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The health of the planet and its people are at risk. The deterioration of the global commons—ie, the natural systems that support life on Earth—is exacerbating energy, food, and water insecurity, and increasing the risk of disease, disaster, displacement, and conflict. In this Commission, we quantify safe and just Earth-system boundaries (ESBs) and assess minimum access to natural resources required for human dignity and to enable escape from poverty. Collectively, these describe a safe and just corridor that is essential to ensuring sustainable and resilient human and planetary health and thriving in the Anthropocene. We then discuss the need for translation of ESBs across scales to inform science-based targets for action by key actors (and the challenges in doing so), and conclude by identifying the system transformations necessary to bring about a safe and just future. Our concept of the safe and just corridor advances research on planetary boundaries and the justice and Earth-system aspects of the Sustainable Development Goals. We define safe as ensuring the biophysical stability of the Earth system, and our justice principles include minimising harm, meeting minimum access needs, and redistributing resources and responsibilities to enhance human health and wellbeing. The ceiling of the safe and just corridor is defined by the more stringent of the safe and just ESBs to minimise significant harm and ensure Earth-system stability. The base of the corridor is defined by the impacts of minimum global access to food, water, energy, and infrastructure for the global population, in the domains of the variables for which we defined the ESBs. Living within the corridor is necessary, because exceeding the ESBs and not meeting basic needs threatens human health and life on Earth. However, simply staying within the corridor does not guarantee justice because within the corridor resources can also be inequitably distributed, aggravating human health and causing environmenta

Safe and just Earth system boundaries (ESBs) for surface water and groundwater (blue water) have been defined for sustainable water management in the Anthropocene. Here we assessed whether minimum human needs could be met with surface water from within individual river basins alone and, where this is not possible, quantified how much groundwater would be required. Approximately 2.6 billion people live in river basins where groundwater is needed because they are already outside the surface water ESB or have insufficient surface water to meet human needs and the ESB. Approximately 1.4 billion people live in river basins where demand-side transformations would be required as they either exceed the surface water ESB or face a decline in groundwater recharge and cannot meet minimum needs within the ESB. A further 1.5 billion people live in river basins outside the ESB, with insufficient surface water to meet minimum needs, requiring both supply- and demand-side transformations. These results highlight the challenges and opportunities of meeting even basic human access needs to water and protecting aquatic ecosystems.

The Paris Agreement has seen the adoption of a 1.5° to 2 °C climate target, based on the belief that climate change becomes ‘dangerous’ above this level. Since then, the scientific community and the countries most affected by global warming have reiterated that the maximum limit to be reached should be 1.5 °C. This paper goes one step further by questioning the reasoning behind the adoption of these targets, arguing that the fossil fuel-dependent political context in which they were adopted has undermined justice concerns. We highlight the political influence of the fossil fuels industry within target-setting negotiations, analyzing the evolution of climate targets and fossil fuel lobbying. We then harness published scientific evidence and the Earth System Justice framework to analyze the impacts of the 1.5 °C target, and the injustices that have so far been implicitly deemed acceptable. We argue that 1 °C would have been a far more just target and was undermined by vested interests and status quo maintenance. Finally, we propose just supply-side policies to ensure an adequate placement of responsibility on the fossil fuel industry. This way we (a) identify political influences and scientific blind spots that have and could continue to hinder climate action, (b) reveal how these influences delayed more ambitious climate objectives, contributing to the adoption of an unjust climate target, and (c) promote a focus on supply-side measures and polluting industries in order to break free from the impasse in the energy transition and foster more just outcomes.

Corporations are responsible for a significant portion of observed impacts on the Earth system, including green-house gas (GHG) emissions, but also water extraction, landuse change and other pressures on nature. These nature-related impacts are essential to consider and capture because they have local impacts on a range of ecosystem functions on which companies and economies depend, but they also fundamentally affect our ability to mitigate and adapt to a changing climate. Furthermore, climate, land and water interact and affect each other in various ways, such that climate change can be exacerbated by degraded ecosystems, which in turn are dependent on water. This paper tests a novel metric developed to capture corporate Earth system impact (ESI) beyond merely direct GHG emissions and explores how such a tool could be used to improve assessments of corporate environmental impacts and support decisions on where to direct public and private investments. We use the mining sector as a test case to illustrate the applicability of the ESI score and examine the impact of the the five largest (by market cap) mining companies in the precious metal mining sector and the top five in the non-precious metal mining sector. We find that many of the mining assets have non-negligible impacts on land and water, and we show that the ESI metric identifies a different set of asset for targeted action than conventional carbon intensity scores would do.

