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Individuals appraise events as a consequence of their own actions (i.e. internal locus of control, LoC) or as the outcome of chance or others' will (i.e. external LoC). We hypothesized that having a more external LoC would be associated with higher risk of tobacco and alcohol use. Few studies have examined this association using large prospective data. We evaluated within the Avon Longitudinal Study of Parents and Children (ALSPAC) the associations between LoC at 16 and tobacco and alcohol consumption at 17 and 21 years using logistic regression. A more external LoC at age 16 (N = 4656) was associated with higher odds of being a weekly smoker at age 17 (OR 1.18, 95% CI 1.10–1.25) and 21 (OR 1.14, 95% CI 1.07–1.21) and with dependence measured using the Fagerström Test of Nicotine Dependence at age 17 (OR 1.26, 95% CI 1.05–1.51) and 21 (OR 1.25, 95% CI 1.05–1.49). Individuals with external LoC at age 16 were more likely to be hazardous drinkers according to the Alcohol Use Disorders Identification Test at age 17 (OR 1.09, 95% CI 1.04–1.15) but not at 21 (OR 1.01, 95% CI 0.96–1.06). Having a more external LoC at age 16 is associated with increased tobacco consumption at age 17 and 21 and alcohol consumption at 17 years. LoC may represent an intervention target for preventing substance use and dependence.

Abstract Introduction?? Weight loss is an independent prognostic factor for decreased survival in cancer patients. The effectiveness of treatment is impaired in patients with weight loss. The aetiology of this weight loss is complex and poorly characterised. Decreased calorie intake may be important. The reasons for decreased intake are unknown. Aims and methods?? To determine in adult patients with cancer, who had not started chemotherapy or radiotherapy, the prevalence of symptoms which carry a risk to nutritional status and how these relate to weight loss, tumour burden and primary tumour site. New patients referred for treatment of any form of gastrointestinal (GI) cancer, non-small cell lung cancer or lung mesothelioma completed a validated questionnaire recording symptoms contributing to weight loss (Patient-generated Subjective Global Assessment?PG-SGA). In a subset of patients without metastatic disease, computed tomography scans were assessed to determine tumour burden. Results?? Between August and October 2004, 122 patients with GI and 29 with lung cancers were recruited. There were 48% of GI and 28% of lung cancer patients who had lost weight. Sixty-two percent of the patients had one or more symptoms at presentation. The frequency of symptoms varied according to the site of disease. The most common symptom at all tumour sites was loss of appetite (38%). There was a weak but significant correlation between the number of symptoms and amount of weight loss (r=0.347). Patients reporting a reduced food intake had more symptoms than patients who had not lost weight. Tumour burden did not correlate with weight loss. Conclusion?? The symptoms in cancer patients occur across different types of primary tumours, may affect food intake and have a part in causing weight loss. More information on the role of symptom management in improving nutritional status is needed. [ABSTRACT FROM AUTHOR]

To examine the risk of lung cancer associated with the codon 72, intron 6 and intron 3 TP53 polymorphisms a meta-analysis of published case-control studies was undertaken. The principle outcome measure was the odds ratio (OR) for the risk of lung cancer using homozygosity of the 'wild-type allele' as the reference group. Data from 13 studies detailing the relationship between lung cancer and the codon 72 polymorphism of TP53 and three studies examining the intron 3 and 6 polymorphisms of TP53 were analysed. The ORs of lung cancer associated with the Pro-Pro and Pro-carrier genotypes of codon 72 were 1.18 [95% confidence interval (CI) 0.99-1.41] and 1.02 (95% CI 0.86-1.20), respectively. The ORs of lung cancer associated with homozygous and variant allele carrier genotypes of the intron 6 (MspI RFLP) polymorphism were 1.13 (95% CI 0.55-2.27) and 1.30 (95% CI 0.75-2.26) and of the intron 3 (16 bp duplication) polymorphism were 1.50 (95% CI 0.76-2.97) and 1.11 (95% CI 0.53-2.35), respectively. Although polymorphic variations in TP53 represent attractive candidate susceptibility alleles for lung cancer the results from this analysis provide little support for this hypothesis. Additional well-designed studies based on sample sizes commensurate with the detection of small genotypic risks may allow a more definitive conclusion. [ABSTRACT FROM AUTHOR]

