Search Results (38)

Background and Aims: An appropriate surveillance system must be established to efficiently identify cases of intraductal papillary mucinous neoplasm (IPMN)-related malignant transformation. We analyzed the initial clinical background that affects long-term prognosis and narrowed the population for whom continued evaluation is inevitable. Methods: We included 1645 patients with IPMN treated at our hospital since 2010. We examined the types and timing of malignant transformation in terms of the worrisome features (WFs). The chi-squared test, log-rank test, and Cox proportional hazards model were used for the analysis (statistical significance at α = 0.05). Results: In total, 123 (7.5%) and 41 patients (2.5%) had IPMN-derived carcinoma (IPMN-DC) and concomitant pancreatic ductal adenocarcinoma (c-PDAC), respectively. Compared with IPMN-DC, a significantly higher proportion of c-PDAC patients were diagnosed with an advanced disease stage that developed earlier. The factors with significantly shorter time for IPMN-DC development were maximum cyst diameter (MCD) ≥ 30 mm, nonbranched type, main pancreatic duct (MPD) diameter ≥ 5 mm, and septal nodal structure (SNS) for IPMN-DC, and MCD ≥ 30 mm, main duct type, MPD ≥ 5 mm, SNS, cyst enlargement (≥2.5 mm/year), and abnormal CA19-9 levels for c-PDAC. Both groups could be significantly stratified by the number of WFs. A relative risk analysis revealed that SNS, MCD ≥ 30 mm, and MPD ≥ 5 mm were significant factors for IPMN-DC, whereas abnormal CA19-9 and SNS were significant for c-PDAC. Conversely, significantly more patients exhibiting these factors initially later developed IPMN-DC or c-PDAC. Conclusions: Ten percent of IPMN cases will develop IPMN-DC or c-PDAC, thereby requiring careful follow-up, especially in cases with SNS, abnormal CA19-9, and MCD ≥ 30 mm. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) prediction in high-risk individuals is essential for early detection and improved outcome. While prior studies have utilized pancreatic radiomics for PDAC prediction, the added value of main pancreatic duct (MPD) features remains unclear. This study aims to assess the additional value of features of the main pancreatic duct (MPD) for predicting PDAC occurrence across different timeframes in advance. Methods: In total, 321 contrast-enhanced CT scans of the MPD and pancreas carried out across control, pre-diagnostic, and diagnostic cohorts were segmented, and radiomics were extracted. A support vector machine (SVM) classifier was used to classify the control and pre-diagnostic cohorts, with model performance assessed using area under the receiver operating characteristic (ROC) curves (AUCs) Results: The MPD diameter and volume significantly increased from the control to the pre-diagnostic and diagnostic CT scans (p < 0.05). The addition of features of the MPD to the pancreas improved the PDAC prediction AUC from 0.83 to 0.96 for subjects 6 months to 3 years in advance, from 0.81 to 0.94 for 3–6 years in advance, and 0.75 to 0.84 for 6–10 years in advance of diagnosis. Additionally, integrating MPD radiomics with diameter and volume significantly improved the AUC from 0.81 to 0.88 for subjects 6 months to 3 years in advance. Conclusions: Radiomic features from abdominal CT scans allow PDAC prediction up to 10 years in advance. Integrating MPD features, including diameter and volume, significantly improves PDAC prediction compared to using radiomics of the pancreas alone. Full article

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis, primarily due to its immunosuppressive tumor microenvironment (TME), which contributes to treatment resistance. Recent research shows that the microbiome, including microbial communities in the oral cavity, gut, bile duct, and intratumoral environments, plays a key role in PDAC development, with microbial imbalances (dysbiosis) promoting inflammation, cancer progression, therapy resistance, and treatment side effects. Microbial metabolites can also affect immune cells, especially natural killer (NK) cells, which are vital for tumor surveillance, therapy response and treatment-related side effects. Dysbiosis can affect NK cell function, leading to resistance and side effects. We propose that a combined biomarker approach, integrating microbiome composition and NK cell profiles, can help predict treatment resistance and side effects, enabling more personalized therapies. This review examines how dysbiosis contributes to NK cell dysfunction in PDAC and discusses strategies (e.g., antibiotics, probiotics, vaccines) to modulate the microbiome and enhance NK cell function. Targeting dysbiosis could modulate NK cell activity, improve the effectiveness of PDAC treatments, and reduce side effects. However, further research is needed to develop unified NK cell–microbiome interaction-based biomarkers for more precise and effective patient outcomes. Full article

