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Biochimica Et Biophysica Acta. Reviews... Sep 2023Pancreatic ductal adenocarcinoma (PDAC) is one of the lethal cancers in the world and its 5-year survival rate is <10%. Due to the unique TME and dense tissue structure,... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is one of the lethal cancers in the world and its 5-year survival rate is <10%. Due to the unique TME and dense tissue structure, its curative efficacy is far from satisfactory,the immunotherapy is even more invalid. According to the recent studies, the gut and tumor microbiota have been proved to play a key role in the development, progression and prognosis of PDAC. Based on the differences of microbiome composition observed in PDAC patients and normal pancreas, many researches have been made focusing on the latent communication between gut and intra-tumor microbiota and PDAC. In this review, we will demonstrate the potential mechanism of the oncogenic effects of GM and IM and their crucial effects on modulating the TME. Besides, we focus on their interaction with chemotherapeutic and immunotherapeutic drugs and inducing the drug resistance, thus enlightening the promising role to be used to monitor the occurrence of PDAC, accurately modulate the immune environment to promote the therapeutic efficacy and predict the prognosis.
Topics: Carcinoma, Pancreatic Ductal; Humans; Animals; Tumor Microenvironment; Gastrointestinal Microbiome; Carcinogenesis; Pancreatic Neoplasms; Bacteria; Neoplasm Metastasis; Antineoplastic Agents
PubMed: 37355177
DOI: 10.1016/j.bbcan.2023.188943 -
Redox Biology Dec 2023Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to support growth. At the same time, this causes significant...
Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to support growth. At the same time, this causes significant dishomeostasis of free radicals. While this is compensated by the upregulation of detoxification mechanisms, it also represents a potential vulnerability. Here we demonstrate that PDA cells are sensitive to the inhibition of the mevalonate pathway (MVP), which supports the biosynthesis of critical antioxidant intermediates and protect from ferroptosis. We attacked the susceptibility of PDA cells to ferroptotic death with selenorganic compounds, including dibenzyl diselenide (DBDS) that exhibits potent pro-oxidant properties and inhibits tumor growth in vitro and in vivo. DBDS treatment induces the mobilization of iron from mitochondria enabling uncontrolled lipid peroxidation. Finally, we showed that DBDS and statins act synergistically to promote ferroptosis and provide evidence that combined treatment is a viable strategy to combat PDA.
Topics: Humans; Ferroptosis; Selenium; Pancreas; Pancreatic Neoplasms; Lipid Peroxidation
PubMed: 38029455
DOI: 10.1016/j.redox.2023.102962 -
Radiologie (Heidelberg, Germany) Dec 2023Autoimmune pancreatitis (AIP) is classified as a distinct form of pancreatitis according to the guidelines. It is characterized by imaging morphologic and histologic... (Review)
Review
CLINICAL ISSUE
Autoimmune pancreatitis (AIP) is classified as a distinct form of pancreatitis according to the guidelines. It is characterized by imaging morphologic and histologic features and is associated with extrapancreatic manifestations in type 1 IgG 4-associated disease. Symptoms and findings almost always improve with administration of steroids. Differentiation from pancreatic ductal adenocarcinoma is required, particularly in the presence of AIP with focal parenchymal involvement.
STANDARD RADIOLOGIC PROCEDURES
If AIP is suspected, abdominal ultrasound and/or endosonography, computed tomography (CT), and preferably magnetic resonance imaging (MRI) are indicated. A distinction is made between parenchymal and ductal changes that specifically indicate the presence of AIP.
METHODOLOGICAL INNOVATIONS AND EVALUATION
The diagnosis of autoimmune pancreatitis should be made based on the International Consensus Criteria (ICDC), in which the five main features (imaging, serology, histology, other organ involvement, response to steroid medication) are assessed. In type 1 AIP, typical imaging changes are sufficient to establish the diagnosis even with negative histology, whereas for type 2 AIP, histologic evidence is required. Imaging changes help in the differential diagnosis from pancreatic cancer.
PRACTICAL RECOMMENDATIONS
The following article addresses and evaluates crucial imaging diagnostic CT and MRI criteria for correct classification of findings, description of results, and differentiation of autoimmune pancreatitis from pancreatic cancer.
