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SummaryBackgroundTemporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma. MethodsThis open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0–1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was –0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16. FindingsBetween Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 [73%] male and 251 [27%] female; 885 [96%] White and 23 [3%] non-White). The median follow-up time was 58 months (IQR 46–73 months) in the ITT population and 58 months (46–72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 [95% CI 0·83 to 1·12] in the ITT population; 0·94 [0·80 to 1·09] in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 [95% CI –0·11 to 0·23] for the ITT population; 0·04 [–0·14 to 0·21] for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 [26%] of 485 patients in the conventional continuation strategy group vs 127 [29%] of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 [11%] vs 48 [11%]); and fatigue (39 [8%] vs 63 [15%]). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1). InterpretationOverall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma. FundingUK National Institute for Health and Care Research.

Background Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM. Methods Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS). Results The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population ( n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44–47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed. Conclusion Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).

Background Metastatic uveal melanoma (mUM) has a poor prognosis, with liver metastases typically presenting a therapeutic challenge. Melphalan/Hepatic Delivery System (Melphalan/HDS) is a drug/medical device combination used for liver-directed treatment of unresectable mUM patients. This study assessed efficacy and safety of Melphalan/HDS versus best alternative care (BAC). Methods Eligible patients with unresectable mUM were randomized (1:1) to receive Melphalan/HDS (3 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of 6 cycles or BAC. Due to slow enrollment and patient reluctance to receive BAC treatment, the study design was amended to a single-arm Melphalan/HDS study, and all efficacy analyses of the randomized study were treated as exploratory. Results The study enrolled 85 patients. Eligible patients were randomized to receive Melphalan/HDS ( n = 43) or BAC ( n = 42), and 72 patients received study treatment (Melphalan/HDS [ n = 40]; BAC [ n = 32]). Exploratory analyses of efficacy endpoints showed numerical differences consistently favoring the Melphalan/HDS arm versus BAC (median overall survival: 18.5 vs. 14.5 months; median progression-free survival: 9.1 vs. 3.3 months; objective response rate: 27.5% vs. 9.4%; and disease control rate: 80.0% vs. 46.9%). Serious adverse events (SAEs) occurred in 51.2% of Melphalan/HDS and in 21.9% of BAC patients. The most common (>5%) SAEs included thrombocytopenia (19.5%), neutropenia (9.8%), leukopenia (9.8%) and febrile neutropenia (7.3%) in Melphalan/HDS patients and cholecystitis, nausea and vomiting (6.3% each) in BAC patients. No treatment-related deaths were observed. Conclusion Treatment with Melphalan/HDS shows clinically meaningful efficacy and demonstrates a favorable benefit-risk profile in patients with unresectable mUM as compared to BAC.

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing for a detailed description of the somatic mutational landscape of ccRCC. We identify candidate driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for therapeutic interventions. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The observations that higher T-cell infiltration is associated with better overall survival and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients. The genomic landscape of clear cell renal cell carcinoma (ccRCC) remains to be comprehensively characterised. Here, whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project was used to identify potential drivers and clinical correlations to inform the development of therapies.

