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  • ItemOpen AccessPublished version Peer-reviewed
    Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal.
    (Elsevier BV, 2018-04-19) Turajlic, Samra; Xu, Hang; Litchfield, Kevin; Rowan, Andrew; Chambers, Tim; Lopez, Jose I; Nicol, David; O'Brien, Tim; Larkin, James; Horswell, Stuart; Stares, Mark; Au, Lewis; Jamal-Hanjani, Mariam; Challacombe, Ben; Chandra, Ashish; Hazell, Steve; Eichler-Jonsson, Claudia; Soultati, Aspasia; Chowdhury, Simon; Rudman, Sarah; Lynch, Joanna; Fernando, Archana; Stamp, Gordon; Nye, Emma; Jabbar, Faiz; Spain, Lavinia; Lall, Sharanpreet; Guarch, Rosa; Falzon, Mary; Proctor, Ian; Pickering, Lisa; Gore, Martin; Watkins, Thomas BK; Ward, Sophia; Stewart, Aengus; DiNatale, Renzo; Becerra, Maria F; Reznik, Ed; Hsieh, James J; Richmond, Todd A; Mayhew, George F; Hill, Samantha M; McNally, Catherine D; Jones, Carol; Rosenbaum, Heidi; Stanislaw, Stacey; Burgess, Daniel L; Alexander, Nelson R; Swanton, Charles; PEACE; TRACERx Renal Consortium; Turajlic, Samra [0000-0001-8846-136X]; Litchfield, Kevin [0000-0002-3725-0914]; Lopez, Jose I [0000-0003-0842-5348]; Horswell, Stuart [0000-0003-2787-1933]; Spain, Lavinia [0000-0002-9356-8812]; Stewart, Aengus [0000-0001-5182-653X]; DiNatale, Renzo [0000-0002-7867-2881]; Mayhew, George F [0000-0003-0609-6018]; Swanton, Charles [0000-0002-4299-3018]
    Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.
  • ItemOpen AccessPublished version Peer-reviewed
    Urine proteomics in the diagnosis of stable angina.
    (Springer Science and Business Media LLC, 2016-04-19) Neisius, Ulf; Koeck, Thomas; Mischak, Harald; Rossi, Sabrina H; Olson, Erin; Carty, David M; Dymott, Jane A; Dominiczak, Anna F; Berry, Colin; Oldroyd, Keith G; Delles, Christian; Rossi, Sabrina [0000-0001-7048-7158]
    BACKGROUND: We have previously described a panel of 238 urinary polypeptides specific for established severe coronary artery disease (CAD). Here we studied this polypeptide panel in patients with a wider range of CAD severity. METHODS: We recruited 60 patients who underwent elective coronary angiography for investigation of stable angina. Patients were selected for either having angiographic evidence of CAD or not (NCA) following coronary angiography (n = 30/30; age, 55 ± 6 vs. 56 ± 7 years, P = 0.539) to cover the extremes of the CAD spectrum. A further 66 patients with severe CAD (age, 64 ± 9 years) prior to surgical coronary revascularization were added for correlation studies. The Gensini score was calculated from coronary angiograms as a measure of CAD severity. Urinary proteomic analyses were performed using capillary electrophoresis coupled online to micro time-of-flight mass spectrometry. The urinary polypeptide pattern was classified using a predefined algorithm and resulting in the CAD238 score, which expresses the pattern quantitatively. RESULTS: In the whole cohort of patients with CAD (Gensini score 60 [40; 98]) we found a close correlation between Gensini scores and CAD238 (ρ = 0.465, P < 0.001). After adjustment for age (β = 0.144; P = 0.135) the CAD238 score remained a significant predictor of the Gensini score (β =0.418; P < 0.001). In those with less severe CAD (Gensini score 40 [25; 61]), however, we could not detect a difference in CAD238 compared to patients with NCA (-0.487 ± 0.341 vs. -0.612 ± 0.269, P = 0.119). CONCLUSIONS: In conclusion the urinary polypeptide CAD238 score is associated with CAD burden and has potential as a new cardiovascular biomarker.
