-
Modern Pathology : An Official Journal... Sep 2023Signet-ring cell (SRC)/poorly cohesive cell carcinoma is an aggressive variant of pancreatic ductal adenocarcinoma (PDAC). This study aimed to clarify its...
Signet-ring cell (SRC)/poorly cohesive cell carcinoma is an aggressive variant of pancreatic ductal adenocarcinoma (PDAC). This study aimed to clarify its clinicopathologic and molecular profiles based on a multi-institutional cohort of 20 cases. The molecular profiles were investigated using DNA and RNA sequencing. The clinicopathologic parameters and molecular alterations were analyzed based on survival indices and using a validation/comparative cohort of 480 conventional PDAC patients. The primary findings were as follows: (1) clinicopathologic features: SRC carcinomas are highly aggressive neoplasms with poor prognosis, and the lungs are elective metastatic sites; (2) survival analysis: a higher SRC component was indicative of poorer prognosis. In particular, the most clinically significant threshold of SRC was 80%, showing statistically significant differences in both disease-specific and disease-free survival; (3) genomic profiles: SRC carcinomas are similar to conventional PDAC with the most common alterations affecting the classic PDAC drivers KRAS (70% of cases), TP53 (55%), SMAD4 (25%), and CDKN2A (20%). EGFR alterations, RET::CCDC6 fusion gene, and microsatellite instability (3 different cases, 1 alteration per case) represent novel targets for precision oncology. The occurrence of SMAD4 mutations was associated with poorer prognosis; (4) pancreatic SRC carcinomas are genetically different from gastric SRC carcinomas: CDH1, the classic driver gene of gastric SRC carcinoma, is not altered in pancreatic SRC carcinoma; (5) transcriptome analysis: the cases clustered into 2 groups, one classical/exocrine-like, and the other squamous-like; and (6) SRC carcinoma-derived organoids can be successfully generated, and their cultures preserve the histologic and molecular features of parental SRC carcinoma. Although pancreatic SRC carcinoma shares similarities with conventional PDAC regarding the most important genetic drivers, it also exhibits important differences. A personalized approach for patients with this tumor type should consider the clinical relevance of histologic determination of the SRC component and the presence of potentially actionable molecular targets.
Topics: Humans; Precision Medicine; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Carcinoma, Signet Ring Cell; Genomics; Prognosis
PubMed: 37355152
DOI: 10.1016/j.modpat.2023.100251 -
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 -
Cancer Biology & Therapy Dec 2023Pancreatic adenocarcinoma (PAAD) is a major cause of mortality related to cancer worldwide. This paper dissected the functions of the CSTF2T/ASH2L/CALB2 axis in PAAD...
Pancreatic adenocarcinoma (PAAD) is a major cause of mortality related to cancer worldwide. This paper dissected the functions of the CSTF2T/ASH2L/CALB2 axis in PAAD progression. CALB2 expression was assessed in PAAD tissues and cells using RT-qPCR and western blot. Subsequent to gain- and loss-of-function experiments in PAAD cells, cell apoptosis, invasion, proliferation, and migration were examined using flow cytometry, Transwell, CCK-8, and Scratch assays. Additionally, the expression of proliferation markers and apoptotic and metastasis- and invasion-related proteins was measured using western blot. The relationship among CALB2, KMT2D, ASH2L, H3K4Me1, and CSTF2T was evaluated using ChIP, RNA pull-down, RIP, and Co-IP assays. A nude mouse transplantation tumor model was established, with observation of tumor growth and metastasis. CALB2 expression was high in PAAD tissues and cells. Mechanistically, KMT2D was enriched in the CALB2 promoter, and CSTF2T bound to and upregulated ASH2L as a RNA binding protein, which was a core component of the KMT2D complex to enhance CALB2 expression through H3K4Me1 upregulation. CALB2 knockdown diminished the viability, invasion, and migration but elevated the apoptosis of PAAD cells. Likewise, CSTF2T knockdown suppressed the growth and metastasis of PAAD cells and transplanted tumors in nude mice, which was counteracted by further CALB2 overexpression. CSTF2T knockdown blocked the ASH2L/CALB2 axis to protect against PAAD growth and metastasis.
