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World Journal of Gastroenterology Jun 2021Pancreatic cancer currently has no subtypes that inform clinical decisions; hence, there exists an opportunity to rearrange the morphological and molecular taxonomy that... (Review)
Review
Pancreatic cancer currently has no subtypes that inform clinical decisions; hence, there exists an opportunity to rearrange the morphological and molecular taxonomy that guides a better understanding of tumor characteristics. Nonetheless, accumulating studies to date have revealed the large-duct type variant, a unique subtype of pancreatic ductal adenocarcinoma (PDA) with cystic features. This subtype often radiographically mimics intraductal papillary mucinous neoplasms (IPMNs) and involves multiple small cysts occasionally associated with solid masses. The "bunch-of-grapes" sign, an imaging characteristic of IPMNs, is absent in large-duct PDA. Large-duct PDA defines the mucin profile, and genetic alterations are useful in distinguishing large-duct PDA from IPMNs. Histologically, neoplastic ducts measure over 0.5 mm, forming large ductal elements. Similar to classic PDAs, this subtype is frequently accompanied by perineural invasion and abundant desmoplastic reactions, and mutations in codon 12 are nearly ubiquitous. Despite such morphological similarities with IPMNs, the prognosis of large-duct PDA is equivalent to that of classic PDA. Differential diagnosis is therefore essential.
Topics: Carcinoma, Pancreatic Ductal; Humans; Mutation; Pancreas; Pancreatic Ducts; Pancreatic Neoplasms
PubMed: 34163110
DOI: 10.3748/wjg.v27.i23.3262 -
Laboratory Investigation; a Journal of... Feb 2021Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Despite the high prevalence of Kras mutations in...
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Despite the high prevalence of Kras mutations in pancreatic cancer patients, murine models expressing the oncogenic mutant Kras (Kras) in mature pancreatic cells develop PDAC at a low frequency. Independent of cell of origin, a second genetic hit (loss of tumor suppressor TP53 or PTEN) is important for development of PDAC in mice. We hypothesized ectopic expression and elevated levels of oncogenic mutant Kras would promote PanIN arising in pancreatic ducts. To test our hypothesis, the significance of elevating levels of K-Ras and Ras activity has been explored by expression of a CAG driven LGSL-Kras allele (cKras) in pancreatic ducts, which promotes ectopic Kras expression. We predicted expression of cKras in pancreatic ducts would generate neoplasia and PDAC. To test our hypothesis, we employed tamoxifen dependent CreER mediated recombination. Hnf1b:CreER;Kras (cKras) mice received 1 (Low), 5 (Mod) or 10 (High) mg per 20 g body weight to recombine cKras in low (cKras), moderate (cKras), and high (cKras) percentages of pancreatic ducts. Our histologic analysis revealed poorly differentiated aggressive tumors in cKras mice. cKras mice had grades of Pancreatic Intraepithelial Neoplasia (PanIN), recapitulating early and advanced PanIN observed in human PDAC. Proteomics analysis revealed significant differences in PTEN/AKT and MAPK pathways between wild type, cKras, cKras, and cKras mice. In conclusion, in this study, we provide evidence that ectopic expression of oncogenic mutant K-Ras in pancreatic ducts generates early and late PanIN as well as PDAC. This Ras rheostat model provides evidence that AKT signaling is an important early driver of invasive ductal derived PDAC.
Topics: Animals; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Mice; Mice, Transgenic; Mutation Rate; Pancreatic Ducts; Pancreatic Neoplasms; Precancerous Conditions; Proto-Oncogene Proteins p21(ras); Recombination, Genetic
PubMed: 33009500
DOI: 10.1038/s41374-020-00490-5 -
BMC Gastroenterology Jul 2022The objectives of this study were to evaluate the relationship between ductal morphometry and ramification patterns in the submandibular gland and pancreas in order to...
BACKGROUND
The objectives of this study were to evaluate the relationship between ductal morphometry and ramification patterns in the submandibular gland and pancreas in order to validate their common fractal dimension.
METHODS
X-ray ductography with software-aided morphometry were obtained by injecting barium sulphate in the ducts of post-mortem submandibular gland and pancreas specimens harvested from 42 adult individuals.
