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1.
Ann Surg ; 277(2): e396-e405, 2023 02 01.
Article in English | MEDLINE | ID: mdl-36745763

ABSTRACT

BACKGROUND: The long-term outcomes following surgical resection for pancreatic ductal adenocarcinoma (PDAC) remains poor, with only 20% of patients surviving 5 years after pancreatectomy. Patient selection for surgery remains suboptimal largely due to the absence of consideration of aggressive tumor biology. OBJECTIVE: The aim of this study was to evaluate traditional staging criteria for PDAC in the setting of molecular subtypes. METHODS: Clinicopathological data were obtained for 5 independent cohorts of consecutive unselected patients, totaling n = 1298, including n = 442 that underwent molecular subtyping. The main outcome measure was disease-specific survival following surgical resection for PDAC stratified according to the American Joint Commission for Cancer (TNM) staging criteria, margin status, and molecular subtype. RESULTS: TNM staging criteria and margin status confers prognostic value only in tumors with classical pancreatic subtype. Patients with tumors that are of squamous subtype, have a poor outcome irrespective of favorable traditional pathological staging [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, P = 0.032]. Margin status has no impact on survival in the squamous subtype (16.0 vs 12.1 months, P = 0.374). There were no differences in molecular subtype or gene expression of tumors with positive resection margin status. CONCLUSIONS: Aggressive tumor biology as measured by molecular subtype predicts poor outcome following pancreatectomy for PDAC and should be utilized to inform patient selection for surgery.


Subject(s)
Carcinoma, Pancreatic Ductal , Carcinoma, Squamous Cell , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/pathology , Prognosis , Carcinoma, Pancreatic Ductal/pathology , Pancreatectomy , Neoplasm Staging , Carcinoma, Squamous Cell/surgery , Retrospective Studies , Survival Rate , Pancreatic Neoplasms
2.
Cancers (Basel) ; 14(21)2022 Oct 28.
Article in English | MEDLINE | ID: mdl-36358721

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC microenvironment is characterised by a dense, fibrotic stroma of which cancer-associated fibroblasts (CAFs) are key players. CAFs and fibrosis were initially thought to be uniformly tumour-promoting, however this doctrine is now being challenged by a wealth of evidence demonstrating CAF phenotypic and functional heterogeneity. Recent technological advances have allowed for the molecular profiling of the PDAC tumour microenvironment at exceptional detail, and these technologies are being leveraged at pace to improve our understanding of this previously elusive cell population. In this review we discuss CAF heterogeneity and recent developments in CAF biology. We explore the complex relationship between CAFs and other cell types within the PDAC microenvironment. We discuss the potential for therapeutic targeting of CAFs, and we finally provide an overview of future directions for the field and the possibility of improving outcomes for patients with this devastating disease.

4.
Gastroenterology ; 160(1): 362-377.e13, 2021 01.
Article in English | MEDLINE | ID: mdl-33039466

ABSTRACT

BACKGROUND & AIMS: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. METHODS: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. RESULTS: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. CONCLUSIONS: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.


Subject(s)
Adenocarcinoma/pathology , DNA Damage/genetics , DNA Repair/genetics , DNA Replication/genetics , Pancreatic Neoplasms/pathology , Adenocarcinoma/genetics , Adenocarcinoma/therapy , Biomarkers , Cell Culture Techniques , Cell Line, Tumor , Humans , Molecular Targeted Therapy , Organoids , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/therapy , Xenograft Model Antitumor Assays
5.
Ann Surg ; 272(2): 366-376, 2020 08.
Article in English | MEDLINE | ID: mdl-32675551

ABSTRACT

OBJECTIVE: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection. BACKGROUND: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease. METHOD: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram. RESULTS: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables. CONCLUSIONS: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.


Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/mortality , Chemotactic Factors/genetics , Pancreatectomy/methods , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/mortality , S100 Proteins/genetics , Aged , Carcinoma, Pancreatic Ductal/surgery , Cause of Death , Cohort Studies , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Nomograms , Pancreatectomy/mortality , Pancreatic Neoplasms/surgery , Patient Selection , Prognosis , Proportional Hazards Models , Retrospective Studies , Risk Assessment , Survival Analysis
6.
Chin Clin Oncol ; 8(2): 16, 2019 Apr.
Article in English | MEDLINE | ID: mdl-31070037

ABSTRACT

Next-generation sequencing is enabling molecularly guided therapy for many cancer types, yet failure rates remain relatively high in pancreatic cancer (PC). The aim of this study is to investigate the feasibility of genomic profiling using endoscopic ultrasound (EUS) biopsy samples to facilitate personalised therapy for PC. Ninty-five patients underwent additional research biopsies at the time of diagnostic EUS. Diagnostic formalin-fixed (FFPE) and fresh frozen EUS samples underwent DNA extraction, quantification and targeted gene sequencing. Whole genome (WGS) and RNA sequencing was performed as proof of concept. Only 2 patients (2%) with a diagnosis of PC had insufficient material for targeted sequencing in both FFPE and frozen specimens. Targeted panel sequencing (n=54) revealed mutations in PC genes (KRAS, GNAS, TP53, CDKN2A, SMAD4) in patients with histological evidence of PC, including potentially actionable mutations (BRCA1, BRCA2, ATM, BRAF). WGS (n=5) of EUS samples revealed mutational signatures that are potential biomarkers of therapeutic responsiveness. RNA sequencing (n=35) segregated patients into clinically relevant molecular subtypes based on transcriptome. Integrated multi-omic analysis of PC using standard EUS guided biopsies offers clinical utility to guide personalized therapy and study the molecular pathology in all patients with PC.