Background: There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy., Trial Design: A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma., Methods: Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals., Interventions: At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death., Objective: To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years., Co-Primary Outcomes: For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire., Results: Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years., Limitations: The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison., Future Work: Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma., Conclusions: Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible., Trial Registration: This trial is registered as ISRCTN06473203., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment ; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Temporary 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., Methods: This 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., Findings: Between 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)., Interpretation: Overall, 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., Funding: UK National Institute for Health and Care Research., Competing Interests: Declaration of interests JEB reports having served as a consultant or adviser for Novartis, Ipsen, Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, and Bayer; honoraria from Novartis, Ipsen, Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, and Bayer; research funding paid to their institution from the National Institute for Health and Care Research; and travel expenses from Ipsen. WG reports consulting fees from Janssen and AbbVie. CR reports honoraria from Bristol-Myers Squibb and Wisai. TE reports trusteeship of Kidney Cancer UK and MacMillan Cancer Support. PN reports consulting fees from Novartis, Agensis, Ionctura, Bristol-Myers Squibb, 4SC, Pfizer, Merck Sharp & Dohme, and Merck; honoraria from Novartis and Immunocore; travel, accommodation, and expenses from Immunocore; membership of REFINE Data Safety Monitoring Board; and trusteeship of Melanoma Focus. TP reports consulting fees from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Seattle Genetics, and Mashup; honoraria from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Seattle Genetics; research funding paid to their institution from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Seattle Genetics; and travel expenses from AstraZeneca, Ipsen, Merck Sharp & Dohme, Pfizer, and Roche. RJ reports consulting fees from Astellas Pharma, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche; honoraria from Astellas Pharma, Bayer, Bristol- Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Pfizer, Roche; research funding paid to their institution from Astellas Pharma, Clovis, Exelixis, and Bayer; and participation in a data safety monitoring board for Roche. NV reports consultancy fees from Bristol-Myers Squibb, 4D Pharma, and Merck Serono; honoraria from Bristol-Myers Squibb, EUSA Pharma, Eisai, and Ipsen; and travel expenses from Ipsen. MW reports consultancy fees from Bristol-Myers Squibb and Sciensus; honoraria from Eisai and Ipsen; and travel expenses from Bristol-Myers Squibb. TW reports honoraria from Bristol-Myers Squibb, Pfizer, Eisai, and Ipsen; travel expenses from Bristol-Myers Squibb, EUSA Pharma, and Ipsen; and participation on data safety monitoring boards for Bristol-Myers Squibb, Pfizer, Eisai, Ipsen, and Merck Sharp & Dohme. RM reports travel expenses from Janssen. PP reports research funding paid to their institution from Pfizer. JL reports consultancy fees from iOnctura, Apple Tree, Merck, Bristol-Myers Squibb, Eisai, Debipharm, and Incyte; honoraria from Eisai, Novartis, Incyte, Merck, TouchIME, TouchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare, Royal College of General Practioners, VJ Oncology, and Agence Unik; research funding paid to their institution from Achilles, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, Novartis, Pfizer, Immunocore, Roche, Aveo, and Pharmacyclics; and travel expenses from Pierre Fabre, Roche, and GlaxoSmithKline. GF reports consultancy fees from Bristol-Myers Squibb and Pfizer; honoraria from Bristol-Myers Squibb, Merck, and Pfizer; and travel expenses from Novartis and Bayer. DM reports funding from Otsuka and AbbVie to their institution; being a sub-panel member for the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research; and being a member of a National Institute for Health and Care Excellence Technology Appraisal Committee. VG reports funding from Siemens Healthineers to their institution. TMW reports research funding paid to their institution from Boston Scientific and Angidynamics. JBr reports being Chair of the NIHR Health Technology Assessment General Funding Committee and NIHR Health Technology Assessment funding paid to their institution. JH reports funding to their institution from the NIHR Health Technology Assessment. PS reports funding from an NIHR Senior Fellowship, European Research Council Advanced Awards; travel expenses from the European School of Oncology Training; and several patents on the development of DNA library cancer vaccines. FC reports honoraria from Bayer. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor., Methods: NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity., Results: In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype., Conclusions: NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery., Clinical Trial Registration: NCT03494816., (© 2022. The Author(s).)

