Publications by authors named "Nigel B Jamieson"

70 Publications

Clinical benefit of surveillance after resection of pancreatic ductal adenocarcinoma: A systematic review and meta-analysis.

Eur J Surg Oncol 2021 May 10. Epub 2021 May 10.

Hepatobiliary and Pancreatic Surgery Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom; College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. Electronic address:

Background: The value of routine surveillance after resection of pancreatic ductal adenocarcinoma (PDAC) is unclear, and expert guidelines 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. A meta-analysis was performed for those studies reporting rates of asymptomatic recurrence, treatment of recurrence and overall survival, according to different surveillance methods.

Results: Ten studies were included in the literature review, with five studies appropriate for meta-analysis (1596 patients). Patients within active surveillance programs were more likely to have recurrence detected at an asymptomatic stage (Pooled Rate: 49.3% vs. 19.1%, p = 0.043). Within studies reporting these outcomes, patients with asymptomatic recurrence were more likely to receive treatment for recurrence (Odds Ratio 3.49; 95% CI: 1.73-7.07; p < 0.001) and had longer overall survival (Mean Difference: 9.5 months; 95% CI: 4.1-14.8; p < 0.001) than those with symptoms at time of recurrence.

Discussion: Routine surveillance after surgery for PDAC appears to detect more patients at an asymptomatic stage. Data from these non-randomised trials also suggest that treatment rates and survival may be superior in patients were recurrence is detected when asymptomatic. As such, these data suggest that routine surveillance may improve patient outcomes, although an appropriately conducted trial would be required to address concerns that various sources of bias may be affecting these results.
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http://dx.doi.org/10.1016/j.ejso.2021.04.031DOI Listing
May 2021

Survival in borderline resectable and locally advanced pancreatic cancer is determined by the duration and response of neoadjuvant therapy.

Eur J Surg Oncol 2021 Apr 30. Epub 2021 Apr 30.

Sydney Medical School, The University of Sydney, Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, NSW, Australia; Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, Sydney, NSW, Australia.

Background: Pancreatic cancer is the 8th commonest cancer and the 5th commonest cause of cancer-related death in Australia, with a 9% average 5-year survival. This study aims to investigate the effects of neoadjuvant treatment on overall survival (OS) and recurrence-free survival (RFS) in borderline resectable (BRPC) and locally advanced (LAPC) pancreatic adenocarcinoma followed by curative resection.

Materials And Methods: Prospectively-collected demographic, medical, surgical and pathological data of patients with BRPC and LAPC treated with both neoadjuvant therapy (NAT) and surgery at a single tertiary referral centre in Australia were reviewed and analysed.

Results: Between 2012 and 2018, 60 patients, 34 with BRPC and 26 with LAPC, were treated with NAT followed by curative resection. The commonest neoadjuvant chemotherapy regimens were Gemcitabine + Abraxane (51.7%) and FOLFIRINOX (35.0%), with 48.3% of patients additionally receiving neoadjuvant radiotherapy. Median RFS was 30 months and median OS was 35 months. On multivariable analysis, inferior OS was predicted by enlarged loco-regional lymph nodes on initial computed tomography (p = 0.032), larger tumour size post-NAT (p = 0.006) and Common Terminology Criteria for Adverse Events post-NAT toxicity greater than grade 2 (p = 0.015). LAPC patients received more neoadjuvant chemotherapy (p = 0.008) and radiotherapy (p = 0.021) than BRPC and achieved a superior pathological response (p = 0.010).

Conclusion: Patients who respond to NAT likely have a favourable disease biology and will progress well following resection. It is these patients who should be selected for more aggressive upfront management, and those with resistant disease should be spared from high-risk surgery.
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http://dx.doi.org/10.1016/j.ejso.2021.04.005DOI Listing
April 2021

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Commun Biol 2021 02 3;4(1):155. Epub 2021 Feb 3.

University of Sydney, Sydney, New South Wales, 2006, Australia.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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http://dx.doi.org/10.1038/s42003-020-01469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859232PMC
February 2021

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer.

