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World Journal of Gastroenterology May 2024Contrast-enhanced endoscopic ultrasound (CH-EUS) can overcome the limitations of endoscopic ultrasound-guided acquisition by identifying microvessels inside... (Review)
Review
Contrast-enhanced endoscopic ultrasound (CH-EUS) can overcome the limitations of endoscopic ultrasound-guided acquisition by identifying microvessels inside inhomogeneous tumours and improving the characterization of these tumours. Despite the initial enthusiasm that oriented needle sampling under CH-EUS guidance could provide better diagnostic yield in pancreatic solid lesions, further studies did not confirm the supplementary values in cases of tissue acquisition guided by CH-EUS. This review details the knowledge based on the available data on contrast-guided procedures. The indications for CH-EUS tissue acquisition include isoechoic EUS lesions with poor visible delineation where CH-EUS can differentiate the lesion vascularisation from the surrounding parenchyma and also the mural nodules within biliopancreatic cystic lesions, which occur in select cases. Additionally, the roles of CH-EUS-guided therapy in patients whose pancreatic fluid collections or bile ducts that have an echogenic content have indications for drainage, and patients who have nonvisualized vessels that need to be highlighted Doppler EUS are presented. Another indication is represented if there is a need for an immediate assessment of the post-radiofrequency ablation of pancreatic neuroendocrine tumours, in which case CH-EUS can be used to reveal the incomplete tumour destruction.
Topics: Humans; Contrast Media; Pancreatic Neoplasms; Endosonography; Pancreas; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Ultrasonography, Interventional; Drainage; Pancreatic Diseases
PubMed: 38813054
DOI: 10.3748/wjg.v30.i17.2311 -
Journal of Hematology & Oncology Jun 2024Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long... (Review)
Review
Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.
Topics: Humans; Pancreatic Neoplasms; Immunotherapy; Tumor Microenvironment; Cancer Vaccines; Immune Checkpoint Inhibitors; Animals; Immunotherapy, Adoptive
PubMed: 38835055
DOI: 10.1186/s13045-024-01561-6 -
Inflammation Research : Official... Sep 2023Nafamostat mesilate (NM), a synthetic broad-spectrum serine protease inhibitor, has been commonly used for treating acute pancreatitis (AP) and other...
OBJECTIVE
Nafamostat mesilate (NM), a synthetic broad-spectrum serine protease inhibitor, has been commonly used for treating acute pancreatitis (AP) and other inflammatory-associated diseases in some East Asia countries. Although the potent inhibitory activity against inflammation-related proteases (such as thrombin, trypsin, kallikrein, plasmin, coagulation factors, and complement factors) is generally believed to be responsible for the anti-inflammatory effects of NM, the precise target and molecular mechanism underlying its anti-inflammatory activity in AP treatment remain largely unknown.
METHODS
The protection of NM against pancreatic injury and inhibitory effect on the NOD-like receptor protein 3 (NLRP3) inflammasome activation were investigated in an experimental mouse model of AP. To decipher the molecular mechanism of NM, the effects of NM on nuclear factor kappa B (NF-κB) activity and NF-κB mediated NLRP3 inflammasome priming were examined in lipopolysaccharide (LPS)-primed THP-1 cells. Additionally, the potential of NM to block the activity of histone deacetylase 6 (HDAC6) and disrupt the association between HDAC6 and NLRP3 was also evaluated.
RESULTS
NM significantly suppressed NLRP3 inflammasome activation in the pancreas, leading to a reduction in pancreatic inflammation and prevention of pancreatic injury during AP. NM was found to interact with HDAC6 and effectively inhibit its function. This property allowed NM to influence HDAC6-dependent NF-κB transcriptional activity, thereby blocking NF-κB-driven transcriptional priming of the NLRP3 inflammasome. Furthermore, NM exhibited the potential to interfere the association between HDAC6 and NLRP3, impeding HDAC6-mediated intracellular transport of NLRP3 and ultimately preventing NLRP3 inflammasome activation.
CONCLUSIONS
Our current work has provided valuable insight into the molecular mechanism underlying the immunomodulatory effect of NM in the treatment of AP, highlighting its promising application in the prevention of NLRP3 inflammasome-associated inflammatory pathological damage.
