Publications by authors named "Jaswinder S Samra"

127 Publications

Clinical suspicion of pancreatic cancer despite negative endoscopic ultrasound-guided fine-needle aspiration biopsy.

ANZ J Surg 2021 Oct 11. Epub 2021 Oct 11.

Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia.

Background: The early and accurate diagnosis of pancreatic ductal adenocarcinoma is vital for improving the efficacy of therapeutic interventions and to provide patients with the best chance of survival. While endoscopic ultrasound-fine needle aspiration (EUS-FNA) has been demonstrated to be a reliable and accurate diagnostic tool for solid pancreatic neoplasms, the ongoing management of patients with a high clinical suspicion for malignancy but with a negative EUS-FNA biopsy result can prove a challenge.

Methods: We describe five patients from a single centre who presented for further work-up of a pancreatic mass and/or imaging features concerning for a periampullary malignancy.

Results: All patients had at least one EUS-FNA biopsy performed which returned no malignant cells on cytology. Despite these negative cytology results, all patients underwent further invasive investigation through upfront resection (pancreaticoduodenectomy) or extra-pancreatic biopsy (laparoscopic biopsy of peritoneal nodule) due to worrisome features on imaging, biochemical factors and clinical presentation culminating in a high degree of suspicion for malignancy. The final tissue histopathological diagnosis in all patients was pancreatic ductal adenocarcinoma.

Conclusion: This case series highlights the important clinical findings, imaging and biochemical features which need to be considered in patients who have high suspicion for malignancy despite having a negative EUS-FNA cytology result. In these patients with a high index of suspicion, surgical intervention through an upfront resection or further invasive investigation should not be delayed.
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http://dx.doi.org/10.1111/ans.17256DOI Listing
October 2021

Sheep in wolf's clothing: squamoid cysts of the pancreatic ducts.

ANZ J Surg 2021 Oct 3. Epub 2021 Oct 3.

Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, New South Wales, Australia.

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http://dx.doi.org/10.1111/ans.17239DOI Listing
October 2021

Urinary metabolite prognostic biomarker panel for pancreatic ductal adenocarcinomas.

Biochim Biophys Acta Gen Subj 2021 Nov 27;1865(11):129966. Epub 2021 Jul 27.

Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, St Leonards, Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia. Electronic address:

Background: Patients with pancreatic ductal adenocarcinoma (PDAC) have a very low survival rate and surgical resection is the only curative intent treatment available. However, the majority of patients relapse after surgery and identification of biomarkers for accurate prognostication of PDAC patients is required. We have recently identified a six biomarker (i.e., trigonelline, glycolate, hippurate, creatine, myoinositol and hydroxyacetone) urinary metabolite panel with very high potential to diagnose PDAC (Int J Cancer 2021;148:1508-18). This study aimed to assess the prognostic ability of these previously identified diagnostic metabolites in the urine of PDAC patients.

Methods: Metabolite data from 88 PDAC patients was statistically assessed for their prognostic ability.

Results: A panel of three metabolites (i.e., trigonelline, hippurate and myoinositol) was able to stratify patients with good- or poor-prognosis based on overall survival. The PDAC patients with abnormal levels of 2 or more metabolites in their urine demonstrated significantly lower survival compared to patients with abnormal levels of one or less metabolites.

Conclusion: These results demonstrate that the selected three metabolite panel could be used to stratify patients based on their prognostic outcomes and if independently validated may lead to the development of a urinary prognostic biomarker test for PDAC.

General Significance: This study highlights the potential of using H-nuclear magnetic resonance spectroscopy for the identification of novel metabolites which can prognosticate cancer patients.
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http://dx.doi.org/10.1016/j.bbagen.2021.129966DOI Listing
November 2021

Serum Biomarker Panel for Diagnosis and Prognosis of Pancreatic Ductal Adenocarcinomas.

Front Oncol 2021 5;11:708963. Epub 2021 Jul 5.

Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

Background: Patients with pancreatic ductal adenocarcinoma (PDAC) have late diagnosis which results in poor prognosis. Currently, surgical resection is the only option for curative intent. Identifying high-risk features for patients with aggressive PDAC is essential for accurate diagnosis, prognostication, and personalised care due to the disease burden and risk of recurrence despite surgical resection. A panel of three biomarkers identified in tumour tissue (S100A4, Ca125 and Mesothelin) have shown an association with poor prognosis and overall survival. The diagnostic and prognostic value of the serum concentration of this particular biomarker panel for patients with PDAC has not been previously studied.