RESULTS
Three cases were excluded from the study because of underlying pathology. There was a significant correlation between the length of the main pancreatic duct (MPD) and the intraglandular portion of the right submandibular duct (SMD) (r = 0.3616; p = 0.028), and left SMD (r = 0.595; p < 0.01), respectively, but their maximal diameters did not correlate (r = 0.139-0.311; p > 0.05). Both dimensions of the SMD showed a significant right-left correlation (p < 0.05). The number of MPD side branches (mean = 37) correlated with the number of side branches of left SMD, but not with the right one (mean = 9). Tortuosity was observed in 54% of the MPD, 32% of the right SMD, and 24% of the left SMD, with mutual association only between the two salivary glands.
CONCLUSIONS
Although the length of intraglandular SMD and MPD correlate, other morphometric ductal features do not, thus suggesting a more complex relationship between the two digestive glands.
Topics: Adult; Head; Humans; Pancreas; Pancreatic Ducts; Salivary Ducts; Submandibular Gland
PubMed: 35906544
DOI: 10.1186/s12876-022-02443-2 -
BMC Gastroenterology Nov 2022Main pancreatic duct (MPD) dilation is a high-risk stigmata/worrisome feature of malignancy in intraductal papillary mucinous neoplasms (IPMNs). The threshold of MPD...
BACKGROUND
Main pancreatic duct (MPD) dilation is a high-risk stigmata/worrisome feature of malignancy in intraductal papillary mucinous neoplasms (IPMNs). The threshold of MPD diameter in predicting malignancy may be related to the lesion location. This study aimed to separately identify the thresholds of MPD for malignancy of IPMNs separately for the head-neck and body-tail.
MATERIALS AND METHODS
A total of 185 patients with pathologically confirmed IPMNs were included. Patient demographic information, clinical data, and pathological features were obtained from the medical records. Those IPMNs with high-grade dysplasia or with associated invasive carcinoma were considered as malignant tumor. Radiological data including lesion location, tumor size, diameter of the MPD, mural nodule, and IPMN types (main duct, MD; branch duct, BD; and mixed type, MT), were collected on computed tomography or magnetic resonance imaging. Serum carbohydrate antigen 19-9 levels, serum carcinoembryonic antigen levels, and the medical history of diabetes mellitus, chronic cholecystitis, and pancreatitis were also collected.
RESULTS
Malignant IPMNs were detected in 31.6% of 117 patients with lesions in the pancreatic head-neck and 20.9% of 67 patients with lesions in the pancreatic body-tail. In MPD-involved IPMNs, malignancy was observed in 54.1% of patients with lesions in the pancreatic head-neck and 30.8% of patients with lesions in the pancreatic body-tail (p < 0.05). The cutoff value of MPD diameter for malignancy was 6.5 mm for lesions in the head-neck and 7.7 mm for lesions in the body-tail in all type of IPMNs. In MPD-involved IPMNs, the threshold was 8.2 mm for lesion in pancreatic head-neck and 7.7 mm for lesions in the body-tail. Multivariate analysis confirmed that MPD diameter ≥ 6.5 mm (pancreatic head-neck) and MPD diameter ≥ 7.7 mm (pancreatic body-tail) were independent predictors of malignancy (p < 0.05). Similar results were observed in MPD-involved IPMNs using 8.2 mm as a threshold.
CONCLUSION
The thresholds of the dilated MPD may be associated with IPMNs locations. Thresholds of 6.5 mm for lesions in the head-neck and 7.7 mm for lesions in the body-tail were observed. For MPD-involved IPMNs alone, threshold for lesions in the head-neck was close to that in the body-tail.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Ducts; Pancreatic Neoplasms; Head; Tomography, X-Ray Computed
PubMed: 36402960
DOI: 10.1186/s12876-022-02577-3 -
Cancer Discovery Oct 2020Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of...
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of gene dosage, we identify a suite of -regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC. SIGNIFICANCE: Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification...
Topics: Adenocarcinoma; Animals; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Mice; Pancreatic Ducts; Prognosis
PubMed: 32703770
DOI: 10.1158/2159-8290.CD-20-0133 -
Human Pathology May 2021Pancreatic intraepithelial neoplasia (PanIN) is a microscopic precursor lesion to pancreatic ductal adenocarcinoma (PDAC); however, there are few biomarkers that...
