior gut spheroids differentiated from human pluripotent stem cells enables retinoic acid-dependent emergence of hepato-biliary-pancreatic organ domains specified at the foregut-midgut boundary organoids in the absence of extrinsic factors. Whereas transplant-derived tissues are dominated by midgut derivatives, long-term-cultured microdissected hepato-biliary-pancreatic organoids develop into segregated multi-organ anlages, which then recapitulate early morphogenetic events including the invagination and branching of three different and interconnected organ structures, reminiscent of tissues derived from mouse explanted foregut-midgut culture. Mis-segregation of multi-organ domains caused by a genetic mutation in HES1 abolishes the biliary specification potential in culture, as seen in vivo8,9. In sum, we demonstrate that the experimental multi-organ integrated model can be established by the juxtapositioning of foregut and midgut tissues, and potentially serves as a tractable, manipulatable and easily accessible model for the study of complex human endoderm organogenesis.
Project description:The improvement of digestive cancer survival results in increased morbidity of noncancerous comorbidities. This study aimed at clarifying causes of death (COD) and predicting overall survival (OS) in patients diagnosed with liver cancer, gallbladder cancer, cholangiocarcinoma, and pancreatic cancer. We used the Surveillance, Epidemic, and End Results database to extract information. Nomograms of multivariate Cox regression was used to predict OS of cancer patients. The models were evaluated using the concordance indexes (C-indexes), the receiver operating characteristic curves and calibration curves. Respectively 58,895, 15,324, 30,708, and 109,995 cases with cancer of liver, gallbladder, bile duct or pancreas were retrieved between 2000 and 2020. Approximately 80% deaths occurred within 1 years after cancer diagnosis. Sequence in noncancerous COD proportion was diverse, while diseases of heart always accounted for a great part. Risks of death from most noncancerous COD were significantly higher than that of the cancer-free population. Nomograms were developed by predictors of interest such as age, therapy and TNM stage. The concordance indexes of nomograms were 0.756, 0.729, 0.763, and 0.760 respectively, well-calibrating to the reality. The 0.5-, 1-, and 2-year areas under the receiver operating characteristic curve were about 0.800, indicating good reliability and accuracy. Noncancerous COD accounted for larger part in gallbladder cancer and cholangiocarcinoma. Noncancerous COD showed an upward trend as follow-up time extended and the majorities were diseases of heart, cerebrovascular disease, chronic liver disease and cirrhosis. The novel OS-nomograms can provide personalized prognosis information with satisfactory accuracy.
Project description:A network of co-hepato/pancreatic stem/progenitors exists in pigs and humans in Brunner's Glands in the submucosa of the duodenum, in peribiliary glands (PBGs) of intrahepatic and extrahepatic biliary trees, and in pancreatic duct glands (PDGs) of intrapancreatic biliary trees, collectively supporting hepatic and pancreatic regeneration postnatally. The network is found in humans postnatally throughout life and, so far, has been demonstrated in pigs postnatally at least through to young adulthood. These stem/progenitors in vivo in pigs are in highest numbers in Brunner's Glands and in PDGs nearest the duodenum, and in humans are in Brunner's Glands and in PBGs in the hepato/pancreatic common duct, a duct missing postnatally in pigs. Elsewhere in PDGs in pigs and in all PDGs in humans are only committed unipotent or bipotent progenitors. Stem/progenitors have genetic signatures in liver/pancreas-related RNA-seq data based on correlation, hierarchical clustering, differential gene expression and principal component analyses (PCA). Gene expression includes representative traits of pluripotency genes (SOX2, OCT4), endodermal transcription factors (e.g. SOX9, SOX17, PDX1), other stem cell traits (e.g. NCAM, CD44, sodium iodide symporter or NIS), and proliferation biomarkers (Ki67). Hepato/pancreatic multipotentiality was demonstrated by the stem/progenitors' responses under distinct ex vivo conditions or in vivo when patch grafted as organoids onto the liver versus the pancreas. Therefore, pigs are logical hosts for translational/preclinical studies for cell therapies with these stem/progenitors for hepatic and pancreatic dysfunctions.
