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1. Expansion of Liver Transplantation Criteria for Hepatocellular Carcinoma from Milan to UCSF in Australia and New Zealand and Justification for Metroticket 2.0.

Author

Barreto, SG, Strasser, SI, McCaughan, GW, Fink, MA, Jones, R, McCall, J, Munn, S, Macdonald, GA, Hodgkinson, P, Jeffrey, GP, Jaques, B, Crawford, M, Brooke-Smith, ME, Chen, JW, Barreto, SG, Strasser, SI, McCaughan, GW, Fink, MA, Jones, R, McCall, J, Munn, S, Macdonald, GA, Hodgkinson, P, Jeffrey, GP, Jaques, B, Crawford, M, Brooke-Smith, ME, and Chen, JW

Abstract

Background: Expansion in liver transplantation (LT) criteria for HCC from Milan to UCSF has not adversely impacted overall survival, prompting further expansion towards Metroticket 2.0 (MT2). In this study, we compared patient survival post-transplant before and after 2007 and long-term outcomes for LT within Milan versus UCSF criteria (to determine the true benefit of the expansion of criteria) and retrospectively validated the MT2 criteria. Methods: Retrospective analysis of ANZLITR (including all patients transplanted for HCC since July 1997). The entire cohort was divided based on criteria used at the time of listing, namely, Milan era (1997−2006) and the UCSF era (2007−July 2015). Results: The overall 5- and 10-year cumulative survival rates for the entire cohort of 691 patients were 78% and 69%, respectively. Patients transplanted in UCSF era had significantly higher 5- and 10-year survival rates than in the Milan era (80% vs. 73% and 72% vs. 65%, respectively; p = 0.016). In the UCSF era, the 5-year survival rate for patients transplanted within Milan criteria was significantly better than those transplanted outside Milan but within UCSF criteria (83% vs. 73%; p < 0.024). Patients transplanted within the MT2 criteria had a significantly better 5- and 10-year survival rate as compared to those outside the criteria (81% vs. 64% and 73% vs. 50%, respectively; p = 0.001). Conclusion: Overall survival following LT for HCC has significantly improved over time despite expanding criteria from Milan to UCSF. Patients fulfilling the MT2 criteria have a survival comparable to the UCSF cohort. Thus, expansion of criteria to MT2 is justifiable.

Published
2022

2. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan

Author

Vennin, C, Melenec, P, Rouet, R, Nobis, M, Cazet, As, Murphy, Kj, Herrmann, D, Reed, Da, Lucas, Mc, Warren, Sc, Elgundi, Z, Pinese, M, Kalna, G, Roden, D, Samuel, M, Zaratzian, A, Grey, St, Da Silva, A, Leung, W, Mathivanan, S, Wang, Yx, Braithwaite, Aw, Christ, D, Benda, A, Parkin, A, Phillips, Pa, Whitelock, Jm, Gill, Aj, Sansom, Oj, Croucher, Dr, Parker, Bl, Pajic, M, Morton, Jp, Cox, Tr, Timpson, P, Johns, Al, Chantrill, La, Chou, A, Steinmann, A, Arshi, M, Dwarte, T, Froio, D, Pereira, B, Ritchie, S, Chambers, Cr, Metcalf, X, Waddell, N, Pearson, Jv, Patch, Am, Nones, K, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Leonard, C, Wood, S, Grimmond, Sm, Hofmann, O, Christ, A, Bruxner, T, Samra, Js, Pavlakis, N, High, Ha, Asghari, R, Merrett, Nd, Pavey, D, Das, A, Cosman, Ph, Ismail, K, O'Connnor, C, Stoita, A, Williams, D, Spigellman, A, Lam, Vw, Mcleod, D, Kirk, J, Kench, Jg, Grimison, P, Cooper, Cl, Sandroussi, C, Goodwin, A, Mead, Rs, Tucker, K, Andrews, L, Texler, M, Forest, C, Epari, Kp, Ballal, M, Fletcher, Dr, Mukhedkar, S, Zeps, N, Beilin, M, Feeney, K, Nguyen, Nq, Ruszkiewicz, Ar, Worthley, C, Chen, J, Brooke-Smith, Me, Papangelis, V, Clouston, Ad, Barbour, Ap, O'Rourke, Tj, Fawcett, Jw, Slater, K, Hatzifotis, M, Hodgkinson, P, Nikfarjam, M, Eshleman, Jr, Hruban, Rh, Wolfgang, Cl, Lawlor, Rt, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Biankin, Av, Dixon, J, Jamieson, Nb, and Chang, Dk