Methods: Retrospectively collected blood samples of PDAC patients (n =120) and healthy controls (n =80) were evaluated for the serum concentration of select biomarkers - S100A4, S100A2, Ca-125, Ca 19-9 and mesothelin. Statistical analyses were performed for diagnostic and prognostic correlation.

Results: A panel of four biomarkers (S100A2, S100A4, Ca-125 and Ca 19-9) achieved high diagnostic potential (AUROC 0.913). Three biomarkers (S100A4, Ca-125 and Ca 19-9) correlated with poor overall survival in a univariable model (). PDAC patients with abnormal levels of 2 or more biomarkers in their serum demonstrated significantly lower survival compared to patients with abnormal levels of one or less biomarker ().

Conclusion And Impact: The identified biomarker panels have shown the potential to diagnose PDAC patients and stratify patients based on their prognostic outcomes. If independently validated, this may lead to the development of a diagnostic and prognosticating blood test for PDAC.
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http://dx.doi.org/10.3389/fonc.2021.708963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287202PMC
July 2021

Machine Learning Algorithms, Applied to Intact Islets of Langerhans, Demonstrate Significantly Enhanced Insulin Staining at the Capillary Interface of Human Pancreatic β Cells.

Metabolites 2021 Jun 7;11(6). Epub 2021 Jun 7.

Charles Perkins Centre, School of Medical Sciences, University of Sydney, Camperdown 2006, Australia.

Pancreatic β cells secrete the hormone insulin into the bloodstream and are critical in the control of blood glucose concentrations. β cells are clustered in the micro-organs of the islets of Langerhans, which have a rich capillary network. Recent work has highlighted the intimate spatial connections between β cells and these capillaries, which lead to the targeting of insulin secretion to the region where the β cells contact the capillary basement membrane. In addition, β cells orientate with respect to the capillary contact point and many proteins are differentially distributed at the capillary interface compared with the rest of the cell. Here, we set out to develop an automated image analysis approach to identify individual β cells within intact islets and to determine if the distribution of insulin across the cells was polarised. Our results show that a U-Net machine learning algorithm correctly identified β cells and their orientation with respect to the capillaries. Using this information, we then quantified insulin distribution across the β cells to show enrichment at the capillary interface. We conclude that machine learning is a useful analytical tool to interrogate large image datasets and analyse sub-cellular organisation.
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http://dx.doi.org/10.3390/metabo11060363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229564PMC
June 2021

Sheep in wolf's clothing: A case of mistaken identity-Intestinal mesenteritis.

ANZ J Surg 2021 Jun 21. Epub 2021 Jun 21.

Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/ans.17023DOI Listing
June 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 Oct 30;47(10):2543-2550. 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
October 2021

Management of a rare cause of upper gastrointestinal bleed: the duodenal gangliocytic paraganglioma.

ANZ J Surg 2021 Mar 25. Epub 2021 Mar 25.

Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/ans.16773DOI Listing
March 2021

The Robotic Spleen Preserving Distal Pancreatectomy Under Temporary Splenic Artery Occlusion: the Royal North Shore Technique.

J Gastrointest Surg 2021 07 15;25(7):1936-1938. Epub 2021 Mar 15.

Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.

There are numerous advantages of splenic vessel preservation in performing the minimally invasive spleen preserving distal pancreatectomy. Dissection along the splenic artery, and a medial to lateral dissection of the splenic vein, is associated with high risk of injury and bleeding. Proximal control of the splenic artery with vessel loops, which require tightening or adjustment with the advent of distal bleeding, is inefficient. Instead, a modified technique (the Royal North Shore Technique), whereby a vascular clamp is placed on the splenic artery, reduces splenic artery inflow and indirectly, splenic vein returns. This allows for more accurate and injury-free dissection of the now non-distended splenic vein and the associated tributaries, and maintains a relatively bloodless field in the event of arterial injury.
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http://dx.doi.org/10.1007/s11605-021-04967-6DOI Listing
July 2021

Increased postoperative pancreatic fistula rate after distal pancreatectomy compared with pancreatoduodenectomy is attributable to a difference in acinar scores.