Topics: Humans; Autoimmune Pancreatitis; Autoimmune Diseases; Pancreatic Neoplasms; Pancreatitis; Steroids
PubMed: 37947862
DOI: 10.1007/s00117-023-01240-6 -
World Journal of Gastroenterology Sep 2023Pancreatic ductal adenocarcinoma (PDAC) remains a significant public health challenge and is currently the fourth leading cause of cancer-related mortality in developed... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) remains a significant public health challenge and is currently the fourth leading cause of cancer-related mortality in developed countries. Despite advances in cancer treatment, the 5-year survival rate for patients with PDAC remains less than 5%. In recent years, neoadjuvant therapy (NAT) has emerged as a promising treatment option for many cancer types, including locally advanced PDAC, with the potential to improve patient outcomes. To analyze the role of NAT in the setting of locally advanced PDAC over the past decade, a systematic literature search was conducted using PubMed and Web of Science. The results suggest that NAT may reduce the local mass size, promote tumor downstaging, and increase the likelihood of resection. These findings are supported by the latest evidence-based medical literature and the clinical experience of our center. Despite the potential benefits of NAT, there are still challenges that need to be addressed. One such challenge is the lack of consensus on the optimal timing and duration of NAT. Improved criteria for patient selection are needed to further identify PDAC patients likely to respond to NAT. In conclusion, NAT has emerged as a promising treatment option for locally advanced PDAC. However, further research is needed to optimize its use and to better understand the role of NAT in the management of this challenging disease. With continued advances in cancer treatment, there is hope of improving the outcomes of patients with PDAC in the future.
Topics: Humans; Neoadjuvant Therapy; Pancreas; Pancreatic Neoplasms; Neoplasms, Second Primary; Carcinoma, Pancreatic Ductal
PubMed: 37744290
DOI: 10.3748/wjg.v29.i35.5094 -
European Radiology Dec 2023To determine informational CT findings for distinguishing autoimmune pancreatitis (AIP) from pancreatic ductal adenocarcinoma (PDAC) and to review their diagnostic... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To determine informational CT findings for distinguishing autoimmune pancreatitis (AIP) from pancreatic ductal adenocarcinoma (PDAC) and to review their diagnostic accuracy.
METHODS
A systematic and detailed literature review was performed through PubMed, EMBASE, and the Cochrane library. Similar descriptors to embody the identical image finding were labeled as a single CT characteristic. We calculated the pooled diagnostic odds ratios (DORs) of each CT characteristic using a bivariate random-effects model.
RESULTS
A total of 145 various descriptors from 15 studies (including 562 AIP and 869 PDAC patients) were categorized into 16 CT characteristics. According to the pooled DOR, 16 CT characteristics were classified into three groups (suggesting AIP, suggesting PDAC, and not informational). Seven characteristics suggesting AIP were diffuse pancreatic enlargement (DOR, 48), delayed homogeneous enhancement (DOR, 46), capsule-like rim (DOR, 34), multiple pancreatic masses (DOR, 16), renal involvement (DOR, 15), retroperitoneal fibrosis (DOR, 13), and bile duct involvement (DOR, 8). Delayed homogeneous enhancement showed a pooled sensitivity of 83% and specificity of 85%. The other six characteristics showed relatively low sensitivity (12-63%) but high specificity (93-99%). Four characteristics suggesting PDAC were discrete pancreatic mass (DOR, 23), pancreatic duct cutoff (DOR, 16), upstream main pancreatic duct dilatation (DOR, 8), and upstream parenchymal atrophy (DOR, 7).
CONCLUSION
Eleven CT characteristics were informational to distinguish AIP from PDAC. Diffuse pancreatic enlargement, delayed homogeneous enhancement, and capsule-like rim suggested AIP with the highest DORs, whereas discrete pancreatic mass suggested PDAC. However, pooled sensitivities of informational CT characteristics were moderate.
CLINICAL RELEVANCE STATEMENT
This meta-analysis underscores eleven distinctive CT characteristics that aid in differentiating autoimmune pancreatitis from pancreatic adenocarcinoma, potentially preventing misdiagnoses in patients presenting with focal/diffuse pancreatic enlargement.
