• Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion.

      Rhost, S; Hughes, E; Harrison, Hannah; Rafnsdottir, S; Jacobsson, H; Gregersson, P; Magnusson, Y; Fitzpatrick, P; Andersson, D; Berger, K; Stahlberg, A; Landberg, Goran; Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden (2018)
      BACKGROUND: Cancer progression is influenced by genetic aberrations in the cancer cell population as well as by other factors including the microenvironment present within a tumour. Direct interactions between various cell types as well as cellular signalling via secreted cytokines can drive key tumourigenic properties associated with disease progression and treatment resistance. Also, cancer stem cell functions are influenced by the microenvironment. This challenging subset of cells has been linked to malignant properties. Within a screen, using in vivo like growth conditions, we identified progranulin as a highly secreted cytokine affecting cancer stem cells in breast cancer. This cytokine is known to play a role in numerous biological and tumour-related processes including therapy resistance in a range of cancer types. METHODS: Different in vitro and in vivo relevant conditions were used to validate breast cancer stem cell expansion mediated by progranulin and its receptor sortilin. Small interfering ribonucleic acid (siRNA) and pharmacological inhibition of sortilin were used to elucidate the role of sortilin as a functional receptor during progranulin-induced breast cancer stem cell propagation, both in vitro and in vivo, using breast cancer xenograft models. In addition, single-cell gene expression profiling as well as a Sox2 reporter breast cancer cell line were used to validate the role of dedifferentiation mediated by progranulin. RESULTS: In various in vivo-like screening assays, progranulin was identified as a potent cancer stem cell activator, highly secreted in ER?-negative breast cancer as well as in ER?-positive breast cancer under hypoxic adaptation. Progranulin exposure caused dedifferentiation as well as increased proliferation of the cancer stem cell pool, a process that was shown to be dependent on its receptor sortilin. Subcutaneous injections of progranulin or its active domain (GRN A) induced lung metastases in breast cancer xenograft models, supporting a major role for progranulin in cancer progression. Importantly, an orally bioavailable small molecule (AF38469) targeting sortilin, blocked GRN A-induced lung metastases and prevented cancer cell infiltration of the skin. CONCLUSION: The collective results suggest that sortilin targeting represents a potential novel breast cancer therapy approach inhibiting tumour progression driven by secretion and microenvironmental influences. KEYWORDS: Breast cancer; Cancer stem cells; Dedifferentiation; Differentiation; Hypoxia; Metastasis; Secretion
    • The p38 alpha stress kinase suppresses aneuploidy tolerance by inhibiting Hif-1 alpha.

      Simoes-Sousa, Susana; Littler, Samantha; Thompson, Sarah L; Minshall, Paul; Whalley, Helen J; Bakker, B; Belkot, Klaudyna; Moralli, D; Bronder, Daniel; Tighe, Anthony; Spierings, DCJ; Bah, Nourdine; Graham, Joshua; Nelson, Louisa; Green, CM; Foijer, F; Townsend, Paul A; Taylor, Stephen S; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4QL (2018)
      Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38 deficiency upregulates the hypoxia-inducible transcription factor Hif-1? and that inhibiting Hif-1? restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1? to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia.
    • Modeling radiation therapy-related risk of heart failure in survivors of pediatric malignancy: early results from the pediatric normal tissue effects in the clinic (PENTEC) group.

      Bates, JE; Keshavarz, H; Rancati, T; Yorke, ED; Gagliardi, G; Aznar, Marianne Camille; Moiseenko, V; Armenian, S; Kremer, L; Chen, MH; Ronckers, CM; van der Pal, H; Cutter, D; Constine, LS; Hodgson, D; Department of Radiation Oncology, University ofFlorida College of Medicine, Gainesville, FL (2018)
    • Long-term outcome of involved node radiation therapy for early stage Hodgkin lymphoma.