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.

Purpose: The 2003 Leibovich score guides prognostication and selection to adjuvant clinical trials for patients with locally advanced renal cell carcinoma (RCC) after nephrectomy. We provide a robust external validation of the 2003 Leibovich score using contemporary data from SORCE, an international, randomized trial of sorafenib after excision of primary RCC., Methods: Data used to derive the 2003 Leibovich score were compared with contemporary data from SORCE. Discrimination and calibration of the metastasis-free survival outcome were assessed in data from patients with clear-cell RCC, using Cox proportional hazards regression, Kaplan-Meier curves, and calculation of Harrell's c indexes. Secondary analyses involved three important SORCE groups: patients with any non-clear-cell subtype, papillary, and chromophobe carcinomas., Results: Four hundred seven recurrences occurred in 982 patients in the Leibovich cohort and 520 recurrences were recorded in 1,445 patients in the primary SORCE cohort. Clear discrimination between intermediate-risk and high-risk SORCE cohorts was shown; hazard ratio 2.74 (95% CI, 2.29 to 3.28), c-index 0.63 (95% CI, 0.61 to 0.65). A hazard ratio of 0.61 (95% CI, 0.53 to 0.70) confirmed poor calibration of the two cohorts. Discrimination was observed in secondary populations, with c-indexes of 0.64 (95% CI, 0.59 to 0.69) for non-clear-cell RCC, 0.63 (95% CI, 0.56 to 0.69) for papillary RCC, and 0.65 (95% CI, 0.55 to 0.76) for chromophobe RCC., Conclusion: The 2003 Leibovich score discriminates between intermediate-risk and high-risk clear-cell and non-clear-cell RCC groups in contemporary data, supporting its use for risk stratification in adjuvant clinical trials. Over time, metastasis-free survival for patients with locally advanced RCC has improved. Contemporary data from adjuvant RCC trials should be used to improve prognostication for patients with RCC., Competing Interests: Tim EisenEmployment: AstraZeneca, RocheLeadership: AstraZeneca, RocheStock and Other Ownership Interests: AstraZeneca, RocheResearch Funding: Bayer (Inst), Pfizer (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: AstraZeneca, RocheOther Relationship: Macmillan Cancer Support, Kidney Cancer UK Grant D. StewartHonoraria: Pfizer, Merck, EUSA PharmaConsulting or Advisory Role: Pfizer, Merck, EUSA Pharma, CMR SurgicalSpeakers' Bureau: PfizerResearch Funding: Pfizer, AstraZeneca, Intuitive Surgical, CRUKTravel, Accommodations, Expenses: Pfizer Axel BexConsulting or Advisory Role: Pfizer (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Ipsen (Inst), Eisai (Inst), Genentech (Inst)Speakers' Bureau: Pfizer, Novartis, Bristol Myers SquibbResearch Funding: Pfizer (Inst) Rick KaplanResearch Funding: AstraZeneca (Inst) Ian D. DavisResearch Funding: Astellas Pharma (Inst), Pfizer (Inst), Roche/Genentech (Inst), MSD Oncology (Inst), AstraZeneca (Inst), Janssen Oncology (Inst), Eisai (Inst), Bayer (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Movember Foundation (Inst), Exelixis (Inst), Ipsen (Inst), Medivation (Inst), Seattle Genetics (Inst), ANZUP Cancer Trials GroupPatents, Royalties, Other Intellectual Property: International Patent Application No: PCT/US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research Martin R. StocklerResearch Funding: Astellas Pharma (Inst), Celgene (Inst), Bayer (Inst), Bionomics (Inst), Medivation (Inst), Sanofi (Inst), Pfizer (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Roche (Inst), Amgen (Inst), Merck Sharp & Dohme (Inst), Tilray (Inst), BeiGene (Inst)Travel, Accommodations, Expenses: Medivation/Pfizer Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Amgen (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Exelixis (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Peloton Therapeutics (Inst), Bellerophon Theraeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Bernard EscudierHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, OncorenaConsulting or Advisory Role: Pfizer, Bristol Myers Squibb, Ipsen, AVEO, OncorenaResearch Funding: BMS