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Current Treatment Options in Oncology Jul 2023Functional pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous diseases in terms of both clinical and pathological aspects. These tumors secrete... (Review)
Review
Functional pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous diseases in terms of both clinical and pathological aspects. These tumors secrete hormones or peptides, which may cause a wide variety of symptoms related to a clinical syndrome. The management of functional pNENs is still challenging for clinicians due to the need to control both tumor growth and specific symptoms. Surgery remains the cornerstone in the management of local disease because it can definitively cure the patient. However, when the disease is not resectable, a broad spectrum of therapeutic options, including locoregional therapy, somatostatin analogs (SSAs), targeted therapies, peptide-receptor radionuclide therapy (PRRT), and chemotherapy, are available. The present review summarizes the main key issues regarding the clinical management of these tumors, providing a specific highlight on their therapeutic approach.
Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatin; Receptors, Somatostatin; Intestinal Neoplasms; Stomach Neoplasms
PubMed: 37103745
DOI: 10.1007/s11864-023-01085-0 -
Nature Aug 2023A growing body of literature suggests that alterations in the human microbiome are causative of disease initiation and progression. Aykut et al. present data supporting...
A growing body of literature suggests that alterations in the human microbiome are causative of disease initiation and progression. Aykut et al. present data supporting the argument that alterations in the gut fungal microbiome (the “mycobiome”), along with the presence of fungal elements within pancreatic tissue (specifically those of the genus , are associated with pancreatic oncogenesis. Upon analyzing the human sequencing data presented in the original manuscript, we found few fungal reads in pancreatic tissue samples and did not identify differences in pancreatic or gut mycobiome composition between healthy and pancreatic ductal adenocarcinoma (PDAC) patients. Our re-analysis of these data does not support an association between an intrinsic pancreatic mycobiome and the development of human PDAC, and illustrates the challenges in analyzing microbiome sequencing data from low biomass samples.
Topics: Humans; Mycobiome; Pancreatic Neoplasms; Pancreas; Carcinogenesis
PubMed: 37532819
DOI: 10.1038/s41586-023-06292-1 -
Cell Reports Jun 2023Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that typically demonstrates resistance to chemotherapy. Tumor-associated macrophages (TAMs) are...
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that typically demonstrates resistance to chemotherapy. Tumor-associated macrophages (TAMs) are essential in tumor microenvironment (TME) regulation, including promoting chemoresistance. However, the specific TAM subset and mechanisms behind this promotion remain unclear. We employ multi-omics strategies, including single-cell RNA sequencing (scRNA-seq), transcriptomics, multicolor immunohistochemistry (mIHC), flow cytometry, and metabolomics, to analyze chemotherapy-treated samples from both humans and mice. We identify four major TAM subsets within PDAC, among which proliferating resident macrophages (proliferating rMφs) are strongly associated with poor clinical outcomes. These macrophages are able to survive chemotherapy by producing more deoxycytidine (dC) and fewer dC kinases (dCKs) to decrease the absorption of gemcitabine. Moreover, proliferating rMφs promote fibrosis and immunosuppression in PDAC. Eliminating them in the transgenic mouse model alleviates fibrosis and immunosuppression, thereby re-sensitizing PDAC to chemotherapy. Consequently, targeting proliferating rMφs may become a potential treatment strategy for PDAC to enhance chemotherapy.