      Nielsen, K; Maraldo, MV; Aznar, Marianne Camille; Petersen, PM; Vogelius, I; Specht, L; Department of Oncology, Section of Radiotherapy,Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (2018)
    • A syngeneic mouse B-cell lymphoma model for pre-clinical evaluation of CD19 CAR T cells.

      Kueberuwa, Gray; Zheng, W; Kalaitsidou, Milena; Gilham, David E; Hawkins, Robert E; Manchester Cancer Research Centre Building, Department Cancer Sciences, University of Manchester (2018)
      The astonishing clinical success of CD19 chimeric antigen receptor (CAR) T-cell therapy has led to the approval of two second generation chimeric antigen receptors (CARs) for acute lymphoblastic leukemia (ALL) andnon-Hodgkin lymphoma (NHL). The focus of the field is now on emulating these successes in other hematological malignancies where less impressive complete response rates are observed. Further engineering of CAR T cells or co-administration of other treatment modalities may successfully overcome obstacles to successful therapy in other cancer settings. We therefore present a model in which others can conduct pre-clinical testing of CD19 CAR T cells. Results in this well tested B-cell lymphoma model are likely to be informative CAR T-cell therapy in general. This protocol allows the reproducible production of mouse CAR T cells through calcium phosphate transfection of Plat-E producer cells with MP71 retroviral constructs and pCL-Eco packaging plasmid followed by collection of secreted retroviral particles and transduction using recombinant human fibronectin fragment and centrifugation. Validation of retroviral transduction, and confirmation of the ability of CAR T cells to kill target lymphoma cells ex vivo, through the use of flow cytometry, luminometry and enzyme-linked immunosorbent assay (ELISA), is also described. Protocols for testing CAR T cells in vivo in lymphoreplete and lymphodepleted syngeneic mice, bearing established, systemic lymphoma are described. Anti-cancer activity is monitored by in vivo bioluminescence and disease progression. We show typical results of eradication of established B-cell lymphoma when utilizing 1st or 2nd generation CARs in combination with lymphodepleting pre-conditioning and a minority of mice achieving long term remissions when utilizing CAR T cells expressing IL-12 in lymphoreplete mice. These protocols can be used to evaluate CD19 CAR T cells with different additional modification, combinations of CAR T cells and other therapeutic agents or adapted for the use of CAR T cells against different target antigens.
    • Improved PDX and CDX data processing-response.

      Khandelwal, Garima; Miller, Crispin J; RNABiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, (2018)
    • A new standard DNA damage (SDD) data format.

      Schuemann, J; McNamara, AL; Warmenhoven, J W; Henthorn, N; Kirkby, Karen J; Merchant, Michael J; Ingram, S; Paganetti, H; Held, KD; Ramos-Mendez J; Faddegon, B; Perl, J; Goodhead, DT; Plante, I; Rabus, H; Nettelbeck, H; Friedland, W; Kundrat, P; Ottolenghi, A; Baiocco, G; Barbieri, S; Dingfelder, M; Incerti, S; Villagrasa, C; Bueno, M; Bernal, MA; Guatelli, S; Sakata, D; Brown, JMC; Francis, Z; Kyriakou, I; Lampe, N; Ballarini, F; Carante, MP; Davidkova, M; Stepan, V; Jia, X; Cucinotta, FA; Schulte, R; Stewart, RD; Carlson, DJ; Galer, S; Kuncic, Z; Lacombe, S; Milligan, J; Cho, SH; Sawakuchi, G; Inaniwa, T; Sato, T; Li, W; Solov'yov, AV; Surdutovich, E; Durante, M; Prise, KM; McMahon, SJ; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (2018)
      Our understanding of radiation-induced cellular damage has greatly improved over the past few decades. Despite this progress, there are still many obstacles to fully understand how radiation interacts with biologically relevant cellular components, such as DNA, to cause observable end points such as cell killing. Damage in DNA is identified as a major route of cell killing. One hurdle when modeling biological effects is the difficulty in directly comparing results generated by members of different research groups. Multiple Monte Carlo codes have been developed to simulate damage induction at the DNA scale, while at the same time various groups have developed models that describe DNA repair processes with varying levels of detail. These repair models are intrinsically linked to the damage model employed in their development, making it difficult to disentangle systematic effects in either part of the modeling chain. These modeling chains typically consist of track-structure Monte Carlo simulations of the physical interactions creating direct damages to DNA, followed by simulations of the production and initial reactions of chemical species causing so-called "indirect" damages. After the induction of DNA damage, DNA repair models combine the simulated damage patterns with biological models to determine the biological consequences of the damage. To date, the effect of the environment, such as molecular oxygen (normoxic vs. hypoxic), has been poorly considered. We propose a new standard DNA damage (SDD) data format to unify the interface between the simulation of damage induction in DNA and the biological modeling of DNA repair processes, and introduce the effect of the environment (molecular oxygen or other compounds) as a flexible parameter. Such a standard greatly facilitates inter-model comparisons, providing an ideal environment to tease out model assumptions and identify persistent, underlying mechanisms. Through inter-model comparisons, this unified standard has the potential to greatly advance our understanding of the underlying mechanisms of radiation-induced DNA damage and the resulting observable biological effects when radiation parameters and/or environmental conditions change.
    • Cell-active small molecule inhibitors of the DNA-damage repair enzyme poly(ADP-ribose) glycohydrolase (PARG): discovery and optimization of orally bioavailable quinazolinedione sulphonamides.