Topics: Mice; Animals; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Pancreatitis; NF-kappa B; Ceruletide; NLR Proteins; Histone Deacetylase 6; Acute Disease; Inflammation; Anti-Inflammatory Agents
PubMed: 37725105
DOI: 10.1007/s00011-023-01794-0 -
Molecules (Basel, Switzerland) Jul 2023Chronic pancreatitis (CP) is a disease characterized by inflammatory recurrence that accompanies the development of pancreatic fibrosis. As the mystery of CP... (Review)
Review
Chronic pancreatitis (CP) is a disease characterized by inflammatory recurrence that accompanies the development of pancreatic fibrosis. As the mystery of CP pathogenesis is gradually revealed, accumulating evidence suggests that the activation of pancreatic stellate cells (PSCs) and the appearance of a myofibroblast-like phenotype are the key gatekeepers in the development of CP. Targeting PSCs to prevent their activation and conversion to a myofibroblast-like phenotype, as well as increasing antioxidant capacity to counteract ongoing oxidative stress, are effective strategies for preventing or treating CP. Therefore, we reviewed the crosstalk between CP and pancreatic fibrosis, summarized the activation mechanisms of PSCs, and investigated potential CP therapeutic strategies targeting PSCs, including, but not limited to, anti-fibrosis therapy, antioxidant therapy, and gene therapy. Meanwhile, the above therapeutic strategies are selected in order to update the available phytopharmaceuticals as novel complementary or alternative approaches for the prevention and treatment of CP to clarify their potential mechanisms of action and their relevant molecular targets, aiming to provide the most comprehensive therapeutic treatment direction for CP and to bring new hope to CP patients.
Topics: Humans; Pancreas; Pancreatic Stellate Cells; Antioxidants; Pancreatitis, Chronic
PubMed: 37513458
DOI: 10.3390/molecules28145586 -
International Immunopharmacology Aug 2023Acute pancreatitis (AP) is an inflammatory condition of the pancreas characterized by oxidative stress and inflammation in its pathophysiology....
BACKGROUND
Acute pancreatitis (AP) is an inflammatory condition of the pancreas characterized by oxidative stress and inflammation in its pathophysiology. Acetyl-11-keto-β-boswellic acid (AKBA) is an active triterpenoid with antioxidant activity. This article seeks to assess the impact of AKBA on AP and investigate its underlying mechanisms.
METHODS
AP was induced in wild-type, Lyz2 Nrf2 mice and Pdx1 Nrf2 mice by caerulein. Serum amylase and lipase levels, along with histological grading, were utilized to evaluate the severity of AP. Murine bone marrow-derived macrophages (BMDMs) were isolated, cultured, and polarized to the M1 subtype. Flow cytometry and ELISA were utilized to identify the macrophage phenotype. Alterations in oxidative stress damage and intracellular ROS were observed. Nrf2/HO-1 signaling pathways were also evaluated.
RESULTS
In a caerulein-induced mouse model of AP, treatment with AKBA reduced blood amylase and lipase activity and ameliorated pancreatic tissue histological and pathological features. Furthermore, AKBA significantly mitigated oxidative stress-induced damage and induced the expression of Nrf2 and HO-1 protein. Additionally, by using conditional knockout mice (Lyz2 Nrf2 and Pdx1 Nrf2 mice), we verified that Nrf2 primarily functions in macrophages rather than acinar cells. In vitro, AKBA inhibits pro-inflammatory M1-subtype macrophage polarization and reduces ROS generation through Nrf2/HO-1 oxidative stress pathway. Moreover, the protective effects of AKBA against AP were abolished in myeloid-specific Nrf2-deficient mice and BMDMs. Molecular docking results revealed interactions between AKBA and Nrf2.
CONCLUSION
Our results confirm that AKBA exerts protective effects against AP in mice by inhibiting oxidative stress in macrophages through the Nrf2/HO-1 Pathway.
Topics: Animals; Mice; Pancreatitis; NF-E2-Related Factor 2; Reactive Oxygen Species; Ceruletide; Acute Disease; Molecular Docking Simulation; Oxidative Stress; Macrophages; Lipase; Amylases
PubMed: 37364326
DOI: 10.1016/j.intimp.2023.110501 -
European Journal of Nuclear Medicine... Nov 2023Anatomical and molecular staging strategies are needed for the personalized treatment of localized pancreatic ductal adenocarcinoma (PDAC). This study evaluated the...
Comparing the clinical value of baseline [ Ga]Ga-FAPI-04 PET/CT and [F]F-FDG PET/CT in pancreatic ductal adenocarcinoma: additional prognostic value of the distal pancreatitis.
PURPOSE
Anatomical and molecular staging strategies are needed for the personalized treatment of localized pancreatic ductal adenocarcinoma (PDAC). This study evaluated the performance of [ Ga]Ga-FAPI-04 and [F]F-FDG PET/CT on the disease staging and prognostic value of patients with localized PDAC on contrast-enhanced (CE)-CT images.
