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Ranking metrics in network meta-analysis (NMA) are computed separately for each outcome. Our aim is to 1) present graphical ways to group competing interventions considering multiple outcomes and 2) use conjoint analysis for placing weights on the various outcomes based on the stakeholders' preferences.We used multidimensional scaling (MDS) and hierarchical tree clustering to visualize the extent of similarity of interventions in terms of the relative effects they produce through a random effects NMA. We reanalyzed a published network of 212 psychosis trials taking three outcomes into account: reduction in symptoms of schizophrenia, all-cause treatment discontinuation and weight gain.Conjoint analysis provides a mathematical method to transform judgements into weights that can be subsequently used to visually represent interventions on a two-dimensional plane or through a dendrogram. These plots provide insightful information about the clustering of interventions.Grouping interventions can help decision makers not only to identify the optimal ones in terms of benefit-risk balance but also choose one from the best cluster based on other grounds such as cost, implementation etc. Placing weights on outcomes allows considering patient profile or preferences.

We report on silicified trilobite sclerites with associated silicified biofilm from the Cambrian Weeks Formation, Utah (USA), that support a role for microbial biofilms in silicification. Silicified sclerites are typically small (500 µm) of silica-cemented matrix. High-resolution scanning electron microscope (SEM) study reveals the presence of two different forms of carbon-rich threads, ribbons and mats, coating both sclerites and silica-cemented matrix. Crystalline-looking biofilm threads and ribbons composed of Si, O, and C are interpreted as silicified biofilm associated with the trilobite silicification. Rippled to smooth biofilm mats composed of more C, less Si and O, and a trace of N are post-silicification. Embedded in the silica of the sclerites and matrix are molds of framboids that we interpret as originally framboidal pyrite that was engulfed by silica. These data indicate that silica precipitation continued into the surrounding matrix following the propagation of sulfate-reducing bacteria feeding on the organic matter present in the sclerite and the neighboring sediment. This strongly supports the model that bacterially mediated decay is key to the silicification of carbonate bioclasts and provides the first direct evidence of a microbial community (biofilm). A literature review reveals that silica extends past the fossil more frequently than is recognized, suggesting that silicified biofilm might be common but overlooked.

To establish whether items included in instruments published in the last decade assessing risk of bias of randomized controlled trials (RCTs) are indeed addressing risk of bias.We searched Medline, Embase, Web of Science, and Scopus from 2010 to October 2021 for instruments assessing risk of bias of RCTs. By extracting items and summarizing their essential content, we generated an item list. Items that two reviewers agreed clearly did not address risk of bias were excluded. We included the remaining items in a survey in which 13 experts judged the issue each item is addressing: risk of bias, applicability, random error, reporting quality, or none of the above.Seventeen eligible instruments included 127 unique items. After excluding 61 items deemed as clearly not addressing risk of bias, the item classification survey included 66 items, of which the majority of respondents deemed 20 items (30.3%) as addressing risk of bias; the majority deemed 11 (16.7%) as not addressing risk of bias; and there proved substantial disagreement for 35 (53.0%) items.Existing risk of bias instruments frequently include items that do not address risk of bias. For many items, experts disagree on whether or not they are addressing risk of bias.

International audience; A numerical FEM (Finite Element Method) model was implemented to represent the mechanical state of the wooden panel of the Mona Lisa, as it is conserved in its exhibition case, and constrained in its auxiliary frame. The model is based on the integration of advanced numerical analysis and various experimental examinations carried out non-invasively on the artwork by the authors during over 15 years. This includes visual, microscopic and X-ray observations together with mechanical measurements and monitoring of panel deformations and constraining external forces. In addition to the development of non-invasive techniques to characterise the mechanical properties of the panel, the FEM model reliably evaluated the strains and stresses generated in the panel by the various actions it experiences. The paper consists of the following parts: (i) a short summary of the experimental measurements and other observations, (ii) a detailed description of the FEM numerical model, of the hypotheses it is based on, and of its advantages and limits, (iii) the main results obtained by running the model. This includes the identification of local strains and stresses, the location of most critical areas, an evaluation of the risk that the existing ancient crack may propagate, and an evaluation of safe ranges for the forces acting on the wooden panel, (iv) the validation criteria for such results, and (v) a discussion about the significance of the mechanical model.