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, due in part to early invasion and metastasis, which in turn involves epithelial–mesenchymal transition (EMT) of the cancer cells. Prompted by the discovery that two PDAC cell lines of the quasi-mesenchymal subtype (PANC-1, MIA PaCa-2) exhibit neuroendocrine differentiation (NED), we asked whether NED is associated with EMT. Using real-time PCR and immunoblotting, we initially verified endogenous expressions of various NED markers, i.e., chromogranin A (CHGA), synaptophysin (SYP), somatostatin receptor 2 (SSTR2), and SSTR5 in PANC-1 and MIA PaCa-2 cells. By means of immunohistochemistry, the expressions of CHGA, SYP, SSTR2, and the EMT markers cytokeratin 7 (CK7) and vimentin could be allocated to the neoplastic ductal epithelial cells of pancreatic ducts in surgically resected tissues from patients with PDAC. In HPDE6c7 normal pancreatic duct epithelial cells and in epithelial subtype BxPC-3 PDAC cells, the expression of CHGA, SYP, and neuron-specific enolase 2 (NSE) was either undetectable or much lower than in PANC-1 and MIA PaCa-2 cells. Parental cultures of PANC-1 cells exhibit EM plasticity (EMP) and harbor clonal subpopulations with both M- and E-phenotypes. Of note, M-type clones were found to display more pronounced NED than E-type clones. Inducing EMT in parental cultures of PANC-1 cells by treatment with transforming growth factor-β1 (TGF-β1) repressed epithelial genes and co-induced mesenchymal and NED genes, except for SSTR5. Surprisingly, treatment with bone morphogenetic protein (BMP)-7 differentially affected gene expressions in PANC-1, MIA PaCa-2, BxPC-3, and HPDE cells. It synergized with TGF-β1 in the induction of vimentin, SNAIL, SSTR2, and NSE but antagonized it in the regulation of CHGA and SSTR5. Phospho-immunoblotting in M- and E-type PANC-1 clones revealed that both TGF-β1 and, surprisingly, also BMP-7 activated SMAD2 and SMAD3 and that in M- but not E-type clones BMP-7 was able to dramatically enhance the activation of SMAD3. From these data, we conclude that in EMT of PDAC cells mesenchymal and NED markers are co-regulated, and that mesenchymal–epithelial transition (MET) is associated with a loss of both the mesenchymal and NED phenotypes. Analyzing NED in another tumor type, small cell carcinoma of the ovary hypercalcemic type (SCCOHT), revealed that two model cell lines of this disease (SCCOHT-1, BIN-67) do express CDH1, SNAI1, VIM, CHGA, SYP, ENO2, and SSTR2, but that in contrast to BMP-7, none of these genes was transcriptionally regulated by TGF-β1. Likewise, in BIN-67 cells, BMP-7 was able to reduce proliferation, while in SCCOHT-1 cells this occurred only upon combined treatment with TGF-β and BMP-7. We conclude that in PDAC-derived tumor cells, NED is closely linked to EMT and TGF-β signaling, which may have implications for the therapeutic use of TGF-β inhibitors in PDAC management. Full article