Topics: Animals; Mice; Pancreatic Neoplasms; Adenocarcinoma; Methylation; Mice, Nude; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic
PubMed: 37287122
DOI: 10.1080/15384047.2023.2216041 -
International Journal of Molecular... May 2024Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all pancreatic cancers and is the most fatal of all cancers. The treatment response from... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all pancreatic cancers and is the most fatal of all cancers. The treatment response from combination chemotherapies is far from satisfactory and surgery remains the mainstay of curative strategies. These challenges warrant identifying effective treatments for combating this deadly cancer. PDAC tumor progression is associated with the robust activation of the coagulation system. Notably, cancer-associated thrombosis (CAT) is a significant risk factor in PDAC. CAT is a concept whereby cancer cells promote thromboembolism, primarily venous thromboembolism (VTE). Of all cancer types, PDAC is associated with the highest risk of developing VTE. Hypoxia in a PDAC tumor microenvironment also elevates thrombotic risk. Direct oral anticoagulants (DOACs) or low-molecular-weight heparin (LMWH) are used only as thromboprophylaxis in PDAC. However, a precision medicine approach is recommended to determine the precise dose and duration of thromboprophylaxis in clinical setting.
Topics: Humans; Venous Thromboembolism; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Anticoagulants; Risk Factors; Animals; Tumor Microenvironment
PubMed: 38891849
DOI: 10.3390/ijms25115661 -
Neuroscience Bulletin Nov 2023Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy, characterized by late diagnosis, aggressive growth, and therapy resistance, leading to... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy, characterized by late diagnosis, aggressive growth, and therapy resistance, leading to a poor overall prognosis. Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape. The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets. In this review, we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC, summarize the potential signaling pathways modulating the neuronal-cancer interaction, and discuss the current and future therapeutic possibilities for this condition.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Signal Transduction; Peripheral Nerves; Tumor Microenvironment
PubMed: 37347365
DOI: 10.1007/s12264-023-01082-1 -
Aging Oct 2023The purpose of the study was to investigate the role of exosome and lipid metabolism-related genes (EALMRGs) mRNA levels in the diagnosis and prognosis of Pancreatic...
OBJECTIVE
The purpose of the study was to investigate the role of exosome and lipid metabolism-related genes (EALMRGs) mRNA levels in the diagnosis and prognosis of Pancreatic Adenocarcinoma (PAAD).
METHODS
The mRNA expression pattern of PAAD and pan-cancers with prognostic data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. EALMRGs were acquired from GeneCards and MSigDB database after merging and deduplication. Prognostic EALMRGs were screened through univariate COX regression analysis, and a prognostic model was constructed based on these genes by least absolute shrinkage and selection operator (LASSO) regression. The prognostic value of EALMRGs was then validated in pan-cancer data. The time characteristics ROC curve analysis was performed to evaluate the effectiveness of the prognostic genes.
RESULTS
We identified 5 hub genes (ABCB1, CAP1, EGFR, PPARG, SNCA) according to high and low-risk groups of prognoses. The risk formula was verified in three other cohort of pancreatic cancer patients and was explored in pan-cancer data. Additionally, T cell and dendritic cell infiltration was significantly increased in low-risk group. The expression of the 5 hub genes was also identified in single-cell sequencing data of pancreatic cancer with pivotal pathways. Additionally, functional enrichment analysis based on pancreatic cancer data in pancreatic cancer showed that protein serine/threonine kinase activity, focal adhesion, actin binding, cell-substrate junction, organic acid transport, and regulation of transporter activity were significant related to the expression of genes in EALMRGs.
CONCLUSIONS
Our risk formula shows potential prognostic value in multiple cancers and manifest pivotal alterations in immune infiltration and biological pathway in pancreatic cancer.