Project description:Background & aimsMetaplasias often have characteristics of developmentally related tissues. Pancreatic metaplastic ducts are usually associated with pancreatitis and pancreatic ductal adenocarcinoma. The tuft cell is a chemosensory cell that responds to signals in the extracellular environment via effector molecules. Commonly found in the biliary tract, tuft cells are absent from normal murine pancreas. Using the aberrant appearance of tuft cells as an indicator, we tested if pancreatic metaplasia represents transdifferentiation to a biliary phenotype and what effect this has on pancreatic tumorigenesis.MethodsWe analyzed pancreatic tissue and tumors that developed in mice that express an activated form of Kras (Kras(LSL-G12D/+);Ptf1a(Cre/+) mice). Normal bile duct, pancreatic duct, and tumor-associated metaplasias from the mice were analyzed for tuft cell and biliary progenitor markers, including SOX17, a transcription factor that regulates biliary development. We also analyzed pancreatic tissues from mice expressing transgenic SOX17 alone (ROSA(tTa/+);Ptf1(CreERTM/+);tetO-SOX17) or along with activated Kras (ROSAtT(a/+);Ptf1a(CreERTM/+);tetO-SOX17;Kras(LSL-G12D;+)).ResultsTuft cells were frequently found in areas of pancreatic metaplasia, decreased throughout tumor progression, and absent from invasive tumors. Analysis of the pancreatobiliary ductal systems of mice revealed tuft cells in the biliary tract but not the normal pancreatic duct. Analysis for biliary markers revealed expression of SOX17 in pancreatic metaplasia and tumors. Pancreas-specific overexpression of SOX17 led to ductal metaplasia along with inflammation and collagen deposition. Mice that overexpressed SOX17 along with Kras(G12D) had a greater degree of transformed tissue compared with mice expressing only Kras(G12D). Immunofluorescence analysis of human pancreatic tissue arrays revealed the presence of tuft cells in metaplasia and early-stage tumors, along with SOX17 expression, consistent with a biliary phenotype.ConclusionsExpression of Kras(G12D) and SOX17 in mice induces development of metaplasias with a biliary phenotype containing tuft cells. Tuft cells express a number of tumorigenic factors that can alter the microenvironment. Expression of SOX17 induces pancreatitis and promotes Kras(G12D)-induced tumorigenesis in mice.
Project description:BackgroundIt has been proven that tumor necrosis is associated with poor prognoses in various solid malignant tumors. However, the prognostic effect of tumor necrosis in hepato-biliary-pancreatic cancers is still unclear. Therefore, this study was performed to evaluate the associations of tumor necrosis with survival outcomes and clinicopathological features in patients with hepato-biliary-pancreatic cancers.MethodsBased on the PRISMA statement, eligible studies were identified from PubMed, Embase, Cochrane Library, and Web of Science from inception until January 2023. The pooled hazard ratios (HRs) and 95% confidence intervals (95%CIs) were calculated to assess the connection between tumor necrosis and hepato-biliary-pancreatic cancers. We then choose which effects model to use to generate pooled HRs and 95% CIs, depending on data heterogeneity.ResultsIn total, 6497 articles were identified, 10 of which were included in this meta-analysis. Our results suggested that the presence of tumor necrosis predicted a poorer outcome for overall survival (HR = 1.54, 95% CI = 1.35-1.77, p < 0.001) and recurrence-free survival (HR = 1.69, 95% CI = 1.37-2.08, p < 0.001). In addition, tumor necrosis was correlated with larger tumor size, a higher frequency of lymph node metastasis, poorer histologic differentiation, and higher recurrence and metastasis rates.ConclusionOur meta-analysis suggests that hepato-biliary-pancreatic cancer patients with tumor necrosis have dismal survival outcomes, and that their tumors have aggressive biological behaviors. Tumor necrosis has the potential to be a promising biomarker for forecasting poor prognosis in these patients.