Background: Poor survival outcomes in periampullary cancer highlight the need for improvement in biomarkers and the development of novel therapies. Redox proteins, including the thioredoxin system, play vital roles in cellular antioxidant systems. Methods: In this retrospective study, thioredoxin (Trx), thioredoxin-interacting protein (TxNIP), and thioredoxin reductase (TrxR) protein expression was assessed in 85 patients with pancreatic ductal adenocarcinoma (PDAC) and 145 patients with distal bile duct or ampullary carcinoma using conventional immunohistochemistry. Results: In patients with PDAC, high cytoplasmic TrxR expression was significantly associated with lymph node metastasis (p = 0.033). High cytoplasmic and nuclear Trx expression was significantly associated with better overall survival (p = 0.018 and p = 0.006, respectively), and nuclear Trx expression remained significant in multivariate Cox regression analysis (p < 0.0001). In distal bile duct and ampullary carcinomas, high nuclear TrxR expression was associated with vascular (p = 0.001) and perineural (p = 0.021) invasion, and low cytoplasmic TxNIP expression was associated with perineural invasion (p = 0.025). High cytoplasmic TxNIP expression was significantly associated with better overall survival (p = 0.0002), which remained significant in multivariate Cox regression analysis (p = 0.013). Conclusions: These findings demonstrate the prognostic importance of Trx system protein expression in periampullary cancers. Full article

The early detection of pancreatic ductal adenocarcinoma (PDAC) is essential for optimal treatment of pancreatic cancer patients. We propose a tumor detection framework to improve the detection of pancreatic head tumors on CT scans. In this retrospective research study, CT images of 99 patients with pancreatic head cancer and 98 control cases from the Catharina Hospital Eindhoven were collected. A multi-stage 3D U-Net-based approach was used for PDAC detection including clinically significant secondary features such as pancreatic duct and common bile duct dilation. The developed algorithm was evaluated using a local test set comprising 59 CT scans. The model was externally validated in 28 pancreatic cancer cases of a publicly available medical decathlon dataset. The tumor detection framework achieved a sensitivity of 0.97 and a specificity of 1.00, with an area under the receiver operating curve (AUROC) of 0.99, in detecting pancreatic head cancer in the local test set. In the external test set, we obtained similar results, with a sensitivity of 1.00. The model provided the tumor location with acceptable accuracy obtaining a DICE Similarity Coefficient (DSC) of 0.37. This study shows that a tumor detection framework utilizing CT scans and secondary signs of pancreatic cancer can detect pancreatic tumors with high accuracy. Full article

Background: Intraductal papillary mucinous neoplasms (IPMNs) have the potential to evolve into pancreatic adenocarcinoma (PDAC). While main-duct IPMNs (MD-IPMNs), involving the main pancreatic duct (MPD), are less common than side-branch IPMNs (SB-IPMNs) or mixed-type IPMNs (mixed-IPMNs), their malignant transformation potential is far greater. Controversy exists between different guidelines in terms of recommended management strategies. This study was aimed at assessing the utility of the radiological follow up of MD-IPMNs and mixed-type IPMNs, including prevalence of worrisome radiological findings as well as clinical and laboratory parameters, and their correlation with the development of progression or pancreatic adenocarcinoma. Methods: Eighty-four patients with MD-IPMNs or mixed-type IPMNs who underwent at least one magnetic resonance cholangiopancreatography (MRCP) were included. Clinical and laboratory data were obtained retrospectively. A cross-sectional analysis was carried out to establish clinical and laboratory parameters associated with development of PDAC. A retrospective cohort analysis was performed on 44 patients who had at least six months of follow up, trying to identify factors correlating with worrisome radiological features. Results: Nine cases (10.7%) of PDAC were recorded in this cohort. The laboratory and imaging factors associated with cyst size progression greater than 5 mm during follow up were elevated alanine transaminase (ALT) levels, the maximal cyst size, and the MPD diameter. Cross-sectional analysis indicated that PDAC was associated with nausea (p = 0.01), as well as increased levels of aspartate aminotransferase (AST) (p = 0.05), gamma glutamyl transpeptidase (GGT) (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01). Conclusions: Elevated levels of liver enzymes were associated with IPMN progression and, subsequently, the development of PDAC. ALT levels, maximal cyst size, and MPD diameter are associated with the progression of cyst size. These data may aid in risk-stratifying patients when determining the follow up approach for IPMNs. Full article