  • ItemOpen AccessPublished version Peer-reviewed
    Impaired renal function impacts negatively on vascular stiffness in patients with coronary artery disease.
    (Springer Science and Business Media LLC, 2013-08-13) Rossi, Sabrina H; McQuarrie, Emily P; Miller, William H; Mackenzie, Ruth M; Dymott, Jane A; Moreno, María U; Taurino, Chiara; Miller, Ashley M; Neisius, Ulf; Berg, Geoffrey A; Valuckiene, Zivile; Hannay, Jonathan A; Dominiczak, Anna F; Delles, Christian; Rossi, Sabrina [0000-0001-7048-7158]
    BACKGROUND: Chronic kidney disease (CKD) and coronary artery disease (CAD) are independently associated with increased vascular stiffness. We examined whether renal function contributes to vascular stiffness independently of CAD status. METHODS: We studied 160 patients with CAD and 169 subjects without CAD. The 4-variable MDRD formula was used to estimate glomerular filtration rate (eGFR); impaired renal function was defined as eGFR <60 mL/min. Carotid-femoral pulse wave velocity (PWV) was measured with the SphygmoCor® device. Circulating biomarkers were assessed in plasma using xMAP® multiplexing technology. RESULTS: Patients with CAD and impaired renal function had greater PWV compared to those with CAD and normal renal function (10.2 [9.1;11.2] vs 7.3 [6.9;7.7] m/s; P < 0.001). In all patients, PWV was a function of eGFR (β = -0.293; P < 0.001) even after adjustment for age, sex, systolic blood pressure, body mass index and presence or absence of CAD. Patients with CAD and impaired renal function had higher levels of adhesion and inflammatory molecules including E-selectin and osteopontin (all P < 0.05) compared to those with CAD alone, but had similar levels of markers of oxidative stress. CONCLUSIONS: Renal function is a determinant of vascular stiffness even in patients with severe atherosclerotic disease. This was paralleled by differences in markers of cell adhesion and inflammation. Increased vascular stiffness may therefore be linked to inflammatory remodeling of the vasculature in people with impaired renal function, irrespective of concomitant atherosclerotic disease.
  • ItemOpen AccessAccepted version Peer-reviewed
    Prognostic factors and prognostic models for renal cell carcinoma: a literature review.
    (Springer Science and Business Media LLC, 2018-12) Klatte, Tobias; Rossi, Sabrina H; Stewart, Grant D; Klatte, Tobias [0000-0002-4392-6861]; Rossi, Sabrina H [0000-0001-7048-7158]; Stewart, Grant D [0000-0003-3188-9140]
    PURPOSE: Following curative treatment for localised renal cell carcinoma (RCC), up to 30% of patients develop tumour recurrence. Prognostic scores are essential to guide individualised surveillance protocols, patient counselling and potentially in the future to guide adjuvant therapy. In metastatic RCC, prognostic scores are routinely used for treatment selection in clinical practice as well as in all major trials. METHODS: We performed a literature review on the current evidence based on prognostic factors and models for localised and metastatic RCC. RESULTS: A number of prognostic factors have been identified, of which tumour node metastasis classification remains the most important. Multiple prognostic models and nomograms have been developed for localised disease, based on a combination of tumour stage, grade, subtype, clinical features, and performance status. However, there is poor level of evidence for their routine use. Prognostic scores for patients with metastatic RCC receiving targeted treatments are used routinely, but have limited accuracy. Molecular markers can improve the accuracy of established prognostic models, but frequently lack external, independent validation. CONCLUSION: Several factors and models predict prognosis of localised and metastatic RCC. They represent valuable tools to provide estimates of clinically important endpoints, but their accuracy should be improved further. Validation of molecular markers is a future research priority.
  • ItemOpen AccessAccepted version Peer-reviewed
    NF-κB-Dependent Lymphoid Enhancer Co-option Promotes Renal Carcinoma Metastasis.
