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Journal of Neuroendocrinology Dec 2023This ENETS guidance paper for well-differentiated nonfunctioning pancreatic neuroendocrine tumours (NF-Pan-NET) has been developed by a multidisciplinary working group,...
This ENETS guidance paper for well-differentiated nonfunctioning pancreatic neuroendocrine tumours (NF-Pan-NET) has been developed by a multidisciplinary working group, and provides up-to-date and practical advice on the management of these tumours. Using the extensive experience of centres treating patients with NF-Pan-NEN, the authors of this guidance paper discuss 10 troublesome questions in everyday clinical practice. Our many years of experience in this field are still being verified in the light of the results of new clinical, which set new ways of proceeding in NEN. The treatment of NF-Pan-NEN still requires a decision of a multidisciplinary team of specialists in the field of neuroendocrine neoplasms.
Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Societies
PubMed: 37877341
DOI: 10.1111/jne.13343 -
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 -
Gastroenterology Jan 2024The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current...
BACKGROUND & AIMS
The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs.
METHODS
By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signaling pathway.
RESULTS
Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs.
CONCLUSIONS
Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.
Topics: Animals; Humans; Mice; Bromodomain Containing Proteins; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Transformation, Neoplastic; Gemcitabine; Neoplastic Stem Cells; Pancreatic Neoplasms; Smad2 Protein; Transcription Factors
PubMed: 37739089
DOI: 10.1053/j.gastro.2023.09.021 -
Nature Cancer Jan 2024Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase...
Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.
Topics: Humans; Glutamine; Cell Line, Tumor; Pancreatic Neoplasms; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Enzyme Inhibitors
PubMed: 37814010
DOI: 10.1038/s43018-023-00647-3 -
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 -
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 Gastroenterology Sep 2023Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, and developing an efficient and reliable approach for its early-stage diagnosis... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, and developing an efficient and reliable approach for its early-stage diagnosis is urgently needed. Precancerous lesions of PDAC, such as pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMN), arise through multiple steps of driver gene alterations in KRAS, TP53, CDKN2A, SMAD4, or GNAS. Hallmark mutations play a role in tumor initiation and progression, and their detection in bodily fluids is crucial for diagnosis. Recently, liquid biopsy has gained attention as an approach to complement pathological diagnosis, and in addition to mutation signatures in cell-free DNA, cell-free RNA, and extracellular vesicles have been investigated as potential diagnostic and prognostic markers. Integrating such molecular information to revise the diagnostic criteria for pancreatic cancer can enable a better understanding of the pathogenesis underlying inter-patient heterogeneity, such as sensitivity to chemotherapy and disease outcomes. This review discusses the current diagnostic approaches and clinical applications of genetic analysis in pancreatic cancer and diagnostic attempts by liquid biopsy and molecular analyses using pancreatic juice, duodenal fluid, and blood samples. Emerging knowledge in the rapidly advancing liquid biopsy field is promising for molecular profiling and diagnosing pancreatic diseases with significant diversity.
Topics: Humans; Pathology, Molecular; Early Detection of Cancer; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Mutation; Liquid Biopsy
PubMed: 37470859
DOI: 10.1007/s00535-023-02024-4 -
International Journal of Surgery... Oct 2023Patients with pancreatic ductal adenocarcinoma (PDAC) are increasingly receiving systemic neoadjuvant chemotherapy (NAC), particularly those with borderline resectable...
Survival benefit and impact of adjuvant chemotherapy following systemic neoadjuvant chemotherapy in patients with resected pancreas ductal adenocarcinoma: a retrospective cohort study.
BACKGROUND
Patients with pancreatic ductal adenocarcinoma (PDAC) are increasingly receiving systemic neoadjuvant chemotherapy (NAC), particularly those with borderline resectable and locally advanced disease. However, the specific role of additional adjuvant chemotherapy (AC) in these patients is unknown. The objective of this study is to further assess the clinical benefit and impact of systemic AC in patients with resected PDAC after NAC.
METHODS
Data on PDAC patients with or without AC following systemic NAC and surgical resection were retrospectively retrieved from the Surveillance, Epidemiology, and End Results (SEER) database between 2006 and 2019. A matched cohort was created using propensity score matching (PSM), and baseline characteristics were balanced to reduce bias. Overall survival (OS) and cancer-specific survival (CSS) were calculated using matching cohorts.