The CD30-postive lymphoproliferative disorders, including lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma, account for up to 30% of all cutaneous T-cell lymphomas (CTCLs) and are the second most common form of CTCLs after mycosis fungoides. Both conditions differ in their clinical presentations; however, they share the expression of the CD30 antigen as a common immunophenotypic hallmark. There is a wide spectrum of management options depending on factors such as extent of disease, staging and treatment tolerability. This Clinical Practice Statement is reflective of the current clinical practice in Australia.

Safe and just Earth system boundaries (ESBs) for surface water and groundwater (blue water) have been defined for sustainable water management in the Anthropocene. Here we assessed whether minimum human needs could be met with surface water from within individual river basins alone and, where this is not possible, quantified how much groundwater would be required. Approximately 2.6 billion people live in river basins where groundwater is needed because they are already outside the surface water ESB or have insufficient surface water to meet human needs and the ESB. Approximately 1.4 billion people live in river basins where demand-side transformations would be required as they either exceed the surface water ESB or face a decline in groundwater recharge and cannot meet minimum needs within the ESB. A further 1.5 billion people live in river basins outside the ESB, with insufficient surface water to meet minimum needs, requiring both supply- and demand-side transformations. These results highlight the challenges and opportunities of meeting even basic human access needs to water and protecting aquatic ecosystems.

Peripheral T-cell lymphomas (PTCL) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared with aggressive B-cell lymphomas. However, such outcomes are heavily dependent on subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine and prednisone remain the standard first-line treatment for most aggressive PTCL, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to understand better the pathogenesis of PTCL to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice.

BACKGROUND: Intestinal metaplasia (IM) is considered a key pivot point in the Correa model of gastric cancer (GC). It is histologically subtyped into the complete and incomplete subtypes, the latter being associated with a greater risk of progression. However, the clinical utility of IM subtyping remains unclear, partially due to the absence of reliable defining biomarkers. METHODS: Based on gene expression data and existing literature, we selected CD10 and Das1 as candidate biomarkers to distinguish complete and incomplete IM glands in tissues from patients without GC (IM-GC) and patients with GC (IM + GC). Immunohistochemical staining of individually subtyped IM glands was scored after blinding by two researchers using tissue belonging to both IM-GC and IM + GC patients. Whole tissue Das1 staining was further assessed using digital image quantification (cellSens Dimension, Olympus). RESULTS: Across both cohorts CD10 stained the IM brush border and was shown to have a high sensitivity (87.5% and 94.9% in IM-GC and IM + GC patients respectively) and specificity (100.0% and 96.7% respectively) with an overall AUROC of 0.944 for complete IM glands. By contrast Das1 stained mainly goblet cells and the apical membrane of epithelial cells, mostly of incomplete IM glands with a low sensitivity (28.6% and 29.3% in IM-GC and IM + GC patients respectively) but high specificity (98.3% and 85.1% respectively) and an overall AUROC of 0.603 for incomplete IM glands. A combined logistic regression model showed a significant increase in AUROC for detecting complete IM glands (0.955 vs 0.970). Whole tissue digital quantification of Das1 staining showed a significant association with incomplete IM compared to complete IM, both in IM-GC and in IM + GC patients (p = 0.016 and p = 0.009 respectively, Mann-Whitney test and unpaired t test used). Additionally, complete IM in IM + GC patients exhibited significantly more Das1 staining than in IM-GC patients (p = 0.019, Mann-Whitney test).

BACKGROUND: Aberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially contributing to differential responses to poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors. Spatial distribution of immune cells in a range of cancers identifies novel disease subtypes and is related to prognosis. In this study we aimed to determine the differences in the TIME of PCa with and without germline (g) HRR mutations. METHODS: We performed gene expression analysis, multiplex immunohistochemistry of T and B cells and quantitative spatial analysis of PCa samples from 36 patients with gHRD and 26 patients with sporadic PCa. Samples were archival tumor tissue from radical prostatectomies with the exception of one biopsy. Results were validated in several independent cohorts. RESULTS: Although the composition of the T cell and B cells was similar in the tumor areas of gHRD-mutated and sporadic tumors, the spatial profiles differed between these cohorts. We describe two T-cell spatial profiles across primary PCa, a clustered immune spatial (CIS) profile characterized by dense clusters of CD4+ T cells closely interacting with PD-L1+ cells, and a free immune spatial (FIS) profile of CD8+ cells in close proximity to tumor cells. gHRD tumors had a more T-cell inflamed microenvironment than sporadic tumors. The CIS profile was mainly observed in sporadic tumors, whereas a FIS profile was enriched in gHRD tumors. A FIS profile was associated with lower Gleason scores, smaller tumors and longer time to biochemical recurrence and metastasis. CONCLUSIONS: gHRD-mutated tumors have a distinct immune microenvironment compared with sporadic tumors. Spatial profiling of T-cells provides additional information beyond T-cell density and is associated with time to biochemical recurrence, time to metastasis

