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Oncotarget Jun 2024
Topics: Humans; Pancreatic Neoplasms; ATP-Binding Cassette Transporters; Carcinoma, Pancreatic Ductal; Molecular Targeted Therapy; Antineoplastic Agents; Animals
PubMed: 38900606
DOI: 10.18632/oncotarget.28597 -
JAMA Oncology Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who...
IMPORTANCE
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection.
OBJECTIVE
To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival.
DESIGN, SETTING, AND PARTICIPANTS
This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023.
INTERVENTIONS
Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression.
MAIN OUTCOMES AND MEASURES
The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator.
RESULTS
Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07).
CONCLUSIONS AND RELEVANCE
This nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02047474.
PubMed: 38900452
DOI: 10.1001/jamaoncol.2024.1575 -
Cureus May 2024Pancreatic ductal adenocarcinoma is exceedingly rare in children. Here, we report the case of a nine-year-old boy diagnosed with pancreatic ductal adenocarcinoma. The...
Pancreatic ductal adenocarcinoma is exceedingly rare in children. Here, we report the case of a nine-year-old boy diagnosed with pancreatic ductal adenocarcinoma. The patient was treated per the National Comprehensive Cancer Network (NCCN) guidelines for adults with pancreatic cancer. Though the patient had multiple episodes of progression, the patient has remained alive with the disease 18 months after the initial diagnosis.
PubMed: 38899258
DOI: 10.7759/cureus.60670 -
Cureus May 2024Pancreatic adenocarcinoma refers to cancer of the pancreatic duct cells. It is normally diagnosed when it is at an advanced stage, making the prognosis poor. Systemic... (Review)
Review
Pancreatic adenocarcinoma refers to cancer of the pancreatic duct cells. It is normally diagnosed when it is at an advanced stage, making the prognosis poor. Systemic chemotherapy is the primary treatment approach for locally advanced or metastatic pancreatic cancer and has been shown to improve survival by eight to 16 weeks. However, it does not directly penetrate malignant tissue and has many side effects, such as hair loss, bone marrow suppression, and many gastrointestinal issues. A newer treatment modality, regional intra-arterial chemotherapy (IAC), focuses on targeting malignant tissue directly to improve survival and decrease systemic side effects. When IAC is used with gemcitabine (GEM) or FLEC (5-fluorouracil, leucovorin, epirubicin, and carboplatin), the response rate for advanced pancreatic cancer is significantly improved. This literature review introduces the use of hepatic intra-arterial chemotherapy in patients with metastatic pancreatic adenocarcinoma.
PubMed: 38899244
DOI: 10.7759/cureus.60696 -
World Journal of Clinical Cases Jun 2024The diagnosis of pancreatic cancer associates an appalling significance. Detection of preinvasive stage of pancreatic cancer will ameliorate the survival of this deadly...
The diagnosis of pancreatic cancer associates an appalling significance. Detection of preinvasive stage of pancreatic cancer will ameliorate the survival of this deadly disease. Premalignant lesions such as Intraductal Papillary Mucinous Neoplasms or Mucinous Cystic Neoplasms of the pancreas are detectable on imaging exams and this permits their management prior their invasive development. Pancreatic intraepithelial neoplasms (PanIN) are the most frequent precursors of pancreatic adenocarcinoma (PDAC), and its particular type PanIN high-grade represents the malignant non-invasive form of PDAC. Unfortunately, PanINs are not detectable on radiologic exams. Nevertheless, they can associate indirect imaging signs which would rise the diagnostic suspicion. When this suspicion is established, the patient will be enrolled in a follow-up strategy that includes performing of blood test and serial imaging test such as computed tomography or magnetic resonance imaging, which will cost in the best-case scenario a burden of healthcare systems, and potential mortality in the worst-case scenario when the patient underwent resection surgery, worthless when there is no moderate or high grade dysplasia in the final histopathology. This issue will be avoid having at its disposal a diagnostic technique capable of detecting high-grade PanIN lesions, such is the cytology of pancreatic juice obtained by nasopancreatic intubation. Herein, we review the possibility of detection of early malignant lesions before they become invasive PADC.
PubMed: 38898835
DOI: 10.12998/wjcc.v12.i17.2935 -
Science Advances Jun 2024Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells....
Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells. However, the mechanisms sustaining stemness and chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we demonstrate that Bicaudal C homolog 1 (BICC1), an RNA binding protein regulating numerous cytoplasmic mRNAs, facilitates chemoresistance and stemness in PDAC. Mechanistically, BICC1 activated tryptophan catabolism in PDAC by up-regulating indoleamine 2,3-dioxygenase-1 (IDO1) expression, a tryptophan-catabolizing enzyme. Increased levels of tryptophan metabolites contribute to NAD synthesis and oxidative phosphorylation, leading to a stem cell-like phenotype. Blocking BICC1/IDO1/tryptophan metabolism signaling greatly improves the gemcitabine (GEM) efficacy in several PDAC models with high BICC1 level. These findings indicate that BICC1 is a critical tryptophan metabolism regulator that drives the stemness and chemoresistance of PDAC and thus a potential target for combinatorial therapeutic strategy against chemoresistance.
Topics: Tryptophan; Humans; Drug Resistance, Neoplasm; Neoplastic Stem Cells; Pancreatic Neoplasms; Cell Line, Tumor; Animals; Mice; Gene Expression Regulation, Neoplastic; Carcinoma, Pancreatic Ductal; Gemcitabine; Deoxycytidine; RNA-Binding Proteins; Indoleamine-Pyrrole 2,3,-Dioxygenase
PubMed: 38896624
DOI: 10.1126/sciadv.adj8650 -
Cancer Research Communications Jun 2024Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma (PDAC)....
Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma (PDAC). However, the mechanistic link with established drivers of this disease remains in part elusive. Here, using a new genetically-engineered mouse model overexpressing constitutively active mouse form of GLI2 and a combination of genome wide assays, we provide evidence of a novel mechanism underlying the interplay between KRAS, a major driver of PDAC development, and GLI2 to control oncogenic gene expression. These mice, also expressing KrasG12D, show significantly reduced median survival rate and accelerated tumorigenesis compared to the KrasG12D only expressing mice. Analysis of the mechanism using RNA-seq demonstrate higher levels of GLI2 targets, particularly tumor growth promoting genes including Ccnd1, N-Myc and Bcl2, in KrasG12D mutant cells. Further, ChIP-seq studies showed that in these cells KrasG12D increases the levels of H3K4me3 at the promoter of GLI2 targets without affecting significantly the levels of other major active chromatin marks. Importantly, Gli2 knockdown reduces H3K4me3 enrichment and gene expression induced by mutant Kras. In summary, we demonstrate that Gli2 plays a significant role in pancreatic carcinogenesis by acting as a downstream effector of KrasG12D to control gene expression.
PubMed: 38896052
DOI: 10.1158/2767-9764.CRC-23-0464 -
BioRxiv : the Preprint Server For... Jun 2024In this study, using RNA-Seq gene expression data and advanced machine learning techniques, we identified distinct gene expression profiles between male and female...
In this study, using RNA-Seq gene expression data and advanced machine learning techniques, we identified distinct gene expression profiles between male and female pancreatic ductal adenocarcinoma (PDAC) patients. Building upon this insight, we developed sex-specific 3-year survival predictive models, which achieved accuracies of 88.47% for males and 88.94% for females, respectively. These models outperformed a single general model despite the smaller sample sizes, highlighting the value of sex-specific analysis. Based on these findings, we created Gap-App, a web application that enables the use of individual gene expression profiles combined with sex information for personalized survival predictions. Gap-App, the first online tool aiming to bridge the gap between complex genomic data and clinical application and facilitating more precise and individualized cancer care, marks a significant advancement in personalized prognosis. The study not only underscores the importance of acknowledging sex differences in personalized prognosis, but also sets the stage for the shift from traditional one-size-fits-all to more personalized and targeted medicine. The GAP-App service is freely available at www.gap-app.org.
PubMed: 38895246
DOI: 10.1101/2024.06.04.597246 -
Diagnostics (Basel, Switzerland) May 2024The emergence of endoscopic ultrasound (EUS) has significantly impacted the diagnosis and management of pancreatic cancer and its associated sequelae. While the... (Review)
Review
The emergence of endoscopic ultrasound (EUS) has significantly impacted the diagnosis and management of pancreatic cancer and its associated sequelae. While the definitive role of EUS for pancreatic cancer remains incompletely characterized by currently available guidelines, EUS undoubtedly offers high diagnostic accuracy, the precise staging of pancreatic neoplasms, and the ability to perform therapeutic and palliative interventions. However, current challenges to EUS include limited specialized expertise and variability in operator proficiency. As the technology and techniques continue to evolve and become more refined, EUS is poised to play an increasingly integral role in shaping pancreatic cancer care.
PubMed: 38893682
DOI: 10.3390/diagnostics14111156 -
Diagnostics (Basel, Switzerland) May 2024Metabolic reprogramming serves as a distinctive feature of cancer, impacting proliferation and metastasis, with aberrant glycosphingolipid expression playing a crucial...
OBJECTIVE
Metabolic reprogramming serves as a distinctive feature of cancer, impacting proliferation and metastasis, with aberrant glycosphingolipid expression playing a crucial role in malignancy. Nevertheless, limited research has investigated the connection between glycosphingolipid metabolism and pancreatic cancer.
METHODS
This study utilized a single-cell sequencing dataset to analyze the cell composition in pancreatic cancer tissues and quantified single-cell metabolism using a newly developed computational pipeline called scMetabolism. A gene signature developed from the differential expressed genes (DEGs), related to epithelial cell glycosphingolipid metabolism, was established to forecast patient survival, immune response, mutation status, and reaction to chemotherapy with pancreatic adenocarcinoma (PAAD).
RESULTS
The single-cell sequencing analysis revealed a significant increase in epithelial cell proportions in PAAD, with high glycosphingolipid metabolism occurring in the cancerous tissue. A six-gene signature prognostic model based on abnormal epithelial glycosphingolipid metabolism was created and confirmed using publicly available databases. Patients with PAAD were divided into high- and low-risk categories according to the median risk score, with those in the high-risk group demonstrating a more unfavorable survival outcome in all three cohorts, with higher rates of gene mutations (e.g., KRAS, CDKN2A), increased levels of immunosuppressive cells (macrophages, Th2 cells, regulatory T cells), and heightened sensitivity to Acetalax and Selumetinlb.
CONCLUSIONS
Abnormal metabolism of glycosphingolipids in epithelial cells may promote the development of PAAD. A model utilizing a gene signature associated with epithelial glycosphingolipids metabolism has been established, serving as a valuable indicator for the prognostic stratification of patients with PAAD.
PubMed: 38893622
DOI: 10.3390/diagnostics14111094