Gastroenterology 2021 01 9;160(1):362-377.e13. Epub 2020 Oct 9.

Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

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.
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http://dx.doi.org/10.1053/j.gastro.2020.09.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167930PMC
January 2021

Clinical and Molecular Risk Factors for Recurrence Following Radical Surgery of Well-Differentiated Pancreatic Neuroendocrine Tumors.

Front Med (Lausanne) 2020 5;7:385. Epub 2020 Aug 5.

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.

Well-differentiated pancreatic neuroendocrine tumors are increasingly diagnosed neoplasms. For localized disease, surgery is the first-line therapy and is curative in most cases. However, although recurrence is a rare event, it can still occur up to 10 years from surgery, worsening the prognosis. Many clinical and pathological factors have been associated with recurrence; however, it is currently unclear how to accurately discern patients at risk for relapse of disease from those that should be considered cured. In this review, we focus on clinical, pathological, and molecular factors associated with recurrence and discuss available prediction tools to assess the risk of recurrence following surgery.
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http://dx.doi.org/10.3389/fmed.2020.00385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419466PMC
August 2020

Precision Oncology in Surgery: Patient Selection for Operable Pancreatic Cancer.

Ann Surg 2020 08;272(2):366-376

Department of Surgery, Universitätsklinikum Erlangen, Erlangen, Germany.

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.
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http://dx.doi.org/10.1097/SLA.0000000000003143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373491PMC
August 2020

Considerations for the treatment of pancreatic cancer during the COVID-19 pandemic: the UK consensus position.

Br J Cancer 2020 09 8;123(5):709-713. Epub 2020 Jul 8.

CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.

The coronavirus disease 2019 (COVID-19) pandemic epicentre has moved to the USA and Europe, where it is placing unprecedented demands on healthcare resources and staff availability. These service constraints, coupled with concerns relating to an increased incidence and severity of COVID-19 among patients with cancer, should lead to re-consideration of the risk-benefit balance for standard treatment pathways. This is of particular importance to pancreatic cancer, given that standard diagnostic modalities such as endoscopy may be restricted, and that disease biology precludes significant delays in treatment. In light of this, we sought consensus from UK clinicians with an interest in pancreatic cancer for management approaches that would minimise patient risk and accommodate for healthcare service restrictions. The outcomes are described here and include recommendations for treatment prioritisation, strategies to bridge to later surgical resection in resectable disease and factors that modify the risk-benefit balance for treatment in the resectable through to the metastatic settings. Priority is given to strategies that limit hospital visits, including through the use of hypofractionated precision radiotherapy and chemoradiotherapy treatment approaches.
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http://dx.doi.org/10.1038/s41416-020-0980-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341025PMC
September 2020

Development and external validation of a prediction model for survival in patients with resected ampullary adenocarcinoma.

Eur J Surg Oncol 2020 09 25;46(9):1717-1726. Epub 2020 May 25.

Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.

Introduction: Ampullary adenocarcinoma (AAC) is a rare malignancy with great morphological heterogeneity, which complicates the prediction of survival and, therefore, clinical decision-making. The aim of this study was to develop and externally validate a prediction model for survival after resection of AAC.

Materials And Methods: An international multicenter cohort study was conducted, including patients who underwent pancreatoduodenectomy for AAC (2006-2017) from 27 centers in 10 countries spanning three continents. A derivation and validation cohort were separately collected. Predictors were selected from the derivation cohort using a LASSO Cox proportional hazards model. A nomogram was created based on shrunk coefficients. Model performance was assessed in the derivation cohort and subsequently in the validation cohort, by calibration plots and Uno's C-statistic. Four risk groups were created based on quartiles of the nomogram score.