      Waszkowycz, Bohdan; Smith, Kate M; McGonagle, Alison E; Jordan, Allan M; Acton, Ben; Fairweather, Emma E; Griffiths, Louise A; Hamilton, Niall M; Hamilton, Nicola S; Hitchin, James R; Hutton, Colin P; James, Dunca I; Jones, CD; Jones, Stuart; Mould, Daniel P; Small, Helen F; Stowell, Alexandra I J; Tucker, JA; Waddell, Ian D; Ogilvie, Donald J; Cancer Research UK Manchester Institute , The University of Manchester , Alderley Park , Maccelsfield SK10 4TG (2018)
      DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however, the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design. 1-Oxetan-3-ylmethyl derivatives 33d and 35d were selected for preliminary investigations in vivo. X-ray crystal structures help rationalize the observed structure-activity relationships of these novel inhibitors.
    • Association of phenotypic characteristics and UV radiation exposure with risk of melanoma on different body sites.

      Ghiasvand, R; Robsahm, TE; Green, Adèle C; Rueegg, CS; Weiderpass, E; Lund, E; Veierod, MB; Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (2018)
      IMPORTANCE: Two pathways have been hypothesized for the development of cutaneous melanoma: one typically affects the head and neck, a site with chronic sun damage, and the other affects the trunk, which is less exposed to the sun. However, the possible cause of limb melanomas is less studied under this hypothesis. OBJECTIVE: To investigate the association between phenotypic characteristics, pattern of UV radiation exposure, and risk of melanoma on different body sites. DESIGN, SETTING, AND PARTICIPANTS: This study used data on 161?540 women with information on phenotypic characteristics and UV radiation exposure who were part of the Norwegian Women and Cancer study, a population-based prospective study established in 1991 with exposure information collected by questionnaires at baseline and every 4 to 6 years during follow-up through 2015. Data analysis was performed from October 2017 through May 2018. EXPOSURES: Participants reported hair color, eye color, untanned skin color, number of small symmetric and large asymmetric nevi, and freckling, as well as histories of sunburns, sunbathing vacations, and indoor tanning in childhood, adolescence, and adulthood. MAIN OUTCOMES AND MEASURES: The Norwegian Women and Cancer study was linked to the Cancer Registry of Norway for data on cancer diagnosis and date of death or emigration. Primary melanoma site was categorized as head and neck, trunk, upper limbs, and lower limbs. RESULTS: During follow-up of the 161?540 women in the study (mean age at study entry, 50 years [range, 34-70 years]; mean age at diagnosis, 60 years [range, 34-87 years]), 1374 incident cases of melanoma were diagnosed. Having large asymmetric nevi was a significant risk factor for all sites and was strongest for the lower limbs (relative risk [RR], 3.38; 95% CI, 2.62-4.38) and weakest for the upper limbs (RR, 1.96; 95% CI, 1.22-3.17; P?=?.02 for heterogeneity). Mean lifetime number of sunbathing vacations was significantly associated with risk of trunk melanomas (RR, 1.14; 95% CI, 1.07-1.22) and lower limb melanomas (RR, 1.12; 95% CI, 1.05-1.19) but not upper limb melanomas (RR, 0.98; 95% CI, 0.88-1.09) and head and neck melanomas (RR, 0.87; 95% CI, 0.73-1.04; P?=?.006 for heterogeneity). Indoor tanning was associated only with trunk melanomas (RR for the highest tertile, 1.49; 95% CI, 1.16-1.92) and lower limb melanomas (RR for the highest tertile, 1.33; 95% CI, 1.00-1.76; P?=?.002 for heterogeneity). Skin color, hair color, small symmetric nevi, and history of sunburns were associated with risk of melanoma on all sites. CONCLUSIONS AND RELEVANCE: These results appear to support the hypothesis of divergent pathways to melanoma and that recreational sun exposure and indoor tanning are associated with melanoma on the lower limbs, the most common site of melanoma in women. These findings appear to have important preventive implications.
    • Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