KEY POINTS
• Diffuse pancreatic enlargement (pooled diagnostic odds ratio [DOR], 48), delayed homogeneous enhancement (46), and capsule-like rim (34) were CT characteristics suggesting autoimmune pancreatitis. • The CT characteristics suggesting autoimmune pancreatitis, except delayed homogeneous enhancement, had a general tendency to show relatively low sensitivity (12-63%) but high specificity (93-99%). • Discrete pancreatic mass (pooled diagnostic odds ratio, 23) was the CT characteristic suggesting pancreatic ductal adenocarcinoma with the highest pooled DORs.
Topics: Humans; Pancreatic Neoplasms; Autoimmune Pancreatitis; Pancreatitis; Adenocarcinoma; Tomography, X-Ray Computed; Autoimmune Diseases; Carcinoma, Pancreatic Ductal; Diagnosis, Differential
PubMed: 37466708
DOI: 10.1007/s00330-023-09959-5 -
Deutsches Arzteblatt International Oct 2023Ampullary or papillary carcinoma is a malignant tumor arising from the mucosa in the region of the major duodenal papilla, also known as the ampulla of Vater. Uniform... (Review)
Review
BACKGROUND
Ampullary or papillary carcinoma is a malignant tumor arising from the mucosa in the region of the major duodenal papilla, also known as the ampulla of Vater. Uniform treatment recommendations are lacking both for the adjuvant situation and for palliative care.
METHODS
A selective literature search was carried out in PubMed in order to identify the most informative publications concerning the epidemiology, clinico-pathological background, and surgical and medical treatment of this condition.
RESULTS
Ampullary carcinoma has an incidence of 0.5 to 0.9 per 100 000 persons and a poor prognosis, with a 5-year survival rate of 41% to 45% for locally confined and 4% to 7% for metastatic disease. Most such tumors are of an intestinal or a pan - creaticobiliary immunohistochemical subtype; the latter has a worse prognosis (median survival, 72-80 vs. 33-41 months). Targeted treatment is not yet available for either subtype, nor is there enough scientific evidence available for the formulation of specific therapeutic recommendations in either the adjuvant or the palliative situation. The treatment of choice for ampullary carcinoma is radical oncological resection of the head of the pancreas with systematic lymphadenectomy. Five-year overall survival is between 10% and 75% depending on the stage. No definitive recommendation for adjuvant therapy can be given. Palliative therapy can be oriented to the published treatment strategies for cancer of the colon, pancreas, and bile duct.
CONCLUSION
The current state of the evidence on the treatment of ampullary carcinoma is poor. Therapeutic decisions should be discussed in an interdisciplinary tumor board and should, in our opinion, take the histological subtype into account.
Topics: Humans; Ampulla of Vater; Adenocarcinoma; Prognosis; Pancreatic Neoplasms; Combined Modality Therapy
PubMed: 37656482
DOI: 10.3238/arztebl.m2023.0195 -
European Radiology Nov 2023
Topics: Humans; Nomograms; Pancreatic Neoplasms; Tomography, X-Ray Computed; Risk Assessment; Adenocarcinoma
PubMed: 37672060
DOI: 10.1007/s00330-023-10193-2 -
Current Oncology (Toronto, Ont.) Oct 2023Pancreatic cancer (PDAC) is one of the most aggressive solid tumors and is showing increasing incidence. The aim of our review is to provide practical help for all... (Review)
Review
Pancreatic cancer (PDAC) is one of the most aggressive solid tumors and is showing increasing incidence. The aim of our review is to provide practical help for all clinical oncologists and to summarize the current management of PDAC using a simple "ABC method" (A-anatomical resectability, B-biological resectability and C-clinical conditions). For anatomically resectable PDAC without any high-risk factors (biological or conditional), the actual standard of care is represented by surgery followed by adjuvant chemotherapy. The remaining PDAC patients should all be treated with initial systemic therapy, though the intent for each is different: for borderline resectable patients, the intent is neoadjuvant; for locally advanced patients, the intent is conversion; and for metastatic PDAC patients, the intent remains just palliative. The actual standard of care in first-line therapy is represented by two regimens: FOLFIRINOX and gemcitabine/nab-paclitaxel. Recently, NALIRIFOX showed positive results over gemcitabine/nab-paclitaxel. There are limited data for maintenance therapy after first-line treatment, though 5-FU or FOLFIRI after initial FOLFIRINOX, and gemcitabine, after initial gemcitabine/nab-paclitaxel, might be considered. We also dedicate space to special rare conditions, such as PDAC with germline BRCA mutations, pancreatic acinar cell carcinoma and adenosquamous carcinoma of the pancreas, with few clinically relevant remarks.
