• A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland.

      Kritikou, Ekaterini A; Sharkey, Andrew; Abell, Kathrine; Came, Paul J; Anderson, Elizabeth; Clarkson, Richard W E; Watson, Christine J; Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK. (2003-08)
      STAT3 is the key mediator of apoptosis in mammary gland. We demonstrate here that LIF is the physiological activator of STAT3, because in involuting mammary glands of Lif(-/-) mice, pSTAT3 is absent and the STAT3 target, C/EBPdelta, is not upregulated. Similar to Stat3 knockouts, Lif(-/-) mammary glands exhibit delayed involution, reduced apoptosis and elevated levels of p53. Significantly, Lif(-/-) glands display precocious development during pregnancy, when pSTAT3 is not normally detected. We show that pERK1/2 is significantly reduced in Lif(-/-) glands at this time, suggesting that at this stage LIF mediates its effects through pERK1/2. Inhibition of LIF-mediated ERK1/2 phosphorylation potentiates the proapoptotic effects of STAT3. LIF therefore signals alternately through ERK1/2, then STAT3, to regulate mammary growth and apoptosis.
    • A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase.

      Patel, Naina; Krishnan, Shekhar; Offman, Marc N; Krol, Marcin; Moss, Catherine X; Leighton, Carly; Van Delft, Frederik W; Holland, Mark; Liu, Jizhong; Alexander, Seema; et al. (2009-07)
      l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL.
    • Dynamic gene regulatory networks drive hematopoietic specification and differentiation.

      Goode, D; Obier, N; Vijayabaskar, M; Lie-A-Ling, Michael; Lilly, Andrew J; Hannah, R; Lichtinger, M; Batta, Kiran; Florkowska, Magdalena; Patel, Rahima; et al. (2016-03-07)
      Metazoan development involves the successive activation and silencing of specific gene expression programs and is driven by tissue-specific transcription factors programming the chromatin landscape. To understand how this process executes an entire developmental pathway, we generated global gene expression, chromatin accessibility, histone modification, and transcription factor binding data from purified embryonic stem cell-derived cells representing six sequential stages of hematopoietic specification and differentiation. Our data reveal the nature of regulatory elements driving differential gene expression and inform how transcription factor binding impacts on promoter activity. We present a dynamic core regulatory network model for hematopoietic specification and demonstrate its utility for the design of reprogramming experiments. Functional studies motivated by our genome-wide data uncovered a stage-specific role for TEAD/YAP factors in mammalian hematopoietic specification. Our study presents a powerful resource for studying hematopoiesis and demonstrates how such data advance our understanding of mammalian development.
    • Dynamic histology of a rat hepatoma and the response to 5-fluorouracil.

      Moore, James V; Hopkins, H A; Looney, W B; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester, England (1980-01)
      The cellular response of the rat hepatoma 3924A to a single intraperitoneal injection of 5-fluorouracil has been measured in respect of the spatial relationship of the cells to the tumour microvasculature. In this tumour the parenchyma is arranged in cords approximately 150 micron thick around central capillaries. For untreated tumours, those cells at distance less than 80 micron from the capillary had a mean [3HTdR labelling index of 39% and a mitotic index of 2.1%, while for those cells more than 80 micron away the values were 14% and 0.8% respectively. Two days after 150 mg/kg of 5-fluorouracil, mean cord thickness was reduced by 25% and did not recover to the control level until 11 days after treatment. This was also true for the mitotic index. Recovery of the labelling index was complete 2 days earlier. Although absolute values of parameters were different in the populations adjacent to and remote from the capillary, the time course of recovery was similar, with a 'growth spur' 7 to 9 days after treatment. The results from this histologically-based assay have been compared with those from biochemical/biophysical assays that sample the overall tumour population.
    • Dynamic induction of drug resistance through a stress-responsive enhancer in acute myeloid leukemia

      Williams, Mark S; Somervaille, Tim CP; Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Oglesby Cancer Research Building Manchester (2020)
    • A dynamic model of proliferation and differentiation in the intestinal crypt based on a hypothetical intraepithelial growth factor.