Subjects
0301 basic medicine, medicine.medical_treatment, Drug Resistance, General Physics and Astronomy, 02 engineering and technology, Mice, Cancer-Associated Fibroblasts, Cell Movement, lcsh:Science, Inbred BALB C, Cancer, education.field_of_study, Mice, Inbred BALB C, Multidisciplinary, Tumor, 021001 nanoscience & nanotechnology, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, 0210 nano-technology, Pancreas, Signal Transduction, Cancer microenvironment, Cell biology, Science, Population, Perlecan, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, Pancreatic cancer, Cell Line, Tumor, medicine, Humans, Animals, Neoplasm Invasiveness, education, Cell Proliferation, Neoplastic, fungi, General Chemistry, Immunotherapy, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Gene Expression Regulation, Drug Resistance, Neoplasm, Cancer cell, Cancer research, biology.protein, Neoplasm, lcsh:Q, Stromal Cells, Tumor Suppressor Protein p53, Heparan Sulfate Proteoglycans
Abstract

Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer., Subtypes of cancer associated fibroblasts can both promote and suppress tumorigenesis. Here, the authors investigate how p53 status in pancreatic cancer cells affects their interaction with cancer associated fibroblasts, and report perlecan as a mediator of the pro-metastatic environment.

Published
2019

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

Author

Lakis, V, Lawlor, RT, Newell, F, Patch, AM, Mafficini, A, Sadanandam, A, Koufariotis, LT, Johnston, RL, Leonard, C, Wood, S, Rusev, B, Corbo, V, Luchini, C, Cingarlini, S, Landoni, L, Salvia, R, Milella, M, Chang, D, Bailey, P, Jamieson, NB, Duthie, F, Gingras, MC, Muzny, DM, Wheeler, DA, Gibbs, RA, Milione, M, Chantrill, LA, Timpson, P, Chou, A, Pajic, M, Murphy, A, Dwarte, T, Hermann, D, Vennin, C, Cox, TR, Pereira, B, Ritchie, S, Reed, DA, Chambers, CR, Metcalf, X, Nobis, M, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Xu, Q, Hofmann, O, Samra, JS, Pavlakis, N, Arena, J, High, HA, Asghari, R, Merrett, ND, Pavey, D, Das, A, Cosman, PH, Ismail, K, O’Connnor, C, Stoita, A, Williams, D, Spigellman, A, Lam, VW, McLeod, D, Kirk, J, Kench, JG, Grimison, P, Sandroussi, C, Goodwin, A, Mead, RS, Tucker, K, Andrews, L, Texler, M, Forest, C, Ballal, M, Fletcher, DR, Zeps, N, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Chen, J, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Barbour, AP, O’Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Nikfarjam, M, Eshleman, JR, Hruban, RH, Wolfgang, CL, Dixon, J, Scardoni, M, Bassi, C, Grimaldi, S, Cantù, C, Bonizzato, G, Bersani, S, Lakis, V, Lawlor, RT, Newell, F, Patch, AM, Mafficini, A, Sadanandam, A, Koufariotis, LT, Johnston, RL, Leonard, C, Wood, S, Rusev, B, Corbo, V, Luchini, C, Cingarlini, S, Landoni, L, Salvia, R, Milella, M, Chang, D, Bailey, P, Jamieson, NB, Duthie, F, Gingras, MC, Muzny, DM, Wheeler, DA, Gibbs, RA, Milione, M, Chantrill, LA, Timpson, P, Chou, A, Pajic, M, Murphy, A, Dwarte, T, Hermann, D, Vennin, C, Cox, TR, Pereira, B, Ritchie, S, Reed, DA, Chambers, CR, Metcalf, X, Nobis, M, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Xu, Q, Hofmann, O, Samra, JS, Pavlakis, N, Arena, J, High, HA, Asghari, R, Merrett, ND, Pavey, D, Das, A, Cosman, PH, Ismail, K, O’Connnor, C, Stoita, A, Williams, D, Spigellman, A, Lam, VW, McLeod, D, Kirk, J, Kench, JG, Grimison, P, Sandroussi, C, Goodwin, A, Mead, RS, Tucker, K, Andrews, L, Texler, M, Forest, C, Ballal, M, Fletcher, DR, Zeps, N, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Chen, J, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Barbour, AP, O’Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Nikfarjam, M, Eshleman, JR, Hruban, RH, Wolfgang, CL, Dixon, J, Scardoni, M, Bassi, C, Grimaldi, S, Cantù, C, Bonizzato, G, and Bersani, S

Abstract

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.

