In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (... more In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper. An additional affiliation has been added for Husen M.
Background In line with the NCRI framework, appropriate staging and classification of pancreatic ... more Background In line with the NCRI framework, appropriate staging and classification of pancreatic cancer, with particular relevance to vascular involvement, is essential to ensure patients are offered all potential treatment options both at diagnosis and post-neoadjuvant therapy. This pan-specialty national collaborative consensus project, supported by PCUK,AUGIS,PSGBI,RCSEng,NCRI,RCR and BSGAR, aimed to develop a succinct radiological reporting template to allow a more consistent and standardized means of detailing all clinically-relevant aspects of pancreatic cancer, which, in addition to the aforementioned benefits, will allow more efficient MDT review, improved ability to audit national practice, and optimized clinical trial design. Methods In stage one, a core group of stakeholders from surgery, radiology and oncology was formed to establish current practice and determine the optimal data-set for a template. This included a blinded radiological validation study of established te...
FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), pro... more FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy,...
456 Background: Surgery first (SF) versus neoadjuvant approach (NAT) to management of potentially... more 456 Background: Surgery first (SF) versus neoadjuvant approach (NAT) to management of potentially resectable pancreatic ductal adenocarcinoma (PDAC) is controversial. This study is unique in utilizing institutional data to offer Markov decision-analysis of overall treatment pathways for resectable PDAC. Methods: An advanced Markov decision analysis model was constructed and populated with data from a retrospective institutional database. Patients presenting with resectable PDAC from 2008-2012 were included in the SF arm. Those presenting with resectable PDAC from 2012-2016 and treated within NAT pathway populated the NAT arm. Model uncertainties were tested with one and two-way deterministic sensitivity analysis and probabilistic Monte Carlo sensitivity analysis set to 1000 cycles with variables altered between highest and lowest observed values. Results: NAT pathway gave an additional 0.58 QALMs (22.43 vs. 21.85 QALMs). Monte Carlo analysis reported indifference between treatment s...
We report the integrative analysis of more than 2,600 whole cancer genomes and their matching nor... more We report the integrative analysis of more than 2,600 whole cancer genomes and their matching normal tissues across 39 distinct tumour types. By studying whole genomes we have been able to catalogue non-coding cancer driver events, study patterns of structural variation, infer tumour evolution, probe the interactions among variants in the germline genome, the tumour genome and the transcriptome, and derive an understanding of how coding and non-coding variations together contribute to driving individual patient's tumours. This work represents the most comprehensive look at cancer whole genomes to date. NOTE TO READERS: This is an incomplete draft of the marker paper for the Pan-Cancer Analysis of Whole Genomes Project, and is intended to provide the background information for a series of in-depth papers that will be posted to BioRixv during the summer of 2017.
median age was 57 (8e93) and median BMI 25 (15e49). DPs were associated with splenectomy in 81% o... more median age was 57 (8e93) and median BMI 25 (15e49). DPs were associated with splenectomy in 81% of cases and performed with minimally invasive techniques in 21%. Overall, median operative time was 200 minutes (54e660). The rate of MC and readmissions were 17% and 14%, respectively. Mortality was 1.4%. Factors associated with MC were BMI, extension of resection and transfusions, while predictors of readmission were postoperative abscess, clinically relevant fistula, and urinary complications. Conclusion: This large bicentric series confirms that DP can be safely performed at high-volume Institutions, with satisfactory morbidity and mortality rates. The occurrence of severe complications after distal pancreatectomy is predicted by factors which are independent from a change in the clinical practice. Efforts should be put in reducing the rates of postoperative fistula and infectious complications in order to impact on the rate of readmissions.