Topics: Humans; Adenocarcinoma; Pancreatic Neoplasms; Lipid Metabolism; Exosomes; Prognosis; RNA, Messenger
PubMed: 37857015
DOI: 10.18632/aging.205130 -
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 -
Drug Resistance Updates : Reviews and... Nov 2023Adenocarcinoma is a common type of malignant tumor, originating from glandular epithelial cells in various organs, such as pancreas, breast, lung, stomach, colon,... (Review)
Review
Adenocarcinoma is a common type of malignant tumor, originating from glandular epithelial cells in various organs, such as pancreas, breast, lung, stomach, colon, rectus, and prostate. For patients who lose the opportunity for radical surgery, medication is available to provide potential clinical benefits. However, drug resistance is a big obstacle to obtain desired clinical prognosis. In this review, we provide a summary of treatment strategies and drug resistance mechanisms in adenocarcinoma of different organs, including pancreatic cancer, gastric adenocarcinoma, colorectal adenocarcinoma, lung adenocarcinoma, and prostate cancer. Although the underlying molecular mechanisms involved in drug resistance of adenocarcinoma vary from one organ to the other, there are several targets that are universal for drug resistance in adenocarcinoma, and targeting these molecules could potentially reverse drug resistance in the treatment of adenocarcinomas.
Topics: Male; Humans; Adenocarcinoma; Prostatic Neoplasms; Colorectal Neoplasms; Pancreatic Neoplasms
PubMed: 37678078
DOI: 10.1016/j.drup.2023.101002 -
The Korean Journal of Gastroenterology... Oct 2023The ampulla of Vater is a small projection formed by the confluence of the main pancreatic duct and common bile duct in the second part of the duodenum. Primary... (Review)
Review
The ampulla of Vater is a small projection formed by the confluence of the main pancreatic duct and common bile duct in the second part of the duodenum. Primary ampullary adenocarcinoma is a rare malignancy, accounting for only 0.2% of gastrointestinal cancers and approximately 7% of all periampullary cancers. Jaundice from a biliary obstruction is the most common symptom of ampullary adenocarcinoma. In the early stages, radical pancreatoduodenectomy is the standard surgical approach. On the other hand, no randomized controlled trial has provided evidence to guide physicians on the choice of adjuvant/palliative chemotherapy because of the rarity of the disease and the paucity of related research. This paper reports the biology, histology, current therapeutic strategies, and potential future therapies of ampullary adenocarcinoma.
Topics: Humans; Ampulla of Vater; Adenocarcinoma; Pancreatic Neoplasms; Common Bile Duct Neoplasms; Duodenal Neoplasms
PubMed: 37876255
DOI: 10.4166/kjg.2023.110 -
Nutrients Oct 2023The incidence of pancreatic cancer is increasing worldwide. The most common form is represented by pancreatic ductal adenocarcinoma (PDAC) which has been shown to be... (Review)
Review
The incidence of pancreatic cancer is increasing worldwide. The most common form is represented by pancreatic ductal adenocarcinoma (PDAC) which has been shown to be linked to chronic inflammation. Notably, the gut microbiota has emerged as a critical player in regulating immune responses and inflammation. Indeed, intestinal dysbiosis, characterized by an imbalance in the gut microbiota composition, can contribute to the initiation of chronic inflammation. Sterile chronic inflammation can occur, probably activated by the translocation of bacterial components, such as lipopolysaccharide (LPS), the major component of Gram-negative microbiota, with the consequent induction of innate mucosal immunity, through the activation of Toll-like receptors (TLRs). Furthermore, the interaction between LPS and TLRs could enhance cancer progression. Recent research has shed light on the pivotal role of nutrition, as a modifiable risk factor, in PDAC immunological processes, particularly focusing on the immuno-modulatory effects of the gut microbiota. Different dietary regimens, fiber intake, immunonutrients, and antioxidants have the potential to either exacerbate or mitigate chronic inflammation, thereby influencing the pathogenesis and natural history of PDAC. These dietary components may affect the gut microbiota composition and, consequently, the level of inflammation, either promoting or protecting against PDAC. In this review of reviews, we discuss the modulatory role of nutrition and the gut microbiota in PDAC's immunological processes to explore a translational therapeutic approach that could improve the survival and quality of life of these patients.
Topics: Humans; Lipopolysaccharides; Quality of Life; Diet; Inflammation; Toll-Like Receptors; Pancreatic Neoplasms; Adenocarcinoma; Dysbiosis
PubMed: 37892540
DOI: 10.3390/nu15204465