    (American Association for Cancer Research (AACR), 2018-07) Rodrigues, Paulo; Patel, Saroor A; Harewood, Louise; Olan, Ioana; Vojtasova, Erika; Syafruddin, Saiful E; Zaini, M Nazhif; Richardson, Emma K; Burge, Johanna; Warren, Anne Y; Stewart, Grant D; Saeb-Parsy, Kourosh; Samarajiwa, Shamith A; Vanharanta, Sakari; Olan, Ioana [0000-0003-0692-1831]; Samarajiwa, Shamith A [0000-0003-1046-0601]
    Metastases, the spread of cancer cells to distant organs, cause the majority of cancer-related deaths. Few metastasis-specific driver mutations have been identified, suggesting aberrant gene regulation as a source of metastatic traits. However, how metastatic gene expression programs arise is poorly understood. Here, using human-derived metastasis models of renal cancer, we identify transcriptional enhancers that promote metastatic carcinoma progression. Specific enhancers and enhancer clusters are activated in metastatic cancer cell populations, and the associated gene expression patterns are predictive of poor patient outcome in clinical samples. We find that the renal cancer metastasis-associated enhancer complement consists of multiple coactivated tissue-specific enhancer modules. Specifically, we identify and functionally characterize a coregulatory enhancer cluster, activated by the renal cancer driver HIF2A and an NF-κB-driven lymphoid element, as a mediator of metastasis in vivo We conclude that oncogenic pathways can acquire metastatic phenotypes through cross-lineage co-option of physiologic epigenetic enhancer states.Significance: Renal cancer is associated with significant mortality due to metastasis. We show that in metastatic renal cancer, functionally important metastasis genes are activated via co-option of gene regulatory enhancer modules from distant developmental lineages, thus providing clues to the origins of metastatic cancer. Cancer Discov; 8(7); 850-65. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.
  • ItemOpen AccessPublished version Peer-reviewed
    Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal
    (Elsevier, 2018-04) Mitchell, TJ; Stewart, grant; Mitchell, Thomas [0000-0003-0761-9503]; Stewart, Grant [0000-0003-3188-9140]
    Clear cell renal cell carcinoma is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cancer. We find hotspots of point mutations in the 5’-UTR of TERT, targeting a MYC-MAX-MAD1 repressor, that result in telomere lengthening. The commonest structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This occurs in childhood or adolescence, is generally the initiating event, and precedes emergence of the tumor’s most recent common ancestor by years to decades. Similar genomic changes drive inherited kidney cancers. Modelling differences in age-incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Targeting essential genes in deleted regions of chromosome 3p could represent a potential preventative strategy for renal cancer.
  • ItemOpen AccessPublished version Peer-reviewed
    Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.
    (Elsevier BV, 2018-04-19) Turajlic, Samra; Xu, Hang; Litchfield, Kevin; Rowan, Andrew; Horswell, Stuart; Chambers, Tim; O'Brien, Tim; Lopez, Jose I; Watkins, Thomas BK; Nicol, David; Stares, Mark; Challacombe, Ben; Hazell, Steve; Chandra, Ashish; Mitchell, Thomas J; Au, Lewis; Eichler-Jonsson, Claudia; Jabbar, Faiz; Soultati, Aspasia; Chowdhury, Simon; Rudman, Sarah; Lynch, Joanna; Fernando, Archana; Stamp, Gordon; Nye, Emma; Stewart, Aengus; Xing, Wei; Smith, Jonathan C; Escudero, Mickael; Huffman, Adam; Matthews, Nik; Elgar, Greg; Phillimore, Ben; Costa, Marta; Begum, Sharmin; Ward, Sophia; Salm, Max; Boeing, Stefan; Fisher, Rosalie; Spain, Lavinia; Navas, Carolina; Grönroos, Eva; Hobor, Sebastijan; Sharma, Sarkhara; Aurangzeb, Ismaeel; Lall, Sharanpreet; Polson, Alexander; Varia, Mary; Horsfield, Catherine; Fotiadis, Nicos; Pickering, Lisa; Schwarz, Roland F; Silva, Bruno; Herrero, Javier; Luscombe, Nick M; Jamal-Hanjani, Mariam; Rosenthal, Rachel; Birkbak, Nicolai J; Wilson, Gareth A; Pipek, Orsolya; Ribli, Dezso; Krzystanek, Marcin; Csabai, Istvan; Szallasi, Zoltan; Gore, Martin; McGranahan, Nicholas; Van Loo, Peter; Campbell, Peter; Larkin, James; Swanton, Charles; TRACERx Renal Consortium; Mitchell, Thomas [0000-0003-0761-9503]
    The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.