Pancreatic cancer (PC) is a dangerous digestive tract tumor that is becoming increasingly common and fatal. The most common form of PC is pancreatic ductal adenocarcinoma (PDAC). Bile acids (BAs) are closely linked to the growth and progression of PC. They can change the intestinal flora, increasing intestinal permeability and allowing gut microbes to enter the bloodstream, leading to chronic inflammation. High dietary lipids can increase BA secretion into the duodenum and fecal BA levels. BAs can cause genetic mutations, mitochondrial dysfunction, abnormal activation of intracellular trypsin, cytoskeletal damage, activation of NF-κB, acute pancreatitis, cell injury, and cell necrosis. They can act on different types of pancreatic cells and receptors, altering Ca²⁺ and iron levels, and related signals. Elevated levels of Ca²⁺ and iron are associated with cell necrosis and ferroptosis. Bile reflux into the pancreatic ducts can speed up the kinetics of epithelial cells, promoting the development of pancreatic intraductal papillary carcinoma. BAs can cause the enormous secretion of Glucagon-like peptide-1 (GLP-1), leading to the proliferation of pancreatic β-cells. Using Glucagon-like peptide-1 receptor agonist (GLP-1RA) increases the risk of pancreatitis and PC. Therefore, our objective was to explore various studies and thoroughly examine the role of BAs in PC. Full article

Pancreatic ductal adenocarcinoma (PDAC) can originate from acinar-to-ductal metaplasia (ADM). Pancreatic acini harboring oncogenic Kras mutations are transdifferentiated to a duct-like phenotype that further progresses to become pancreatic intraepithelial neoplasia (PanIN) lesions, giving rise to PDAC. Although ADM formation is frequently observed in Kras^G12D transgenic mouse models of PDAC, the exact mechanisms of how oncogenic Kras^G12D regulates this process remain an enigma. Herein, we revealed a new downstream target of oncogenic Kras, cytokine CCL9, during ADM formation. Higher levels of CCL9 and its receptors, CCR1 and CCR3, were detected in ADM regions of the pancreas in p48^cre:Kras^G12D mice and human PDAC patients. Knockdown of CCL9 in Kras^G12D-expressed pancreatic acini reduced Kras^G12D-induced ADM in a 3D organoid culture system. Moreover, exogenously added recombinant CCL9 and overexpression of CCL9 in primary pancreatic acini induced pancreatic ADM. We also showed that, functioning as a downstream target of Kras^G12D, CCL9 promoted pancreatic ADM through upregulation of the intracellular levels of reactive oxygen species (ROS) and metalloproteinases (MMPs), including MMP14, MMP3 and MMP2. Blockade of MMPs via its generic inhibitor GM6001 or knockdown of specific MMP such as MMP14 and MMP3 decreased CCL9-induced pancreatic ADM. In p48^cre:Kras^G12D transgenic mice, blockade of CCL9 through its specific neutralizing antibody attenuated pancreatic ADM structures and PanIN lesion formation. Furthermore, it also diminished infiltrating macrophages and expression of MMP14, MMP3 and MMP2 in the ADM areas. Altogether, our results provide novel mechanistic insight into how oncogenic Kras enhances pancreatic ADM through its new downstream target molecule, CCL9, to initiate PDAC. Full article