Pancreatic intraepithelial neoplasia (PanIN) is a microscopic precursor lesion to pancreatic ductal adenocarcinoma (PDAC); however, there are few biomarkers that segregate high-grade PanIN/PDAC from low-grade PanIN lesions. mAb Das-1 is a monoclonal antibody against a colonic epithelial antigen that is reactive to premalignant conditions of the upper gastrointestinal tract including Barrett's esophagus, incomplete-type gastric intestinal metaplasia, and intraductal papillary mucinous neoplasm of the pancreas at high risk of malignancy. We sought to examine a role for Das-1 expression in differentiating high-grade PanIN/PDAC from low-grade PanIN lesions. We examined surgical specimens from 86 patients and 2 autopsied pancreata (74 with and 14 without PDAC) with 107 distinct PanIN lesions, 74 PDAC cases, and 32 associated lymph node metastases, with internal controls of normal pancreatic ducts observed in 56 cases. All of the normal pancreatic duct controls (0/56) and low-grade PanIN (0/95) lesions were nonreactive to Das-1. Das-1 expression among high-grade PanIN (7/12, 58%), PDAC (55/74, 74%), and lymph node metastasis (21/32, 66%) cases was significantly higher (p < 0.0001). Clinicopathologically, Das-1 reactivity was significantly correlated with nodal metastasis (p = 0.021). Overall, the sensitivity, specificity, and accuracy of Das-1 in segregating high-grade PanIN/PDAC from low-grade PanIN lesions and normal ducts were 72%, 100%, and 90%, respectively. Thus, mAb Das-1 reacts with high specificity with high-grade PanIN and PDAC and may help in preoperative diagnosis and/or clinical risk stratification.
Topics: Adenocarcinoma in Situ; Aged; Antibodies; Antibodies, Monoclonal; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Female; Humans; Male; Middle Aged; Neoplasm Grading; Pancreatic Neoplasms; Sensitivity and Specificity
PubMed: 33524436
DOI: 10.1016/j.humpath.2021.01.003 -
PloS One 2022Three-dimensional surgical simulation, already in use for hepatic surgery, can be used in pancreatic surgery. However, some problems still need to be overcome to achieve...
Three-dimensional surgical simulation, already in use for hepatic surgery, can be used in pancreatic surgery. However, some problems still need to be overcome to achieve more precise pancreatic surgical simulation. The present study evaluates the performance of SYNAPSE VINCENT® (version 6.6, Fujifilm Medical Co., Ltd., Tokyo, Japan) in the semiautomated surgical simulation of the pancreatic parenchyma, pancreatic ducts, and peripancreatic vessels using an artificial intelligence (AI) engine designed with deep learning algorithms. One-hundred pancreatic cancer patients and a control group of 100 nonpancreatic cancer patients were enrolled. The evaluation methods for visualizing the extraction were compared using the Dice coefficient (DC). In the pancreatic cancer patients, tumor size, position, and stagewise correlations with the pancreatic parenchymal DC were analyzed. The relationship between the pancreatic duct diameter and the DC, and between the manually and AI-measured diameters of the pancreatic duct were analyzed. In the pancreatic cancer/control groups, the pancreatic parenchymal DC and pancreatic duct extraction were 0.83/0.86 and 0.84/0.77. The DC of the arteries (portal veins/veins) and associated sensitivity and specificity were 0.89/0.88 (0.89/0.88), 0.85/0.83 (0.85/0.82), and 0.82/0.81 (0.84/0.81), respectively. No correlations were observed between pancreatic parenchymal DC and tumor size, position, or stage. No correlation was observed between the pancreatic duct diameter and the DC. A positive correlation (r = 0.61, p<0.001) was observed between the manually and AI-measured diameters of the pancreatic duct. Extraction of the pancreatic parenchyma, pancreatic duct, and surrounding vessels with the SYNAPSE VINCENT® AI engine assumed to be useful as surgical simulation.
Topics: Humans; Deep Learning; Artificial Intelligence; Pancreatic Ducts; Pancreatic Neoplasms; Algorithms
PubMed: 36306322
DOI: 10.1371/journal.pone.0276600 -
BMC Surgery Jun 2020The mortality following pancreaticoduodenectomy has markedly decreased but remains an important challenge for the complexity of operation and technical skills involved....
BACKGROUND
The mortality following pancreaticoduodenectomy has markedly decreased but remains an important challenge for the complexity of operation and technical skills involved. The present study aimed to clarify the impact of individualized pancreaticoenteric anastomosis and management to postoperative pancreatic fistula.
METHODS
Data from 529 consecutive pancreaticoduodenectomies were retrospectively analysed from the Hepatobiliary and Pancreatic Surgery Unit I, Peking Cancer Hospital. The pancreaticoenteric anastomosis was determined based on the pancreatic texture and diameter of the main pancreatic duct. The amylase value of the drainage fluid was dynamically monitored postoperatively on days 3, 5 and 7. A low speed intermittent irrigation was performed in selected patients. Intraoperative and postoperative results were collected and compared between the pancreaticogastrostomy (PG) group and pancreaticojejunostomy (PJ) group.