Applied Immunohistochemistry & Molecular Morphology, 2016
Background: Clinical translation of immunohistochemistry (IHC) biomarkers requires reliable and r... more Background: Clinical translation of immunohistochemistry (IHC) biomarkers requires reliable and reproducible cutoffs or thresholds for interpretation of immunostaining. Most IHC biomarker research focuses on the clinical relevance (diagnostic, prognostic, or predictive utility) of cutoffs, with less emphasis on observer agreement using these cutoffs. From the literature, we identified 3 commonly used cutoffs of 10% positive epithelial cells, 20% positive epithelial cells, and moderate to strong staining intensity (+2/+3 hereafter) to use for investigating observer agreement. Materials and Methods: A series of 36 images of microarray cores stained for 4 different IHC biomarkers, with variable staining intensity and percentage of positive cells, was used for investigating interobserver and intraobserver agreement. Seven pathologists scored the immunostaining in each image using the 3 cutoffs for positive and negative staining. Kappa (κ) statistic was used to assess the strength of agr...
Purpose Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outc... more Purpose Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. Patients and Methods We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater. Results Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34; 95% CI, 1.69 to 6.62; P < .001) and both validation cohorts (HR, 5.65; 95% CI, 2.77 to 11.5; P...
Pancreatic acinar cell carcinoma is relatively rare (1 to 2% of pancreatic malignancies) but may ... more Pancreatic acinar cell carcinoma is relatively rare (1 to 2% of pancreatic malignancies) but may be under-recognized. In contrast to pancreatic ductal adenocarcinoma, most acinar cell carcinomas lack mutations in KRAS, DPC, CDKN2A or TP53, but appear to have a high incidence of gene rearrangements, with up to 20% reported to be driven by BRAF fusions. With the development of a new class of RET-specific tyrosine kinase inhibitors, which appear to have particularly strong activity against RET gene rearranged tumours, there is now considerable interest in identifying RET gene rearrangements across a wide range of cancers. RET rearrangements have been reported to occur at a very low incidence (<1%) in all pancreatic carcinomas. We postulated that given its unique molecular profile, RET gene rearrangements may be common in acinar cell carcinomas. We performed fluorescent in-situ hybridization (FISH) studies on a cohort of 40 acinar cell spectrum tumours comprising 36 pure acinar cell carcinomas, three pancreatoblastomas and one mixed acinar-pancreatic neuroendocrine tumour. RET gene rearrangements were identified in 3 (7.5%) cases and BRAF gene rearrangements in 5 (12.5%). All gene rearranged tumours were pure acinar cell carcinomas. Our findings indicate that amongst all pancreatic carcinomas, acinar carcinomas are highly enriched for potentially actionable gene rearrangements in RET or BRAF. FISH testing is inexpensive and readily available in the routine clinical setting and may have a role in the assessment of all acinar cell carcinomas-at this stage to recruit patients for clinical trials of new targeted therapies, but perhaps in the near future as part of routine care.
Introduction CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 p... more Introduction CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC). Methods The treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic (‘COVID’ cohort, 16/03/2020-10/05/2020), with 12-month follow-up. Results Among 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, ...
Pancreatic Ductal Adenocarcinoma (PDAC) long-term outcomes following surgical resection remain po... more Pancreatic Ductal Adenocarcinoma (PDAC) long-term outcomes following surgical resection remain poor, with only 20% of patients surviving 5 years post pancreatectomy. With its immune-privileged nature, starting from the early pre-neoplastic state, it appears to easily evade the antitumor immune response. Although there is rationale for targeting PDAC immune pathways, little benefit has been observed to date. The aim of the study was to interrogate the immune landscape of PDAC utilising the Nanostring GeoMx Digital Spatial Profiler (DSP), enabling high-plex proteomic characterisation whilst maintaining tumor microenvironment (TME) topographical features. We assessed tumor samples from 28 treatment-naive PDAC cases represented in a multiregional FFPE tissue microarray (TMA) for which extensive IHC, molecular, genomic characterisation and clinicopathological follow-up data is available. Multiplex immunofluorescent staining for nuclei, panCK, aSMA and CD3 was used to guide region select...