      Gerike, T G; Paulus, U; Potten, Christopher S; Loeffler, M; Institut für Medizinische Informatik, Statistik und Epidemiologie, Leipzig, Germany. (1998-04)
      A widely accepted model of the temporal and spatial organization of proliferation and differentiation in intestinal epithelial is based on a cellular pedigree with all cells descending from a few active stem cells and undergoing a sequence of transitory divisions until the non-proliferating maturing cell stages develop. Model simulations have shown that such a pedigree concept can explain a large variety of data. However, so far there is neither a direct experimental proof for the existence of an intrinsic age structure in the transitory proliferative cell stages nor for the distinction between stem and transitory cells. It is our objective to suggest an alternative model which is based on evidence for intercellular communications such as might be mediated through gap junctions. We consider the diffusion of a hypothetical intraepithelial growth factor in a chain of cells which are connected via gap junctions. Individual cells can divide if a critical growth factor concentration is exceeded. Simulation studies show that the model is consistent with many observed features of the small intestinal crypt in steady state and after perturbation.
    • Dynamic of broad H3K4me3 domains uncover an epigenetic switch between cell identity and cancer-related genes

      Belhocine, M.; Simonin, M.; Abad Flores, J. D.; Cieslak, A.; Manosalva, I.; Pradel, L.; Smith, C.; Mathieu, E. L.; Charbonnier, G.; Martens, J. H. A.; et al. (2021)
      Broad domains of H3K4 methylation have been associated with consistent expression of tissue-specific, cell identity, and tumor suppressor genes. Here, we identified broad domain-associated genes in healthy human thymic T cell populations and a collection of T-Acute Lymphoblastic Leukemia (T-ALL) primary samples and cell lines. We found that broad domains are highly dynamic throughout T cell differentiation and their varying breadth allows the distinction between normal and neoplastic cells. While broad domains preferentially associate with cell identity and tumor suppressor genes in normal thymocytes, they flag key oncogenes in T-ALL samples. Moreover, the expression of broad domain-associated genes, both coding and noncoding, is frequently deregulated in T-ALL. Using two distinct leukemic models, we demonstrated that the ectopic expression of T-ALL oncogenic transcription factor preferentially impacts the expression of broad domain-associated genes in pre-leukemic cells. Finally, an H3K4me3 demethylase inhibitor differentially targets T-ALL cell lines depending on the extent and number of broad domains. Our results show that the regulation of broad H3K4me3 domains is associated with leukemogenesis and suggest that the presence of these structures might be used as epigenetic prioritization of cancer-relevant genes, including long non-coding RNAs.
    • Dynamics of telomere shortening in neutrophils and T lymphocytes during ageing and the relationship to skewed X chromosome inactivation patterns.

      Robertson, Jane D; Gale, Rosemary E; Wynn, Robert F; Dougal, Mark; Linch, David C; Testa, Nydia G; Chopra, Rajesh; Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. (2000-05)
      Human haemopoiesis undergoes profound changes throughout life, resulting in compromised regenerative capacity of haemopoietic stem cells. It has been suggested that telomere shortening results in senescence of haemopoietic stem cell subsets and may influence the balance between stem cell renewal and proliferation. Telomere length and telomerase activity was measured in whole blood leucocytes, neutrophils and T cells from cord blood and individuals aged from 1 year to 96 years. Rapid telomere shortening [700 base pairs (bp)] was demonstrated in the first year of life, followed by a gradual decline of 31 bp/year. T cells were shown to have longer telomeres than neutrophils (mean difference 372 bp, P = < 0.001) but demonstrated similar rates of shortening (20 +/- 0.3 bp/year vs. 22 +/- 0.3 bp/year). Telomerase was detectable in T cells but not in neutrophils, suggesting that telomerase is not the rate-limiting step for regulation of telomere length in haemopoietic cells. Stem cell utilization as measured by X chromosome inactivation patterns was found to be independent of telomere length. This supports the concept that age-dependent skewed haemopoiesis is the result of random stem cell loss or X-allelic exclusion rather than telomeric senescence. These studies provide insight into the ageing process and a reference point for evaluating replicative stress in individuals of different age groups.
    • The dynamics of tumor cords in an irradiated mouse mammary carcinoma with a large hypoxic cell component.