Topics: Humans; Animals; Mice; Drug Resistance, Neoplasm; Multiomics; Deoxycytidine; Cell Line, Tumor; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Macrophages; Fibrosis; Tumor Microenvironment
PubMed: 37285267
DOI: 10.1016/j.celrep.2023.112620 -
Cancer Metastasis Reviews Dec 2023Surgical resection, when combined with chemotherapy, has been shown to significantly improve the survival rate of patients with pancreatic ductal adenocarcinoma (PDAC).... (Review)
Review
Surgical resection, when combined with chemotherapy, has been shown to significantly improve the survival rate of patients with pancreatic ductal adenocarcinoma (PDAC). However, this treatment option is only feasible for a fraction of patients, as more than 50% of cases are diagnosed with metastasis. The multifaceted process of metastasis is still not fully understood, but recent data suggest that transcriptional and epigenetic plasticity play significant roles. Interfering with epigenetic reprogramming can potentially control the adaptive processes responsible for metastatic progression and therapy resistance, thereby enhancing treatment responses and preventing recurrence. This review will focus on the relevance of histone-modifying enzymes in pancreatic cancer, specifically on their impact on the metastatic cascade. Additionally, it will also provide a brief update on the current clinical developments in epigenetic therapies.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Epigenesis, Genetic
PubMed: 37659057
DOI: 10.1007/s10555-023-10132-z -
Journal of Veterinary Internal Medicine 2023Currently, no specific treatment is available for acute onset pancreatitis (AP), and management relies on symptomatic and supportive standard of care (SOC). Fuzapladib...
BACKGROUND
Currently, no specific treatment is available for acute onset pancreatitis (AP), and management relies on symptomatic and supportive standard of care (SOC). Fuzapladib is a novel leukocyte function-associated antigen type-1 (LFA-1) activation inhibitor, blocking activation and subsequent adhesion and migration of neutrophils, potentially decreasing the risk of pancreatitis progression and systemic inflammation.
OBJECTIVE
Evaluate the safety and clinical response of dogs with AP after 3 days of administration of fuzapladib.
ANIMALS
Sixty-one client-owned dogs with presumptive AP.
METHODS
Randomized, masked, and placebo controlled multicenter study. Sixty-one dogs with AP were included for safety assessment, whereas 35 evaluable cases (fuzapladib, n = 16; placebo, n = 19) were included for clinical evaluation. Clinical improvement was assessed based on the change in the modified clinical activity index (MCAI) score on Day 3 compared to Day 0. Secondary variables included canine acute pancreatitis clinical severity index (CAPCSI) scores and serum concentrations of canine pancreatic lipase immunoreactivity, cytokines, and C-reactive protein.
RESULTS
Fuzapladib was well tolerated by all treated dogs. Mean change in MCAI scores was significantly higher in the fuzapladib-treated (-7.75) than the placebo group (-5.68; P = .02, 95% confidence interval [CI] for the difference, -4.33, -0.35), suggesting clinical improvement in fuzapladib-treated dogs. No significant difference was found in any of the secondary variables between groups.
CONCLUSIONS AND CLINICAL RELEVANCE
Administration of fuzapladib to dogs was safe, and a favorable response was detected in 2 clinical activity scores. Effects of fuzapladib on survival and duration of hospitalization were not studied.
Topics: Animals; Dogs; Acute Disease; C-Reactive Protein; Cytokines; Dog Diseases; Inflammation; Pancreatitis; Anti-Inflammatory Agents
PubMed: 37811705
DOI: 10.1111/jvim.16897 -
Oncology Research 2024Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies. The Kirsten rat sarcoma virus (KRAS) oncogene is mutated in up to 90% of... (Review)
Review
Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies. The Kirsten rat sarcoma virus (KRAS) oncogene is mutated in up to 90% of all pancreatic ductal adenocarcinomas (PDACs) and constitutes an attractive target for therapy. However, the most common KRAS mutations in PDAC are G12D (44%), G12V (34%) and G12R (20%) that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer. KRAS G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%-3% of PDAC. Recently, the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development. The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor (GEF) Son of Sevenless 1 that drives KRAS. These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.
Topics: Humans; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Mutation; Molecular Targeted Therapy; Carcinoma, Pancreatic Ductal; Antineoplastic Agents; Animals
PubMed: 38686056
DOI: 10.32604/or.2024.045356 -
Gut Nov 2023Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Differentiation from chronic pancreatitis (CP) is currently inaccurate in about one-third of cases....