Background The clinical benefit and acceptability to patients of routine surveillance after resec... more Background The clinical benefit and acceptability to patients of routine surveillance after resection of pancreatic ductal adenocarcinoma (PDAC) remains unclear. Furthermore, expert guidelines around the world offer conflicting recommendations. This study is a systematic review of evidence for surveillance programs. Methods A systematic review of studies evaluating different surveillance methods was undertaken. Meta-analyses were performed for those studies reporting rates of asymptomatic recurrence, treatment of recurrence and overall survival, according to different surveillance methods. Results There were ten studies included in the literature review. Five studies were appropriate for meta-analysis (1,596 patients). If enrolled in an active surveillance program, patients were more likely to have recurrence detected at an asymptomatic stage (Pooled Rate: 49.3% vs. 19.1%, p = 0.043). In terms of clinical outcomes, patients with asymptomatic recurrence were more likely to receive tr...
Molecular subtyping has demonstrated 2 subtypes in pancreatic adenocarcinoma (PDAC), but currentl... more Molecular subtyping has demonstrated 2 subtypes in pancreatic adenocarcinoma (PDAC), but currently this does not influence decision making prior to surgical resection. In this study of 1298 patients, of which 442 were molecularly subtyped, we show that margin status is not prognostic in patients with a squamous subtype tumor.
Background: The narra1ve surrounding the management of poten1ally resectable pancrea1c cancer is ... more Background: The narra1ve surrounding the management of poten1ally resectable pancrea1c cancer is complex. Resec1on rates are low, the risk of opera1ve morbidity and mortality are high, and survival outcomes remain poor. Surgical resec1on is the only poten1ally cura1ve treatment but 5year survival rates for resected cases are between only 7% and 25%. The aim of this study was to create a prognos1c Bayesian network that pre-opera1vely makes personalized predic1ons of post-resec1on survival 1me of 12months or less and also performs post-opera1ve prognos1c upda1ng. Methods 1: Bayesian Network Based on probability theory, Bayesian networks (BN) model rela1onships between variables based on a graphical formalism of a joint or mul1variate probability distribu1on over a set of variables. This is formalized as: BN= (G,Pr). G is a graphical structure and Pr is the probability distribu1on. Within the graphical structure of a BN, G, variables are modeled as nodes (V(G)) with causal rela1onships between parent and child nodes represented by directed arcs (A(G)): G = V(G), A(G). Within a BN any number of nodes can be included therefore: V(G)= {V 1, V 2 ….V n } where n>1. Directed arcs, A(G), represent the probabilis1c influence between parent (V p)and child (V c) nodes. The dependence and independence between nodes is defined by the joint probability distribu1on (Pr): Pr(V 1, V 2 ….V n)= Π n i 1 Pr(V p /π(V c)) where π(V c) represents the covariates of parent nodes to V c. Each node therefore has a condi1onal probability table represen1ng the probability of each value contained within that node given the condi1on of all its parent nodes. Through Bayes theorem the prior distribu1on and observed data are combined to update knowledge in the form of the posterior distribu1on. Missing data is handled through probabilis1c inference with predic1ons made based on global averages of the pa1ent popula1on. In this way BN allow the modeling of the dynamic rela1onships between variables contained within the complex healthcare process, with predic1ons evolving and accuracy improving as more informa1on becomes available. Methods 2: A Bayesian network was created using AgenaRisk soeware by synthesizing data from 77 PubMed post-resec1on survival analysis studies (n=31,214) through a two-stage weigh1ng process. Input variables included: inflammatory markers, tumour factors, tumour markers, pa1ent factors and, if applicable, response to neoadjuvant treatment for pre-opera1ve predic1ons. Prognos1c upda1ng was performed by inclusion of post-opera1ve input variables including: pathology results and adjuvant therapy. Methods 3: Sensi1vity Analysis Pearl's inwards analysis and broadcas1ng analysis were used to perform sensi1vity analysis. Hence sensi1vity was defined as S(X=x, T=t) and determined by seAng values for all source variables, X, and assessing the impact on the target node, T, then changing only the target node, T, and assessing the changes on the source set, X, respec1vely with joint sensi1vity of T to perturba1ons in source nodes defined as:S(X=x,T=t) = p(T=t|e,X=x)p(T=t|e) where p(T=t|e) is the current probability