Results: Overall, 1007 patients were available for development of the model. Predictors in the final Cox model included age, resection margin, tumor differentiation, pathological T stage and N stage (8th AJCC edition). Internal cross-validation demonstrated a C-statistic of 0.75 (95% CI 0.73-0.77). External validation in a cohort of 462 patients demonstrated a C-statistic of 0.77 (95% CI 0.73-0.81). A nomogram for the prediction of 3- and 5-year survival was created. The four risk groups showed significantly different 5-year survival rates (81%, 57%, 22% and 14%, p < 0.001). Only in the very-high risk group was adjuvant chemotherapy associated with an improved overall survival.

Conclusion: A prediction model for survival after curative resection of AAC was developed and externally validated. The model is easily available online via www.pancreascalculator.com.
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http://dx.doi.org/10.1016/j.ejso.2020.04.011DOI Listing
September 2020

Pancreatoduodenectomy With Arterial Resection for Locally Advanced Pancreatic Cancer of the Head: A Systematic Review.

Pancreas 2020 May/Jun;49(5):621-628

From the Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, Sydney, New South Wales.

The development of increasingly effective chemotherapy regimens and increasing tumor necrosis is allowing radical pancreatectomy to be re-evaluated. This systematic review examines the outcome of patients with locally advanced cancer of the pancreatic head after pancreatectomy with arterial resection. Electronic searches were performed on PubMed and Medline databases between January 2000 and December 2018. The end points were to determine the safety and overall survival after arterial resection in pancreatectomy. Thirteen studies with 467 patients were included. Celiac, hepatic, mesenteric, and splenic arteries were resected across all studies. The median overall morbidity was 52% (range, 37%-100%) and with major complications occurring in a median of 25% (range, 12%-54%) of patients. The median 90-day mortality was 5% (range, 0%-17%). R0 was achieved in 66% (range, 43%-100%) and R1 in 31% (range, 0%-74%). The median survival was 17 (range, 7-29) months with a 1- and 3-year survival of 59% (range, 16%-92%) and 17% (range, 0%-13%), respectively. Pancreatectomy with arterial resection may be safely performed in high-volume centers with acceptable survival results in highly selected patients. Pooling of data through a multi-institutional registry will allow a more accurate assessment of the safety and efficacy of this treatment strategy.
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http://dx.doi.org/10.1097/MPA.0000000000001551DOI Listing
May 2021

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer.

Cell Rep 2020 05;31(6):107625

The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst and Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.
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http://dx.doi.org/10.1016/j.celrep.2020.107625DOI Listing
May 2020

Biology and Clinical Application of Regulatory RNAs in Hepatocellular Carcinoma.

Hepatology 2021 Jan 20;73 Suppl 1:38-48. Epub 2020 Nov 20.

The Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.

Most of the human genome consists of DNA genes that are translated into RNAs but not into proteins. These RNA molecules are named noncoding RNAs (ncRNA). While in the past it was thought that ncRNAs would be redundant without relevant functions, it is now well established that ncRNAs identify a class of regulatory molecules that finely tune cell homeostasis and are deregulated in disease states, including hepatocellular carcinoma (HCC). Of note, the number of ncRNAs within a cell increases progressively, with the complexity of the species indicating their essential role in the maintenance of regulatory networks that affect the intricacy of the organism. ncRNAs have been demonstrated to mediate HCC development and progression by affecting intrinsic cancer cell signaling and crosstalk between malignant cells and the microenvironment. Moreover, ncRNAs hold promise as clinical biomarkers, but further evidence is warranted before their translation and integration within clinical practice.
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http://dx.doi.org/10.1002/hep.31225DOI Listing
January 2021

Risk factors for development of diabetes mellitus (Type 3c) after partial pancreatectomy: A systematic review.

Clin Endocrinol (Oxf) 2020 05 18;92(5):396-406. Epub 2020 Feb 18.

Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia.

Objectives: Type 3c diabetes mellitus (T3cDM) occurring post pancreatectomy can be challenging to treat due to the frequent combination of decreased circulating levels of insulin and glucagon and concurrent exocrine insufficiency. Relatively, little is known regarding the risk factors for development of T3cDM post pancreatectomy. Our aim was to review the literature and assess what is known of the risk factors for the development of new-onset DM following partial pancreatic resection and where possible determines the incidence, time of onset and the management approach to hyperglycaemia in this context.