  • ItemOpen AccessPublished version Peer-reviewed
    Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.
    (Elsevier BV, 2018-04-19) Mitchell, Thomas J; Turajlic, Samra; Rowan, Andrew; Nicol, David; Farmery, James HR; O'Brien, Tim; Martincorena, Inigo; Tarpey, Patrick; Angelopoulos, Nicos; Yates, Lucy R; Butler, Adam P; Raine, Keiran; Stewart, Grant D; Challacombe, Ben; Fernando, Archana; Lopez, Jose I; Hazell, Steve; Chandra, Ashish; Chowdhury, Simon; Rudman, Sarah; Soultati, Aspasia; Stamp, Gordon; Fotiadis, Nicos; Pickering, Lisa; Au, Lewis; Spain, Lavinia; Lynch, Joanna; Stares, Mark; Teague, Jon; Maura, Francesco; Wedge, David C; Horswell, Stuart; Chambers, Tim; Litchfield, Kevin; Xu, Hang; Stewart, Aengus; Elaidi, Reza; Oudard, Stéphane; McGranahan, Nicholas; Csabai, Istvan; Gore, Martin; Futreal, P Andrew; Larkin, James; Lynch, Andy G; Szallasi, Zoltan; Swanton, Charles; Campbell, Peter J; TRACERx Renal Consortium; Mitchell, Thomas [0000-0003-0761-9503]; Stewart, Grant [0000-0003-3188-9140]; Lynch, Andy [0000-0002-7876-7338]
    Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.
  • ItemOpen AccessPublished version Peer-reviewed
    Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.
    (Elsevier BV, 2018-04-09) Arce Vargas, Frederick; Furness, Andrew JS; Litchfield, Kevin; Joshi, Kroopa; Rosenthal, Rachel; Ghorani, Ehsan; Solomon, Isabelle; Lesko, Marta H; Ruef, Nora; Roddie, Claire; Henry, Jake Y; Spain, Lavinia; Ben Aissa, Assma; Georgiou, Andrew; Wong, Yien Ning Sophia; Smith, Myles; Strauss, Dirk; Hayes, Andrew; Nicol, David; O'Brien, Tim; Mårtensson, Linda; Ljungars, Anne; Teige, Ingrid; Frendéus, Björn; TRACERx Melanoma; TRACERx Renal; TRACERx Lung consortia; Pule, Martin; Marafioti, Teresa; Gore, Martin; Larkin, James; Turajlic, Samra; Swanton, Charles; Peggs, Karl S; Quezada, Sergio A; Litchfield, Kevin [0000-0002-3725-0914]; Ruef, Nora [0000-0001-5211-3363]; Spain, Lavinia [0000-0002-9356-8812]; Hayes, Andrew [0000-0002-9832-4219]; Ljungars, Anne [0000-0002-2158-0601]; Pule, Martin [0000-0002-8347-9867]; Turajlic, Samra [0000-0001-8846-136X]; Swanton, Charles [0000-0002-4299-3018]; Quezada, Sergio A [0000-0002-9763-1700]
    With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.
  • ItemOpen AccessAccepted version Peer-reviewed
    Hypothermic Machine Preservation Benefits Deceased Donor Kidneys With Short Cold Ischemic Times.
    (Ovid Technologies (Wolters Kluwer Health), 2018-08) Hosgood, Sarah A; Hosgood, Sarah [0000-0002-8039-143X]
  • ItemOpen AccessAccepted version Peer-reviewed
    Redefining futility in DCD liver transplantation in the era of novel perfusion technologies.