J Hepatobiliary Pancreat Sci 2021 Jun 19;28(6):533-541. Epub 2021 Mar 19.

Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, St. Leonards, NSW, Australia.

Background: Postoperative pancreatic fistula (POPF) is a potentially lethal complication of pancreatic surgery. POPF rate is consistently higher after distal pancreatectomy (DP) compared with pancreatoduodenectomy (PD). The acinar score of the remnant pancreas is associated with postoperative pancreatitis and POPF. This study aimed to: (i) confirm the difference in POPF rate after DP vs PD; (ii) confirm the association between acinar score and POPF; and (iii) evaluate the difference in acinar scores between DP and PD.

Methods: Patients undergoing DP or PD at a single institution from 2011 to 2017 were included. Hematoxylin and eosin-stained slides of the pancreatic resection margin were evaluated for all patients and scored for acinar cell density. Clinicopathological data were retrieved from a prospectively maintained database.

Results: Two hundred and ninety-four patients were included in the analysis (206 PD, 88 DP). The POPF rate was significantly higher after DP than PD (20.4% vs 11.2%, P = .043). Acinar score >50 was independently associated with the development of POPF (OR 6.457, P = .003). DP was associated with a higher median acinar score than PD (65 vs 50, P < .001).

Conclusion: The POPF rate is significantly higher after DP compared with PD and is attributable to a higher acinar score of the pancreatic resection margin.
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http://dx.doi.org/10.1002/jhbp.934DOI Listing
June 2021

Safety and Efficacy of Pancreaticoduodenectomy in Octogenarians.

Front Surg 2021 2;8:617286. Epub 2021 Feb 2.

Department of Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, NSW, Australia.

Pancreaticoduodenectomy (PD) remains the only hope of a cure in selected patients with pancreatic adenocarcinoma (PAC). With an aging population, there will be an increasing number of very elderly patients being diagnosed with PAC of whom a selected proportion would be suitable for PD. However, the literature on outcomes of elderly patients after PD remains ambiguous. Therefore, the aim of this study was to examine the safety and efficacy of PD in octogenarians with PAC. A retrospective analysis of 304 patients with PAC undergoing PD. Patients were divided into two age groups using age of 80 years old as the cut-off. Overall mortality and major morbidity rates were 0.5 and 18.5%, respectively. The octogenarian group had a higher rate of mortality (6.3%, = 1, < 0.001), a higher rate of major morbidity (37.5%, = 6, = 0.042) and a longer hospital stay ( = 0.035). However, median survival of octogenarians was 15.6 months. Multivariate analysis showed age was not identified as a prognostic factor for major morbidity and overall survival. Age alone should not be an exclusion criterion for consideration of PD. With careful selection, PD can be safely performed in octogenarians. Elderly patients should be referred to a specialized unit for an objective assessment to determine the suitability for this aggressive but potential curative approach.
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http://dx.doi.org/10.3389/fsurg.2021.617286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884922PMC
February 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

Structural and functional polarisation of human pancreatic beta cells in islets from organ donors with and without type 2 diabetes.

Diabetologia 2021 Mar 5;64(3):618-629. Epub 2021 Jan 5.

Charles Perkins Centre, Discipline of Physiology, School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia.

Aims/hypothesis: We hypothesised that human beta cells are structurally and functional polarised with respect to the islet capillaries. We set out to test this using confocal microscopy to map the 3D spatial arrangement of key proteins and live-cell imaging to determine the distribution of insulin granule fusion around the cells.

Methods: Human pancreas samples were rapidly fixed and processed using the pancreatic slice technique, which maintains islet structure and architecture. Slices were stained using immunofluorescence for polarity markers (scribble, discs large [Dlg] and partitioning defective 3 homologue [Par3]) and presynaptic markers (liprin, Rab3-interacting protein [RIM2] and piccolo) and imaged using 3D confocal microscopy. Isolated human islets were dispersed and cultured on laminin-511-coated coverslips. Live 3D two-photon microscopy was used on cultured cells to image exocytic granule fusion events upon glucose stimulation.