      Moore, James V; Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, England. (1988-02)
      The tumor cord model represents a histologically based framework for interpretation of radiobiological phenomena, particularly the resistance to radiation conferred by absence of oxygen. For the mammary carcinoma T50/80 grown in B6D2F1 male mice, average oxygenation was poor, based on tumor growth delay after irradiation. There was no improvement in radiobiological oxygenation for several days after a high dose of radiation. This was consistent with events in the cords of the tumor, where although up to 20% of all cells became pyknotic by 8 hr, the cords did not shrink for at least 2 days. The cellular kinetics of populations of intact and dead cells, adjacent to and remote from the capillaries of the cords, were examined for up to 60 hr after irradiation and it was found that: (i) before treatment, average LI (adjacent) was 13% and LI (remote) was 2%, (ii) after irradiation, cells expressed pyknosis after passing through the S phase of the cell cycle, so that (iii) at early intervals there was a larger proportional rise in pyknotic cells in the adjacent than the remote zone. However, (iv) at later intervals there was always a higher proportion of dead cells in the remote zone.
    • E-cadherin inhibits cell surface localization of the pro-migratory 5T4 oncofetal antigen in mouse embryonic stem cells.

      Spencer, Helen L; Eastham, Angela M; Merry, Catherine L R; Southgate, Thomas D; Perez-Campo, Flor-Maria; Soncin, Francesca; Ritson, Sarah; Kemler, Rolf; Stern, Peter L; Ward, Christopher M; et al. (2007-08)
      Epithelial-mesenchymal transition (EMT) events occur during embryonic development and are important for the metastatic spread of epithelial tumors. We show here that spontaneous differentiation of mouse embryonic stem (ES) cells is associated with an E- to N-cadherin switch, up-regulation of E-cadherin repressor molecules (Snail and Slug proteins), gelatinase activity (matrix metalloproteinase [MMP]-2 and -9), and increased cellular motility, all characteristic EMT events. The 5T4 oncofetal antigen, previously shown to be associated with very early ES cell differentiation and altered motility, is also a part of this coordinated process. E- and N-cadherin and 5T4 proteins are independently regulated during ES cell differentiation and are not required for induction of EMT-associated transcripts and proteins, as judged from the study of the respective knockout ES cells. Further, abrogation of E-cadherin-mediated cell-cell contact in undifferentiated ES cells using neutralizing antibody results in a reversible mesenchymal phenotype and actin cytoskeleton rearrangement that is concomitant with translocation of the 5T4 antigen from the cytoplasm to the cell surface in an energy-dependent manner. E-cadherin null ES cells are constitutively cell surface 5T4 positive, and although forced expression of E-cadherin cDNA in these cells is sufficient to restore cell-cell contact, cell surface expression of 5T4 antigen is unchanged. 5T4 and N-cadherin knockout ES cells exhibit significantly decreased motility during EMT, demonstrating a functional role for these proteins in this process. We conclude that E-cadherin protein stabilizes cortical actin cytoskeletal arrangement in ES cells, and this can prevent cell surface localization of the promigratory 5T4 antigen.
    • An E. coli ada transgenic clone of Nicotiana tabacum var. Xanthi has increased sensitivity to the mutagenic action of alkylating agents, maleic hydrazide and gamma-rays.