[Background] Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC)., [Objective] To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and circulating tumor DNA (ctDNA) in the ABACUS trial., [Design, setting, and participants] ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy., [Intervention] Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected., [Outcome measurements and statistical analysis] The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements., [Results and limitations] The median follow-up time was 25 mo (95% confidence interval [CI] 25–26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21–41). Two-year DFS and OS were 68% (95% CI 58–76) and 77% (95% CI 68–85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65–94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio [HR] 0.60 [95% CI 0.24–1.5], p = 0.26, and 0.72 [95% CI 0.31–1.7], p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 [95% CI 0.09–0.68], p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 [95% CI 1.3–13], p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work., [Conclusions] Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future, [Patient summary] We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy., Bernadett Szabados—research funding from MSD and Roche; honoraria from Roche, MSD, and BMS. Mark Kockx—employee of CellCarta. Zoe June Assaf—employee of Roche. Pieter-Jan van Dam—employee of CellCarta. Alejo Rodriguez-Vida—research funding and honoraria from Roche, BMS, and Pfizer; research funding from Novartis and Astellas. Ignacio Duran—research funding and honoraria from Roche, BMS, Pfizer, and Johnson & Johnson; research funding from Astellas. Simon J. Crabb—research funding and honoraria from Roche, MSD, Pfizer, Exelixis, and Clovis. Michiel S. Van Der Heijden—research funding and honoraria from BMS, AstraZeneca, MSD, Novartis, Pfizer, MSD, and Seattle Genetics. Albert Font Pous—research funding and honoraria from MSD, Pfizer, and Astellas. Gwenaelle Gravis—research funding and honoraria from Roche, AstraZeneca, Pfizer, and Astellas. Urbano Anido Herranz—research funding and honoraria from Roche, MSD, Exelixis, and Astellas. Andrew Prothoroe—research funding and honoraria from Astellas, Pfizer, Novartis, and BMS. Alain Ravaud—research funding and honoraria from MSD, Roche, BMS, and Pfizer. Denis Maillet—research funding and honoraria from MSD and Roche. Maria Jose Mendez—research funding and honoraria from Roche and Pfizer. Cristina Suarez—research funding and honoraria from Pfizer, BMS, Roche, AstraZeneca, and Astellas. Mark Linch—research funding and honoraria from BMS, Roche, Pfizer, Astellas, and AstraZeneca. Aaron Prendergast and Charlotte Tyson—no conflicts. Diana Stanoeva, Sofie Daelemans, and Miche Rombouts— employee of CellCarta. Sanjeev Mariathasan—employee of Genentech. Joy S. Tea—employee of Roche. Kelly Mousa—no conflicts. Romain Banchereau—employee of Genentech. Daniel Castellano—research funding and honoraria from Astellas, BMS, Roche, and AstraZeneca. Thomas Powles—honoraria from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; research funding from AstraZeneca, BMS, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; travel/accommodation/expenses from Roche, Pfizer, MSD, AstraZeneca, and Ipsen.

Cabozantinib is an oral tyrosine kinase inhibitor (TKI) with activity against several receptors involved in the angiogenesis pathway, including vascular endothelial growth factor receptor (VEGFR), c-MET and AXL. The antiangiogenic properties of cabozantinib led to its use as a monotherapy for the treatment of metastatic renal cell cancer (RCC), and quickly resulted in this treatment becoming part of the standard of care for these tumors. Since the advent of immune checkpoint inhibitors (ICIs), new standards of care have emerged in first-line settings, involving dual ICI or ICI-VEGF-TKI (including ICI-cabozantinib) combination treatments, and leading to a more complex algorithm of care. Cabozantinib remains an option in second-line settings and is still a first-line standard of care treatment in cases where the use of ICIs is contraindicated. This review focuses on the selection of patients who may benefit most from cabozantinib therapy, including those with bone and brain metastases and those with a non-clear cell RCC histology. The need to consider disease-related symptoms, comorbidities, age, drug interactions and biomarker analyses in the choice of therapeutic strategy is also highlighted. Finally, the perspectives for the use of cabozantinib in RCC treatment are discussed.