Published
2021

4. Lost in translation: Returning germline genetic results in genome-scale cancer research

Author

Johns, AL, McKay, SH, Humphris, JL, Pinese, M, Chantrill, LA, Mead, RS, Tucker, K, Andrews, L, Goodwin, A, Leonard, C, High, HA, Nones, K, Waddell, N, Patch, AM, Merrett, ND, Pavlakis, N, Kassahn, KS, Samra, JS, Miller, DK, Chang, DK, Pajic, M, Pearson, JV, Grimmond, SM, Zeps, N, Gill, AJ, Biankin, AV, Chin, VT, Chou, A, Steinmann, A, Arshi, M, Drury, A, Froio, D, Morgan, A, Timpson, P, Hermann, D, Vennin, C, Warren, S, Wu, J, Pinho, AV, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Wood, S, Xu, C, Hofmann, O, Wilson, PJ, Christ, A, Bruxner, T, Samra, S, Arena, J, Mittal, A, Asghari, R, Pavey, D, Das, A, Cosman, PH, Ismail, K, O'Connnor, C, Williams, D, Spigellman, A, Lam, W, McLeod, D, Nagrial, AM, Kirk, J, James, V, Grimison, P, Cooper, CL, Sandroussi, C, Forest, C, Epari, KP, Ballal, M, Fletcher, DR, Mukhedkar, S, Beilin, M, Feeney, K, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Martin, P, Barbour, AP, O'Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Hruban, RH, Wolfgang, CL, Hodgin, M, Lawlor, RT, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Bailey, P, Martin, S, Musgrove, EA, Johns, AL, McKay, SH, Humphris, JL, Pinese, M, Chantrill, LA, Mead, RS, Tucker, K, Andrews, L, Goodwin, A, Leonard, C, High, HA, Nones, K, Waddell, N, Patch, AM, Merrett, ND, Pavlakis, N, Kassahn, KS, Samra, JS, Miller, DK, Chang, DK, Pajic, M, Pearson, JV, Grimmond, SM, Zeps, N, Gill, AJ, Biankin, AV, Chin, VT, Chou, A, Steinmann, A, Arshi, M, Drury, A, Froio, D, Morgan, A, Timpson, P, Hermann, D, Vennin, C, Warren, S, Wu, J, Pinho, AV, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Wood, S, Xu, C, Hofmann, O, Wilson, PJ, Christ, A, Bruxner, T, Samra, S, Arena, J, Mittal, A, Asghari, R, Pavey, D, Das, A, Cosman, PH, Ismail, K, O'Connnor, C, Williams, D, Spigellman, A, Lam, W, McLeod, D, Nagrial, AM, Kirk, J, James, V, Grimison, P, Cooper, CL, Sandroussi, C, Forest, C, Epari, KP, Ballal, M, Fletcher, DR, Mukhedkar, S, Beilin, M, Feeney, K, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Martin, P, Barbour, AP, O'Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Hruban, RH, Wolfgang, CL, Hodgin, M, Lawlor, RT, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Bailey, P, Martin, S, and Musgrove, EA

Abstract

Background: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. Methods: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. Results: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. Conclusion: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning

Published
2017

5. RON is not a prognostic marker for resectable pancreatic cancer

Author

Tactacan, Carole M, Chang, David K, Cowley, Mark J, Humphrey, Emily S, Jianmin, Wu, Gill, Anthony J, Chou, Angela, Nones, Katia, Grimmond, Sean M, Sutherland, Robert L, Biankin, Andrew V, Daly, Roger J, Biankin, Av, Johns, Al, Mawson, A, Chang, Dk, Scarlett, Cj, Brancato, Ma, Rowe, Sj, Simpson, Sl, Martyn-Smith, M, Chantrill, La, Chin, Vt, Chou, A, Cowley, Mj, Caplan, W, Humphris, Jl, Jones, Md, Mead, R, Nagrial, Am, Pajic, M, Pettit, J, Pinese, M, Rooman, I, Wu, Jun, Daly, Rj, Musgrove, Ea, Sutherland, Rl, Grimmond, Sm, Waddell, N, Kassahn, Ks, Miller, Dk, Wilson, Pj, Patch, Am, Song, S, Harliwong, I, Idrisoglu, S, Nourse, C, Nourbakhsh, E, Manning, S, Wani, S, Gongora, M, Anderson, Michela, Holmes, O, Leonard, C, Taylor, D, Wood, JOHN STEPHAN, Xu, C, Nones, K, Fink, Julika, Christ, A, Bruxner, T, Cloonan, N, Newell, F, Pearson, Jv, Samra, Js, Gill, Aj, Nickpavlakis, Guminski, A, Toon, C, Asghari, R, Merrett, Nd, Pavey, Da, Das, A, Cosman, Ph, Ismail, K, O'Connor, C, Lam, Vw, Mcleod, D, Pleass, Hc, James, V, Kench, Jg, Cooper, Cl, Joseph, D, Sandroussi, C, Crawford, M, Texler, M, Forrest, C, Laycock, A, Epari, Kp, Ballal, M, Fletcher, Dr, Mukhedkar, S, Spry, Na, Deboer, B, Chai, M, Feeney, K, Zeps, N, Beilin, M, Nguyen, Nq, Ruszkiewicz, Ar, Worthley, C, Tan, Cp, Debrencini, T, Chen, J, Brooke-Smith, Me, Papangelis, V, Tang, H, Barbour, Ap, Clouston, Ad, Martin, P, O'Rourke, Tj, Chiang, A, Fawcett, Jw, Slater, K, Yeung, S, Hatzifotis, M, Hodgkinson, P, Christophi, C, Nikfarjam, M, Eshleman, Jr, Hruban, Rh, Maitra, A, Iacobuzio-Donahue, Ca, Schulick, Rd, Wolfgang, Cl, Morgan, Ra, Scarpa, A, Lawlor, Rt, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Tempero, Ma., and Basic (bio-) Medical Sciences

Subjects
Oncology, Male, Receptor Protein-Tyrosine Kinases/analysis, Cancer Research, Receptor tyrosine kinase, Kaplan-Meier Estimate, Surgical oncology, 80 and over, Prospective cohort study, Pancreatic Neoplasms/metabolism, Biomarker, Gemcitabine, Chemotherapy, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Blotting, Western, Female, Humans, Immunohistochemistry, Middle Aged, Pancreatic Neoplasms, Prognosis, Proportional Hazards Models, Receptor Protein-Tyrosine Kinases, Tissue Array Analysis, Tumor, Blotting, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Adenocarcinoma/metabolism, CA19-9, Western, Research Article, medicine.drug, medicine.medical_specialty, lcsh:RC254-282, Biomarkers, Tumor/analysis, Breast cancer, Internal medicine, Pancreatic cancer, medicine, Genetics, business.industry, Cancer, medicine.disease, business, aged, 80 and over, Biomarkers
Abstract

Background The receptor tyrosine kinase RON exhibits increased expression during pancreatic cancer progression and promotes migration, invasion and gemcitabine resistance of pancreatic cancer cells in experimental models. However, the prognostic significance of RON expression in pancreatic cancer is unknown. Methods RON expression was characterized in several large cohorts, including a prospective study, totaling 492 pancreatic cancer patients and relationships with patient outcome and clinico-pathologic variables were assessed. Results RON expression was associated with outcome in a training set, but this was not recapitulated in the validation set, nor was there any association with therapeutic responsiveness in the validation set or the prospective study. Conclusions Although RON is implicated in pancreatic cancer progression in experimental models, and may constitute a therapeutic target, RON expression is not associated with prognosis or therapeutic responsiveness in resected pancreatic cancer.

Published
2012

6. Expansion of Liver Transplantation Criteria for Hepatocellular Carcinoma from Milan to UCSF in Australia and New Zealand and Justification for Metroticket 2.0.