BACKGROUND: Lymphoma is a malignancy of lymphocytes and lymphoid tissues comprising a heterogeneous group of diseases, with up to 80 entities now described. Lymphoma is the 6th most common cancer in Australia, affecting patients of all ages, with rising incidence rates. With the proliferation of efficacious novel agents, therapeutic strategies are increasingly diverse and survival is improving. There is a clear need for contemporary robust and detailed data on diagnostic, investigational and management strategies for this disease in Australia, New Zealand and worldwide, to inform and benchmark local and international standards of care. Clinical quality registries can provide these data, and support development of strategies to address variations in management, including serving as platforms for clinical trials and other research activities. The Lymphoma and Related Diseases Registry (LaRDR) was developed to capture details of patient demographics, disease characteristics, and management throughout their disease course and therapy and to develop outcome benchmarks nationally and internationally for lymphoma. This report describes the aims, development and implementation of the LaRDR, as well as challenges addressed in the process. METHODS: The LaRDR was established in 2016 as a multicentre, collaborative project at sites across Australia with a secure online database which collects prospective data on patients with a new diagnosis of lymphoma or chronic lymphocytic leukaemia (CLL). LaRDR development required multidisciplinary participation including specialist haematology, information technology, and biostatistical support, as well as secure funding. Here we describe the database development, data entry, ethics approval process, registry governance and support for participating sites and the coordinating centre. RESULTS: To date more than 5,300 patients have been enrolled from 28 sites in Australia and New Zealand. Multiple challenges arose during the development, wh

Most NUTM1-rearranged neoplasms (NRNs) have fusions between NUTM1 and BRD (bromodomain-containing) family members and are termed NUT carcinomas (NCs) because they show some squamous differentiation. However, some NRNs are associated with fusions between NUTM1 and members of the MAD (MAX dimerization) gene family of MYC antagonists. Here we describe a small round cell malignancy from the gastro-esophageal junction with a previously unreported fusion between NUTM1 and the MAD family member MXI1. In contrast to NCs, the MXI1-NUTM1 tumor did not show squamous differentiation and did not express MYC, TP63 or SOX2, genes known to be targets of BRD-NUTM1 proteins and critical for NC oncogenesis. Transcriptome analysis showed paradoxical enrichment of MYC target genes in the MXI1-NUTM1 tumor despite the lack of MYC expression. When expressed in vitro MXI1-NUTM1 partially phenocopied MYC, enhancing cell proliferation and cooperating with oncogenic HRAS to produce anchorage-independent cell growth. These data provide evidence that MAD family members, which are normally repressors of MYC activity, can be converted into MYC-like mimics by fusion to NUTM1. The pathological features and novel oncogenic mechanism of the MXI1-NUTM1 tumor show that identification of NUTM1 fusion partners can be important for accurate diagnostic classification of some NRN subtypes, and potentially may guide therapeutic options.

Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared to aggressive B-cell lymphomas. However, such outcomes are heavily dependent upon subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remain the standard first-line treatment for most aggressive PTCLs, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to better understand the pathogenesis of PTCLs to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice. This article is protected by copyright. All rights reserved.

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MB

Keeping the Earth system in a stable and resilient state, to safeguard Earth's life support systems while ensuring that Earth's benefits, risks, and related responsibilities are equitably shared, constitutes the grand challenge for human development in the Anthropocene. Here, we describe a framework that the recently formed Earth Commission will use to define and quantify target ranges for a “safe and just corridor” that meets these goals. Although “safe” and “just” Earth system targets are interrelated, we see safe as primarily referring to a stable Earth system and just targets as being associated with meeting human needs and reducing exposure to risks. To align safe and just dimensions, we propose to address the equity dimensions of each safe target for Earth system regulating systems and processes. The more stringent of the safe or just target ranges then defines the corridor. Identifying levers of social transformation aimed at meeting the safe and just targets and challenges associated with translating the corridor to actors at multiple scales present scope for future work.