Results: Assessment of the distribution of endocrine cells across human islets found that, despite distinct islet-to-islet complexity and variability, including multi-lobular islets, and intermixing of alpha and beta cells, there is still a striking enrichment of alpha cells at the islet mantle. Measures of cell position demonstrate that most beta cells contact islet capillaries. Subcellularly, beta cells consistently position polar determinants, such as Par3, Dlg and scribble, with a basal domain towards the capillaries and apical domain at the opposite face. The capillary interface/vascular face is enriched in presynaptic scaffold proteins, such as liprin, RIM2 and piccolo. Interestingly, enrichment of presynaptic scaffold proteins also occurs where the beta cells contact peri-islet capillaries, suggesting functional interactions. We also observed the same polarisation of synaptic scaffold proteins in islets from type 2 diabetic patients. Consistent with polarised function, isolated beta cells cultured onto laminin-coated coverslips target insulin granule fusion to the coverslip.

Conclusions/interpretation: Structural and functional polarisation is a defining feature of human pancreatic beta cells and plays an important role in the control of insulin secretion.
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http://dx.doi.org/10.1007/s00125-020-05345-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864831PMC
March 2021

Formation of a splenic artery aneurysm within a pancreatic mucinous cystic neoplasm.

ANZ J Surg 2021 06 20;91(6):E407-E408. Epub 2020 Nov 20.

Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/ans.16443DOI Listing
June 2021

A unique urinary metabolomic signature for the detection of pancreatic ductal adenocarcinoma.

Int J Cancer 2021 03 12;148(6):1508-1518. Epub 2020 Nov 12.

Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.

Our study aimed to identify a urinary metabolite panel for the detection/diagnosis of pancreatic ductal adenocarcinoma (PDAC). PDAC continues to have poor survival outcomes. One of the major reasons for poor prognosis is the advanced stage of the disease at diagnosis. Hence, identification of a novel and cost-effective biomarker signature for early detection/diagnosis of PDAC could lead to better survival outcomes. Untargeted metabolomics was employed to identify a novel metabolite-based biomarker signature for PDAC diagnosis. Urinary metabolites from 92 PDAC patients (56 discovery cohort and 36 validation cohort) were compared with 56 healthy volunteers using H nuclear magnetic resonance spectroscopy. Multivariate (partial-least squares discriminate analysis) and univariate (Mann-Whitney's U-test) analyses were performed to identify a metabolite panel which can be used to detect PDAC. The selected metabolites were further validated for their diagnostic potential using the area under the receiver operating characteristic (AUROC) curve. Statistical analysis identified a six-metabolite panel (trigonelline, glycolate, hippurate, creatine, myoinositol and hydroxyacetone), which demonstrated high potential to diagnose PDAC, with AUROC of 0.933 and 0.864 in the discovery and validation cohort, respectively. Notably, the identified panel also demonstrated very high potential to diagnose early-stage (I and II) PDAC patients with AUROC of 0.897. These results demonstrate that the selected metabolite signature could be used to detect PDAC and will pave the way for the development of a urinary test for detection/diagnosis of PDAC.
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http://dx.doi.org/10.1002/ijc.33368DOI Listing
March 2021

Genomic characterization of malignant progression in neoplastic pancreatic cysts.

Nat Commun 2020 08 14;11(1):4085. Epub 2020 Aug 14.

Service de Pathologie, AP-HP, Hôpital Cochin, Université Paris Descartes, Paris, France.

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.
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http://dx.doi.org/10.1038/s41467-020-17917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428044PMC
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

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

Neoadjuvant therapy for pancreatic cancer changes the composition of the pancreatic parenchyma.

HPB (Oxford) 2020 11 2;22(11):1631-1636. Epub 2020 Apr 2.

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

Background: Postoperative pancreatic fistula (POPF) remains a prominent complication following pancreatic cancer resections. The primary aim of this study was to evaluate the histological changes that occur in the pancreas due to neoadjuvant therapy (NAT) by comparing the acinar, collagen and fat scores in resected PDAC specimens of patients who did and did not receive NAT. Secondary aims included (1) the difference in rates of POPF in PDAC patients who received NAT versus upfront resection; and (2) the association between acinar/collagen/fat scores and the development of POPF.

Methods: Consecutive patients who underwent pancreaticoduodenectomy for PDAC, with and without NAT were included for analysis. Acinar, collagen and fat scores were determined from histology slides of the pancreatic resection margin.