Author

Barreto SG, Strasser SI, McCaughan GW, Fink MA, Jones R, McCall J, Munn S, Macdonald GA, Hodgkinson P, Jeffrey GP, Jaques B, Crawford M, Brooke-Smith ME, and Chen JW

Abstract

Background: Expansion in liver transplantation (LT) criteria for HCC from Milan to UCSF has not adversely impacted overall survival, prompting further expansion towards Metroticket 2.0 (MT2). In this study, we compared patient survival post-transplant before and after 2007 and long-term outcomes for LT within Milan versus UCSF criteria (to determine the true benefit of the expansion of criteria) and retrospectively validated the MT2 criteria. Methods: Retrospective analysis of ANZLITR (including all patients transplanted for HCC since July 1997). The entire cohort was divided based on criteria used at the time of listing, namely, Milan era (1997−2006) and the UCSF era (2007−July 2015). Results: The overall 5- and 10-year cumulative survival rates for the entire cohort of 691 patients were 78% and 69%, respectively. Patients transplanted in UCSF era had significantly higher 5- and 10-year survival rates than in the Milan era (80% vs. 73% and 72% vs. 65%, respectively; p = 0.016). In the UCSF era, the 5-year survival rate for patients transplanted within Milan criteria was significantly better than those transplanted outside Milan but within UCSF criteria (83% vs. 73%; p < 0.024). Patients transplanted within the MT2 criteria had a significantly better 5- and 10-year survival rate as compared to those outside the criteria (81% vs. 64% and 73% vs. 50%, respectively; p = 0.001). Conclusion: Overall survival following LT for HCC has significantly improved over time despite expanding criteria from Milan to UCSF. Patients fulfilling the MT2 criteria have a survival comparable to the UCSF cohort. Thus, expansion of criteria to MT2 is justifiable.

Published
2022
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7. Gastrointestinal Adenocarcinoma Incidence and Survival Trends in South Australia, 1990-2017.

Author

Schell D, Ullah S, Brooke-Smith ME, Hollington P, Yeow M, Karapetis CS, Watson DI, Pandol SJ, Roberts CT, and Barreto SG

Abstract

Background & Aims: Globally, there has been a concerning rise in the incidence of young-onset cancers. The aim of this study was to provide trends in the incidence and survival of gastrointestinal adenocarcinomas (oesophagus, stomach, pancreas, and colorectal) in South Australia over a 27-year period., Methods: This is a cross-sectional analysis of a prospective longitudinal database including all cases of gastrointestinal adenocarcinomas prospectively reported to the South Australian (State) Cancer Registry from 1990 to 2017., Results: A total of 28,566 patients diagnosed with oesophageal, stomach, pancreatic, or colorectal adenocarcinoma between 1990 and 2017 were included in the study. While the overall incidence for gastrointestinal adenocarcinomas in individuals >50 years has decreased since 2000 (IRR of 0.97 (95% CI 0.94-1.00; p = 0.06)) compared to 1990-1999, the rate amongst individuals aged 18-50 has significantly increased (IRR 1.41 (95% CI 1.27-1.57; p < 0.001)) during the same reference time period. Although noted in both sexes, the rate of increase in incidence was significantly greater in males (11.5 to 19.7/100,000; p < 0.001). The overall survival from adenocarcinomas across all subsites improved in the >50-year cohort in the last decade (HR 0.89 (95% CI 0.86-0.93; p < 0.001)) compared to 1990-1999. In individuals aged 18-50 years, there has only been a significant improvement in survival for colorectal cancer (HR 0.82 (95% CI 0.68-0.99; p < 0.04)), but not the other subsites. A lower overall survival was noted for males in both age cohorts (18-50 years-HR 1.24 (95% CI 1.09-1.13; p < 0.01) and >50 years-HR 1.13 (95% CI 1.10-1.16; p < 0.001), respectively) compared to females., Conclusions: This study from South Australia demonstrates a significant increase in young-onset gastrointestinal adenocarcinomas over the last 28 years, with a greater increase in the male sex. The only significant improvement in survival in this cohort has been noted in colorectal cancer patients.

Published
2022
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8. Exploring pre-surgery donor-specific antibodies in the context of organ shortage in liver transplant.