Background: Surgery-first approach is the current standard of care for resectable pancreatic ductal adenocarcinoma (PDAC), and a proportion of these cases will require venous resection. This study aimed to identify parameters on staging computed tomography (CT) that predict the need for venous resection during pancreaticoduodenectomy (PD) for resectable PDAC. Methods: We conducted a retrospective analysis of prospectively collected data on patients who underwent PD for resectable staged PDAC (as per NCCN criteria) between 2011 and 2020. Staging CTs were independently reviewed by two specialist radiologists blinded to the clinical outcomes. Univariate and multivariate risk analyses were performed. Results: In total, 296 PDs were included. Venous resection was performed in 62 (21%) cases. There was a higher rate of resection margin positivity in the vein resection group (72.6% vs. 48.7%, p = 0.001). Tumour at the neck of the pancreas, superior mesenteric vein involvement of ≥10 mm and pancreatic duct dilatation were identified as independent predictors for venous resection. Discussion: Staging CT parameters can predict the need for venous resection during PD for resectable cases of PDAC. This may assist in surgical planning, patient selection and counselling. Future efforts should concentrate on validating these results or identifying additional predictors in a multicentre and prospective setting. Full article

The serum level of CA 19-9 is a prognostic marker for pancreatic ductal adenocarcinoma (PDAC). We evaluated the ability of the expression level of methionyl-tRNA synthetase 1 (MARS1)—which facilitates cancer growth by modulating protein synthesis and the cell cycle—to predict the prognosis of PDAC. Immunohistochemical (IHC) staining was performed on pancreatic specimens obtained from patients with PDAC who were undergoing surgery. High MARS1 expression was defined as equal to, or greater than, that in normal acinar cells. Low MARS1 expression was defined as weaker than in normal acinar cells, and stronger than in the pancreatic duct epithelium. Univariate and multivariate analyses were performed on other factors related to prognosis. Among 137 PDAC patients, no significant differences in baseline characteristics were found between those with high (n = 82) and low (n = 55) MARS1 expression. The median overall survival time of patients with high MARS1 expression was shorter than that of those with low expression (15.2 versus 17.2 months, log-rank test p = 0.044). The median disease-free survival (DFS) was not significantly different between the two groups. However, the DFS was shorter in patients with high than in those with low MARS1 expression (8.9 versus 11.2 months, log-rank test p = 0.067). In a multivariate analysis, lymph node metastasis and high MARS1 expression were associated with a poor prognosis of PDAC. Elevated MARS1 expression detected by IHC staining is associated with a poor prognosis of PDAC, suggesting that MARS1 has potential as a prognostic marker. Full article

Many studies highlighted the importance of the IK channel for the proliferation and the migration of different types of cancer cells, showing how IK blockers could slow down cancer growth. Based on these data, we wanted to characterize the effects of IK blockers on melanoma metastatic cells and to understand if such effects were exclusively IK-dependent. For this purpose, we employed two different blockers, namely clotrimazole and senicapoc, and two cell lines: metastatic melanoma WM266-4 and pancreatic cancer Panc-1, which is reported to have little or no IK expression. Clotrimazole and senicapoc induced a decrease in viability and the migration of both WM266-4 and Panc-1 cells irrespective of IK expression levels. Patch-clamp experiments on WM266-4 cells revealed Ca²⁺-dependent, IK-like, clotrimazole- and senicapoc-sensitive currents, which could not be detected in Panc-1 cells. Neither clotrimazole nor senicapoc altered the intracellular Ca²⁺ concentration. These results suggest that the effects of IK blockers on cancer cells are not strictly dependent on a robust presence of the channel in the plasma membrane, but they might be due to off-target effects on other cellular targets or to the blockade of IK channels localized in intracellular organelles. Full article