France (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Ipsen, MSD James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais Steven JoniauConsulting or Advisory Role: Janssen, AstraZeneca, Bayer, Astellas PharmaSpeakers' Bureau: Astellas Pharma, Janssen, IpsenResearch Funding: Janssen (Inst), Astellas Pharma (Inst), Ipsen (Inst), Bayer (Inst), Ferring (Inst)Travel, Accommodations, Expenses: Janssen, Ipsen, Astellas Pharma, Ferring Joaquim BellmuntStock and Other Ownership Interests: Rainier TherapeuticsHonoraria: UpToDateConsulting or Advisory Role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, Bristol Myers SquibbResearch Funding: Millennium (Inst), Sanofi (Inst), Pfizer/EMD Serono (Inst)Travel, Accommodations, Expenses: Pfizer, MSD Oncology, Ipsen Mahesh K.B. ParmarResearch Funding: AstraZeneca (Inst), Astellas Pharma (Inst), Janssen (Inst), Clovis Oncology (Inst) Angela MeadeResearch Funding: AstraZeneca (Inst)No other potential conflicts of interest were reported. Tim EisenEmployment: AstraZeneca, RocheLeadership: AstraZeneca, RocheStock and Other Ownership Interests: AstraZeneca, RocheResearch Funding: Bayer (Inst), Pfizer (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: AstraZeneca, RocheOther Relationship: Macmillan Cancer Support, Kidney Cancer UK Grant D. StewartHonoraria: Pfizer, Merck, EUSA PharmaConsulting or Advisory Role: Pfizer, Merck, EUSA Pharma, CMR SurgicalSpeakers' Bureau: PfizerResearch Funding: Pfizer, AstraZeneca, Intuitive Surgical, CRUKTravel, Accommodations, Expenses: Pfizer Axel BexConsulting or Advisory Role: Pfizer (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Ipsen (Inst), Eisai (Inst), Genentech (Inst)Speakers' Bureau: Pfizer, Novartis, Bristol Myers SquibbResearch Funding: Pfizer (Inst) Rick KaplanResearch Funding: AstraZeneca (Inst) Ian D. DavisResearch Funding: Astellas Pharma (Inst), Pfizer (Inst), Roche/Genentech (Inst), MSD Oncology (Inst), AstraZeneca (Inst), Janssen Oncology (Inst), Eisai (Inst), Bayer (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Movember Foundation (Inst), Exelixis (Inst), Ipsen (Inst), Medivation (Inst), Seattle Genetics (Inst), ANZUP Cancer Trials GroupPatents, Royalties, Other Intellectual Property: International Patent Application No: PCT/US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research Martin R. StocklerResearch Funding: Astellas Pharma (Inst), Celgene (Inst), Bayer (Inst), Bionomics (Inst), Medivation (Inst), Sanofi (Inst), Pfizer (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Roche (Inst), Amgen (Inst), Merck Sharp & Dohme (Inst), Tilray (Inst), BeiGene (Inst)Travel, Accommodations, Expenses: Medivation/Pfizer Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Amgen (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Exelixis (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Peloton Therapeutics (Inst), Bellerophon Theraeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Bernard EscudierHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, OncorenaConsulting or Advisory Role: Pfizer, Bristol Myers Squibb, Ipsen, AVEO, OncorenaResearch Funding: BMS France (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Ipsen, MSD James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais Steven JoniauConsulting or Advisory Role: Janssen, AstraZeneca, Bayer, Astellas PharmaSpeakers' Bureau: Astellas Pharma, Janssen, IpsenResearch Funding: Janssen (Inst), Astellas Pharma (Inst), Ipsen (Inst), Bayer (Inst), Ferring (Inst)Travel, Accommodations, Expenses: Janssen, Ipsen, Astellas Pharma, Ferring Joaquim BellmuntStock and Other Ownership Interests: Rainier TherapeuticsHonoraria: UpToDateConsulting or Advisory Role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, Bristol Myers SquibbResearch Funding: Millennium (Inst), Sanofi (Inst), Pfizer/EMD Serono (Inst)Travel, Accommodations, Expenses: Pfizer, MSD Oncology, Ipsen Mahesh K.B. ParmarResearch Funding: AstraZeneca (Inst), Astellas Pharma (Inst), Janssen (Inst), Clovis Oncology (Inst) Angela MeadeResearch Funding: AstraZeneca (Inst)No other potential conflicts of interest were reported.

Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1- 13 C]pyruvate (HP- 13 C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP- 13 C-MRI and conventional proton ( 1 H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant ( k PL ) between 13 C-pyruvate and 13 C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing k PL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional 1 H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset ( p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP- 13 C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP- 13 C-MRI may non-invasively characterize metabolic phenotypes within renal cancer.

Objective: This study offers direction for interaction between physical therapists and patients about cancer-related pain during physical training. The study may increase awareness of rehabilitation strategies for cancer-related pain during and after cancer treatment. Methods: Qualitative study, evaluating results of two qualitative studies. Data has been collected using semi-structured interviews, in which topics were discussed with patients and physical therapists. Respondents were adult patients with cancer in the Northern Netherlands with moderate to severe pain who followed physical training with a (oncologic) physical therapist. The physical therapists were respondents specialized in oncology and working with patients with cancer in a primary care setting in in the Netherlands. Data were analyzed using thematic analysis. Results: Eighteen patients and fifteen physical therapists were interviewed. Data was categorized in statements regarding "patients' needs", "patients' experiences" and "clinical reasoning of the physical therapist". "Patients' needs" for education were personal and included needs for information about the cause, course and effect of pain in relation to cancer and/or medical treatment, needs for practical tools for reducing pain, needs for strategies dealing with pain in daily activities, and needs for information about additional treatment and care options. When discussing 'patients' experiences', patients mentioned that physical therapists are cautious to express their expectations of the progress of pain and to offer pain education with respect to the cause of pain, dealing with pain and limitations in daily life, exercising, posture, learning self-care and information about additional treatment and care options in cancer-related pain. Patients provided insight into their educational, mental, and social support relative to experiences with physical therapists. Additionally, when discussing the communication they experienced with physical therapists, patients used descriptors such as accessibility, empathy, trust, knowledge and eliminating uncertainties. Interviews with physical therapists regarding their clinical reasoning process in cancer-related pain described that they identified pain from anamnesis (medical history review) and performed screening and analysis for pain secondary to cancer (treatment), as type of pain and pain influencing factors. Thoughts and experiences about pain, the use of pain clinometry, the establishment of objectives and interventions for physical therapy and multidisciplinary treatment of cancer-related pain were also described. Conclusion: Patients with cancer-related pain during physical training have personal needs regarding pain education and experience that specialized oncologic physical therapists focus on patient-centered information and self-management support. Specialized oncologic physical therapists analyze pain in the anamnesis and keep in mind the origin and impact of pain for the patient during screening and treatment. Different methods of pain management are used. It is recommended that physical therapists who give physical training take the initiative to repeatedly discuss pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Eisen, Kooijstra, Groeneweg, Verseveld and Hidding.)

Introduction: Pharmacological combinations using immune checkpoint inhibition (ICI), tyrosine kinase inhibition (TKIs), and mammalian target of rapamycin inhibitors (mTOR) have improved survival in metastatic clear cell renal cell cancer (mccRCC). Despite improvements in survival, complete durable responses are rare., Areas Covered: Molecular pathways involved in mccRCC and drugs targets are highlighted. The background and rationale for combination therapy are covered. Results from combination trials are reviewed and potential approaches with biomarker-stratified treatment and novel experimental agents are examined. PubMed Central and ClinicalTrials.gov were searched. Search terms used to identify clinical trials were '(metastatic renal cell cancer OR renal cell carcinoma OR mccRCC OR mRCC OR RCC OR kidney cancer) AND (combination OR combined).', Expert Opinion: First-line standard of care has moved to combination therapy with ICI-ICI and TKI-ICI combinations; VEGF-mTORi is available in subsequent lines. Combining targeted treatments without validated biomarkers is imprecise, and combinations may lead to overtreatment of a subset of patients, exposing them to unnecessary toxicity. The aim of combinations must be clear: improvement in overall survival (OS) and complete response (CR). Recent data suggest a role for novel biomarker stratification rather traditional risk groups. Further combination approaches with triplets and quadruplets should be biomarker directed.