Author

Barreto SG, Brooke-Smith ME, Neo EL, Dolan P, Leibbrandt R, Emery T, Carroll R, Wigg A, and Chen JW

Subjects
Cohort Studies, Female, Follow-Up Studies, Graft Rejection prevention & control, Humans, Immunosuppressive Agents therapeutic use, Liver Function Tests, Male, Middle Aged, Retrospective Studies, South Australia, T-Lymphocytes immunology, Antibody Specificity immunology, Graft Rejection immunology, Liver immunology, Liver Transplantation methods, Tissue Donors supply & distribution
Abstract

Background: There is a growing disparity between the number of liver transplant (LT) candidates and availability of suitable liver allografts. Antibody-mediated rejection (AMR), secondary to positive donor-specific antibodies (DSA), remains a concern in liver transplantation. This study aimed to correlate expression of DSA on pre-transplant screening and outcomes of LT, specifically development of AMR in liver allografts and liver function profile in the post-operative period., Methods: Data of consecutive patients undergoing orthotopic LT (OLT) at the South Australian Liver Transplant Unit was analysed. All patients underwent DSA testing pre-transplant., Results: Within a cohort of 96 patients, over a post-OLT median follow-up of 849 days, only 2 patients (2%) developed AMR. While both patients had a positive DSA test preoperatively, overall DSA positivity was noted in 31% patients, with a specificity for prediction of AMR of 0.708. No significant association was noted between AMR (p = 0.092), T cell-mediated rejection/TCMR (p = 0.797) or late hepatic artery thrombosis/LHAT (p = 0.521). There was no significant interaction effect between DSA positivity and serum bilirubin or transaminases over a period of 100 days., Conclusion: AMR following LT is uncommon. A positive DSA pre-transplant does not imply a definite risk of AMR. Also, there does not exist a significant interaction in time between DSA expression and serum bilirubin or transaminase levels. Until there emerges evidence to the contrary, it appears reasonable to consider DSA-positive donors within the broad context of marginal donors in the context of a worldwide shortage of LT donor allografts.

Published
2019
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10. Distribution and pathological features of pancreatic, ampullary, biliary and duodenal cancers resected with pancreaticoduodenectomy.

Author

Chandrasegaram MD, Chiam SC, Chen JW, Khalid A, Mittinty ML, Neo EL, Tan CP, Dolan PM, Brooke-Smith ME, Kanhere H, and Worthley CS

Subjects
Adult, Aged, Aged, 80 and over, Ampulla of Vater surgery, Biliary Tract Neoplasms surgery, Common Bile Duct Neoplasms surgery, Duodenal Neoplasms surgery, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Pancreatic Neoplasms surgery, Prognosis, Retrospective Studies, Ampulla of Vater pathology, Biliary Tract Neoplasms pathology, Common Bile Duct Neoplasms pathology, Duodenal Neoplasms pathology, Pancreatic Neoplasms pathology, Pancreaticoduodenectomy
Abstract

Background: Pancreatic cancer (PC) has the worst survival of all periampullary cancers. This may relate to histopathological differences between pancreatic cancers and other periampullary cancers. Our aim was to examine the distribution and histopathologic features of pancreatic, ampullary, biliary and duodenal cancers resected with a pancreaticoduodenectomy (PD) and to examine local trends of periampullary cancers resected with a PD., Methods: A retrospective review of PD between January 2000 and December 2012 at a public metropolitan database was performed. The institutional ethics committee approved this study., Results: There were 142 PDs during the study period, of which 70 cases were pre-2010 and 72 post-2010, corresponding to a recent increase in the number of cases. Of the 142 cases, 116 were for periampullary cancers. There were also proportionately more PD for PC (26/60, 43% pre-2010 vs 39/56, 70% post-2010, P = 0.005). There were 65/116 (56%) pancreatic, 29/116 (25%), ampullary, 17/116 (15%) biliary and 5/116 (4%) duodenal cancers. Nodal involvement occurred more frequently in PC (78%) compared to ampullary (59%), biliary (47%) and duodenal cancers (20%), P = 0.002. Perineural invasion was also more frequent in PC (74%) compared to ampullary (34%), biliary (59%) and duodenal cancers (20%), P = 0.002. Microvascular invasion was seen in 57% pancreatic, 38% ampullary, 41% biliary and 20% duodenal cancers, P = 0.222. Overall, clear margins (R0) were achieved in fewer PC 41/65 (63%) compared to ampullary 27/29 (93%; P = 0.003) and biliary cancers 16/17 (94%; P = 0.014)., Conclusions: This study highlights that almost half of PD was performed for cancers other than PC, mainly ampullary and biliary cancers. The volume of PD has increased in recent years with an increased proportion being for PC. PC had higher rates of nodal and perineural invasion compared to ampullary, biliary and duodenal cancers.