OBJECTIVE
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Differentiation from chronic pancreatitis (CP) is currently inaccurate in about one-third of cases. Misdiagnoses in both directions, however, have severe consequences for patients. We set out to identify molecular markers for a clear distinction between PDAC and CP.
DESIGN
Genome-wide variations of DNA-methylation, messenger RNA and microRNA level as well as combinations thereof were analysed in 345 tissue samples for marker identification. To improve diagnostic performance, we established a random-forest machine-learning approach. Results were validated on another 48 samples and further corroborated in 16 liquid biopsy samples.
RESULTS
Machine-learning succeeded in defining markers to differentiate between patients with PDAC and CP, while low-dimensional embedding and cluster analysis failed to do so. DNA-methylation yielded the best diagnostic accuracy by far, dwarfing the importance of transcript levels. Identified changes were confirmed with data taken from public repositories and validated in independent sample sets. A signature of six DNA-methylation sites in a CpG-island of the protein kinase C beta type gene achieved a validated diagnostic accuracy of 100% in tissue and in circulating free DNA isolated from patient plasma.
CONCLUSION
The success of machine-learning to identify an effective marker signature documents the power of this approach. The high diagnostic accuracy of discriminating PDAC from CP could have tremendous consequences for treatment success, once the result from still a limited number of liquid biopsy samples would be confirmed in a larger cohort of patients with suspected pancreatic cancer.
Topics: Humans; Pancreatic Neoplasms; Pancreatitis, Chronic; Carcinoma, Pancreatic Ductal; DNA Methylation; DNA; Biomarkers, Tumor
PubMed: 37709492
DOI: 10.1136/gutjnl-2023-330155 -
Clinical and Translational... Aug 2023Drug induced acute pancreatitis is a difficult diagnosis for clinicians. We previously published an "Evidence-Based Classification System" on Drug-Induced Acute...
INTRODUCTION
Drug induced acute pancreatitis is a difficult diagnosis for clinicians. We previously published an "Evidence-Based Classification System" on Drug-Induced Acute Pancreatitis widely used by clinicians to assist in the identification of drugs. Unfortunately, this prior analysis based only on published case reports has been misunderstood. The prior review did not include studies with higher evidentiary value, such as randomized trials, case-control studies, and/or pharmacoepidemiologic studies. The use of the prior classification system has led to many patients being inappropriately labeled as having drug-induced acute pancreatitis. We now propose a "Revised" Evidence- Based Classification System for the purpose of determining which drugs cause acute pancreatitis based on the Grading of Recommendations, Development, and Evaluation criteria.
METHODS
A search of the English Language literature was performed to identify all case reports with medication and/or drug induced acute pancreatitis. We divided the drugs implicated as causing acute pancreatitis into four groups based on the quality of evidence as defined by GRADE quality parameters.
RESULTS
Although 141 drugs were identified in the literature as causing acute pancreatitis, only 106 drugs published in the literature as causing acute pancreatitis were high quality case reports. Only 3 drugs had evidence as causing acute pancreatitis from randomized controlled clinical trials, including 6-mercaptopurine and azathioprine.
DISCUSSION
The vast majority of drugs implicated as causing acute pancreatitis in the literature have low or very low quality of evidence supporting those claims.
Topics: Humans; Pancreatitis; Acute Disease; Case-Control Studies
PubMed: 37440319
DOI: 10.14309/ctg.0000000000000621 -
Molecular Cancer Dec 2023Circular RNAs (circRNAs) play important roles in the occurrence and development of cancer and chemoresistance. DNA damage repair contributes to the proliferation of...
hsa_circ_0007919 induces LIG1 transcription by binding to FOXA1/TET1 to enhance the DNA damage response and promote gemcitabine resistance in pancreatic ductal adenocarcinoma.
BACKGROUND
Circular RNAs (circRNAs) play important roles in the occurrence and development of cancer and chemoresistance. DNA damage repair contributes to the proliferation of cancer cells and resistance to chemotherapy-induced apoptosis. However, the role of circRNAs in the regulation of DNA damage repair needs clarification.