      Velemínský, J; Angelis, K; Babůrek, I; Gichner, T; Satava, J; Bríza, J; Margison, Geoffrey P; Institute of Experimental Botany, Academy of Sciences, Prague, Czech Republic. (1994-05-01)
      Two transgenic clones X3 and X15 of Nicotiana tabacum var. Xanthi, heterozygous in two genes (a1 and a2) for chloroplast differentiation and transformed with the E. coli DNA repair gene ada cloned downstream from the 1' direction of the dual mas promoter, differed in the expression of the ada gene, in the number of copies of integrated T-DNA and in the response to the mutagenic action of alkylating and non-alkylating agents. The X3 genome contained four copies and the X15 genome one copy of T-DNA, nevertheless the expression of the ada gene, measured by the activity of O6-alkylguanine DNA alkyltransferase (ATase), was about six times higher in X15 than in X3. ATase activity in both clones was highest in extracts from callus whereas very low (X15) or no (X3) activity was detected in leaf extracts. This may explain the lack of difference between X15 and non-transformed tobacco (NTX) in the frequency of N-methyl-N-nitrosourea (MNU)-induced somatic mutations in leaves. In contrast, the frequency of somatic mutations in X3 was about 2-5 times higher than in NTX and X15 after the same doses of MNU, methyl methanesulfonate, maleic hydrazide and gamma-rays. Alteration of plant gene(s) essential in mutation pathway(s) by insertion of T-DNA or by somaclonal variation may explain the higher sensitivity of the X3 clone.
    • The E. coli ogt gene.

      Margison, Geoffrey P; Cooper, Donald P; Potter, P M; Carcinogenesis Department, Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, Great Britain. (2010-08-18)
    • The E1E4 protein of human papillomavirus type 16 associates with a putative RNA helicase through sequences in its C terminus.

      Doorbar, John; Elston, Robert C; Napthine, Sawsan; Raj, Kenneth; Medcalf, Elizabeth; Jackson, Deborah; Coleman, Nick; Griffin, Heather M; Masterson, Philip; Stacey, Simon N; et al. (2000-11)
      Human papillomavirus type 16 (HPV16) infects cervical epithelium and is associated with the majority of cervical cancers. The E1E4 protein of HPV16 but not those of HPV1 or HPV6 was found to associate with a novel member of the DEAD box protein family of RNA helicases through sequences in its C terminus. This protein, termed E4-DBP (E4-DEAD box protein), has a molecular weight of 66,000 (66K) and can shuttle between the nucleus and the cytoplasm. It binds to RNA in vitro, including the major HPV16 late transcript (E1E4. L1), and has an RNA-independent ATPase activity which can be partially inhibited by E1E4. E4-DBP was detectable in the cytoplasm of cells expressing HPV16 E1E4 (in vivo and in vitro) and could be immunoprecipitated as an E1E4 complex from cervical epithelial cell lines. In cell lines lacking cytoplasmic intermediate filaments, loss of the leucine cluster-cytoplasmic anchor region of HPV16 E1wedgeE4 resulted in both proteins colocalizing exclusively to the nucleoli. Two additional HPV16 E1E4-binding proteins, of 80K and 50K, were identified in pull-down experiments but were not recognized by antibodies to E4-DBP or the conserved DEAD box motif. Sequence analysis of E4-DBP revealed homology in its E4-binding region with three Escherichia coli DEAD box proteins involved in the regulation of mRNA stability and degradation (RhlB, SrmB, and DeaD) and with the Rrp3 protein of Saccharomyces cerevisiae, which is involved in ribosome biogenesis. The synthesis of HPV16 coat proteins occurs after E1E4 expression and genome amplification and is regulated at the level of mRNA stability and translation. Identification of E4-DBP as an HPV16 E1E4-associated protein indicates a possible role for E1E4 in virus synthesis.
    • E2 enzymes in genome stability: pulling the strings behind the scenes

      Osborne, Hugh C; Irving, E.; Forment, J. V.; Schmidt, Christine K; Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, 555 Wilmslow Road, Manchester M20 4GJ (2021)
      Ubiquitin and ubiquitin-like proteins (UBLs) function as critical post-translational modifiers in the maintenance of genome stability. Ubiquitin/UBL-conjugating enzymes (E2s) are responsible, as part of a wider enzymatic cascade, for transferring single moieties or polychains of ubiquitin/UBLs to one or multiple residues on substrate proteins. Recent advances in structural and mechanistic understanding of how ubiquitin/UBL substrate attachment is orchestrated indicate that E2s can exert control over chain topology, substrate-site specificity, and downstream physiological effects to help maintain genome stability. Drug discovery efforts have typically focussed on modulating other members of the ubiquitin/UBL cascades or the ubiquitin-proteasome system. Here, we review the current standing of E2s in genome stability and revisit their potential as pharmacological targets for developing novel anti-cancer therapies.
    • EACR-MRS conference on Seed and Soil: In Vivo Models of Metastasis.