Design: Medline and Embase databases were reviewed using specific keyword criteria. Original manuscripts published in 1990 or later included. Articles with study population <20, lacking information on new-onset DM, follow-up duration or specifically targeting rare procedures/pathology were excluded. The Newcastle Ottawa Quality Assessment form was applied. Results reported according to PRISMA guidelines. Pooled effect size calculated using random effects model.

Patients: Thirty six articles were identified that described a total of 5636 patients undergoing pancreaticoduodenectomy, 3922 patients having distal pancreatectomy and 315 with central pancreatectomy.

Results: The incidence of new-onset DM was significantly different between different types of resection from 9% to 24% after pancreaticoduodenectomy (pooled estimate 16%; 95% CI: 14%-17%), 3%-40% after distal pancreatectomy (pooled estimate 21%; 95% CI: 16%-25%) and 0%-14% after central pancreatectomy (pooled estimate 6%; 95% CI: 3%-9%). Surgical site, higher preoperative HbA1c, fasting plasma glucose and lower remnant pancreatic volume had strongest associations with new-onset DM.

Conclusions: This systematic review supports that risk of development of T3cDM is associated with type of pancreatic resection, lower remnant pancreatic volume and higher preoperative HbA1c.
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http://dx.doi.org/10.1111/cen.14168DOI Listing
May 2020

Evaluation of Fluorodeoxyglucose Positron Emission Tomography Scanning in the Neoadjuvant Therapy Paradigm in Pancreatic Ductal Adenocarcinoma.

Pancreas 2020 02;49(2):224-229

Department of Nuclear Medicine.

Objectives: Little data exist on the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) in operable pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant (NA) therapy.

Methods: Consecutively treated patients with potentially operable PDAC were recruited from a quaternary referral center between 2015 and 2018. Data were collated on demographic, clinical, radiological, treatment, and disease-free and overall survival (OS) outcome measures, correlated with FDG-PET findings.

Results: Of 115 patients recruited, 61% were deemed upfront operable (n = 70), 33% borderline (n = 38), and 6% (n = 7) locally advanced. Ninety-five (83%) received NA chemotherapy with 23 (24%) sequential radiotherapy. Sixty-nine (73%) treated with NA were resected, 37 (54%) attained an R0 resection, 43 (62%) had N1 disease with median tumor viability of 50%. The median OS in the entire cohort was 30.48 months and in those who received NA chemotherapy followed by resection 37.98 months. Twelve percent (n = 13) were upstaged during NA therapy by PET. Preoperative standardized uptake value maximum of less than 5 versus 5 or greater after NA predicted for improved OS, 42.95 months versus 26.05 months, P = 0.02.

Conclusions: In this real-world cohort study of PDAC, the utility of FDG-PET in informing the patient treatment pathway was meaningfully demonstrated.
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http://dx.doi.org/10.1097/MPA.0000000000001472DOI Listing
February 2020

Observation or resection of pancreatic intraductal papillary mucinous neoplasm: An ongoing tug of war.

World J Gastrointest Oncol 2019 Dec;11(12):1092-1100

Department of Gastrointestinal Surgery, HPB Unit, Stavanger University Hospital, Stavanger 4068, Norway.

An increasing number of patients are being referred to pancreatic centres around the world due to often incidentally discovered cystic neoplasms of the pancreas. The evaluation and management of pancreatic cystic neoplasms is a controversial topic and with existing guidelines based on a lack of strong evidence there is discordance between centres and guidelines with regard to when to offer surgery and when to favour surveillance. The frequency, duration and modality of surveillance is also controversial as this is resource-consuming and must be balanced against the perceived benefits and risks involved. While there is consensus that the risk of malignancy should be balanced against the life-expectancy and comorbidities, the indications for surgery and surveillance strategies vary among the guidelines. Thus, the tug of war between surveillance or resection continues. Here we discuss the recommendations from guidelines with further accumulating data and emerging reports on intraductal papillary mucinous neoplasm in the literature.
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http://dx.doi.org/10.4251/wjgo.v11.i12.1092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937444PMC
December 2019

Multi-institutional Development and External Validation of a Nomogram to Predict Recurrence After Curative Resection of Pancreatic Neuroendocrine Tumors.