Cutaneous neurofibromas (cNF), present in 95% of individuals with neurofibromatosis 1 (NF1), are considered as one of the greatest medical burden because of physical disfigurement. No specific score evaluates their impact on quality of life (QoL).To develop a specific score assessing cNF-related QoL.Through a multidisciplinary workshop including 10 patients, 3 expert-in-NF1 physicians, 3 health care workers (nurses and psychologist) and 1 methodologist, the French version of the Skindex-16 was modified by adding 3 items. The new cNF-Skindex was validated among patients with NF1 recruited in the ComPaRe online cohort, in France (N = 284). Construct validity was assessed by comparing it with the EQ-5D-5L, its visual analogue scale and the MYMOP2 and by assessing its association with patients' characteristics. Reliability was assessed by a test-retest. An English version of the tool was developed using a back-forward translation.A total of 228 individuals with NF1, with cNF answered the 19-item questionnaire. These items fitted into 3 domains: emotions, symptoms, functioning. One was dropped during analysis because90% responders were not concerned. The cNF-Skindex significantly correlated with the EQ-5D-5L (N = 193) and MYMOP2 (N = 210) indicating good external validity: rs 0.38 (P 0.001), and 0.58 (P 0.001), respectively. Having50 cNF was the only independent variable associated with the total score cNF-Skindex (β = 15.88, 95%CI 6.96-24.81, P = 0.001), and with the 3 sub-scores: 'functioning' (β = 2.65, 95%CI 0.71-4.59, P = 0.008), 'emotions' (β = 17.03, 95%CI 4.11-29.96, P = 0.010) and 'symptoms' (β = 3.90, 95%CI 1.95-5.85, P 0.001). Test-retest reliability (N = 133) found an ICC at 0.96 demonstrating good reproducibility.The cNF-Skindex demonstrated excellent psychometric properties. The global and sub-scores were increased with higher number of cNF arguing for its use in further trials aiming to reduce their number or prevent their development. Cross-cultural validation and evaluation of its responsiveness are the next steps.

The effect of the sequential combination of chemotherapy and immune checkpoint inhibitors (ICIs) remains unclear. Here, we evaluated the efficacy of different chemotherapy regimens administered after ICIs in advanced non-small cell lung cancer (NSCLC), compared to the same regimens administered without previous ICIs.We retrospectively included all patients treated between 2015 and 2019 for an advanced NSCLC, receiving a salvage chemotherapy just after ICI (CAI group) comparing them to ICI naive patients (CWPI group) undergoing the same chemotherapy at Bordeaux University Hospital. The primary outcome was the time to treatment discontinuation (TTD), and secondary endpoints were overall survival (OS) and overall response rate (ORR).A total of 152 patients were included, with 34/23 (CAI/CWPI) receiving paclitaxel/bevacizumab (PB), 24/11 paclitaxel (P), 27/12 gemcitabine (G) and 6/15 pemetrexed (PE). Characteristics were comparable, except for CAI treated with PB (more patients with an ECOG PS ≤1 [p 0.001]). Median number of lines received was higher in CAI for all groups. There was no difference between CAI and CWPI for TTD, OS and ORR. However, PB was associated with a nonsignificant increase in OS in the CAI group (HR = 0.65; 95% CI: 0.38-1.2, p = 0.17].Our data showed no difference in TTD, OS and ORR regardless of chemotherapy, but a trend towards an increased OS with PB when given after an ICI, while patients received chemotherapy later in the CAI group. This suggests that a sequential combination of ICI followed by chemotherapy could be an interesting strategy in advanced NSCLC for selected patients.

Because of the limits in conceptualisation of care coordination linked to a large array of care coordination models and definitions available, a care coordination framework is needed with a particular focus on the micro level.To develop an evidence-based reference framework for person-centred care coordination interventions based on international validated definitions.This two-step mixed-methods study included first, a scoping review of reviews focus on the impact of care coordination interventions and then, a nominal group technique. The scoping review aimed at identifying the components of the four dimensions of the framework (contexts, activities, actors and tools, and effects). The nominal group technique was to select the relevant components of the dimension 'activities' of the reference framework.The scoping review selected 52 articles from the 1407 retrieved at first. The nominal group selected the 66 most relevant activities from the 159 retrieved in the literature (28 activities of care organisation, 24 activities of care, and 14 activities of facilitation).This operational framework focused on care coordination at the micro level, is a useful and innovative tool, applicable in any clinical condition, and in any health care system for describing, implementing and evaluating care coordination programmes.