      Teles Alves, I; Cohen, N; Ersan, P; Eyre, Rachel; Godet, I; Holovanchuk, D; Jackstadt, R; Kyjacova, L; Mahal, K; Noguera-Castells, A; et al. (2017-12)
      New experimental tools are urgently required to better understand the metastatic process. The importance of such tools is underscored by the fact that many anti-cancer therapies are generally ineffective against established metastases. This makes a major contribution to the fact that metastatic spread is responsible for over 90% of cancer patient deaths. It was therefore timely that the recent "Seed and Soil: In Vivo Models of Metastasis" conference held in Berlin, Germany (27-29 of November 2017) aimed to give an in-depth overview of the latest research models and tools for studying metastasis, and to showcase recent findings from world-leading metastasis researchers. This Meeting Report summarises the major themes of this ground-breaking conference.
    • EANO-EURACAN clinical practice guideline for diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma

      Franceschi, E; Hofer, S; Brandes, AA; Frappaz, D; Kortmann, RD; Bromberg, J; Dangouloff-Ros, V; Boddaert, N; Hattingen, E; Wiestler, B; et al. (2019)
      The European Association of Neuro-Oncology (EANO) and EUropean RAre CANcer (EURACAN) guideline provides recommendations for the diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma. The guideline is based on the 2016 WHO classification of tumours of the CNS and on scientific developments published since 1980. It aims to provide direction for diagnostic and management decisions, and for limiting unnecessary treatments and cost. In view of the scarcity of data in adults with medulloblastoma, we base our recommendations on adult data when possible, but also include recommendations derived from paediatric data if justified. Our recommendations are a resource for professionals involved in the management of post-pubertal and adult patients with medulloblastoma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
    • EARL: a multicentre phase III randomised trial to evaluate the efficacy of endobronchial electrocautery with autofluorescence bronchoscopy (AFB) surveillance versus AFB surveillance alone in high-grade bronchial dysplasia

      Kalinke, L.; Thakrar, R.; Daniels, H.; Rintoul, R.; Booton, R.; Hackshaw, Allan; Janes, S.; Lungs for Living Research Unit, London, United Kingdom (2020)
      Introduction: Bronchial pre-invasive lesions are precursors of squamous cell cancer. However, not every pre-invasive lesion is destined to this; some lesions may remain stable or even regress to normal epithelium. Performing surveillance with autofluorescence bronchoscopy (AFB), we have shown that 50% of high-grade lesions (HGLs), i.e. severe dysplasia/carcinoma in-situ, progress to cancer (unpublished). Their treatment remains controversial. Guidelines advocate surgical management. This carries inherent risk and its benefit has not been proven in a randomised trial; new lesions also develop, so a tissue-sparing strategy is needed. Methods: We are conducting a Cancer Research UK-funded, international multi-centre randomised trial to examine whether thermal ablation using bronchoscopic electrocautery of HGLs prevents their progression to cancer. Participants will be randomised to electrocautery and AFB surveillance or AFB surveillance alone. The trial will run across four centres (University College London Hospital, Wythenshawe, Papworth and VUmc, Amsterdam)and opens in December 2019. We aim to recruit 106 participants within 3 years. Referral criteria are: 1. Individuals with HGLs found incidentally on bronchial biopsy or at resection margins post-operatively (even if found up to one year previously) 2. Individuals with abnormal sputum cytology, but normal CT and/or bronchoscopy All participants will have a chest CT, pulmonary function tests and AFB at baseline, and then AFB at 6, 12, 24 and 36 months. Participants can receive two electrocautery treatments per year over the 3-year trial period. Results: The primary endpoint is the time to progression of any HGL in a patient to invasive lung cancer. Secondary outcomes are (i) cancer-free and overall survival, (ii) health-related quality of life and (iii) cost-effectiveness. Conclusion: The EARL trial is the first Phase III randomised trial of an endobronchial therapy for the prevention of lung cancer. If successful, it will address the unmet clinical need for a proven tissue-sparing therapy for this high-risk population.
    • Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program.