METHODS
Patients with suspected localized PDAC on CE-CT were recruited for static [ Ga]Ga-FAPI-04 and [F]F-FDG and PET/CT, and select patients underwent simultaneous 60-min dynamic Ga-FAPI-04 PET/CT. The diagnostic and staging performances of the static PET/CT results were evaluated by delineating regions of interest in the primary tumor, whole pancreas, and distal pancreas in both types of scans and then evaluating correlations between the PET/CT findings and clinicopathological characteristics. Furthermore, Kaplan-Meier and hazard ratio (log-rank) methods were used to evaluate the prognostic value of the combined dynamic [ Ga]Ga-FAPI-04 and static [F]F-FDG PET/CT method.
RESULTS
We included 49 patients with histologically confirmed PDAC adenocarcinomas; 32 underwent 60-min dynamic [ Ga]Ga-FAPI-04 PET/CT imaging simultaneously. The static [ Ga]Ga-FAPI-04 method had significantly higher accuracy and uptake values than the static [F]F-FDG method for primary PDAC lesions, metastatic lymph nodes, and distal metastases. Furthermore, 18.4% and 10.2% of the patients' stages changed after using the [ Ga]Ga-FAPI-04 and [F]F-FDG PET/CT methodologies, respectively, compared to the CE-CT-designated stage. The Ki values obtained from dynamic [ Ga]Ga-FAPI-04 PET/CT did not differ between PDAC and distal obstructive pancreatitis lesions. Pathologically enlarged tumor size, poor differentiation, and perineural invasion were associated with increased [ Ga]Ga-FAPI-04 uptake but not with [F]F-FDG uptake. The preoperative prognostic performance of [ Ga]Ga-FAPI-04 was better than that of [F]F-FDG. Interestingly, combined [ Ga]Ga-FAPI-04 and [F]F-FDG uptake results in the whole pancreas could further stratify patients based on their postoperative prognosis.
CONCLUSION
[ Ga]Ga-FAPI-04 PET/CT was more sensitive and accurate than [F]F-FDG PET/CT for tumor, node, and metastasis staging of PDAC identified on CE-CT. Additionally, [ Ga]Ga-FAPI-04 uptake was significantly associated with pathologically aggressive tumor features. Combined [ Ga]Ga-FAPI-04 and [F]F-FDG PET/CT findings improved the prognostic value, potentially providing a non-invasive guide for clinical management. Finally, increased fibroblast activity in PDAC-induced obstructive pancreatitis may be associated with poor patient survival rates.
Topics: Humans; Positron Emission Tomography Computed Tomography; Fluorodeoxyglucose F18; Prognosis; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Quinolines; Pancreatitis; Adenocarcinoma; Gallium Radioisotopes
PubMed: 37493664
DOI: 10.1007/s00259-023-06297-y -
World Journal of Gastroenterology Feb 2024Pancreatitis and pancreatic cancer (PC) stand as the most worrisome ailments affecting the pancreas. Researchers have dedicated efforts to unraveling the mechanisms... (Review)
Review
Pancreatitis and pancreatic cancer (PC) stand as the most worrisome ailments affecting the pancreas. Researchers have dedicated efforts to unraveling the mechanisms underlying these diseases, yet their true nature continues to elude their grasp. Within this realm, oxidative stress is often believed to play a causal and contributory role in the development of pancreatitis and PC. Excessive accumulation of reactive oxygen species (ROS) can cause oxidative stress, and the key enzyme responsible for inducing ROS production in cells is nicotinamide adenine dinucleotide phosphate hydrogen oxides (NOX). NOX contribute to pancreatic fibrosis and inflammation by generating ROS that injure acinar cells, activate pancreatic stellate cells, and mediate macrophage polarization. Excessive ROS production occurs during malignant transformation and pancreatic carcinogenesis, creating an oxidative microenvironment that can cause abnormal apoptosis, epithelial to mesenchymal transition and genomic instability. Therefore, understanding the role of NOX in pancreatic diseases contributes to a more in-depth exploration of the exact pathogenesis of these diseases. In this review, we aim to summarize the potential roles of NOX and its mechanism in pancreatic disorders, aiming to provide novel insights into understanding the mechanisms underlying these diseases.
Topics: Humans; Reactive Oxygen Species; NADP; Epithelial-Mesenchymal Transition; NADPH Oxidases; Oxidative Stress; Pancreatitis
PubMed: 38414585
DOI: 10.3748/wjg.v30.i5.429 -
Pancreatology : Official Journal of the... Dec 2023The George E Palade Prize is the highest honour awarded by the International Association of Pancreatology, that recognises an individual who has made outstanding...