Metazoans establish mutually beneficial interactions with their resident microorganisms. However, our understanding of the microbial cues contributing to host physiology remains elusive. Previously, we identified a bacterial machinery encoded by the dlt operon involved in Drosophila melanogaster’s juvenile growth promotion by Lactiplantibacillus plantarum. Here, using crystallography combined with biochemical and cellular approaches, we investigate the physiological role of an uncharacterized protein (DltE) encoded by this operon. We show that lipoteichoic acids (LTAs) but not wall teichoic acids are D-alanylated in Lactiplantibacillus plantarumNC8 cell envelope and demonstrate that DltE is a D-Ala carboxyesterase removing D-Ala from LTA. Using the mutualistic association of L. plantarumNC8 and Drosophila melanogaster as a symbiosis model, we establish that D-alanylated LTAs (D-Ala-LTAs) are direct cues supporting intestinal peptidase expression and juvenile growth in Drosophila. Our results pave the way to probing the contribution of D-Ala-LTAs to host physiology in other symbiotic models.

Overall survival (A) and progression-free survival (B) by baseline tumor PD-L1 expression (PD-L1 {greater than or equal to}1% and PD-L1

Comparison of OS stratified by genotype and treatment group

Adverse events occurring in >10% of patients

Allele frquency

Supplementary Table S1. A, Patient characteristics included in the study (Fig. 7, A and B). B, Patient characteristics included in the study (Fig. 7, C and D).

Supplementary Figure S7: Recapitulated schema.

Association between DFS and genotype subgroups within each treatment group or the combined sunitinib and placebo groups

Purpose: The PREINSUT study characterized factors predictive of response to sunitinib given before planned nephrectomy in patients with metastatic renal cell carcinoma (mRCC).Patients and Methods: This French multicenter, prospective, open-label, phase II trial (NCT00930345) included treatment-naïve patients with clear-cell mRCC. Patients received two cycles of sunitinib before nephrectomy. The primary objective was to evaluate the potential of circulating angiogenesis-related biomarkers measured before and on treatment for identifying responders based on primary renal tumor (PRT) size change. Secondary objectives were to evaluate the ability of biomarkers to predict progression-free survival (PFS) and overall survival (OS).Results: Thirty-two patients were enrolled. The median PFS was 4.5 months, and the median OS was 12.4 months. OS was significantly longer in responding patients (28.8 vs. 11.1 months; P = 0.03). Of 27 patients evaluable for PRT response, nine (33.3%) had a ≥10% decrease in PRT size. Baseline biomarkers significantly associated with outcome were endothelial progenitor cells (PRT response); vascular endothelial growth factor (VEGF)-A, stromal cell–derived factor-1 (SDF-1), soluble VEGF receptors (sVEGFR)1 and 2 (PFS); and SDF-1 and sVEGFR1 (OS). During treatment, changes in biomarkers associated with outcome were SDF-1 and platelet-derived growth factor (PDGF)-BB (PRT response), sVEGFR2 (PFS), and SDF-1 and sVEGFR1 (OS). There was no correlation between plasma sunitinib or its active metabolite steady-state trough concentrations and clinical outcome.Conclusions: Angiogenesis-related parameters that could reflect hypoxia seem to be associated with worse outcome in mRCC. As blood biomarkers are not subjected to tumor heterogeneity and allow longitudinal follow-up, circulating angiogenesis profile has a promising place in antiangiogenic therapy guidance. Clin Cancer Res; 24(22); 5534–42. ©2018 AACR.

Distribution of RS results in T3 patients in the gene signature cohort. Abbreviations: RS, recurrence score; T3, stage III tumor.

PDF file - 57KB, Supplemental Figure 1 contains the longitudinal plot of model-adjusted fold change from baseline for plasma VEGF.