Published
2015
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11. Anticoagulation policy after venous resection with a pancreatectomy: a systematic review.

Author

Chandrasegaram MD, Eslick GD, Lee W, Brooke-Smith ME, Padbury R, Worthley CS, Chen JW, and Windsor JA

Subjects
Anticoagulants adverse effects, Guideline Adherence, Humans, Postoperative Hemorrhage chemically induced, Practice Guidelines as Topic, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Venous Thrombosis etiology, Venous Thrombosis mortality, Venous Thrombosis prevention & control, Anticoagulants therapeutic use, Blood Vessel Prosthesis Implantation adverse effects, Blood Vessel Prosthesis Implantation mortality, Blood Vessel Prosthesis Implantation standards, Pancreatectomy adverse effects, Pancreatectomy mortality, Pancreatectomy standards, Portal Vein surgery
Abstract

Background: Portal vein (PV) resection is used increasingly in pancreatic resections. There is no agreed policy regarding anticoagulation., Methods: A systematic review was performed to compare studies with an anticoagulation policy (AC+) to no anticoagulation policy (AC-) after venous resection., Results: There were eight AC+ studies (n = 266) and five AC- studies (n = 95). The AC+ studies included aspirin, clopidogrel, heparin or warfarin. Only 50% of patients in the AC+ group received anticoagulation. There were more prosthetic grafts in the AC+ group (30 versus 2, Fisher's exact P < 0.001). The overall morbidity and mortality was similar in both groups. Early PV thrombosis (EPVT) was similar in the AC+ group and the AC- group (7%, versus 3%, Fisher's exact P = 0.270) and was associated with a high mortality (8/20, 40%). When prosthetic grafts were excluded there was no difference in the incidence of EPVT between both groups (1% vs 2%, Fisher's exact test P = 0.621)., Conclusion: There is significant heterogeneity in the use of anticoagulation after PV resection. Overall morbidity, mortality and EPVT in both groups were similar. EPVT has a high associated mortality. While we have been unable to demonstrate a benefit for anticoagulation, the incidence of EPVT is low in the absence of prosthetic grafts., (© 2013 International Hepato-Pancreato-Biliary Association.)

Published
2014
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12. A case of pancreatic cancer in the setting of autoimmune pancreatitis with nondiagnostic serum markers.

Author

Chandrasegaram MD, Chiam SC, Nguyen NQ, Ruszkiewicz A, Chung A, Neo EL, Chen JW, Worthley CS, and Brooke-Smith ME

Abstract

Background. Autoimmune pancreatitis (AIP) often mimics pancreatic cancer. The diagnosis of both conditions is difficult preoperatively let alone when they coexist. Several reports have been published describing pancreatic cancer in the setting of AIP. Case Report. The case of a 53-year-old man who presented with abdominal pain, jaundice, and radiological features of autoimmune pancreatitis, with a "sausage-shaped" pancreas and bulky pancreatic head with portal vein impingement, is presented. He had a normal serum IgG4 and only mildly elevated Ca-19.9. Initial endoscopic ultrasound-(EUS-) guided fine-needle aspiration (FNA) of the pancreas revealed an inflammatory sclerosing process only. A repeat EUS guided biopsy following biliary decompression demonstrated both malignancy and features of autoimmune pancreatitis. At laparotomy, a uniformly hard, bulky pancreas was found with no sonographically definable mass. A total pancreatectomy with portal vein resection and reconstruction was performed. Histology revealed adenosquamous carcinoma of the pancreatic head and autoimmune pancreatitis and squamous metaplasia in the remaining pancreas. Conclusion. This case highlights the diagnostic and management difficulties in a patient with pancreatic cancer in the setting of serum IgG4-negative, Type 2 AIP.

Published
2013
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14. Galanin in the regulation of pancreatic vascular perfusion.