      Duffy, DL; Zhu, G; Li, X; Sanna, M; Iles, MM; Jacobs, LC; Evans, DM; Yazar, S; Beesley, J; Law, MH; Kraft, P; Visconti, A; Taylor, JC; Lui, F; Wright, MJ; Henders, AK; Bowdler, L; Glass, D; Ikram, AM; Uitterlinden, AG; Madden, PA; Heath, AC; Nelson, EC; Green, Adèle C; Chanock, S; Barrett, JH; Brown, MA; Hayward, NK; MacGregor, S; Sturm, RA; Hewitt, AW; Kayser, M; Hunter, DJ; Newton, Bishop JA; Spector, TD; Montgomery, GW; Mackey, DA; Smith, GD; Nijsten, TE; Bishop, DT; Bataille, V; Falchi, M; Han, J; Martin, NG; QIMR Berghofer Medical Research Institute, Brisbane, Australia. (2018)
      The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.
    • Challenges in assessing the sunscreen - Melanoma Association.

      Rueegg, CS; Stenehjem, JS; Egger, M; Ghiasvand, R; Cho, E; Lund, E; Weiderpass, E; Green, Adèle C; Veierod, MB; Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway (2018)
      Whether sunscreen use affects melanoma risk has been widely studied with contradictory results. To answer this question we performed a systematic review of all published studies, accounting for sources of heterogeneity and bias. We searched for original articles investigating the sunscreen-melanoma association in humans to 28.02.2018. We then used random-effects meta-analysis to combine estimates of the association, stratified by study design. Stratified meta-analysis and meta-regression were used to identify sources of heterogeneity. We included 21'069 melanoma cases from 28 studies published 1979-2018: 23 case-control (11 hospital-based, 12 population-based), 1 ecological, 3 cohort and 1 randomized controlled trial (RCT). There was marked heterogeneity across study designs and among case-control studies but adjustment for confounding by sun exposure, sunburns and phenotype systematically moved estimates towards decreased melanoma risk amongst sunscreen users. Ever- vs. never-use of sunscreen was inversely associated with melanoma in hospital-based case-control studies (adjusted odds ratio (OR)=0.57, 95%confidence interval (CI) 0.37-0.87, pheterogeneity <0.001), the ecological study (rate ratio=0.48, 95%CI 0.35-0.66), and the RCT (hazard ratio (HR)=0.49, 95%CI 0.24-1.01). It was not associated in population-based case-control studies (OR=1.17, 95%CI 0.90-1.51, pheterogeneity <0.001) and was positively associated in the cohort studies (HR=1.27, 95%CI 1.07-1.51, pheterogeneity =0.236). The association differed by latitude (pinteraction =0.042), region (pinteraction =0.008), adjustment for naevi/freckling (pinteraction =0.035), and proportion of never-sunscreen-users (pinteraction =0·012). Evidence from observational studies on sunscreen use and melanoma risk was weak and heterogeneous, consistent with the challenges of controlling for innate confounding by indication. The only RCT showed a protective effect of sunscreen. KEYWORDS: Sunscreen; melanoma; meta-analysis; skin cancer; sun protection
    • Early human hemogenic endothelium generates primitive and definitive hematopoiesis in vitro.