value for T, given evidence e and p(T=t|e, X=x) is the new value of T for the set of source variable, X. Hence inwards analysis and broadcas1ng results were equivocal as: p(T=t|e,X=x)p(T=t|e) = p(X=x| T=t,e)p(X=x|e). The results of BBN sensi1vity analysis showed that for the pre-opera1ve BBNs tumour factors had the greatest impact on outcomes, followed by pa1ent factors. When post-opera1ve data was incorporated into the BBN post-opera1ve factors and surgical pathology had greatest impact on output followed by tumour factors and pa1ent factors. Results: The performance of the model was validated against a 20year, prospec1vely maintained pa1ent database from a ter1ary referral centre. Individual pa1ent data was entered into the BN and the personalized pre and post-opera1ve predic1ons of poor prognosis were recorded and assessed against that individual's actual survival 1me therefore deeming predic1ons to be true or false. This gave a pool of 387 and 251 pa1ents against which the predic1ve performance of the pre and post-opera1ve models were validated respec1vely. Pre-opera1ve Results Post-opera1ve Results Discussion/ Conclusion: This Bayesian network is currently unique in the way it u1lizes PubMed and pa1ent level data to translate the exis1ng empirical evidence surrounding poten1ally resectable pancrea1c cancer to make personalized prognos1c predic1ons. We believe such a tool is vital in facilita1ng beler shared decision-making in clinical prac1ce and could be further developed to offer a vehicle for delivering personalized precision medicine in the future.
444 Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mort... more 444 Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality worldwide. Lymph node involvement and resection margin status play important roles in predicting relapse. Resectable disease occurs in only 15–20% of total patients who present with PDAC. Unfortunately, margin involvement (R1) occurs in 70–80% of these patients. Emerging evidence has shown that the use of neoadjuvant chemotherapy and localised radiotherapy to downsize the tumours and increase the margin clearance (R0) rate may improve the overall survival of PDAC patients.We report a neoadjuvant therapy approach in the non-clinical trial setting of our large, tertiary cancer centre. Methods: We prospectively collected the outcome data and toxicity of 53 patients diagnosed with borderline resectable or initially non-resectable PDAC between 2012 and 2014. These patients received either FOLFIRINOX (FFX) or Gemcitabine/Capecitabine (GemCap) combination chemotherapies. Following restagi...
Pancreas-specific complications (PSCs), comprising postoperative pancreatic fistula, haemorrhage ... more Pancreas-specific complications (PSCs), comprising postoperative pancreatic fistula, haemorrhage and intra-abdominal collections, are drivers of morbidity and mortality after pancreaticoduodenectomy (PD). A serum amylase concentration of 130 units/l or more on postoperative day (POD) 0 has been shown to be an objective surrogate of pancreatic texture, a determinant of PSCs. This study evaluated serial measurements of C-reactive protein (CRP) to refine PSC risk stratification. Consecutive patients undergoing PD between 2008 and 2014, with vascular resection if required and without preoperative chemoradiotherapy, had serum investigations from the day before operation until discharge. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold value of serum CRP with clinically relevant PSCs for up to 30 days after discharge as outcome measure. Of 230 patients, 95 (41·3 per cent) experienced a clinically relevant PSC. A serum CRP level of 180 mg/l or higher ...
Abdominal surgery performed in patients with significant liver disease and portal hypertension is... more Abdominal surgery performed in patients with significant liver disease and portal hypertension is associated with high mortality rates, with even poorer outcomes associated with complex pancreaticobiliary operations. We report on a patient requiring portal decompression via transjugular intrahepatic portosystemic shunt (TIPS) prior to a pancreaticoduodenectomy. The 49-year-old patient presented with pain, jaundice and weight loss. At ERCP an edematous ampulla was biopsied, revealing high-grade dysplasia within a distal bile duct adenoma. Liver biopsy was performed to investigate portal hypertension, confirming congenital hepatic fibrosis (CHF). A TIPS was performed to enable a pancreaticoduodenectomy. Prophylactic TIPS can be performed for preoperative portal decompression for patients requiring pancreatic resection. A potentially curative resection was performed when abdominal surgery was initially thought impossible. Notably, CHF has been associated with the development of cholang...