Results: One hundred and thirty-four patients were included. There was a significant decrease in the median acinar score (48 vs 23, p = 0.003) and increase in the collagen score (28 vs 50, p = 0.011) for patients who received NAT and a significant correlation with the number of cycles of NAT. This study found no statistical difference between NAT and the development of POPF.

Conclusion: The use of NAT in the treatment of PDAC changes the composition of the pancreas.
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http://dx.doi.org/10.1016/j.hpb.2020.03.007DOI Listing
November 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

The AGITG GAP Study: A Phase II Study of Perioperative Gemcitabine and Nab-Paclitaxel for Resectable Pancreas Cancer.

Ann Surg Oncol 2020 Jul 29;27(7):2506-2515. Epub 2020 Jan 29.

Prince of Wales Hospital, Sydney, NSW, Australia.

Background: While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated with higher complete resection rates (R0) in resectable PDAC, while the secondary objectives were to determine the utility of radiological assessment of response to preoperative chemotherapy and the safety and efficacy of nab-gem as perioperative therapy.

Methods: Patients were recruited from eight Australian sites, and 42 patients with radiologically defined resectable PDAC and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Participants received two cycles of preoperative nab-paclitaxel 125 mg/m and gemcitabine 1000 mg/m on days 1, 8, and 15 (28-day cycle) presurgery, and four cycles postoperatively. Early response to chemotherapy was measured with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans on day 15.

Results: Preoperative nab-gem was completed by 93% of participants, but only 63% postoperatively. Thirty-six patients had surgery: 6 (17%) were unresectable, 15 (52%) had R0 (≥ 1 mm) resections, 14 (48%) had R1 (< 1 mm) resections, and 1 patient did not have PDAC. Median progression-free survival was 12.3 months and median overall survival (OS) was 23.5 months: R0 patients had an OS of 35 months versus 25.6 months for R1 patients after surgery. Seven patients had not progressed after 43 months.

Conclusions: The GAP trial demonstrated that perioperative nab-gem was tolerable. Although the primary endpoint of an 85% R0 rate was not met, the R0 rate was similar to trials using a > 1 mm R0 resection definition, and survival rates were comparable with recent adjuvant studies.
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http://dx.doi.org/10.1245/s10434-020-08205-2DOI Listing
July 2020

Pancreatic resection in patients with synchronous extra-pancreatic malignancy: outcomes and complications.

ANZ J Surg 2020 03 13;90(3):290-294. Epub 2020 Jan 13.

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

Background: Patients may present with a resectable pancreatic tumour in the context of a concurrent primary extra-pancreatic malignancy. These patients pose a dilemma regarding their suitability for surgery. We evaluated our experience with such patients who underwent pancreatic resection with curative intent and detailed their outcomes and rationale for surgical decision-making.

Methods: A retrospective review of patients with pancreatic concurrent extra-pancreatic primary malignancy who underwent pancreatic resection at our institution over a 12-year period (2005-2016) was performed. Clinical, histopathological and perioperative outcomes were reviewed.

Results: Ten patients with a median age of 74 years (40-85 years) were identified. Secondary primary tumours included thyroid (n = 2), gastrointestinal (n = 4), small bowel neuroendocrine (n = 1), renal (n = 1) and haematological malignancies (n = 2). Pancreatic tumours included pancreatic ductal adenocarcinomas (n = 6), solid pseudopapillary neoplasms (n = 2) and ampullary carcinomas (n = 2). After a median follow up of 41.3 months (31.3-164 months), 8 of 10 patients were still alive. Two patients died due to metastatic disease from the secondary malignancy (small bowel neuroendocrine tumour and sigmoid colon adenocarcinoma). The post-operative complication rate was 30% with no perioperative 90-day mortality.

Conclusion: Selected patients with a pancreatic and concurrent primary extra-pancreatic malignancy may undergo curative pancreatic resection with favourable outcomes.
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http://dx.doi.org/10.1111/ans.15651DOI Listing
March 2020

Management of patients with hepatocellular adenoma: a single-institution experience.

ANZ J Surg 2020 05 13;90(5):786-790. Epub 2020 Jan 13.

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

Background: Hepatocellular adenoma (HCA) is a rare benign liver tumour that may cause diagnostic and management dilemmas. This study describes the clinical and histopathological characteristics of patients who were treated for HCA in a tertiary referral hospital over a 17-year period.