METHODS
RNA sequencing analysis was applied to identify the differentially expressed circRNAs. qRT-PCR was conducted to confirm the expression of hsa_circ_0007919, and CCK-8, FCM, single-cell gel electrophoresis and IF assays were used to analyze the proliferation, apoptosis and gemcitabine (GEM) resistance of pancreatic ductal adenocarcinoma (PDAC) cells. Xenograft model and IHC experiments were conducted to confirm the effects of hsa_circ_0007919 on tumor growth and DNA damage in vivo. RNA sequencing and GSEA were applied to confirm the downstream genes and pathways of hsa_circ_0007919. FISH and nuclear-cytoplasmic RNA fractionation experiments were conducted to identify the cellular localization of hsa_circ_0007919. ChIRP, RIP, Co-IP, ChIP, MS-PCR and luciferase reporter assays were conducted to confirm the interaction among hsa_circ_0007919, FOXA1, TET1 and the LIG1 promoter.
RESULTS
We identified a highly expressed circRNA, hsa_circ_0007919, in GEM-resistant PDAC tissues and cells. High expression of hsa_circ_0007919 correlates with poor overall survival (OS) and disease-free survival (DFS) of PDAC patients. Hsa_circ_0007919 inhibits the DNA damage, accumulation of DNA breaks and apoptosis induced by GEM in a LIG1-dependent manner to maintain cell survival. Mechanistically, hsa_circ_0007919 recruits FOXA1 and TET1 to decrease the methylation of the LIG1 promoter and increase its transcription, further promoting base excision repair, mismatch repair and nucleotide excision repair. At last, we found that GEM enhanced the binding of QKI to the introns of hsa_circ_0007919 pre-mRNA and the splicing and circularization of this pre-mRNA to generate hsa_circ_0007919.
CONCLUSIONS
Hsa_circ_0007919 promotes GEM resistance by enhancing DNA damage repair in a LIG1-dependent manner to maintain cell survival. Targeting hsa_circ_0007919 and DNA damage repair pathways could be a therapeutic strategy for PDAC.
Topics: Humans; Gemcitabine; RNA, Circular; RNA Precursors; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; DNA Damage; MicroRNAs; Cell Proliferation; Cell Line, Tumor; Mixed Function Oxygenases; Proto-Oncogene Proteins; Hepatocyte Nuclear Factor 3-alpha
PubMed: 38044421
DOI: 10.1186/s12943-023-01887-8 -
Internal and Emergency Medicine Nov 2023Overweight and obesity are some of the most important health challenges. Many diseases are related to these metabolic disorders, and, among them, the pancreatic fat... (Review)
Review
Overweight and obesity are some of the most important health challenges. Many diseases are related to these metabolic disorders, and, among them, the pancreatic fat accumulation, also called "pancreatic steatosis" or "nonalcoholic fatty pancreas", seems to have an emerging role in different conditions. There are different method to evaluate the fat content in the pancreas, such as histology, different imaging techniques and endoscopic ultrasound, but there is no gold standard for the correct diagnosis and for the identification of "inter/intralobular" and "intra-acinar" pancreatic fat. However, the fat storage in the pancreas is linked to chronic inflammation and to several conditions, such as acute and chronic pancreatitis, type 2 diabetes mellitus and pancreatic cancer. In addition, pancreatic fat accumulation has also been demonstrated to play a role in surgical outcome after pancreatectomy, in particular for the development of postoperative pancreatic fistula. Different possible therapeutic approaches have been proposed, but there is still a lack of evidence. The aim of this review is to report the current evidence about the relationship between the obesity, the pancreatic fat accumulation and its potential role in pancreatic diseases.
Topics: Humans; Diabetes Mellitus, Type 2; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Obesity
PubMed: 37462859
DOI: 10.1007/s11739-023-03364-y