The George E Palade Prize is the highest honour awarded by the International Association of Pancreatology, that recognises an individual who has made outstanding contributions to the understanding of the pancreas and pancreatic diseases. The 2023 Palade Prize was awarded to Professor Minoti Apte, University of New South Wales Sydney on September 16, 2023 during the Joint Meeting of the International Association of Pancreatology and the Indian Pancreas Club, held in Delhi, India. This paper summarises her Palade lecture wherein she reflects on her journey as a medical graduate, an academic and a researcher, with a particular focus on her team's pioneering work on pancreatic stellate cell biology and the role of these cells in health and disease. While there has been much progress in this field with the efforts of researchers worldwide, there is much still to be learned; thus it is a topic with ample scope for innovative research with the potential to translate into better outcomes for patients with pancreatic disease.
Topics: Female; Humans; Awards and Prizes; Pancreas; Pancreatic Diseases; Pancreatic Stellate Cells
PubMed: 37973449
DOI: 10.1016/j.pan.2023.10.024 -
Surgery Today Dec 2023Although reports suggest that the pancreatic volume decreases after gastrectomy for gastric cancer, the relationship between the pancreatic volume and secretory function...
PURPOSE
Although reports suggest that the pancreatic volume decreases after gastrectomy for gastric cancer, the relationship between the pancreatic volume and secretory function after gastrectomy remains unclear. In this study, we examined the relationship between the pancreatic volume and exocrine and endocrine functions after total gastrectomy.
METHODS
The pancreatic volumes of 18 distal gastrectomy and 15 total gastrectomy patients were retrospectively measured using computed tomography volumetry up to 5 years postoperatively. Ten low anterior resection patients were selected as controls. In addition, the pancreatic volume and exocrine function evaluated by fecal elastase and the insulin secretory function evaluated by glucagon tolerance testing were prospectively examined before and one year after surgery in nine cases of total gastrectomy.
RESULTS
After low anterior resection, the pancreatic volume did not change, but after distal and total gastrectomy, the pancreatic volume decreased continuously until the fifth year. After total gastrectomy, fecal elastase decreased significantly from 865.8 μg/g to 603.2 μg/g in the first year (p = 0.0316), and the insulin secretion capacity also decreased significantly from 3.83 ng/mL to 2.26 ng/mL (p = 0.0019).
CONCLUSIONS
The pancreatic volume decreases continuously after gastrectomy for gastric cancer, and the pancreatic exocrine and endocrine functions decrease along with pancreatic atrophy after total gastrectomy.
Topics: Humans; Atrophy; Gastrectomy; Pancreatic Diseases; Pancreatic Elastase; Retrospective Studies; Stomach Neoplasms
PubMed: 37084095
DOI: 10.1007/s00595-023-02685-x -
Pharmacological Research Aug 2023Pancreatic cancer (PC) is a serious gastrointestinal tract disease for which the 5-year survival rate is less than 10%, even in developed countries such as the USA. The...
Pancreatic cancer (PC) is a serious gastrointestinal tract disease for which the 5-year survival rate is less than 10%, even in developed countries such as the USA. The genomic profile alterations and dysregulated biological mechanisms commonly occur in PC. Macroautophagy/autophagy is a cell death process that is maintained at a basal level in physiological conditions, whereas its level often changes during tumorigenesis. The function of autophagy in human cancers is dual and can be oncogenic and onco-suppressor. Autophagy is a potent controller of tumorigenesis in PC. The supportive autophagy in PC escalates the growth rate of PC cells and its suppression can mediate cell death. Autophagy also determines the metastasis of PC cells, and it can control the EMT in affecting migration. Moreover, starvation and hypoxia can stimulate glycolysis, and glycolysis induction can be mediated by autophagy in enhancing tumorigenesis in PC. Furthermore, protective autophagy stimulates drug resistance and gemcitabine resistance in PC cells, and its inhibition can enhance radiosensitivity. Autophagy can degrade MHC-I to mediate immune evasion and also regulates polarization of macrophages in the tumor microenvironment. Modulation of autophagy activity is provided by silibinin, ursolic acid, chrysin and huaier in the treatment of PC. Non-coding RNAs are also controllers of autophagy in PC and its inhibition can improve therapy response in patients. Moreover, mitophagy shows dysregulation in PC, which can enhance the proliferation of PC cells. Therefore, a bioinformatics analysis demonstrates the dysregulation of autophagy-related proteins and genes in PC as biomarkers.
Topics: Humans; Cell Line, Tumor; Pancreatic Neoplasms; Autophagy; Carcinogenesis; Tumor Microenvironment
PubMed: 37336429
DOI: 10.1016/j.phrs.2023.106822