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Background Minimally invasive oesophagectomy (MIO) has a steep learning curve. We report our outcomes of a standardized 25 mm circular-stapled anastomosis using a trans-orally placed anvil (Orvil™). The objective of this study is to report the initial experience of introducing two-stage MIO to an Australian tertiary health service. Methods We describe our consecutive case series of all MIOs performed from a prospectively maintained database. We assessed the morbidity and mortality of MIO at our institution. We compared our first 30 cases to the second cohort of 32 cases. Results There were 62 two-stage MIOs performed from 2011 to 2015. The average age was 65 years. Median length of stay was 13 days (5-72 days). Median number of total lymph nodes was 14. Conversion occurred in three patients (5%). Major morbidity was 45%. Delayed gastric emptying 6% (n = 4), pneumonia 6% (n = 4), chyle leak 6% (n = 4), pulmonary embolus 2% (n = 1) and grade II or III anastomotic leak 5% (n = 4). One conduit ischaemia (2%) required reoperation and formation of oesophagostomy. There was one post-operative death within 30 days. There were five post-oesophagectomy hiatal hernias requiring re-operation (8%). There was a significant improvement in operative time (minutes) from the first to second cohort 588 versus 464 (P-value 0.01). Conclusion The introduction of two-stage MIO to the Australian setting can be safely instituted. Our unit was still within a learning curve after 30 cases.

Minimally invasive oesophagectomy (MIO) has a steep learning curve. We report our outcomes of a standardized 25 mm circular-stapled anastomosis using a trans-orally placed anvil (Orvil™). The objective of this study is to report the initial experience of introducing two-stage MIO to an Australian tertiary health service.We describe our consecutive case series of all MIOs performed from a prospectively maintained database. We assessed the morbidity and mortality of MIO at our institution. We compared our first 30 cases to the second cohort of 32 cases.There were 62 two-stage MIOs performed from 2011 to 2015. The average age was 65 years. Median length of stay was 13 days (5-72 days). Median number of total lymph nodes was 14. Conversion occurred in three patients (5%). Major morbidity was 45%. Delayed gastric emptying 6% (n = 4), pneumonia 6% (n = 4), chyle leak 6% (n = 4), pulmonary embolus 2% (n = 1) and grade II or III anastomotic leak 5% (n = 4). One conduit ischaemia (2%) required reoperation and formation of oesophagostomy. There was one post-operative death within 30 days. There were five post-oesophagectomy hiatal hernias requiring re-operation (8%). There was a significant improvement in operative time (minutes) from the first to second cohort 588 versus 464 (P-value 0.01).The introduction of two-stage MIO to the Australian setting can be safely instituted. Our unit was still within a learning curve after 30 cases.

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.

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Background: Acute care surgical teams are a new concept in the provision of emergency general surgery. Juggling emergency patients around the surgeons' and staffs' elective commitments resulted in semi-emergency procedures routinely being delayed. In an era of increasing financial pressure and the recent introduction of ‘safe work hours’ practices, the need for a new system which optimized available resources became apparent. Methods: At Fremantle Hospital we developed a new system in a concerted effort to minimize the waiting time for general surgical referrals in the Emergency Department, as well as to move semi-urgent operating from the afterhours to the daytime. To analyse the impact of the ASU, data were collected during February, March, and April 2009 and compared with data from the same period in 2008. Results: Although most referrals were received afterhours, over 85% of operations were performed during working hours compared with 72% in the 2008 period. The time from referral to review decreased from an average of 3.2 h in 2008 to 2.1 h. The mean duration of stay in 2009 was 3 days, which was a reduction from 4.2 days in 2008. An increase in weekend discharge rates was seen after the introduction of the ASU. Conclusion: Despite an increased workload, more referrals were seen and more operations performed during working hours and the time from referral to review was reduced. Higher discharge rates and reduced length of stays increased the availability of beds. We have demonstrated a successful new model which continues to evolve.