Ann Surg 2019 Sep 24. Epub 2019 Sep 24.

Unit of General and Pancreatic Surgery, University and Hospital Trust of Verona, Italy.

Objective: To develop a nomogram estimating the probability of recurrence free at 5 years after resection for localized grade 1 (G1)/ grade 2 (G2) pancreatic neuroendocrine tumors (PanNETs).

Background: Among patients undergoing resection of PanNETs, approximately 17% experience recurrence. It is not established which patients are at risk, with no consensus on optimal follow-up.

Method: A multi-institutional database of patients with G1/G2 PanNETs treated at 2 institutions was used to develop a nomogram estimating the rate of freedom from recurrence at 5 years after curative resection. A second cohort of patients from 3 additional institutions was used to validate the nomogram. Prognostic factors were assessed by univariate analysis using Cox regression model. The nomogram was internally validated using bootstrap resampling method and on the external cohort. Performance was assessed by concordance index (c-index) and a calibration curve.

Results: The nomogram was constructed using a cohort of 632 patients. Overall, 68% of PanNETs were G1, the median follow-up was 51 months, and we observed 74 recurrences. Variables included in the nomogram were the number of positive nodes, tumor diameter, Ki-67, and vascular/perineural invasion. The model bias-corrected c-index from the internal validation was 0.85, which was higher than European Neuroendocrine Tumors Society/American Joint Committee on Cancer 8th staging scheme (c-index 0.76, P = <0.001). On the external cohort of 328 patients, the nomogram c-index was 0.84 (95% confidence interval 0.79-0.88).

Conclusion: Our externally validated nomogram predicts the probability of recurrence-free survival at 5 years after PanNETs curative resection, with improved accuracy over current staging systems. Estimating individual recurrence risk will guide the development of personalized surveillance programs after surgery.
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http://dx.doi.org/10.1097/SLA.0000000000003579DOI Listing
September 2019

RET gene rearrangements occur in a subset of pancreatic acinar cell carcinomas.

Mod Pathol 2020 04 26;33(4):657-664. Epub 2019 Sep 26.

Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia.

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.
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http://dx.doi.org/10.1038/s41379-019-0373-yDOI Listing
April 2020

The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy.

J Pathol 2019 11 30;249(3):332-342. Epub 2019 Jul 30.

Centre for Tumour Biology, Barts Cancer Institute, CRUK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, London, UK.

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed that high levels of β6 mRNA correlated strongly with significantly poorer survival (n = 491 cases, p = 3.17 × 10 ). In two separate cohorts, we showed that over 80% of PDACs expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration, and invasion. Treatment of both αvβ6-positive human PDAC xenografts and transgenic mice bearing αvβ6-positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p < 0.0001) and increased survival (log-rank test, p < 0.05). Antibody therapy was associated with suppression of tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated caspase-3) and suppression of the pro-tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA-positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852434PMC
November 2019

Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis.

J Natl Cancer Inst 2019 08;111(8):782-794

See the Notes section for the full list of authors' affiliations.

Background: FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated.

Methods: We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III-IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method.

Results: We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III-IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX.

Conclusions: This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.
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http://dx.doi.org/10.1093/jnci/djz073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695305PMC
August 2019

Feasibility and clinical utility of endoscopic ultrasound guided biopsy of pancreatic cancer for next-generation molecular profiling.

Chin Clin Oncol 2019 Apr;8(2):16

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.

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.
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http://dx.doi.org/10.21037/cco.2019.04.06DOI Listing
April 2019

Management of post-pancreatectomy haemorrhage using resuscitative endovascular balloon occlusion of the aorta.

Langenbecks Arch Surg 2019 Mar 13;404(2):253-255. Epub 2019 Feb 13.

Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, Sydney, Australia.

Background: Delayed massive post-pancreatectomy haemorrhage (PPH) is a highly lethal complication after pancreatectomy. Angiographic procedures have led to improved outcomes in the management of these patients. In the setting of an acute haemorrhage, laparotomy and packing are often required to help stablise the patient. However, re-operative surgery in the post-pancreatectomy setting is technically challenging.

Methods: A novel strategy of incorporating the resuscitative endovascular balloon occlusion of the aorta (REBOA) is described.

Results: Two patients where the specific application of this technique uses the REBOA were described.

Conclusion: The REBOA serves as a useful adjunct in haemorrhage control and haemodynamic stablisation to allow successful management of delayed massive PPH.
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http://dx.doi.org/10.1007/s00423-019-01759-0DOI Listing
March 2019

Histopathologic Predictors of Survival and Recurrence in Resected Ampullary Adenocarcinoma: International Multicenter Cohort Study.

Ann Surg 2020 12;272(6):1086-1093

Department of Surgery, University Hospital of Southampton NHS Foundation Trust, Southampton, UK.

Objective: The aim of the study was to define histopathologic characteristics that independently predict overall survival (OS) and disease-free survival (DFS), in patients who underwent resection of an ampullary adenocarcinoma with curative intent.

Summary Background Data: A broad range of survival rates have been described for adenocarcinoma of the ampulla of Vater, presumably due to morphological heterogeneity which is a result of the different epitheliums ampullary adenocarcinoma can arise from (intestinal or pancreaticobiliary). Large series with homogenous patient selection are scarce.

Methods: A retrospective multicenter cohort analysis of patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma in 9 European tertiary referral centers between February 2006 and December 2017 was performed. Collected data included demographics, histopathologic details, survival, and recurrence. OS and DFS analyses were performed using Kaplan-Meier curves and Cox proportional hazard models.

Results: Overall, 887 patients were included, with a mean age of 66 ± 10 years. The median OS was 64 months with 1-, 3-, 5-, and 10-year OS rates of 89%, 63%, 52%, and 37%, respectively. Histopathologic subtype, differentiation grade, lymphovascular invasion, perineural invasion, T-stage, N-stage, resection margin, and adjuvant chemotherapy were correlated with OS and DFS. N-stage (HR = 3.30 [2.09-5.21]), perineural invasion (HR = 1.50 [1.01-2.23]), and adjuvant chemotherapy (HR = 0.69 [0.48-0.97]) were independent predictors of OS in multivariable analysis, whereas DFS was only adversely predicted by N-stage (HR = 2.65 [1.65-4.27]).

Conclusions: Independent predictors of OS in resected ampullary cancer were N-stage, perineural invasion, and adjuvant chemotherapy. N-stage was the only predictor of DFS. These findings improve predicting survival and recurrence after resection of ampullary adenocarcinoma.
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http://dx.doi.org/10.1097/SLA.0000000000003177DOI Listing
December 2020

The Beneficial Effects of Minimizing Blood Loss in Pancreatoduodenectomy.

Ann Surg 2019 07;270(1):147-157

Departments of Surgery at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Objective: The aim of this study was to elucidate the impact of intraoperative blood loss on outcomes following pancreatoduodenectomy (PD).

Background: The negative impact of intraoperative blood loss on outcomes in PD has long been suspected but not well characterized, particularly those factors that may be within surgeons' control.

Methods: From 2001 to 2015, 5323 PDs were performed by 62 surgeons from 17 institutions. Estimated blood loss (EBL) was discretized (0 to 300, 301 to 750, 751 to 1300, and >1300 mL) using optimal scaling methodology. Multivariable regression, adjusted for patient, surgeon, and institutional variables, was used to identify associations between EBL and perioperative outcomes. Factors associated with both increased and decreased EBL were elucidated. The relative impact of surgeon-modifiable contributors was estimated through beta coefficient standardization.