    (Elsevier BV, 2018-06) Oniscu, Gabriel C; Watson, Christopher JE; Wigmore, Stephen J; Watson, Christopher [0000-0002-0590-4901]
  • ItemOpen AccessPublished version Peer-reviewed
    Time trends in service provision and survival outcomes for patients with renal cancer treated by nephrectomy in England 2000-2010.
    (Wiley, 2018-10) Hsu, Ray CJ; Barclay, Matthew; Loughran, Molly A; Lyratzopoulos, Georgios; Gnanapragasam, Vincent J; Armitage, James N; Hsu, Ray CJ [0000-0002-0959-1666]
    OBJECTIVE: To describe the temporal trends in nephrectomy practice and outcomes for English patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Adult RCC nephrectomy patients treated between 2000 and 2010 were identified in the National Cancer Data Repository and Hospital Episode Statistics, and followed-up until date of death or 31 December 2015 (n = 30 763). We estimated the annual frequency for each nephrectomy type, the hospital and surgeon numbers and their case volumes. We analysed short-term surgical outcomes, as well as 1- and 5-year relative survivals. RESULTS: Annual RCC nephrectomy number increased by 66% during the study period. Hospital number decreased by 24%, whilst the median annual hospital volume increased from 10 to 23 (P < 0.01). Surgeon number increased by 27% (P < 0.01), doubling the median consultant number per hospital. The proportion of minimally invasive surgery (MIS) nephrectomies rose from 1% to 46%, whilst the proportion of nephron-sparing surgeries (NSS) increased from 5% to 16%, with 29% of all T1 disease treated with partial nephrectomy in 2010 (P < 0.01). The 30-day mortality rate halved from 2.4% to 1.1% and 90-day mortality decreased from 4.9% to 2.6% (P < 0.01). The 1-year relative survival rate increased from 86.9% to 93.4%, whilst the 5-year relative survival rate rose from 68.2% to 81.2% (P < 0.01). Improvements were most notable in patients aged ≥65 years and those with T3 and T4 disease. CONCLUSIONS: Surgical RCC management has changed considerably with nephrectomy centralisation and increased NSS and MIS. In parallel, we observed significant improvements in short- and long-term survival particularly for elderly patients and those with locally advanced disease.
  • ItemOpen AccessPublished version Peer-reviewed
    Epidemiology and screening for renal cancer.
    (Springer Science and Business Media LLC, 2018-09) Rossi, Sabrina H; Klatte, Tobias; Usher-Smith, Juliet; Stewart, Grant D; Rossi, Sabrina H [0000-0001-7048-7158]; Klatte, Tobias [0000-0002-4392-6861]; Usher-Smith, Juliet [0000-0002-8501-2531]; Stewart, Grant D [0000-0003-3188-9140]
    PURPOSE: The widespread use of abdominal imaging has affected the epidemiology of renal cell carcinoma (RCC). Despite this, over 25% of individuals with RCC have evidence of metastases at presentation. Screening for RCC has the potential to downstage the disease. METHODS: We performed a literature review on the epidemiology of RCC and evidence base regarding screening. Furthermore, contemporary RCC epidemiology data was obtained for the United Kingdom and trends in age-standardised rates of incidence and mortality were analysed by annual percentage change statistics and joinpoint regression. RESULTS: The incidence of RCC in the UK increased by 3.1% annually from 1993 through 2014. Urinary dipstick is an inadequate screening tool due to low sensitivity and specificity. It is unlikely that CT would be recommended for population screening due to cost, radiation dose and increased potential for other incidental findings. Screening ultrasound has a sensitivity and specificity of 82-83% and 98-99%, respectively; however, accuracy is dependent on tumour size. No clinically validated urinary nor serum biomarkers have been identified. Major barriers to population screening include the relatively low prevalence of the disease, the potential for false positives and over-diagnosis of slow-growing RCCs. Individual patient risk-stratification based on a combination of risk factors may improve screening efficiency and minimise harms by identifying a group at high risk of RCC. CONCLUSION: The incidence of RCC is increasing. The optimal screening modality and target population remain to be elucidated. An analysis of the benefits and harms of screening for patients and society is warranted.