RESULTS
The study enrolled a total of 1589 patients, with 623 (39.2%) in the AC group and 966 (51.8%) in the non-AC group [mean age, 64.0 (9.9) years; 766 (48.2%) were females and 823 (51.8%) were males]. All patients received NAC, and among the crude population, 582 (36.6%) received neoadjuvant radiotherapy, while 168 (10.6%) received adjuvant radiotherapy. Following the 1:1 PSM, 597 patients from each group were evaluated further. The AC and non-AC groups had significantly different median OS (30.0 vs. 25.0 months, P =0.002) and CSS (33.0 vs. 27.0 months, P =0.004). After multivariate Cox regression analysis, systemic AC was independently associated with improved survival ( P =0.003, HR=0.782; 95% CI, 0.667-0.917 for OS; P =0.004, HR=0.784; 95% CI, 0.663-0.926 for CSS), and age, tumor grade, and AJCC N staging were also independent predictors of survival. Only patients younger than 65 years old and those with a pathological N1 category showed a significant association between systemic AC and improved survival in the subgroup analysis adjusted for these covariates.
CONCLUSION
Systemic AC provides a significant survival benefit in patients with resected PDAC following NAC compared to non-AC patients. Our study discovered that younger patients, patients with aggressive tumors and potentially well response to NAC might benefit from AC to achieve prolonged survival after curative tumor resection.
Topics: Male; Female; Humans; Middle Aged; Aged; Neoadjuvant Therapy; Retrospective Studies; Neoplasm Staging; Pancreatic Neoplasms; Chemotherapy, Adjuvant; Carcinoma, Pancreatic Ductal; Pancreas
PubMed: 37418574
DOI: 10.1097/JS9.0000000000000589 -
International Journal of Radiation... Nov 2023Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted...
A Multi-Institutional Phase 2 Trial of Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided On-Table Adaptive Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Cancer.
PURPOSE
Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC).
METHODS AND MATERIALS
Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to SMART.
RESULTS
One hundred thirty-six patients (LAPC 56.6%, BRPC 43.4%) were enrolled between January 2019 and January 2022. Mean age was 65.7 (36-85) years. Head of pancreas lesions were most common (66.9%). Induction chemotherapy mostly consisted of (modified)FOLFIRINOX (65.4%) or gemcitabine/nab-paclitaxel (16.9%). Mean CA19-9 after induction chemotherapy and before SMART was 71.7 U/mL (0-468). On-table adaptive replanning was performed for 93.1% of all delivered fractions. Median follow-up from diagnosis and SMART was 16.4 and 8.8 months, respectively. The incidence of acute grade ≥3 GI toxicity possibly or probably attributed to SMART was 8.8%, including 2 postoperative deaths that were possibly related to SMART in patients who had surgery. There was no acute grade ≥3 GI toxicity definitely related to SMART. One-year overall survival from SMART was 65.0%.
CONCLUSIONS
The primary endpoint of this study was met with no acute grade ≥3 GI toxicity definitely attributed to ablative 5-fraction SMART. Although it is unclear whether SMART contributed to postoperative toxicity, we recommend caution when pursuing surgery, especially with vascular resection after SMART. Additional follow-up is ongoing to evaluate late toxicity, quality of life, and long-term efficacy.
Topics: Humans; Aged; Pancreatic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Prospective Studies; Radiotherapy Planning, Computer-Assisted; Quality of Life; Pancreas; Magnetic Resonance Spectroscopy; Radiosurgery
PubMed: 37210048
DOI: 10.1016/j.ijrobp.2023.05.023 -
Current Oncology (Toronto, Ont.) Sep 2023Gastroentero-pancreatic Neuroendocrine Neoplasms (GEP-NENs) are a diverse group of rare tumors that arise from neuroendocrine cells in the gastrointestinal tract and... (Review)
Review
Gastroentero-pancreatic Neuroendocrine Neoplasms (GEP-NENs) are a diverse group of rare tumors that arise from neuroendocrine cells in the gastrointestinal tract and pancreas, and they can vary significantly in terms of clinical behavior and prognosis. Immunotherapy, particularly immune checkpoint inhibitors, has shown remarkable success in various malignancies by harnessing the body's immune system to target and eliminate cancer cells. Immune checkpoint inhibitor clinical studies in GEP-NENs have yielded promising outcomes, particularly in individuals with advanced and refractory disease. Objective responses and disease stabilization have been observed in some cases, even in those previously unresponsive to traditional treatments like chemotherapy or targeted therapies. However, it's important to note that the efficacy of immunotherapy in GEP-NENs can vary widely depending on tumor characteristics, the immune microenvironment, and patient factors. As such, identifying predictive biomarkers to select the most suitable patients for immunotherapy remains an ongoing challenge. Immunotherapy has considerable potential for treating GEP-NENs, but research is still in its early stages. Several combinations are being explored to enhance the effectiveness of immunotherapy and improve the outcomes of treatment, such as combining immunotherapy with other targeted therapies or chemotherapy.
Topics: Humans; Immunotherapy; Neuroendocrine Tumors; Pancreatic Neoplasms; Pancreas; Immune Checkpoint Inhibitors; Tumor Microenvironment
PubMed: 37754542
DOI: 10.3390/curroncol30090627