Results: The median EBL of the series was 400 mL [interquartile range (IQR) 250 to 600]. Intra-, post-, and perioperative transfusion rates were 15.8%, 24.8%, and 37.2%, respectively. Progressive EBL zones correlated with intra- but not postoperative transfusion in a dose-dependent fashion (P < 0.001), with a key threshold of 750 mL EBL (8.14% vs 40.9%; P < 0.001). Increasing blood loss significantly correlated with poor perioperative outcomes. Factors associated with increased EBL were trans-anastomotic stent placement, neoadjuvant chemotherapy, pancreaticogastrostomy reconstruction, multiorgan or vascular resection, and elevated operative time, of which 38.7% of the relative impact was "potentially modifiable" by the surgeon. Conversely, female sex, small duct, soft gland, minimally invasive approach, pylorus-preservation, biological sealant use, and institutional volume (≥67/year) were associated with decreased EBL, of which 13.6% was potentially under the surgeon's influence.

Conclusion: Minimizing blood loss contributes to fewer intraoperative transfusions and better perioperative outcomes for PD. Improvements might be achieved by targeting modifiable factors that influence EBL.
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http://dx.doi.org/10.1097/SLA.0000000000002714DOI Listing
July 2019

Identification of an Optimal Cut-off for Drain Fluid Amylase on Postoperative Day 1 for Predicting Clinically Relevant Fistula After Distal Pancreatectomy: A Multi-institutional Analysis and External Validation.

Ann Surg 2019 02;269(2):337-343

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Objective: The aim of this study was to investigate the relationship between drain fluid amylase value on the first postoperative day (DFA1) and clinically relevant fistula (CR-POPF) after distal pancreatectomy (DP), and to identify the cut-off of DFA1 that optimizes CR-POPF prediction.

Background: DFA1 is a well-recognized predictor of CR-POPF after pancreatoduodenectomy, but its role in DP is largely unexplored.

Methods: DFA1 levels were correlated with CR-POPF in 2 independent multi-institutional sets of DP patients: developmental (n = 338; years 2012 to 2017) and validation cohort (n = 166; years 2006 to 2016). Cut-off choice was based on Youden index calculation, and its ability to predict CR-POPF occurrence was tested in a multivariable regression model adjusted for clinical, demographic, operative, and pathological variables.

Results: In the developmental set, median DFA1 was 1745 U/L and the CR-POPF rate was 21.9%. DFA1 correlated with CR-POPF with an area under the curve of 0.737 (P < 0.001). A DFA1 of 2000 U/L had the highest Youden index, with 74.3% sensitivity and 62.1% specificity. Patients in the validation cohort displayed different demographic and operative characteristics, lower values of DFA1 (784.5 U/L, P < 0.001), and reduced CR-POPF rate (10.2%, P < 0.001). However, a DFA1 of 2000 U/L had the highest Youden index in this cohort as well, with 64.7% sensitivity and 75.8% specificity. At multivariable analysis, DFA1 ≥2000 U/L was the only factor significantly associated with CR-POPF in both cohorts.

Conclusion: A DFA1 of 2000 U/L optimizes CR-POPF prediction after DP. These results provide the substrate to define best practices and improve outcomes for patients receiving DP.
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http://dx.doi.org/10.1097/SLA.0000000000002532DOI Listing
February 2019

Risk Factors and Mitigation Strategies for Pancreatic Fistula After Distal Pancreatectomy: Analysis of 2026 Resections From the International, Multi-institutional Distal Pancreatectomy Study Group.

Ann Surg 2019 01;269(1):143-149

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Objective: To identify a clinical fistula risk score following distal pancreatectomy.

Background: Clinically relevant pancreatic fistula (CR-POPF) following distal pancreatectomy (DP) is a dominant contributor to procedural morbidity, yet risk factors attributable to CR-POPF and effective practices to reduce its occurrence remain elusive.

Methods: This multinational, retrospective study of 2026 DPs involved 52 surgeons at 10 institutions (2001-2016). CR-POPFs were defined by 2016 International Study Group criteria, and risk models generated using stepwise logistic regression analysis were evaluated by c-statistic. Mitigation strategies were assessed by regression modeling while controlling for identified risk factors and treating institution.