In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (... more In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper. An additional affiliation has been added for Husen M.
Background In line with the NCRI framework, appropriate staging and classification of pancreatic ... more Background In line with the NCRI framework, appropriate staging and classification of pancreatic cancer, with particular relevance to vascular involvement, is essential to ensure patients are offered all potential treatment options both at diagnosis and post-neoadjuvant therapy. This pan-specialty national collaborative consensus project, supported by PCUK,AUGIS,PSGBI,RCSEng,NCRI,RCR and BSGAR, aimed to develop a succinct radiological reporting template to allow a more consistent and standardized means of detailing all clinically-relevant aspects of pancreatic cancer, which, in addition to the aforementioned benefits, will allow more efficient MDT review, improved ability to audit national practice, and optimized clinical trial design. Methods In stage one, a core group of stakeholders from surgery, radiology and oncology was formed to establish current practice and determine the optimal data-set for a template. This included a blinded radiological validation study of established te...
FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), pro... more FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy,...
456 Background: Surgery first (SF) versus neoadjuvant approach (NAT) to management of potentially... more 456 Background: Surgery first (SF) versus neoadjuvant approach (NAT) to management of potentially resectable pancreatic ductal adenocarcinoma (PDAC) is controversial. This study is unique in utilizing institutional data to offer Markov decision-analysis of overall treatment pathways for resectable PDAC. Methods: An advanced Markov decision analysis model was constructed and populated with data from a retrospective institutional database. Patients presenting with resectable PDAC from 2008-2012 were included in the SF arm. Those presenting with resectable PDAC from 2012-2016 and treated within NAT pathway populated the NAT arm. Model uncertainties were tested with one and two-way deterministic sensitivity analysis and probabilistic Monte Carlo sensitivity analysis set to 1000 cycles with variables altered between highest and lowest observed values. Results: NAT pathway gave an additional 0.58 QALMs (22.43 vs. 21.85 QALMs). Monte Carlo analysis reported indifference between treatment s...
We report the integrative analysis of more than 2,600 whole cancer genomes and their matching nor... more We report the integrative analysis of more than 2,600 whole cancer genomes and their matching normal tissues across 39 distinct tumour types. By studying whole genomes we have been able to catalogue non-coding cancer driver events, study patterns of structural variation, infer tumour evolution, probe the interactions among variants in the germline genome, the tumour genome and the transcriptome, and derive an understanding of how coding and non-coding variations together contribute to driving individual patient's tumours. This work represents the most comprehensive look at cancer whole genomes to date. NOTE TO READERS: This is an incomplete draft of the marker paper for the Pan-Cancer Analysis of Whole Genomes Project, and is intended to provide the background information for a series of in-depth papers that will be posted to BioRixv during the summer of 2017.
median age was 57 (8e93) and median BMI 25 (15e49). DPs were associated with splenectomy in 81% o... more median age was 57 (8e93) and median BMI 25 (15e49). DPs were associated with splenectomy in 81% of cases and performed with minimally invasive techniques in 21%. Overall, median operative time was 200 minutes (54e660). The rate of MC and readmissions were 17% and 14%, respectively. Mortality was 1.4%. Factors associated with MC were BMI, extension of resection and transfusions, while predictors of readmission were postoperative abscess, clinically relevant fistula, and urinary complications. Conclusion: This large bicentric series confirms that DP can be safely performed at high-volume Institutions, with satisfactory morbidity and mortality rates. The occurrence of severe complications after distal pancreatectomy is predicted by factors which are independent from a change in the clinical practice. Efforts should be put in reducing the rates of postoperative fistula and infectious complications in order to impact on the rate of readmissions.