Subject(s)
Biomarkers, Tumor/genetics , Endoscopic Ultrasound-Guided Fine Needle Aspiration/methods , High-Throughput Nucleotide Sequencing/methods , Image-Guided Biopsy/methods , Molecular Targeted Therapy , Pancreatic Neoplasms/genetics , Patient Selection , Feasibility Studies , Humans , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/therapy , Prognosis
7.
Clin Cancer Res ; 23(7): 1638-1646, 2017 Apr 01.
Article in English | MEDLINE | ID: mdl-28373362

ABSTRACT

Pancreatic cancer has become the third leading cause of cancer-related death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet only 20% of patients will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers and beyond that, a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient subgroups. With the development of next-generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection. Incorporating preclinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large-scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development. Clin Cancer Res; 23(7); 1638-46. ©2017 AACRSee all articles in this CCR Focus section, "Pancreatic Cancer: Challenge and Inspiration."


Subject(s)
Genomics , Molecular Targeted Therapy , Pancreatic Neoplasms/genetics , Precision Medicine , High-Throughput Nucleotide Sequencing , Humans , Mutation , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Patient Selection
8.
Ann Surg Oncol ; 24(5): 1295-1303, 2017 May.
Article in English | MEDLINE | ID: mdl-27873100

ABSTRACT

BACKGROUND: Not all patients respond equally to neoadjuvant chemoradiotherapy (nCRT), with subsequent effects on survival. The systemic inflammatory response has been shown to predict long-term outcomes in colorectal cancer. The current study examined the association between systemic inflammation and nCRT in patients with rectal cancer. METHODS: Between 1999 and 2010, patients who underwent nCRT were identified. Serum measurements of hemoglobin, C-reactive protein, albumin, modified Glasgow prognostic score (mGPS), and differential white cell counts were obtained before and after nCRT. The Rödel scoring system measured pathologic tumor regression, and magnetic resonance imaging and computed tomography determined radiologic staging. RESULTS: The study included 79 patients. Of these patients, 37% were radiologically downstaged, and 44% were categorized as showing a good pathologic response (Rödel scores 3 and 4). As a validated measure of the systemic inflammatory response, mGPS (P = 0.022) was associated with a poor pathologic response to nCRT. A radiologic response was associated with a good pathologic response to treatment (P = 0.003). A binary logistic regression model identified mGPS (odds ratio [OR] 0.27; 95% confidence interval [CI] 0.07-0.96; P = 0.043) and radiologic response (OR 0.43; 95% CI 0.18-0.99; P = 0.048) as strong independent predictors of a pathologic response to treatment. CONCLUSION: The current study showed that a systemic inflammatory response before nCRT is associated with a poor pathologic response. Further study in a prospective controlled trial setting is warranted.


Subject(s)
Adenocarcinoma/therapy , Inflammation/blood , Lymphocytes , Neutrophils , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/secondary , Adult , Aged , Aged, 80 and over , C-Reactive Protein/metabolism , Chemoradiotherapy, Adjuvant , Female , Hemoglobins/metabolism , Humans , Lymphocyte Count , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Platelet Count , Prognosis , Radiology , Rectal Neoplasms/diagnostic imaging , Risk Factors , Serum Albumin/metabolism
9.
Scott Med J ; 60(1): 23-8, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25416185

ABSTRACT

OBJECTIVES: The aim of this study was to determine whether there has been a change in annual ruptured abdominal aortic aneurysm admissions and elective abdominal aortic aneurysm repairs in a tertiary vascular surgery department. METHODS: All patients admitted with ruptured abdominal aortic aneurysm from 1987 to 2009 and all undergoing elective abdominal aortic aneurysm repair from 1995 to 2009 were identified from the local surgical audit database. Annual ruptured abdominal aortic aneurysm admissions were calculated and compared in the first and second halves of the study period. RESULTS: During a 23-year period, 888 patients (male 728, female 158, gender was not documented for two patients) were identified with a ruptured abdominal aortic aneurysm. The annual number of admissions remained relatively constant from 1987 to 1997, with a mean of 44 (95% CI 39.91-48.09). There was a significant decrease to a mean of 33.67 per annum (95% CI 28.53-38.8) in the period 1998-2009, p = 0.006. The mean mortality was 39.8% and showed no significant decrease. There was no increase in the number of elective abdominal aortic aneurysm repairs during the study period. CONCLUSIONS: This study suggests that the incidence of ruptured abdominal aortic aneurysms is decreasing, mirroring the trend seen in other cardiovascular disease. As such, further analysis as to the cost-effectiveness of a Scottish screening programme is merited.


Subject(s)
Aortic Aneurysm, Abdominal/epidemiology , Aortic Aneurysm, Abdominal/surgery , Aortic Rupture/epidemiology , Aortic Rupture/surgery , Mass Screening/statistics & numerical data , Vascular Surgical Procedures/statistics & numerical data , Aged , Cost-Benefit Analysis , Elective Surgical Procedures/statistics & numerical data , Female , Humans , Incidence , Male , Middle Aged , Postoperative Complications , Program Evaluation , Scotland/epidemiology , Vascular Surgical Procedures/methods
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