Results: CR-POPF occurred following 306 (15.1%) DPs. Risk factors independently associated with CR-POPF included: age (<60 yrs: OR 1.42, 95% CI 1.05-1.82), obesity (OR 1.54, 95% CI 1.19-2.12), hypoalbuminenia (OR 1.63, 95% CI 1.06-2.51), the absence of epidural anesthesia (OR 1.59, 95% CI 1.17-2.16), neuroendocrine or nonmalignant pathology (OR 1.56, 95% CI 1.18-2.06), concomitant splenectomy (OR 1.99, 95% CI 1.25-3.17), and vascular resection (OR 2.29, 95% CI 1.25-3.17). After adjusting for inherent risk between cases by multivariable regression, the following were not independently associated with CR-POPF: method of transection, suture ligation of the pancreatic duct, staple size, the use of staple line reinforcement, tissue patches, biologic sealants, or prophylactic octreotide. Intraoperative drainage was associated with a greater fistula rate (OR 2.09, 95% CI 1.51-3.78) but reduced fistula severity (P < 0.001).

Conclusions: From this large analysis of pancreatic fistula following DP, CR-POPF occurrence cannot be reliably predicted. Opportunities for developing a risk score model are limited for performing risk-adjusted analyses of mitigation strategies and surgeon performance.
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http://dx.doi.org/10.1097/SLA.0000000000002491DOI Listing
January 2019

Characterization and Optimal Management of High-risk Pancreatic Anastomoses During Pancreatoduodenectomy.

Ann Surg 2018 04;267(4):608-616

The Ohio State University Wexner Medical Center, Columbus, OH.

Objective: The aim of this study was to identify the optimal fistula mitigation strategy following pancreaticoduodenectomy.

Background: The utility of technical strategies to prevent clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreatoduodenectomy (PD) may vary by the circumstances of the anastomosis. The Fistula Risk Score (FRS) identifies a distinct high-risk cohort (FRS 7 to 10) that demonstrates substantially worse clinical outcomes. The value of various fistula mitigation strategies in these particular high-stakes cases has not been previously explored.

Methods: This multinational study included 5323 PDs performed by 62 surgeons at 17 institutions. Mitigation strategies, including both technique related (ie, pancreatogastrostomy reconstruction; dunking; tissue patches) and the use of adjuvant strategies (ie, intraperitoneal drains; anastomotic stents; prophylactic octreotide; tissue sealants), were evaluated using multivariable regression analysis and propensity score matching.

Results: A total of 522 (9.8%) PDs met high-risk FRS criteria, with an observed CR-POPF rate of 29.1%. Pancreatogastrostomy, prophylactic octreotide, and omission of externalized stents were each associated with an increased rate of CR-POPF (all P < 0.001). In a multivariable model accounting for patient, surgeon, and institutional characteristics, the use of external stents [odds ratio (OR) 0.45, 95% confidence interval (95% CI) 0.25-0.81] and the omission of prophylactic octreotide (OR 0.49, 95% CI 0.30-0.78) were independently associated with decreased CR-POPF occurrence. In the propensity score matched cohort, an "optimal" mitigation strategy (ie, externalized stent and no prophylactic octreotide) was associated with a reduced rate of CR-POPF (13.2% vs 33.5%, P < 0.001).

Conclusions: The scenarios identified by the high-risk FRS zone represent challenging anastomoses associated with markedly elevated rates of fistula. Externalized stents and omission of prophylactic octreotide, in the setting of intraperitoneal drainage and pancreaticojejunostomy reconstruction, provides optimal outcomes.
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http://dx.doi.org/10.1097/SLA.0000000000002327DOI Listing
April 2018

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

Hypermutation In Pancreatic Cancer.

Gastroenterology 2017 01 15;152(1):68-74.e2. Epub 2016 Nov 15.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
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http://dx.doi.org/10.1053/j.gastro.2016.09.060DOI Listing
January 2017
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