  • ItemOpen AccessAccepted version Peer-reviewed
    A randomized trial of normothermic preservation in liver transplantation.
    (Springer Science and Business Media LLC, 2018-05) Nasralla, David; Coussios, Constantin C; Mergental, Hynek; Akhtar, M Zeeshan; Butler, Andrew J; Ceresa, Carlo DL; Chiocchia, Virginia; Dutton, Susan J; García-Valdecasas, Juan Carlos; Heaton, Nigel; Imber, Charles; Jassem, Wayel; Jochmans, Ina; Karani, John; Knight, Simon R; Kocabayoglu, Peri; Malagò, Massimo; Mirza, Darius; Morris, Peter J; Pallan, Arvind; Paul, Andreas; Pavel, Mihai; Perera, M Thamara PR; Pirenne, Jacques; Ravikumar, Reena; Russell, Leslie; Upponi, Sara; Watson, Chris JE; Weissenbacher, Annemarie; Ploeg, Rutger J; Friend, Peter J; Consortium for Organ Preservation in Europe; Watson, Christopher [0000-0002-0590-4901]
    Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.
  • ItemOpen AccessPublished version Peer-reviewed
    Correction to: The effect of cationically-modified phosphorylcholine polymers on human osteoblasts in vitro and their effect on bone formation in vivo.
    (Springer Science and Business Media LLC, 2018-02-22) Lawton, Jonathan M; Habib, Mariam; Ma, Bingkui; Brooks, Roger A; Best, Serena M; Lewis, Andrew L; Rushton, Neil; Bonfield, William; Best, Serena [0000-0001-7866-8607]
    The article "The effect of cationically modified phosphorylcholine polymers on human osteoblasts in vitro and their effect on bone formation in vivo", written by Jonathan M. Lawton, Mariam Habib, Bingkui Ma, Roger A. Brooks, Serena M. Best, Andrew L. Lewis, Neil Rushton and William Bonfield, was originally published Online First without open access. After publication in volume 28, issue 9, page 144 it was noticed that the copyright was wrong in the PDF version of the article. The copyright of the article should read as "
  • ItemOpen AccessAccepted version Peer-reviewed
    TRACERx Renal: Deterministic evolutionary trajectories govern primary tumour growth
    (Elsevier) Mitchell, TJ; Mitchell, Thomas [0000-0003-0761-9503]
    The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analysed 1206 primary tumour regions from 101 patients recruited into the multi-centre prospective study, TRACERx Renal. We observe up to 30 driver events per tumour, and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumours characterised by early fixation of multiple mutational and copy number drivers, with disseminated metastases; to highly branched tumours with >10 subclonal drivers and extensive parallel evolution, presenting with solitary metastases. We identify genetic diversity and chromosomal instability complexity as determinants of patient outcome. Our insights reconcile the variable clinical behaviour of ccRCC, and suggest evolutionary potential as a biomarker for both intervention and surveillance.
  • ItemOpen AccessPublished version Peer-reviewed
    DNA methylation defines regional identity of human intestinal epithelial organoids and undergoes dynamic changes during development.