Applied Immunohistochemistry & Molecular Morphology, 2016
Background: Clinical translation of immunohistochemistry (IHC) biomarkers requires reliable and r... more Background: Clinical translation of immunohistochemistry (IHC) biomarkers requires reliable and reproducible cutoffs or thresholds for interpretation of immunostaining. Most IHC biomarker research focuses on the clinical relevance (diagnostic, prognostic, or predictive utility) of cutoffs, with less emphasis on observer agreement using these cutoffs. From the literature, we identified 3 commonly used cutoffs of 10% positive epithelial cells, 20% positive epithelial cells, and moderate to strong staining intensity (+2/+3 hereafter) to use for investigating observer agreement. Materials and Methods: A series of 36 images of microarray cores stained for 4 different IHC biomarkers, with variable staining intensity and percentage of positive cells, was used for investigating interobserver and intraobserver agreement. Seven pathologists scored the immunostaining in each image using the 3 cutoffs for positive and negative staining. Kappa (κ) statistic was used to assess the strength of agr...
Purpose Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outc... more Purpose Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. Patients and Methods We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater. Results Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34; 95% CI, 1.69 to 6.62; P < .001) and both validation cohorts (HR, 5.65; 95% CI, 2.77 to 11.5; P...
Pancreatic acinar cell carcinoma is relatively rare (1 to 2% of pancreatic malignancies) but may ... more Pancreatic acinar cell carcinoma is relatively rare (1 to 2% of pancreatic malignancies) but may be under-recognized. In contrast to pancreatic ductal adenocarcinoma, most acinar cell carcinomas lack mutations in KRAS, DPC, CDKN2A or TP53, but appear to have a high incidence of gene rearrangements, with up to 20% reported to be driven by BRAF fusions. With the development of a new class of RET-specific tyrosine kinase inhibitors, which appear to have particularly strong activity against RET gene rearranged tumours, there is now considerable interest in identifying RET gene rearrangements across a wide range of cancers. RET rearrangements have been reported to occur at a very low incidence (<1%) in all pancreatic carcinomas. We postulated that given its unique molecular profile, RET gene rearrangements may be common in acinar cell carcinomas. We performed fluorescent in-situ hybridization (FISH) studies on a cohort of 40 acinar cell spectrum tumours comprising 36 pure acinar cell carcinomas, three pancreatoblastomas and one mixed acinar-pancreatic neuroendocrine tumour. RET gene rearrangements were identified in 3 (7.5%) cases and BRAF gene rearrangements in 5 (12.5%). All gene rearranged tumours were pure acinar cell carcinomas. Our findings indicate that amongst all pancreatic carcinomas, acinar carcinomas are highly enriched for potentially actionable gene rearrangements in RET or BRAF. FISH testing is inexpensive and readily available in the routine clinical setting and may have a role in the assessment of all acinar cell carcinomas-at this stage to recruit patients for clinical trials of new targeted therapies, but perhaps in the near future as part of routine care.
Introduction CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 p... more Introduction CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC). Methods The treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic (‘COVID’ cohort, 16/03/2020-10/05/2020), with 12-month follow-up. Results Among 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, ...
Pancreatic Ductal Adenocarcinoma (PDAC) long-term outcomes following surgical resection remain po... more Pancreatic Ductal Adenocarcinoma (PDAC) long-term outcomes following surgical resection remain poor, with only 20% of patients surviving 5 years post pancreatectomy. With its immune-privileged nature, starting from the early pre-neoplastic state, it appears to easily evade the antitumor immune response. Although there is rationale for targeting PDAC immune pathways, little benefit has been observed to date. The aim of the study was to interrogate the immune landscape of PDAC utilising the Nanostring GeoMx Digital Spatial Profiler (DSP), enabling high-plex proteomic characterisation whilst maintaining tumor microenvironment (TME) topographical features. We assessed tumor samples from 28 treatment-naive PDAC cases represented in a multiregional FFPE tissue microarray (TMA) for which extensive IHC, molecular, genomic characterisation and clinicopathological follow-up data is available. Multiplex immunofluorescent staining for nuclei, panCK, aSMA and CD3 was used to guide region select...