      Hoogenkamp, Maarten; Lichtinger, Monika; Krysinska, Hanna; Lancrin, Christophe; Clarke, Deborah; Williamson, Andrew J K; Mazzarella, Luca; Ingram, Richard; Jorgensen, Helle; Fisher, Amanda; et al. (2009-07-09)
      At the cellular level, development progresses through successive regulatory states, each characterized by their specific gene expression profile. However, the molecular mechanisms regulating first the priming and then maintenance of gene expression within one developmental pathway are essentially unknown. The hematopoietic system represents a powerful experimental model to address these questions and here we have focused on a regulatory circuit playing a central role in myelopoiesis: the transcription factor PU.1, its target gene colony-stimulating-factor 1 receptor (Csf1r), and key upstream regulators such as RUNX1. We find that during ontogeny, chromatin unfolding precedes the establishment of active histone marks and the formation of stable transcription factor complexes at the Pu.1 locus and we show that chromatin remodeling is mediated by the transient binding of RUNX1 to Pu.1 cis-elements. By contrast, chromatin reorganization of Csf1r requires prior expression of PU.1 together with RUNX1 binding. Once the full hematopoietic program is established, stable transcription factor complexes and active chromatin can be maintained without RUNX1. Our experiments therefore demonstrate how individual transcription factors function in a differentiation stage-specific manner to differentially affect the initiation versus maintenance of a developmental program.
    • Early detection of melanoma in specialised primary care practice in Australia

      Green, Adèle C; Pandeya, N.; Morton, S.; Simonidis, J.; Whiteman, D. C.; Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, 4006, Australia; CRUK Manchester and Faculty of Biology, Medicine and Health, University of Manchester, Manchester, (2020)
      Background: Primary care skin cancer clinics facilitate early treatment of melanoma in Australia. We investigated the clinical and histopathological features of melanomas diagnosed and treated in an established clinic in Brisbane. Methods: Retrospective audit of medical records of patients diagnosed with in situ or invasive primary cutaneous melanoma in a primary care clinic specializing in skin cancer, 2000-2017. Demographic and clinical data were standardly extracted by a medically-trained investigator. We used descriptive analyses to assess characteristics of patients and melanomas, and examine surgical management according to tumour thickness. Results: Of 380 patients (median age 57 years; 57 % male) newly diagnosed with 497 histologically-confirmed primary cutaneous melanomas, 369 were in situ and 128 invasive. Of the 369 in situ melanomas, 143 (39 %) were on the trunk and 87 (24 %) on the head and neck; 247 (67 %) were diagnosed by shave biopsy; and 141 (38 %) referred for wide local excision (WLE). Of the 128 invasive melanomas, only 21 (16 %) had thickness ≥ 0.8 mm and these occurred more often on head and neck than thin invasive melanomas (p = 0.02). The majority of invasive melanomas were diagnosed by excision biopsy, and WLE was carried out in a median of 3 days (melanomas ≥ 0.8 mm) and 2 days (<0.8 mm). The doctor detected the majority of in situ (83 %) and thin invasive (73 %) melanomas during surveillance, compared with 48 % of thicker invasive melanomas ≥ 0.8 mm (p < 0.001). Conclusion: In Australia, specialised primary care practice plays a major role in detection and treatment of early primary melanoma.
    • Early detection of melanoma: a consensus report from the Australian Skin and Skin Cancer Research Centre Melanoma Screening Summit

      Janda, M; Cust, AE; Neale, RE; Aitken, JF; Baade, PD; Green, Adèle C; Khosrotehrani, K; Mar, V; Soyer, HP; Whiteman, DC; et al. (2020)