Background: Surgeons are noticing increasing numbers of cholecystectomy waiting list patients presenting with complications of their gallstones. In this study, we analysed the outcome of these to ascertain natural history and outcome. Methods: Data for 5298 waiting list patients in Western Australia, from 1999 to 2006, were analysed. Negative binomial regression was used to analyse waiting times data with Waitlist Year, Urgency Category and Aboriginality, after adjusting for Gender, Location and Age at Cholecystectomy. Results: The overall median waiting time for surgery was 40 days (interquartile range (IQR) = 15–103). The median waiting times for Urgent, Semi-Urgent, and Routine categories were 21 (IQR = 8–63), 44 (IQR = 20–97) and 50 (IQR = 17–131) days, respectively. While waiting for surgery, 240 (5%) patients had gallstone-related admissions. Eighty (33.3%) patients had previous gallstone-related admissions prior to their enrolment on the waiting list. Analysis of the crude odds ratio showed that the probability of readmission during wait for surgery was three times more, when the surgery was not performed within the recommended time. Aboriginal and Torres Strait Islanders wait 1.77 times longer than non aboriginals (P < 0.001) and waiting time decreased with more recent calendar years. (P= 0.001) Patients in the metropolitan hospitals waited twice as long compared with the regional hospitals (P < 0.001). Conclusion: Approximately 5% of patients on the waiting list for an elective cholecystectomy were readmitted to the hospital for gallstone-related problems. Proper categorization of patients and definitive surgical treatment of acute gallbladder disease at index presentation might decrease this readmission rate. More effort needs to be made to ensure equity of access for gallstone patients.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Nature 543, 65–71 (2017); doi:10.1038/nature21063 It has been brought to our attention that in Fig. 2d of this Article, an incorrect Sanger trace was used to represent the breakpoint of the EWSR1 and FLI1 type 2 fusion. This was due to an error during manuscript preparation, when we inadvertently inserted the electrophoretic trace referring to EWSR1 splicing variants.

Acute care surgical teams are a new concept in the provision of emergency general surgery. Juggling emergency patients around the surgeons' and staffs' elective commitments resulted in semi-emergency procedures routinely being delayed. In an era of increasing financial pressure and the recent introduction of 'safe work hours' practices, the need for a new system which optimized available resources became apparent.At Fremantle Hospital we developed a new system in a concerted effort to minimize the waiting time for general surgical referrals in the Emergency Department, as well as to move semi-urgent operating from the afterhours to the daytime. To analyse the impact of the ASU, data were collected during February, March, and April 2009 and compared with data from the same period in 2008.Although most referrals were received afterhours, over 85% of operations were performed during working hours compared with 72% in the 2008 period. The time from referral to review decreased from an average of 3.2 h in 2008 to 2.1 h. The mean duration of stay in 2009 was 3 days, which was a reduction from 4.2 days in 2008. An increase in weekend discharge rates was seen after the introduction of the ASU.Despite an increased workload, more referrals were seen and more operations performed during working hours and the time from referral to review was reduced. Higher discharge rates and reduced length of stays increased the availability of beds. We have demonstrated a successful new model which continues to evolve.

Background: Neoadjuvant therapy, radical lymphadenectomy and treatment in high-volume centres have been proposed to improve outcomes for resectable oesophageal tumours. The aim of the present study was to review the oesophagectomy experience of a single surgeon with a moderate caseload who uses neoadjuvant therapy selectively and performs a conservative lymphadenectomy. Methods: A retrospective review of prospectively collected data was performed. The study included 125 consecutive attempted oesophageal resections performed by a single surgeon (RC) from 1993 to 2006. Results: All patients were staged with computed tomography and also laparoscopy for lower third and junctional tumours. Endoscopic ultrasound was used in 69%. Seventy-seven per cent were adenocarcinomas. Neoadjuvant therapy was used selectively in 23%. One hundred and twenty-one resections were carried out, giving an overall resection rate of 97% with an R0 resection in 82%. In-hospital mortality was 0.8%, clinical anastomotic leak 1.7% and median length of stay 14 days. Overall median and 5-year survival were 46 months and 47%. Stage-specific 5-year survival was 100%, 71%, 41% and 21% for stages 0, I, II and III, respectively. Isolated local recurrence occurred in 8%. Conclusions: A moderate volume surgeon with specialist training in oesophageal resectional surgery can achieve a low mortality and anastomotic leak rate with good survival outcomes. The role for neoadjuvant therapy and radical lymphadenectomy is controversial and remains to be clearly defined. Accurate preoperative staging is essential for selection of patients for curative surgery with or without neoadjuvant therapy and for comparison of results.