Eukaryotic initiation factor 4E (eIF4E) is an oncogene over-expressed in a variety of cancers. It is responsible for regulation of synthesis of proteins involved in progression to the malignant phenotype, including cyclin D1, Mcl-1 and VEGF. The oncogenic activity of eIF4E has been shown to be dependent on phosphorylation at serine 209 by the mitogen-activating protein kinase signal integrating kinases (MNKs). This work investigates the role of the MNK proteins in the proliferation and survival of breast and kidney cancer cells. Inhibition of the MNKs with a chemical kinase inhibitor resulted in inhibition of proliferation through cell cycle arrest, with no induction of apoptosis. This is consistent with a reduction in cyclin D1 protein. Combination of mTOR inhibition and inhibition of the MNK proteins in kidney cancer cells resulted in an additive but not synergistic effect on inhibition of proliferation. siRNA knockdown of the MNKs resulted in a reduction in eIF4E phosphorylation but did not inhibit proliferation or induce cell cycle arrest in a renal cancer cell line. The generation of an eIF4E mutant with phospho-mimetic activity induced partial insensitivity to the MNK kinase inhibitor suggesting some specificity of activity of this agent through the MNK proteins. Inhibition of the MNKs resulted in a reduction in cyclin D1 mRNA with no reduction in transcription. An accumulation of cyclin D1 RNA was seen in the nuclear compartment following treatment with MNK inhibitor suggesting inhibition of nuclear export of cyclin D1 RNA and subsequent degradation. Gene expression array analysis revealed regulation of genes with key functions in cellular metabolism. The MNK kinases are thus worthy of further investigation as a therapeutic target in breast and renal cancer. More potent and specific inhibitors of the MNK kinases than CGP57380 are required for this to be clinically relevant.

Background There is a growing body of literature supporting positive associations between natural environments and better health. The type, quality and quantity of green and blue space (‘green-space’) in proximity to the home might be particularly important for less mobile populations, such as for some older people. However, considerations of measurement and definition of green-space, beyond single aggregated metrics, are rare. This constitutes a major source of uncertainty in current understanding of public health benefits derived from natural environments. We aimed to improve our understanding of how such benefits are conferred to different demographic groups through a comprehensive evaluation of the physical and spatial characteristics of urban green infrastructure. Methods We employed a green infrastructure (GI) approach combining a high-resolution spatial dataset of land-cover and function with area-level demographic and socio-economic data. This allowed for a comprehensive characterization of a densely populated, polycentric city-region. We produced multiple GI attributes including, for example, urban vegetation health. We used a series of step-wise multi-level regression analyses to test associations between population chronic morbidity and the functional, physical and spatial components of GI across an urban socio-demographic gradient. Results GI attributes demonstrated associations with health in all socio-demographic contexts even where associations between health and overall green cover were non-significant. Associations varied by urban socio-demographic group. For areas characterised by having higher proportions of older people (‘older neighbourhoods’), associations with better health were exhibited by land-cover diversity, informal greenery and patch size in high income areas and by proximity to public parks and recreation land in low income areas. Quality of GI was a significant predictor of good health in areas of low income and low GI cover. Proximity of publicly accessible GI was also significant. Conclusions The influence of urban GI on population health is mediated by green-space form, quantity, accessibility, and vegetation health. People in urban neighbourhoods that are characterised by lower income and older age populations are disproportionately healthy if their neighbourhoods contain accessible, good quality public green-space. This has implications for strategies to decrease health inequalities and inform international initiatives, such as the World Health Organisation’s Age-Friendly Cities programme.

Since the late 2000s, the availability of high-quality cadmium zinc telluride (CdZnTe) has greatly increased. The excellent spectroscopic performance of this material has enabled the development of detectors with volumes exceeding 1 cm3 for use in the detection of nuclear materials. CdZnTe is also of great interest to the photon science community for applications in X-ray imaging cameras at synchrotron light sources and free electron lasers. Historically, spatial variations in the crystal properties and temporal instabilities under high-intensity irradiation has limited the use of CdZnTe detectors in these applications. Recently, Redlen Technologies have developed high-flux-capable CdZnTe material (HF-CdZnTe), which promises improved spatial and temporal stability. In this paper, the results of the characterization of 10 HF-CdZnTe detectors with dimensions of 20.35 mm × 20.45 mm × 2.00 mm are presented. Each sensor has 80 × 80 pixels on a 250-μm pitch and were flip-chip-bonded to the STFC HEXITEC ASIC. These devices show excellent spectroscopic performance at room temperature, with an average Full Width at Half Maximum (FWHM) of 0.83 keV measured at 59.54 keV. The effect of tellurium inclusions in these devices was found to be negligible; however, some detectors did show significant concentrations of scratches and dislocation walls. An investigation of the detector stability over 12 h of continuous operation showed negligible changes in performance.