    (BMJ, 2019-01) Kraiczy, Judith; Nayak, Komal M; Howell, Kate J; Ross, Alexander; Forbester, Jessica; Salvestrini, Camilla; Mustata, Roxana; Perkins, Sally; Andersson-Rolf, Amanda; Leenen, Esther; Liebert, Anke; Vallier, Ludovic; Rosenstiel, Philip C; Stegle, Oliver; Dougan, Gordon; Heuschkel, Robert; Koo, Bon-Kyoung; Zilbauer, Matthias; Kraiczy, Judith [0000-0001-9073-6318]
    OBJECTIVE: Human intestinal epithelial organoids (IEOs) are increasingly being recognised as a highly promising translational research tool. However, our understanding of their epigenetic molecular characteristics and behaviour in culture remains limited. DESIGN: We performed genome-wide DNA methylation and transcriptomic profiling of human IEOs derived from paediatric/adult and fetal small and large bowel as well as matching purified human gut epithelium. Furthermore, organoids were subjected to in vitro differentiation and genome editing using CRISPR/Cas9 technology. RESULTS: We discovered stable epigenetic signatures which define regional differences in gut epithelial function, including induction of segment-specific genes during cellular differentiation. Established DNA methylation profiles were independent of cellular environment since organoids retained their regional DNA methylation over prolonged culture periods. In contrast to paediatric and adult organoids, fetal gut-derived organoids showed distinct dynamic changes of DNA methylation and gene expression in culture, indicative of an in vitro maturation. By applying CRISPR/Cas9 genome editing to fetal organoids, we demonstrate that this process is partly regulated by TET1, an enzyme involved in the DNA demethylation process. Lastly, generating IEOs from a child diagnosed with gastric heterotopia revealed persistent and distinct disease-associated DNA methylation differences, highlighting the use of organoids as disease-specific research models. CONCLUSIONS: Our study demonstrates striking similarities of epigenetic signatures in mucosa-derived IEOs with matching primary epithelium. Moreover, these results suggest that intestinal stem cell-intrinsic DNA methylation patterns establish and maintain regional gut specification and are involved in early epithelial development and disease.
  • ItemOpen AccessAccepted version Peer-reviewed
    Long-term Outcomes of Follow-up for Initially Localised Clear Cell Renal Cell Carcinoma: RECUR Database Analysis.
    (Elsevier BV, 2019-09) Dabestani, Saeed; Beisland, Christian; Stewart, Grant D; Bensalah, Karim; Gudmundsson, Eirikur; Lam, Thomas B; Gietzmann, William; Zakikhani, Paimaun; Marconi, Lorenzo; Fernandéz-Pello, Sergio; Monagas, Serenella; Williams, Samuel P; Torbrand, Christian; Powles, Thomas; Van Werkhoven, Erik; Meijer, Richard; Volpe, Alessandro; Staehler, Michael; Ljungberg, Börje; Bex, Axel; Stewart, Grant [0000-0003-3188-9140]
    BACKGROUND: Optimal follow-up (FU) strategy to detect potentially curable (PC) recurrences after treatment of localised clear cell renal cell carcinoma (ccRCC) is unclear. This study retrospectively analysed a large international database to determine recurrence patterns and overall survival (OS), as part of a wider project to issue recommendations on FU protocols. OBJECTIVE: To analyse associations between RCC recurrences in patients with ccRCC, their risk group stratifications, treatments, and subsequent outcomes. DESIGN, SETTING, AND PARTICIPANTS: Nonmetastatic ccRCC patients treated with curative intent between 1 January 2006 and 31 December 2011, with at least 4 yr of FU, were included. Patient, tumour and recurrence characteristics, Leibovich score, and management and survival data were recorded. Isolated local, solitary, and oligometastatic (three or fewer lesions at a single site) recurrences were considered PC, while all others were probably incurable (PI). INTERVENTION: Primarily curative surgical treatment of ccRCC while at recurrence detection metastasectomy, systemic therapy, best supportive care, or observation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incidence, time to recurrence (TTR), and OS were measured. Competing risk analysis, Kaplan-Meier, and Cox regression models were used. RESULTS AND LIMITATION: Of 1265 patients with ccRCC, 286 had a recurrence, with 131 being PC and 155 PI. Five-year cumulative risks of recurrence for low- (n=53), intermediate- (n=105), and high-risk (n=128) patients were, respectively, 7.2%, 23.2%, and 61.6%, of whom 52.8%, 37.1%, and 30.5% were PC, respectively. Median TTR was 25.0 for PC patients versus 17.3 mo for PI patients (p=0.004). Median OS was longer in PC compared with that in PI patients (p<0.001). Competing risk analysis showed highest risk of ccRCC-related death in younger and high-risk patients. Limitations were no data on comorbidities, retrospective cohort, and insufficient data excluding 12% of cohort. CONCLUSIONS: Low-risk group recurrences are rare and develop later. Treatment of recurrences with curative intent is disappointing, especially in high-risk patients. An age- and risk score-dependent FU approach is suggested. PATIENT SUMMARY: We analysed data from eight European countries, and found that the incidence of the kidney cancer recurrence and patient survival correlated with clinical factors known to predict cancer recurrence reliably and age. We conclude that these factors should be used to design follow-up strategies.
