ROR1 and ROR2 expression in pancreatic cancer

Background: The Wnt receptors ROR1 and ROR2 are generating increased interest as cancer therapeutic targets but remain understudied in pancreatic ductal adenocarcinoma (PDAC). Compared to canonical Wnt/ β-catenin signalling, the role of noncanonical Wnt signalling in PDAC remains largely unknown. Only one study has investigated the prognostic significance of the noncanonical Wnt signalling receptor, ROR2 in PDAC. No studies have investigated the prognostic role of ROR1 in PDAC. Methods: Here, we performed analysis of ROR1 and ROR2 mRNA expression in three publicly available datasets ICGC-PACA-AU (n = 81), TCGA-PAAD (n = 150) and CPTAC-PDAC (n = 137). ROR1 and ROR2 protein expression from the CPTAC-PDAC discovery cohort were also analysed. Immunohistochemistry (IHC) using the validated anti ROR1 monoclonal antibody (4A5) was performed on the Australian Pancreatic Cancer Genome Initiative (APGI) cohort of PDAC samples (n = 152). Association between ROR1 cytoplasmic staining intensity and clinicopathological parameters including stage, grade and overall survival (OS) was investigated. Results: High ROR1 mRNA expression levels correlated with a favourable OS outcome in all of the ICGC-PACA-AU, TCGA-PAAD and CPTAC-PDAC cohorts. ROR1 protein expression was not associated with stage, grade or OS in the APGI cohort. Conclusion: ROR1 and ROR2 have potential as prognostic markers when measured at the mRNA level in PDAC. Our IHC cohort did not support ROR1 protein expression in predicting OS, and highlighted the discrepancy of prognostic biomarkers when measured by MS, IHC and RNAseq

Using a Delphi process to determine optimal care for patients with pancreatic cancer

Aim Overall 5-year survival for pancreatic cancer is ~5%. Optimising the care that pancreatic cancer patients receive may be one way of improving outcomes. The objective of this study was to establish components of care which Australian health professionals believe important to optimally manage patients with pancreatic cancer. Methods Using a Delphi process, a multi-disciplinary panel of 250 health professionals were invited to provide a list of factors they considered important for optimal care of pancreatic cancer patients. They were then asked to score and then rescore (from one (no importance/disagree) to 10 (very important/agree) the factors. The mean and coefficient of variation scores were calculated and categorised into three levels of importance. Results Overall 63 (66% of those sent the final questionnaire; 25% of those initially invited) health professionals from 9 disciplines completed the final scoring of 55 statements/factors encompassing themes of presentation/staging, surgery and biliary obstruction, multi-disciplinary team details and oncology. Mean scores ranged from 3.7 to 9.7 with the highest related to communication and patient assessment. There was substantial intra- and inter- disciplinary variation in views about MDT membership and roles. Conclusion Overall the opinions of Australian health professionals reflect international guideline recommended care; however they identified a number of additional factors focusing on where patients should be treated, the importance of clear communication and the need for multi-disciplinary care which were not included in current clinical practice guidelines. Differences in priorities between specialty groups were also identified

Identification of unique neoantigen qualities in long-term survivors of 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 survivors1,2, 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

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and 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, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but 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 post-platinum therapy

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

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

Learning practical skills

Practical, or procedural, skills in healthcare share many features with psychomotor skills in other unrelated disciplines. Since this is the case, we can refer to the published scientific literature on psychomotor skills in general in order to understand how best to teach procedural skills to students, and how best to assess them. It may then be possible to formulate the principles and objectives that govern a curriculum in procedural skills. These principles and objectives will dictate the requisite learning experiences to be included in the curriculum. Consideration may then be given to the types of training media appropriate for the objectives at each stage of the curriculum

Three-dimensional printing technology in surgery

Background: Three-dimensional printing has become an increasingly widespread technology, becoming more accessible to individuals, small businesses and organisations. It represents the ability to manufacture objects of various substrate material using computer aided 3D plans. This article aims to explore the various uses of this technology in medicine and surgery including future directions and applications Method: A generalised review of past and current articles was performed exploring the known uses of three-dimensional printing in medicine and surgery. Results: Broadly, the applications include; education for health professionals and patients, surgical planning and decision-making, custom prostheses, tissue scaffolds, and customised surgical instrument manufacturing. Future directions include bionic prostheses, live tissue grafts, and whole organ printing

Education and imaging : hepatobiliary and pancreatic : iatrogenic hemobilia

Hemobilia is a term that is used to describe bleeding into the biliary tract. The most common cause is bleeding after percutaneous biopsy of the liver. This complication can occur in up to 1% of patients and is more common in the elderly and in those who have multiple biopsies, particularly in the presence of liver tumors. Other causes for hemobilia include liver trauma, percutaneous transhepatic cholangiography, percutaneous biliary drains, hepatic artery or portal vein aneurysms, liver abscesses, gallstones and spontaneous bleeding from liver tumors, particularly hepatocellular carcinomas

Review : photochemical tissue bonding (PTB) methods for sutureless tissue adhesion

Every year more and more medical devices are being implanted in the human body. Sutures are currently the gold standard for attachment of these devices, but they have associated issues such as needle trauma, unsuitability for certain tissues, such as eye or lung, and require skilled surgeons. A variety of sutureless methods have been developed to overcome some of these issues. Sutureless methods developed include fibrin glue, cyanoacrylates, scaffolds and bio-inspired adhesives. A sutureless method that is receiving increasing attention is Photochemical Tissue Bonding (PTB). This method involves using photoactive dyes and light-activation to initiate a chemical reaction that forms cross-links with collagen. In this review, we describe the current status of PTB. A variety of dyes have been identified and the literature analysed to identify the most promising photoactive dyes for PTB. Rose Bengal appears to be the most promising of the dyes identified as it produces the strongest bonding of all the dyes and its use is associated with minimal thermal damage. Development of applications for Rose Bengal is an area of active research with multiple articles published in the last 5 years. The outlook is promising for PTB and Rose Bengal to provide clinically viable solutions for tissue adhesion