Author

Brooke-Smith ME, Carati CJ, Bhandari M, Toouli J, and Saccone GT

Subjects
Animals, Blood Pressure drug effects, Female, Galanin analogs & derivatives, Galanin pharmacology, Immunohistochemistry, Male, Microcirculation drug effects, Microcirculation physiology, Pancreas drug effects, Pancreas physiology, Receptors, Galanin antagonists & inhibitors, Receptors, Galanin physiology, Regional Blood Flow drug effects, Substance P analogs & derivatives, Substance P pharmacology, Trichosurus, Galanin physiology, Pancreas blood supply
Abstract

Objectives: Acute pancreatitis is associated with compromised pancreatic microcirculation. Galanin is a vasoactive neuropeptide, but its role in the regulation of pancreatic vascular perfusion (PVP) is unclear., Methods: Localization of galanin immunoreactivity was investigated by immunohistochemistry, and the effects of bolus doses of galanin or the antagonist galantide on blood pressure (BP) and PVP (by laser Doppler fluxmetry) were determined in anesthetized possums., Results: Galanin immunoreactivity was abundant in the possum pancreas particularly around blood vessels. Galanin (0.001-10 nmol) produced a dose-dependent increase in BP (to 177% of baseline) and a complex PVP response consisting of a transient increase, then a fall below baseline with recovery to above baseline. Galantide (0.003-30 nmol) caused a dose-dependent biphasic response in BP, with a reduction, recovery, then a further fall, followed by recovery, whereas PVP increased (178%) then fell (to 56%) of baseline. Similar effects were produced by continuous intravenous infusion of galanin (1 and 10 nmol) or galantide (3 and 30 nmol). The second-phase response of these agents is probably a passive response of the pancreatic vasculature to systemic cardiovascular effects., Conclusions: These data suggest that galanin acutely reduces PVP, whereas galantide increases it, implying galanin may be important in the regulation of PVP.

Published
2008
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15. Highly selective inhibition of inducible nitric oxide synthase ameliorates experimental acute pancreatitis.

Author

Sandstrom P, Brooke-Smith ME, Thomas AC, Grivell MB, Saccone GT, Toouli J, and Svanvik J

Subjects
Acute Disease, Amino Acids blood, Amylases blood, Animals, Central Venous Pressure, Disease Models, Animal, Female, Hematocrit, Lipase blood, Lysine analogs & derivatives, Lysine pharmacology, Male, Nitric Oxide Synthase Type II metabolism, Pancreatitis pathology, Trichosurus, Water-Electrolyte Balance, Enzyme Inhibitors pharmacology, Nitric Oxide Synthase Type II antagonists & inhibitors, Pancreatitis drug therapy, Pancreatitis metabolism, Quinazolines pharmacology
Abstract

Objectives: Inducible nitric oxide synthase (iNOS) activity is increased in experimental acute pancreatitis. The aim of this study was to evaluate treatment with the selective iNOS inhibitors AR-C (AR-C102222AA) and L-NIL (L-N6-(1-iminoethyl)-lysine) in experimental acute pancreatitis., Methods: Acute pancreatitis was induced in anesthetized Australian possums by topical administration of carbachol on the sphincter of Oddi. AR-C treatment was 2 intravenous infusions (2.5 micromol/kg over 15 minutes) at 2 and 4 hours after acute pancreatitis induction. L-NIL treatment was an intraarterial infusion (1 mg/kg/h) from 2 hours after acute pancreatitis induction. At 8 hours, pancreatic tissue was harvested and inflammation assessed (histologic score). Blood samples were collected for plasma amylase, lipase, and amino acid levels. Blood pressure, central venous pressure, supplementary fluids, and urine output were monitored., Results: Treatment with AR-C or L-NIL reduced the plasma levels of amylase and the volume of supplementary fluids and improved the histological score (all P < 0.05). In animals with acute pancreatitis, plasma arginine levels were reduced (P < 0.05), while citrulline and ornithine levels increased (P < 0.05), consistent with increased nitric oxide production. Treatment with AR-C ameliorated the reduced arginine level., Conclusions: Treatment with AR-C or L-NIL, commencing 2 hours after the induction of acute pancreatitis, has significant and beneficial effects in experimental acute pancreatitis in Australian possums.

Published
2005

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