      Garcia-Alegria, E; Menegatti, S; Fadlullah, Muhammad Z H; Menendez, P; Lacaud, Georges; Kouskoff, Valerie; Developmental Haematopoiesis Group, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK (2018)
      The differentiation of human embryonic stem cells (hESCs) to hematopoietic lineages initiates with the specification of hemogenic endothelium, a transient specialized endothelial precursor of all blood cells. This in vitro system provides an invaluable model to dissect the emergence of hematopoiesis in humans. However, the study of hematopoiesis specification is hampered by a lack of consensus in the timing of hemogenic endothelium analysis and the full hematopoietic potential of this population. Here, our data reveal a sharp decline in the hemogenic potential of endothelium populations isolated over the course of hESC differentiation. Furthermore, by tracking the dynamic expression of CD31 and CD235a at the onset of hematopoiesis, we identified three populations of hematopoietic progenitors, representing primitive and definitive subsets that all emerge from the earliest specified hemogenic endothelium. Our data establish that hemogenic endothelium populations endowed with primitive and definitive hematopoietic potential are specified simultaneously from the mesoderm in differentiating hESCs.
    • Study protocol for the DETECTIVE study: an international collaborative study to develop consensus statements for deferred treatment with curative intent for localised prostate cancer.

      Lam, TBL; MacLennan, S; Plass, K; Willemse, PM; Mason, MD; Cornford, P; Donaldson, J; Davis, NF; Dell'Oglio, P; Fankhauser, C; Grivas, N; Ingels, A; Lardas, M; Liew, M; Pang, KH; Paterson, C; Omar, MI; Zattoni, F; Buddingh, KT; Van den Broeck, T; Cumberbatch, MG; Fossati, N; Gross, T; Moris, L; Schoots, IG; van den Bergh, RCN; Briers, E; Fanti, S; De, SM; Gillessen, Silke; Grummet, JP; Henry, AM; van der Poel, HG; van der Kwast, TH; Rouviere, O; Tilki, D; Wiegel, T; N'Dow, J; Van, PH; Mottet, N; Academic Urology Unit, University of Aberdeen, Aberdeen, UK (2018)
    • Combined inhibition of PI3K beta and mTOR Inhibits growth of PTEN-null tumors.

      Lynch, James T; Polanska, UM; Hancox, U; Delpuech, O; Maynard, J; Trigwell, Cath; Eberlein, Cath; Lenaghan, C; Polanski, Radoslaw; Avivar-Valderas, A; Cumberbatch, M; Klinowska, T; Critchlow, SE; Cruzalegui, F; Barry, ST; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge (2018)
      Loss of the tumor suppressor PTEN confers a tumor cell dependency on the PI3K? isoform. Achieving maximal inhibition of tumor growth through PI3K pathway inhibition requires sustained inhibition of PI3K signaling; however, efficacy is often limited by suboptimal inhibition or reactivation of the pathway. To select combinations that deliver comprehensive suppression of PI3K signaling in PTEN-null tumors, the PI3K? inhibitor AZD8186 was combined with inhibitors of kinases implicated in pathway reactivation in an extended cell proliferation assay. Inhibiting PI3K? and mTOR gave the most effective antiproliferative effects across a panel of PTEN-null tumor cell lines. The combination of AZD8186 and the mTOR inhibitor vistusertib was also effective in vivo controlling growth of PTEN-null tumor models of TNBC, prostate, and renal cancers. In vitro, the combination resulted in increased suppression of pNDRG1, p4EBP1, as well as HMGCS1 with reduced pNDRG1 and p4EBP1 more closely associated with effective suppression of proliferation. In vivo biomarker analysis revealed that the monotherapy and combination treatment consistently reduced similar biomarkers, while combination increased nuclear translocation of the transcription factor FOXO3 and reduction in glucose uptake. These data suggest that combining the PI3K? inhibitor AZD8186 and vistusertib has potential to be an effective combination treatment for PTEN-null tumors. 
    • Curvature delays growth-induced wrinkling