Background The clinical benefit and acceptability to patients of routine surveillance after resec... more Background The clinical benefit and acceptability to patients of routine surveillance after resection of pancreatic ductal adenocarcinoma (PDAC) remains unclear. Furthermore, expert guidelines around the world offer conflicting recommendations. This study is a systematic review of evidence for surveillance programs. Methods A systematic review of studies evaluating different surveillance methods was undertaken. Meta-analyses were performed for those studies reporting rates of asymptomatic recurrence, treatment of recurrence and overall survival, according to different surveillance methods. Results There were ten studies included in the literature review. Five studies were appropriate for meta-analysis (1,596 patients). If enrolled in an active surveillance program, patients were more likely to have recurrence detected at an asymptomatic stage (Pooled Rate: 49.3% vs. 19.1%, p = 0.043). In terms of clinical outcomes, patients with asymptomatic recurrence were more likely to receive tr...
Molecular subtyping has demonstrated 2 subtypes in pancreatic adenocarcinoma (PDAC), but currentl... more Molecular subtyping has demonstrated 2 subtypes in pancreatic adenocarcinoma (PDAC), but currently this does not influence decision making prior to surgical resection. In this study of 1298 patients, of which 442 were molecularly subtyped, we show that margin status is not prognostic in patients with a squamous subtype tumor.
Background: The narra1ve surrounding the management of poten1ally resectable pancrea1c cancer is ... more Background: The narra1ve surrounding the management of poten1ally resectable pancrea1c cancer is complex. Resec1on rates are low, the risk of opera1ve morbidity and mortality are high, and survival outcomes remain poor. Surgical resec1on is the only poten1ally cura1ve treatment but 5year survival rates for resected cases are between only 7% and 25%. The aim of this study was to create a prognos1c Bayesian network that pre-opera1vely makes personalized predic1ons of post-resec1on survival 1me of 12months or less and also performs post-opera1ve prognos1c upda1ng. Methods 1: Bayesian Network Based on probability theory, Bayesian networks (BN) model rela1onships between variables based on a graphical formalism of a joint or mul1variate probability distribu1on over a set of variables. This is formalized as: BN= (G,Pr). G is a graphical structure and Pr is the probability distribu1on. Within the graphical structure of a BN, G, variables are modeled as nodes (V(G)) with causal rela1onships between parent and child nodes represented by directed arcs (A(G)): G = V(G), A(G). Within a BN any number of nodes can be included therefore: V(G)= {V 1, V 2 ….V n } where n>1. Directed arcs, A(G), represent the probabilis1c influence between parent (V p)and child (V c) nodes. The dependence and independence between nodes is defined by the joint probability distribu1on (Pr): Pr(V 1, V 2 ….V n)= Π n i 1 Pr(V p /π(V c)) where π(V c) represents the covariates of parent nodes to V c. Each node therefore has a condi1onal probability table represen1ng the probability of each value contained within that node given the condi1on of all its parent nodes. Through Bayes theorem the prior distribu1on and observed data are combined to update knowledge in the form of the posterior distribu1on. Missing data is handled through probabilis1c inference with predic1ons made based on global averages of the pa1ent popula1on. In this way BN allow the modeling of the dynamic rela1onships between variables contained within the complex healthcare process, with predic1ons evolving and accuracy improving as more informa1on becomes available. Methods 2: A Bayesian network was created using AgenaRisk soeware by synthesizing data from 77 PubMed post-resec1on survival analysis studies (n=31,214) through a two-stage weigh1ng process. Input variables included: inflammatory markers, tumour factors, tumour markers, pa1ent factors and, if applicable, response to neoadjuvant treatment for pre-opera1ve predic1ons. Prognos1c upda1ng was performed by inclusion of post-opera1ve input variables including: pathology results and adjuvant therapy. Methods 3: Sensi1vity Analysis Pearl's inwards analysis and broadcas1ng analysis were used to perform sensi1vity analysis. Hence sensi1vity was defined as S(X=x, T=t) and determined by seAng values for all source variables, X, and assessing the impact on the target node, T, then changing only the target node, T, and assessing the changes on the source set, X, respec1vely with joint sensi1vity of T to perturba1ons in source nodes defined as:S(X=x,T=t) = p(T=t|e,X=x)p(T=t|e) where p(T=t|e) is the current probability value for T, given evidence e and