  • ItemOpen AccessAccepted version Peer-reviewed
    Pancreas-sparing, ampulla-preserving duodenectomy for major duodenal (D1-D2) perforations.
    (Oxford University Press (OUP), 2018-10) Di Saverio, S; Segalini, E; Birindelli, A; Todero, S; Podda, M; Rizzuto, A; Tugnoli, G; Biondi, A; Birindelli, A [0000-0003-0514-9157]
    BACKGROUND: Ideal surgical treatment for acute duodenal injuries should offer a definitive treatment, with low morbidity and mortality. It should be simple and easily reproducible by acute care surgeons in an emergency. Duodenal injury, due to major perforated or bleeding peptic ulcers or iatrogenic/traumatic perforation, represents a surgical challenge, with high morbidity and mortality. The aim was to review definitive surgery with pancreas-sparing, ampulla-preserving duodenectomy for these patients. METHODS: Pancreas-sparing, ampulla-preserving D1-D2 duodenectomy was used for patients presenting with major duodenal injuries over a 5-year interval. The ampulla was identified and preserved using a transcystic/transpapillary tube. The outcomes were recorded. RESULTS: Ten patients were treated with this technique; seven had perforated or bleeding peptic ulcers, two had iatrogenic perforations and one blunt abdominal trauma. Their mean age was 78 (range 65-84) years. Four patients were haemodynamically unstable. The location of the duodenal injury was always D1 and/or D2, above or in close proximity to the ampulla of Vater. The surgical approach was open in nine patients and laparoscopic in one. The mean duration of surgery was 264 (range 170-377) min. All patients were transferred to the ICU after surgery (mean ICU stay 4·4 (range 1-11) days), and the overall mean hospital stay was 17·8 (range 10-32) days. Six patients developed major postoperative complications: cardiorespiratory failure in five and gastrointestinal complications in four. Surgical reoperation was needed in one patient for postoperative necrotizing and bleeding pancreatitis. Two patients died from their complications. CONCLUSION: Pancreas-sparing, ampulla-preserving D1-D2 duodenectomy for emergency treatment of major duodenal perforations is feasible and associated with satisfactory outcomes.
  • ItemOpen AccessPublished version Peer-reviewed
    Laser Capture and Deep Sequencing Reveals the Transcriptomic Programmes Regulating the Onset of Pancreas and Liver Differentiation in Human Embryos.
    (Elsevier BV, 2017-11-14) Jennings, Rachel E; Berry, Andrew A; Gerrard, David T; Wearne, Stephen J; Strutt, James; Withey, Sarah; Chhatriwala, Mariya; Piper Hanley, Karen; Vallier, Ludovic; Bobola, Nicoletta; Hanley, Neil A; Vallier, Ludovic [0000-0002-3848-2602]
    To interrogate the alternative fates of pancreas and liver in the earliest stages of human organogenesis, we developed laser capture, RNA amplification, and computational analysis of deep sequencing. Pancreas-enriched gene expression was less conserved between human and mouse than for liver. The dorsal pancreatic bud was enriched for components of Notch, Wnt, BMP, and FGF signaling, almost all genes known to cause pancreatic agenesis or hypoplasia, and over 30 unexplored transcription factors. SOX9 and RORA were imputed as key regulators in pancreas compared with EP300, HNF4A, and FOXA family members in liver. Analyses implied that current in vitro human stem cell differentiation follows a dorsal rather than a ventral pancreatic program and pointed to additional factors for hepatic differentiation. In summary, we provide the transcriptional codes regulating the start of human liver and pancreas development to facilitate stem cell research and clinical interpretation without inter-species extrapolation.