Methods: A retrospective review was performed of prospectively collected data of all patients treated for HCA within the Northern Upper GI Surgical unit between 2002 and 2018. Immunohistochemical β-catenin expression was evaluated.

Results: Thirty-two patients had histological or radiologically confirmed HCA. Twenty-eight patients underwent 30 operations and four patients were treated conservatively. The median age of the operative group was 43 years (range 19-83) and most patients were female (95%). The median body mass index was 28.7 (range 20-51), and nine patients (33%) were obese. Seven patients (25%) had multifocal HCA. Evidence of prior bleed or rupture or a perceived risk of either a bleed or malignant change (i.e. tumours ≥50 mm) were the most common indications for resection. There were no perioperative mortalities. Nuclear expression of β-catenin by immunohistochemical staining was negative in all cases and there was no malignancy identified in any of the resected lesions. Two patients required transarterial embolization and two patients required a second liver resection for residual HCA.

Conclusion: HCA is a rare lesion predominantly affecting females. Haemorrhage is seen frequently on imaging studies, occasionally requiring urgent angioembolization and/or surgical intervention. Malignant transformation and immunohistochemical β-catenin expression are uncommon. HCA may be multifocal and residual tumours usually require ongoing surveillance and occasionally further intervention.
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http://dx.doi.org/10.1111/ans.15648DOI Listing
May 2020

International validation and update of the Amsterdam model for prediction of survival after pancreatoduodenectomy for pancreatic cancer.

Eur J Surg Oncol 2020 05 28;46(5):796-803. Epub 2019 Dec 28.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands. Electronic address:

Background: The objective of this study was to validate and update the Amsterdam prediction model including tumor grade, lymph node ratio, margin status and adjuvant therapy, for prediction of overall survival (OS) after pancreatoduodenectomy for pancreatic cancer.

Methods: We included consecutive patients who underwent pancreatoduodenectomy for pancreatic cancer between 2000 and 2017 at 11 tertiary centers in 8 countries (USA, UK, Germany, Italy, Sweden, the Netherlands, Korea, Australia). Model performance for prediction of OS was evaluated by calibration statistics and Uno's C-statistic for discrimination. Validation followed the TRIPOD statement.

Results: Overall, 3081 patients (53% male, median age 66 years) were included with a median OS of 24 months, of whom 38% had N2 disease and 77% received adjuvant chemotherapy. Predictions of 3-year OS were fairly similar to observed OS with a calibration slope of 0.72. Statistical updating of the model resulted in an increase of the C-statistic from 0.63 to 0.65 (95% CI 0.64-0.65), ranging from 0.62 to 0.67 across different countries. The area under the curve for the prediction of 3-year OS was 0.71 after updating. Median OS was 36, 25 and 15 months for the low, intermediate and high risk group, respectively (P < 0.001).

Conclusions: This large international study validated and updated the Amsterdam model for survival prediction after pancreatoduodenectomy for pancreatic cancer. The model incorporates readily available variables with a fairly accurate model performance and robustness across different countries, while novel markers may be added in the future. The risk groups and web-based calculator www.pancreascalculator.com may facilitate use in daily practice and future trials.
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http://dx.doi.org/10.1016/j.ejso.2019.12.023DOI Listing
May 2020

Microbiology of pancreatoduodenectomy and recommendations for antimicrobial prophylaxis.

ANZ J Surg 2020 03 19;90(3):283-289. Epub 2019 Nov 19.

Department of Microbiology and Infectious Diseases, Royal North Shore Hospital, Sydney, New South Wales, Australia.

Background: The microbiology of pancreatoduodenectomy is challenging and published guidelines regarding perioperative antimicrobial prophylaxis are variable with poor adherence.

Methods: A retrospective analysis of the microbiological results of 294 consecutive patients who underwent pancreatoduodenectomy was performed. Intraoperative specimen culture results were available for 50 patients and their medical records were reviewed to determine the following demographics and factors; age; sex; tumour location, histopathology, grade and stage; neoadjuvant chemotherapy and radiotherapy; preoperative biliary stenting; surgeon; surgery type and antimicrobial prophylaxis coverage. Outcomes assessed included; post-operative infections, mortality (all and 90-day), and intensive care unit and hospital admission durations. Univariate analysis with chi-squared testing was performed.