p(T=t|e, X=x) is the new value of T for the set of source variable, X. Hence inwards analysis and broadcas1ng results were equivocal as: p(T=t|e,X=x)p(T=t|e) = p(X=x| T=t,e)p(X=x|e). The results of BBN sensi1vity analysis showed that for the pre-opera1ve BBNs tumour factors had the greatest impact on outcomes, followed by pa1ent factors. When post-opera1ve data was incorporated into the BBN post-opera1ve factors and surgical pathology had greatest impact on output followed by tumour factors and pa1ent factors. Results: The performance of the model was validated against a 20year, prospec1vely maintained pa1ent database from a ter1ary referral centre. Individual pa1ent data was entered into the BN and the personalized pre and post-opera1ve predic1ons of poor prognosis were recorded and assessed against that individual's actual survival 1me therefore deeming predic1ons to be true or false. This gave a pool of 387 and 251 pa1ents against which the predic1ve performance of the pre and post-opera1ve models were validated respec1vely. Pre-opera1ve Results Post-opera1ve Results Discussion/ Conclusion: This Bayesian network is currently unique in the way it u1lizes PubMed and pa1ent level data to translate the exis1ng empirical evidence surrounding poten1ally resectable pancrea1c cancer to make personalized prognos1c predic1ons. We believe such a tool is vital in facilita1ng beler shared decision-making in clinical prac1ce and could be further developed to offer a vehicle for delivering personalized precision medicine in the future.
444 Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mort... more 444 Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality worldwide. Lymph node involvement and resection margin status play important roles in predicting relapse. Resectable disease occurs in only 15–20% of total patients who present with PDAC. Unfortunately, margin involvement (R1) occurs in 70–80% of these patients. Emerging evidence has shown that the use of neoadjuvant chemotherapy and localised radiotherapy to downsize the tumours and increase the margin clearance (R0) rate may improve the overall survival of PDAC patients.We report a neoadjuvant therapy approach in the non-clinical trial setting of our large, tertiary cancer centre. Methods: We prospectively collected the outcome data and toxicity of 53 patients diagnosed with borderline resectable or initially non-resectable PDAC between 2012 and 2014. These patients received either FOLFIRINOX (FFX) or Gemcitabine/Capecitabine (GemCap) combination chemotherapies. Following restagi...
Pancreas-specific complications (PSCs), comprising postoperative pancreatic fistula, haemorrhage ... more Pancreas-specific complications (PSCs), comprising postoperative pancreatic fistula, haemorrhage and intra-abdominal collections, are drivers of morbidity and mortality after pancreaticoduodenectomy (PD). A serum amylase concentration of 130 units/l or more on postoperative day (POD) 0 has been shown to be an objective surrogate of pancreatic texture, a determinant of PSCs. This study evaluated serial measurements of C-reactive protein (CRP) to refine PSC risk stratification. Consecutive patients undergoing PD between 2008 and 2014, with vascular resection if required and without preoperative chemoradiotherapy, had serum investigations from the day before operation until discharge. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold value of serum CRP with clinically relevant PSCs for up to 30 days after discharge as outcome measure. Of 230 patients, 95 (41·3 per cent) experienced a clinically relevant PSC. A serum CRP level of 180 mg/l or higher ...
Abdominal surgery performed in patients with significant liver disease and portal hypertension is... more Abdominal surgery performed in patients with significant liver disease and portal hypertension is associated with high mortality rates, with even poorer outcomes associated with complex pancreaticobiliary operations. We report on a patient requiring portal decompression via transjugular intrahepatic portosystemic shunt (TIPS) prior to a pancreaticoduodenectomy. The 49-year-old patient presented with pain, jaundice and weight loss. At ERCP an edematous ampulla was biopsied, revealing high-grade dysplasia within a distal bile duct adenoma. Liver biopsy was performed to investigate portal hypertension, confirming congenital hepatic fibrosis (CHF). A TIPS was performed to enable a pancreaticoduodenectomy. Prophylactic TIPS can be performed for preoperative portal decompression for patients requiring pancreatic resection. A potentially curative resection was performed when abdominal surgery was initially thought impossible. Notably, CHF has been associated with the development of cholang...
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Papers by Nigel Jamieson