OBJECTIVE: Gastric cancer patients generally have a poor outcome, particularly those with advanced-stage disease which is defined by the increased invasion of cancer locally and is associated with higher metastatic potential. This study aimed to identify genes that were functional in the most fundamental hallmark of cancer, namely invasion. We then wanted to assess their value as biomarkers of gastric cancer progression and recurrence. DESIGN: Data from a cohort of patients profiled on cDNA expression arrays was interrogated using K-means analysis. This genomic approach classified the data based on patterns of gene expression allowing the identification of the genes most correlated with the invasion of GC. We evaluated the functional role of a key protein from this analysis in invasion and as a biomarker of recurrence after curative resection. RESULTS: Expression of secreted frizzled-related protein 4 (SFRP4) was identified as directly proportional to gastric cancer invasion. This finding was validated in multiple, independent datasets and its functional role in invasion was also confirmed using invasion assays. A change in serum levels of SFRP4 after curative resection, when coupled with AJCC stage, can accurately predict the risk of disease recurrence after curative therapy in an assay we termed PredictR. CONCLUSIONS: This simple ELISA-based assay can help predict recurrence of disease after curative gastric cancer surgery irrespective of adjuvant therapy. The results require further evaluation in a prospective trial but would help in the rational prescription of cancer therapies and surveillance to prevent under or over treatment of patients after curative resection.

Richter syndrome (RS), an aggressive lymphoma occurring in the context of chronic lymphocytic leukaemia/small lymphocytic lymphoma, is associated with poor prognosis when treated with conventional immunochemotherapy, therefore, improved treatments are required. Immune checkpoint blockade has shown efficacy in some B-cell malignancies and modest responses in early clinical trials for RS. We investigated the immune checkpoint profile of RS as a basis to inform rational therapeutic investigations in RS. Formalin-fixed, paraffin-embedded biopsies of RS (n = 19), de novo diffuse large B-cell lymphoma (DLBCL; n = 58), transformed indolent lymphomas (follicular [tFL], n = 16; marginal zone [tMZL], n = 24) and non-transformed small lymphocytic lymphoma (SLL; n = 15) underwent gene expression profiling using the NanoString Human Immunology panel. Copy number assessment was performed using next-generation sequencing. Immunohistochemistry (IHC) for LAG3 and PD-1 was performed. LAG3 gene expression was higher in RS compared to DLBCL (P = 0·0002, log2FC 1·96), tFL (P < 0·0001, log2FC 2·61), tMZL (P = 0·0004, log2FC 1·79) and SLL (P = 0·0057, log2FC 1·45). LAG3 gene expression correlated with the gene expression of human leukocyte antigen Class I and II, and related immune genes and immune checkpoints. IHC revealed LAG3 protein expression on both malignant RS cells and tumour-infiltrating lymphocytes. Our findings support the investigation of LAG3 inhibition to enhance anti-tumour responses in RS.

Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas with distinct clinical presentations, histopathologic features, treatment approaches and outcomes. The cutaneous T-cell lymphomas, which include mycosis fungoides and Sézary syndrome, account for the majority of the cutaneous lymphomas. This Clinical Practice Statement is reflective of the current clinical practice in Australia. An expanded form of the Clinical Practice Statement (and updates), along with helpful patient resources and access to support groups, can be found at the following (http://www.australasianlymphomaalliance.org.au).

Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas with distinct clinical presentations, histopathologic features, treatment approaches and outcomes. The cutaneous T-cell lymphomas, which include mycosis fungoides and Sezary syndrome, account for the majority of the cutaneous lymphomas. This Clinical Practice Statement is reflective of the current clinical practice in Australia. An expanded form of the Clinical Practice Statement (and updates), along with helpful patient resources and access to support groups, can be found at the following (http://www.australasianlymphomaalliance.org.au).Copyright © 2020 The Australasian College of Dermatologists

Purpose Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma-mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. Patients and Methods Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. Results Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation-positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. Conclusion BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit.Copyright © 2019 Am