Results: Intraoperative specimen cultures were positive in 48 (96%) patients and polymicrobial in 45 (90%) patients with a predominance of Enterobacteriaceae (38/76%), Enterococcus species (27/54%), and Candida species (25/50%). Isolates were potentially susceptible to the current perioperative antimicrobial prophylaxis regimen of ceftriaxone with or without metronidazole in only six patients. However, only neoadjuvant radiotherapy was associated with statistically significant increased intensive care unit and hospital admission durations.

Conclusion: Although this study was probably underpowered to detect any statistically significant associations, perioperative antimicrobial prophylaxis coverage of the operative field microbiological milieu of pancreatoduodenectomy is logical and current guidelines may be inadequate.
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http://dx.doi.org/10.1111/ans.15560DOI Listing
March 2020

Preoperative cardiac and respiratory investigations do not predict cardio-respiratory complications after pancreatectomy.

ANZ J Surg 2020 01 17;90(1-2):97-102. Epub 2019 Oct 17.

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

Background: The process of undergoing a pancreatic resection places a patient under notable physiologic strain throughout the perioperative journey, with well recognized risks of postoperative cardiopulmonary complications. Preoperative preparations and screening often incorporate a barrage of testing, including electrocardiograms, transthoracic echocardiography, chest X-rays and spirometric evaluations. However, the current literature does not demonstrate whether these common tests provide any predictive correlation with postoperative cardiopulmonary complications. This retrospective study is structured to identify complications in post-pancreatic resection patients and assess for a predictive correlation with preoperative test results.

Methods: A retrospective analysis of all patients having undergone a pancreatic resection at a single tertiary centre, between 2014 and 2016. The inpatient medical records were reviewed for 30-day postoperative complications, including acute myocardial infarction, cardiac dysrhythmia, pulmonary embolism, pneumonia or pleural effusions. The results of routine preoperative diagnostic tests and complication rates were analysed.

Results: A total of 244 patients, median age of 66 years (range 18-88 years) were included in the study. Of these, 11 patients experienced a cardiac complication and 16 patients experienced a respiratory complication. Among those who experienced cardiac events, only two patients had abnormalities in their preoperative electrocardiograms. Patients who sustained a cardiac or respiratory event did not have any evidence of abnormality in their preoperative transthoracic echocardiography or respiratory investigations, respectively.

Conclusion: Despite the recommendation that high-risk procedures such as pancreatic resections warrant thorough, routine, preoperative cardiac and respiratory investigation, a more functional preoperative assessment should be considered to stratify and predict postoperative outcomes.
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http://dx.doi.org/10.1111/ans.15515DOI Listing
January 2020

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

MiRNA-3653 Is a Potential Tissue Biomarker for Increased Metastatic Risk in Pancreatic Neuroendocrine Tumours.

Endocr Pathol 2019 Jun;30(2):128-133

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

Pancreatic neuroendocrine tumours (PNETs) are relatively uncommon, accounting for 1-2% of all pancreatic neoplasms. Tumour grade (based on the Ki67 proliferative index and mitotic rate) is associated with metastatic risk across large cohorts; however, predicting the behaviour of individual tumours can be difficult. Therefore, any tool which could further stratify metastatic risk may be clinically beneficial. We sought to investigate microRNA (miRNA) expression as a marker of metastatic disease in PNETs. Tumours from 37 patients, comprising 23 with locoregional disease (L) and 14 with distant metastases (DM), underwent miRNA profiling. In total 506 miRNAs were differentially expressed between the L and DM groups, with four miRNAs (miR-3653 upregulated, and miR-4417, miR-574-3p and miR-664b-3p downregulated) showing statistical significance. A database search demonstrated that miRNA-3653 was associated with ATRX abnormalities. Mean survival between the two groups was correlated with mean expression of miRNA-3653; however, this did not reach statistical significance (p = 0.204). Although this is a small study, we conclude that miRNA-3653 upregulation may be associated with an increased risk of metastatic disease in PNETS, perhaps through interaction with ATRX and the alternate lengthening of telomeres pathway.
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http://dx.doi.org/10.1007/s12022-019-9570-yDOI Listing
June 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
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