      Jia, F; Pearce, Simon P; Goriely, A; School of Manufacturing Science and Engineering, Southwest University of Science and Technology, Sichuan 621010, China (2018)
      Wrinkling patterns can be induced by the growth of a thin elastic film over a soft elastic substrate. While there is a good understanding of how this pattern is initiated on a flat geometry, wrinkling patterns over a curved surface are more complicated. Here, we consider this phenomenon within the framework of large deformation morphoelasticity by investigating surface wrinkling of a growing thin elastic film bonded to a large elastic cylinder. The system has two important dimensionless parameters: the ratio ? of the film thickness by the cylinder radius and the relative stiffness of the two layers ?. Depending on the values of ? and ? we identify four different regimes for which we find the critical growth and wrinkling mode number. By combining asymptotic methods with numerical computations we determine the effect of the curvature on the bifurcation and establish that it always induces a delay at the bifurcation: Larger growth is needed on a curved surface to induce the same wrinkling instability. These results are crucial to understand pattern formation on surface with varying curvatures.
    • What Do the Guidelines Say for Metastatic Prostate Cancer Starting Androgen Deprivation Therapy? National Comprehensive Cancer Network, European Society for Medical Oncology, and European Association of Urology recommendations

      Yu, EY; Gillessen, Silke; Mottet, N; Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA; (2018)
      Clinical trial data forms the foundation of how we treat men with metastatic prostate cancer who are initiating therapy. However, clinical trial data does not answer everything; hence, good clinical practice, pragmatism, and occasionally extrapolation drives how we manage these patients. Fortunately, multiple international guideline committees meet regularly and offer clinical guidance. In this mini-review, we focus on the United States National Comprehensive Cancer Network, European Society for Medical Oncology, and European Association of Urology (EAU) recommendations for the initial treatment of metastatic prostate cancer.
    • Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI

      Jones, DK; Alexander, DC; Bowtell, R; Cercignani, M; Dell'Acqua, F; McHugh, Damien J; Miller, KL; Palombo, M; Parker, Geoff JM; Rudrapatna, US; Tax, CMW; Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Maindy Road, Cardiff (2018)
      The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of ?, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'.
    • Mutation pattern analysis reveals polygenic mini-drivers associated with relapse after surgery in lung adenocarcinoma

      Bennett, Laura; Howell, Matthew; Memon, Danish; Smowton, Christopher; Zhou, Cong; Miller, Crispin J; RNA Biology Group, CRUK Manchester Institute, The University of Manchester, Alderley Park, Manchester, SK10 4TG, UK (2018)
      The genomic lesions found in malignant tumours exhibit a striking degree of heterogeneity. Many tumours lack a known driver mutation, and their genetic basis is unclear. By mapping the somatic mutations identified in primary lung adenocarcinomas onto an independent coexpression network derived from normal tissue, we identify a critical gene network enriched for metastasis-associated genes. While individual genes within this module were rarely mutated, a significant accumulation of mutations within this geneset was predictive of relapse in lung cancer patients that have undergone surgery. Since it is the density of mutations within this module that is informative, rather than the status of any individual gene, these data are in keeping with a 'mini-driver' model of tumorigenesis in which multiple mutations, each with a weak effect, combine to form a polygenic driver with sufficient power to significantly alter cell behaviour and ultimately patient outcome. These polygenic mini-drivers therefore provide a means by which heterogeneous mutation patterns can generate the consistent hallmark changes in phenotype observed across tumours.
    • The impact of changing the prevalence of overweight/obesity and physical inactivity in Australia: an estimate of the proportion of potentially avoidable cancers 2013-2037