Background and study aims There are limited longitudinal data regarding detection rates for sessile serrated adenoma/polyps (SSADR) and right-sided hyperplastic polyps (RHPDR) that constitute the proximal serrated lesion detection rate (PSLDR). Recently, a minimum PSLDR of 4.5 % has been suggested. This study was designed to assess SSADR, PSLDR and adenoma detection rate (ADR) for a newly qualified gastroenterologist and compare them to published data and to assess the change in SSADR, PSLDR and ADR over time for potential improvement with experience. Patients and methods All colonoscopies performed by a single colonoscopist (AM), at one Australian ambulatory direct-access endoscopy center over 4 years from 2011 to 2015 were retrospectively analyzed. Histology was reported by a single expert pathologist (SL). ADR, SSADR, RHPDR and PSLDR were recorded. Results A total of 841 colonoscopies were performed on 637 patients. Of them, 454 (54 %) were males. Mean age was 59 years. Of the colonoscopies, 87 % were performed for patients with ASA scores of 1 – 2, 422 (50.2 %) were for screening or surveillance, 374 (44.5 %) for investigation of symptoms and 45 (5.4 %) had therapeutic indications. Conventional adenomas were detected in 346 colonoscopies (ADR = 41.1 %), SSA/P in 124 (SSADR = 14.7 %) and RHP in the absence of SSA/P in 35 (RHPDR = 4.2 %). PSLDR was 18.9 %. ADR was stable over time (range 33 %-50 %). SSADR and PSLDR increased over time [SSADR: 8.6 % (2011), 8.4 % (2012), 14.9 % (2013), 18.5 % (2014), 25.0 % (2015); PSLDR: 10.5 % (2011), 11.3 % (2012), 16.8 % (2013), 27.2 % (2014), 29.4 % (2015)]. There was a statistically significant improvement in SSADR (IRR 1.37) and PSLDR (IRR 1.36) over the study period (P < 0.001), whereas the ADR remained stable (IRR 1.04, P = 0.334). Conclusions SSADR and PSLDR in this unselected direct-access cohort are high and exceed previously reported detection rates in the final 2 years. Detection rates improved with experi

Background: The Planetary Boundaries concept (PBc) has emerged as a key global sustainability concept in international sustainable development arenas. Initially presented as an agenda for global sustainability research, it now shows potential for sustainability governance. We use the fact that it is widely cited in scientific literature (>3500 citations) and an extensively studied concept to analyse how it has been used and developed since its first publication. Design: From the literature that cites the PBc, we select those articles that have the terms 'planetary boundaries' or 'safe operating space' in either title, abstract or keywords. We assume that this literature substantively engages with and develops the PBc. Results: We find that 6% of the citing literature engages with the concept. Within this fraction of the literature we distinguish commentaries—that discuss the context and challenges to implementing the PBc, articles that develop the core biogeophysical concept and articles that apply the concept by translating to sub-global scales and by adding a human component to it. Applied literature adds to the concept by explicitly including society through perspectives of impacts, needs, aspirations and behaviours. Discussion: Literature applying the concept does not yet include the more complex, diverse, cultural and behavioural facet of humanity that is implied in commentary literature. We suggest there is need for a positive framing of sustainability goals—as a Safe Operating Space rather than boundaries. Key scientific challenges include distinguishing generalised from context-specific knowledge, clarifying which processes are generalizable and which are scalable, and explicitly applying complex systems' knowledge in the application and development of the PBc. We envisage that opportunities to address these challenges will arise when more human social dimensions are integrated, as we learn to feed the global sustainability vision with a plurality of bottom

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.Copyright © 2018, The Author(s).

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare form of T-cell lymphoma that occurs after implantation of breast prostheses. We performed comprehensive next generation sequencing based genomic characterization of 11 cases of BIA-ALCL including sequence variant detection on 180 genes frequently mutated in haematological malignancy, genome-wide copy number assessment, structural variant detection involving the T-cell receptor loci and TRB deep-sequencing. We observed sequence variants leading to JAK/STAT activation in 10 out of 11 patients. We also observed germline TP53 mutations in two cases. In addition we detected a recurrent copy number loss involving RPL5 as well as copy number amplifications involving TNFRSF11A [RANK] (in 2 cases), MYC, P2RX7, TMEM119 and PDGFRA. In summary, our comprehensive genomic characterisation of 11 cases of BIA-ALCL has provided insight into potential pathobiological mechanisms (JAK/STAT, MYC and TP53) as well as identifying targets for future therapeutic intervention (TNFRSF11A, PDGFRA) in this rare entity.