Topics: Humans; Pancreatic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Carcinoma, Pancreatic Ductal; Paclitaxel; Pancreas; Oncologists
PubMed: 37999114
DOI: 10.3390/curroncol30110694 -
Journal of Clinical Pathology Nov 2023Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is one of the most well-established precursors of pancreatic cancer. Its progression to acquire... (Review)
Review
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is one of the most well-established precursors of pancreatic cancer. Its progression to acquire invasiveness is a complex process, based on the accumulation of morphological and genetic alterations. Recent advances in DNA sequencing also showed that co-occurring IPMNs and pancreatic cancers could be totally independent, further complicating our understanding of this complex scenario. The distinction between IPMN and related pancreatic cancer vs IPMN and co-occurring-but not related-pancreatic cancer is a challenging task in routine diagnostic activity, but may have important implications for precision oncology. Of note, recent multiregional sequencing-based studies focused not only on IPMN multi-step tumourigenesis, but also on the divergent intratumoural heterogeneity of this neoplasm. Globally considered, there are three different situations in which co-occurring IPMNs and invasive carcinomas can be found in the same pancreata, indicated with different terminologies: (1) IPMN-associated carcinoma: this definition indicates a carcinoma arising from an IPMN and can be also defined as IPMN-derived carcinoma, sequential or likely related; (2) independent IPMN and invasive carcinoma: the two lesions are not related, and this situation is defined as concomitant, de novo or likely independent; (3) branch-off pathway, where an invasive carcinoma and an adjacent IPMN develop divergently in a forked fashion from a common ancestral clone. In this review, we aim at clarifying the most important nomenclature/definitions of these different situations, also providing an overview of the molecular state-of-the-art and of the clinical implications of this complex landscape.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Intraductal Neoplasms; Pathology, Molecular; Adenocarcinoma, Mucinous; Precision Medicine; Pancreatic Neoplasms; Retrospective Studies
PubMed: 37500498
DOI: 10.1136/jcp-2023-209012 -
Gastroenterology Jul 2023Pancreatic ductal adenocarcinoma (PDA), with its highly metastatic propensity, is one of the most lethal subtypes of pancreatic cancer. Although recent large-scale...
BACKGROUND & AIMS
Pancreatic ductal adenocarcinoma (PDA), with its highly metastatic propensity, is one of the most lethal subtypes of pancreatic cancer. Although recent large-scale transcriptomic studies have demonstrated that heterogeneous gene expressions play an essential role in determining molecular phenotypes of PDA, biological cues for and consequences of distinct transcriptional programs remain unclear.
METHODS
We developed an experimental model that enforces the transition of PDA cells toward a basal-like subtype. We combined epigenome and transcriptome analyses with extensive in vitro and in vivo evaluations of tumorigenicity to demonstrate the validity of basal-like subtype differentiation in association with endothelial-like enhancer landscapes via TEA domain transcription factor 2 (TEAD2). Finally, we used loss-of-function experiments to investigate the importance of TEAD2 in regulating reprogrammed enhancer landscape and metastasis in basal-like PDA cells.
RESULTS
Aggressive characteristics of the basal-like subtype are faithfully recapitulated in vitro and in vivo, demonstrating the physiological relevance of our model. Further, we showed that basal-like subtype PDA cells acquire a TEAD2-dependent proangiogenic enhancer landscape. Genetic and pharmacologic inhibitions of TEAD2 in basal-like subtype PDA cells impair their proangiogenic phenotypes in vitro and cancer progression in vivo. Last, we identify CD109 as a critical TEAD2 downstream mediator that maintains constitutively activated JAK-STAT signaling in basal-like PDA cells and tumors.
CONCLUSIONS
Our findings implicate a TEAD2-CD109-JAK/STAT axis in the basal-like differentiated pancreatic cancer cells and as a potential therapeutic vulnerability.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Pancreas; Cell Differentiation; Gene Expression Regulation, Neoplastic; TEA Domain Transcription Factors
PubMed: 36907523
DOI: 10.1053/j.gastro.2023.02.049