Background: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7 th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE)., Methods: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by K trans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging., Discussion: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda., Trial Registration: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 ., (© 2021. The Author(s).)

Purpose: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI., Method: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival., Results: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001)., Conclusions: Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS., Trial Registration: EudraCtNo: 2005-004502-82., Competing Interests: The authors have read the journal’s policy and have the following competing interests: ANP has received a speaker fee and travel expenses from GE Healthcare. SJW has received travel expenses from IPSEN. GDS has received educational grants from Pfizer, Astra Zeneca, and Intuitive Surgical; consultancy fees from Merck, Pfizer, EUSA Pharma and CMR Surgical; travel expenses and speaker fees from Pfizer. AW received a single Scientific Advisory Board fee from Roche. TE has received research support from Pfizer and AstraZeneca, and honoraria from Pfizer. TE was employed by AstraZeneca during part of the study duration and is now employed by Roche, and holds stock in AstraZeneca and Roche. Pfizer provided the study drug Sunitinib and an educational grant for the translational endpoint analysis, reported separately. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intention-to-treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1α, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.

Background: The NLST reported a significant 20% reduction in lung cancer mortality with three annual low-dose CT (LDCT) screens and the Dutch-Belgian NELSON trial indicates a similar reduction. We present the results of the UKLS trial., Methods: From October 2011 to February 2013, we randomly allocated 4 055 participants to either a single invitation to screening with LDCT or to no screening (usual care). Eligible participants (aged 50-75) had a risk score (LLPv2) ≥ 4.5% of developing lung cancer over five years. Data were collected on lung cancer cases to 31 December 2019 and deaths to 29 February 2020 through linkage to national registries. The primary outcome was mortality due to lung cancer. We included our results in a random-effects meta-analysis to provide a synthesis of the latest randomised trial evidence., Findings: 1 987 participants in the intervention and 1 981 in the usual care arms were followed for a median of 7.3 years (IQR 7.1-7.6), 86 cancers were diagnosed in the LDCT arm and 75 in the control arm. 30 lung cancer deaths were reported in the screening arm, 46 in the control arm, (relative rate 0.65 [95% CI 0.41-1.02]; p=0.062). The meta-analysis indicated a significant reduction in lung cancer mortality with a pooled overall relative rate of 0.84 (95% CI 0.76-0.92) from nine eligible trials., Interpretation: The UKLS trial of single LDCT indicates a reduction of lung cancer death of similar magnitude to the NELSON and NLST trials and was included in a meta-analysis of nine randomised trials which provides unequivocal support for lung cancer screening in identified risk groups., Funding: NIHR Health Technology Assessment programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation., Competing Interests: JKF has received fees from AstraZeneca (Speaker's Bureau) and advisory boards of Epigenomics; NUCLEIX Ltd. AstraZeneca, iDNA; Grant Support: Janssen Research & Development, LLC. RCR is on the advisory boards of AstraZeneca and Roche. DRB has received speaker remuneration from AstraZeneca, Roche, MSD, BMS, Johnson and Johnson. KB has received personal fees from Astra Zeneca outside the submitted work. TE receives research support from AstraZeneca, Bayer, Pfizer; is employed by Roche (from March 2020) and was employed by AstraZeneca (to March 2020) and has stock in AstraZeneca and Roche; is a trustee of Macmillan Cancer Support.  AN has current grants and contracts with BRC, DART; Honoraria Aidence BV, AstraZeneca; Support from BLF, and as the clinical lead for NTLHC. No competing interests from all other co-authors., (© 2021 The Authors.)

The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations. Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39. CTA #: 20363/0380/001-0001. MREC #: 17/LO/1875. ClinicalTrials.gov Identifier: NCT03288532 RAMPART grant number: MC&#95;UU&#95;12023/25. . RAMPART Protocol version 5.0., (Copyright © 2021. Published by Elsevier Inc.)

Background: 20-60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting., Methods/design: RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3-11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART)., Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39, CTA #: 20363/0380/001-0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532, RAMPART grant number: MC&#95;UU&#95;12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Purpose: Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib., Patients and Methods: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS)., Results: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib., Conclusions: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN., (©2021 American Association for Cancer Research.)