Anemia and iron deficiency (ID) are common complications in patients with pancreatic ductal adenocarcinoma (PDAC), but their underlying causes remain unclear. This study investigated the incidence and characteristics of anemia and micronutrient deficiencies in PDAC patients before initiating chemotherapy. A total of 103 PDAC patients were included, comprising 67 in the palliative and 36 in the adjuvant groups. The overall incidence of anemia was 42.7% (n = 44), with comparable rates in both groups. Normocytic and normochromic anemia were predominant, with mild and moderate cases observed in 32% and 10.7% of the cohort, respectively. ID was evident in 51.4% of patients, with absolute ID more frequent in the adjuvant than in the palliative group (19.4% vs. 13.4%). Functional ID occurred more often in the palliative than in the adjuvant group (41.8% vs. 25%). Vitamin B12 and folate deficiency occurred in <5% (n = 5) of patients. Furthermore, 8.7% (n = 9) of patients had chronic kidney disease and anemia. To elucidate mechanisms of iron deficiency, the study explored the expression of iron regulators (hepcidin (HEP), ferroportin (FPN), and ZIP14 protein) and mitochondrial mass in PDAC tissue with immunohistochemical (IHC) staining and Perl’s Prussian blue to detect iron deposits on available tumor samples (n = 56). ZIP14 expression was significantly higher in less advanced tumors (p = 0.01) and correlated with mitochondrial mass (p < 0.001), potentially indicating its role in local iron homeostasis. However, no significant impact of tissue iron regulators on patient survival was observed. Perl’s Prussian blue staining revealed iron deposits within macrophages, but not in pancreatic duct cells. Furthermore, the GEPIA database was used to compare mRNA expression of iron regulators (HEP, FPN, and ZIP14) and other genes encoding iron transport and storage, including Transferrin Receptor Protein 1 (TfR1) and both ferritin chain subunits (FTH and FTL), in PDAC and normal pancreatic samples. FPN, TfR1, FTH, and FTL showed higher expression in tumor tissues, indicating increased iron usage by cancer. ZIP14 expression was higher in the pancreas than in PDAC and was correlated with FPN expression. The study highlights the importance of baseline iron status assessment in managing PDAC patients due to the high incidence of anemia and iron deficiency. Furthermore, ZIP14, in addition to HEP and FPN, may play a crucial role in local iron homeostasis in PDAC patients, providing valuable insights into the underlying mechanisms of iron dysregulation. Full article

Adult pancreatic acinar cells show high plasticity allowing them to change in their differentiation commitment. Pancreatic acinar-to-ductal metaplasia (ADM) is a cellular process in which the differentiated pancreatic acinar cells transform into duct-like cells. This process can occur as a result of cellular injury or inflammation in the pancreas. While ADM is a reversible process allowing pancreatic acinar regeneration, persistent inflammation or injury can lead to the development of pancreatic intraepithelial neoplasia (PanIN), which is a common precancerous lesion that precedes pancreatic ductal adenocarcinoma (PDAC). Several factors can contribute to the development of ADM and PanIN, including environmental factors such as obesity, chronic inflammation and genetic mutations. ADM is driven by extrinsic and intrinsic signaling. Here, we review the current knowledge on the cellular and molecular biology of ADM. Understanding the cellular and molecular mechanisms underlying ADM is critical for the development of new therapeutic strategies for pancreatitis and PDAC. Identifying the intermediate states and key molecules that regulate ADM initiation, maintenance and progression may help the development of novel preventive strategies for PDAC. Full article

Fully covered self-expandable metallic stents (FCSEMSs) are inserted in patients with unresectable pancreatic ductal adenocarcinoma (PDAC) to resolve malignant distal bile duct obstructions. Some patients receive FCSEMSs during primary endoscopic retrograde cholangiopancreatography (ERCP), and others receive FCSEMSs during a later session, after the placement of a plastic stent. We aimed to evaluate the efficacy of FCSEMSs for primary use or following plastic stent placement. A total of 159 patients with pancreatic adenocarcinoma (m:f, 102:57) who had achieved clinical success underwent ERCP with the placement of FCSEMSs for palliation of obstructive jaundice. One-hundred and three patients had received FCSEMSs in a first ERCP, and 56 had received FCSEMSs after prior plastic stenting. Twenty-two patients in the primary metal stent group and 18 in the prior plastic stent group had recurrent biliary obstruction (RBO). The RBO rates and self-expandable metal stent patency duration did not differ between the two groups. An FCSEMS longer than 6 cm was identified as a risk factor for RBO in patients with PDAC. Thus, choosing an appropriate FCSEMS length is an important factor in preventing FCSEMS dysfunction in patients with PDAC with malignant distal bile-duct obstruction. Full article