      Wilson, LF; Baade, PD; Green, Ad�le C; Jordan, SJ; Kendall, BJ; Neale, RE; Olsen, CM; Youlden, DR; Webb, PM; Whiteman, DC; Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, 4006, Australia (2018)
      Globally, 39% of the world's adult population is overweight or obese and 23% is insufficiently active. These percentages are even larger in high-income countries with 58% overweight/obese and 33% insufficiently active. Fourteen cancer types have been declared by the World Cancer Research Fund to be causally associated with being overweight or obese: oesophageal adenocarcinoma, stomach cardia, colon, rectum, liver, gallbladder, pancreas, breast, endometrium, ovary, advanced/fatal prostate, kidney, thyroid and multiple myeloma. Colon, postmenopausal breast and endometrial cancers have also been judged causally associated with physical inactivity. We aimed to quantify the proportion of cancer cases that would be potentially avoidable in Australia if the prevalence of overweight/obesity and physical inactivity in the population could be reduced. We used the simulation modelling software PREVENT 3.01 to calculate the proportion of avoidable cancers over a 25-year period under different theoretical intervention scenarios that change the prevalence of overweight/obesity and physical inactivity in the population. Between 2013 and 2037, 10-13% of overweight/obesity-related cancers in men and 7-11% in women could be avoided if overweight and obesity were eliminated in the Australian population. If everyone in the population met the Australian physical activity guidelines for cancer prevention (i.e. engaged in at least 300 min of moderate-intensity physical activity per week), an estimated 2-3% of physical inactivity-related cancers could be prevented in men (colon cancer) and 1-2% in women (colon, breast and endometrial cancers). This would translate to the prevention of up to 190,500 overweight/obesity-related cancers and 19,200 inactivity-related cancers over 25 years.
    • Omega-3 fatty acid supplement skin cancer prophylaxis in lung transplant recipients: A randomized, controlled pilot trial

      Miura, K; Vail, A; Chambers, D; Hopkins, PM; Ferguson, L; Grant, M; Rhodes, LE; Green, Ad�le C; Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (2018)
      BACKGROUND: Lung transplant recipients (LTRs) are at very high risk of skin cancer. Omega-3 fatty acids (FAs) are anti-inflammatory and immune-modulating and could potentially reduce this risk. We assessed the feasibility of omega-3 FA supplementation to reduce skin cancer among these patients. METHODS: LTRs aged 18+ years, at least 1 year post-transplant, were recruited from the outpatient clinic of The Prince Charles Hospital, Brisbane. Participants were randomly allocated to 4-times-daily supplements containing either omega-3 FA (3.36 eicosapentaenoic acid [EPA]?+?docosahexaenoic acid) or placebo (4 g olive oil) for 12 months. Primary outcomes were rates of recruitment, retention, adherence (assessed by plasma omega-3 FA), and safety. Secondary outcomes were incident skin cancers. RESULTS: Among 106 eligible lung transplant recipients, 49 consented to take part (46%) with 25 allocated to omega-3 FA and 24 to placebo supplements. Of these, 22 (88%) and 20 (83%), respectively, completed the trial. After 12 months, median plasma EPA increased substantially in the intervention group (125.0 to 340.0 �mol/L), but not the placebo group (98.0 to 134.5 �mol/L). In the intervention group, 6 patients developed skin cancers compared with 11 in the placebo group, giving an odds ratio (95% confidence interval) of 0.34 (0.09 to 1.32). There were no serious, active intervention-related adverse events. CONCLUSIONS: This pilot trial among LTRs showed acceptable recruitment and high retention and adherence. We demonstrated a signal for reduction of new skin cancer cases in those taking omega-3 FA supplements, which supports the notion that a larger, more definitive trial is warranted.