RESULTS
From 2010 to 2019, 529 consecutive patients underwent pancreaticoduodenectomy. Pancreaticogastrostomy was performed in 364 patients; pancreaticojejunostomy was performed in 150 patients respectively. The clinically relevant pancreatic fistula (CR-POPF) was 9.8% and mortality was zero. The soft pancreas, diameter of main pancreatic duct≤3 mm, BMI ≥ 25, operation time > 330 min and pancreaticogastrostomy was correlated with postoperative pancreatic fistula significantly. The CR-POPF of PJ was significantly higher than that of PG in soft pancreas patients; the operation time of PJ was shorter than that of PG significantly in hard pancreas patients. Intraoperative blood loss and operation time of PG was less than that of PJ significantly in normal pancreatic duct patients (p < 0.05).
CONCLUSIONS
Individualized pancreaticoenteric anastomosis should be determined based on the pancreatic texture and pancreatic duct diameter. The appropriate anastomosis and postoperative management could prevent mortality.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amylases; Anastomosis, Surgical; Drainage; Female; Humans; Male; Middle Aged; Pancreas; Pancreatic Diseases; Pancreatic Ducts; Pancreatic Fistula; Pancreaticoduodenectomy; Pancreaticojejunostomy; Retrospective Studies; Stomach; Therapeutic Irrigation; Young Adult
PubMed: 32571289
DOI: 10.1186/s12893-020-00791-y -
International Journal of Molecular... May 2021Identification of pancreatic ductal adenocarcinoma (PDAC) and precursor lesions in histological tissue slides can be challenging and elaborate, especially due to tumor...
Identification of pancreatic ductal adenocarcinoma (PDAC) and precursor lesions in histological tissue slides can be challenging and elaborate, especially due to tumor heterogeneity. Thus, supportive tools for the identification of anatomical and pathological tissue structures are desired. Deep learning methods recently emerged, which classify histological structures into image categories with high accuracy. However, to date, only a limited number of classes and patients have been included in histopathological studies. In this study, scanned histopathological tissue slides from tissue microarrays of PDAC patients ( = 201, image patches = 81.165) were extracted and assigned to a training, validation, and test set. With these patches, we implemented a convolutional neuronal network, established quality control measures and a method to interpret the model, and implemented a workflow for whole tissue slides. An optimized EfficientNet algorithm achieved high accuracies that allowed automatically localizing and quantifying tissue categories including pancreatic intraepithelial neoplasia and PDAC in whole tissue slides. SmoothGrad heatmaps allowed explaining image classification results. This is the first study that utilizes deep learning for automatic identification of different anatomical tissue structures and diseases on histopathological images of pancreatic tissue specimens. The proposed approach is a valuable tool to support routine diagnostic review and pancreatic cancer research.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Carcinoma, Pancreatic Ductal; Deep Learning; Female; Humans; Male; Middle Aged; Neural Networks, Computer; Pancreatic Ducts; Pancreatic Neoplasms
PubMed: 34065423
DOI: 10.3390/ijms22105385 -
Nature Communications Jul 2019Cystic fibrosis (CF) is a genetic disorder caused by defective CF Transmembrane Conductance Regulator (CFTR) function. Insulin producing pancreatic islets are located in...
Cystic fibrosis (CF) is a genetic disorder caused by defective CF Transmembrane Conductance Regulator (CFTR) function. Insulin producing pancreatic islets are located in close proximity to the pancreatic duct and there is a possibility of impaired cell-cell signaling between pancreatic ductal epithelial cells (PDECs) and islet cells as causative in CF. To study this possibility, we present an in vitro co-culturing system, pancreas-on-a-chip. Furthermore, we present an efficient method to micro dissect patient-derived human pancreatic ducts from pancreatic remnant cell pellets, followed by the isolation of PDECs. Here we show that defective CFTR function in PDECs directly reduced insulin secretion in islet cells significantly. This uniquely developed pancreatic function monitoring tool will help to study CF-related disorders in vitro, as a system to monitor cell-cell functional interaction of PDECs and pancreatic islets, characterize appropriate therapeutic measures and further our understanding of pancreatic function.
Topics: Adolescent; Child; Child, Preschool; Coculture Techniques; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Female; Humans; Insulin; Islets of Langerhans; Lab-On-A-Chip Devices; Male; Microdissection; Organoids; Pancreatic Ducts; Primary Cell Culture
PubMed: 31311920
DOI: 10.1038/s41467-019-11178-w