Purpose:Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC.Patients and Methods:Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics.Results:Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3–22.9); n = 65; HR, 0.45 (95% CI, 0.3–0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33–0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged.Conclusions:NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population.See related commentary by Hwang et al., p. 5

Purpose: Adjuvant sunitinib prolonged disease-free survival (DFS; HR, 0.76) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov NCT00375674). The 16-gene Recurrence Score (RS) assay was previously developed and validated to estimate risk for disease recurrence in patients with RCC after nephrectomy. This analysis further validated the prognostic value of RS assay in patients from S-TRAC and explored the association of RS results with prediction of sunitinib benefit.Patients and Methods: The analysis was prospectively designed with prespecified genes, algorithm, endpoints, and analytical methods. Primary RCC was available from 212 patients with informed consent; primary analysis focused on patients with T3 RCC. Gene expression was quantitated by RT-PCR. Time to recurrence (TTR), DFS, and renal cancer–specific survival (RCSS) were analyzed using Cox proportional hazards regression.Results: Baseline characteristics were similar between patients with and those without RS results, and between the sunitinib and placebo arms among patients with RS results. RS results predicted TTR, DFS, and RCSS in both arms, with the strongest results observed in the placebo arm. When high versus low RS groups were compared, HR for recurrence was 9.18 [95% confidence interval (CI), 2.15–39.24; P < 0.001) in the placebo arm; interaction of RS results with treatment was not significant.Conclusions: The strong prognostic performance of the 16-gene RS assay was confirmed in S-TRAC, and the RS assay is now supported by level IB evidence. RS results may help identify patients at high risk for recurrence who may derive higher absolute benefit from adjuvant therapy. Clin Cancer Res; 24(18); 4407–15. ©2018 AACR.

Supplementary Figure S1. Tyrosine kinase Inhibitor stimulated VEGFC expression. Tyrosine kinase inhibitors stimulate VEGFC expression in RCC cell lines and primary RCC cells but not in normal cells.

Purpose: Fibroblast growth factor (FGF) signaling regulates tumor growth and vascularization and partly mediates antiangiogenic escape from VEGF receptor (VEGFR) inhibitors. Dovitinib (TKI258) is a tyrosine kinase inhibitor (TKI) that inhibits FGF receptor (FGFR), VEGFR, and platelet-derived growth factor receptor, which are known drivers of antiangiogenic escape, angiogenesis, and tumor growth in renal cell carcinoma (RCC).Experimental Design: Patients with advanced or metastatic RCC were treated with oral dovitinib 500 mg/day (5-days-on/2-days-off schedule). The study population was enriched for patients previously treated with a VEGFR TKI and an mTOR inhibitor.Results: Of 67 patients enrolled, 55 patients (82.1%) were previously treated with ≥1 VEGFR TKI and ≥1 mTOR inhibitor (per-protocol efficacy set). The 8-week overall response rate and disease control rate in this population were 1.8% and 52.7%, respectively. Disease control rate during the entire study period was 56.4% (50.9% ≥4 months). Median progression-free survival and overall survival in the entire population were 3.7 and 11.8 months, respectively. Pharmacodynamic analyses demonstrated dovitinib-induced inhibition of VEGFR (as determined by increased levels of placental growth factor and decreased levels of soluble VEGFR2) and FGFR (as determined by increased FGF23 serum measures). The most frequently reported treatment-related adverse events of all grades included nausea (65.7%), diarrhea (62.7%), vomiting (61.2%), decreased appetite (47.8%), and fatigue (32.8%).Conclusion: Dovitinib was shown to be an effective and tolerable therapy for patients with metastatic RCC who had progressed following treatment with VEGFR TKIs and mTOR inhibitors. Clin Cancer Res; 20(11); 3012–22. ©2014 AACR.

The gene/gene groups and algorithm included in calculating the RS. The RS is derived from the reference-normalized expression measurements, scaled from 0 to 100: Unscaled RS = -0.45 Ã- VN group score -0.31 Ã- IR group score + 0.27 Ã- CGD group score + 0.04 Ã- IL6. RS = 26.4 Ã- (unscaled RS + 3.7). The score is scaled: if RS is 100, then RS=100. Abbreviation: RS, recurrence score.

Purpose:In the S-TRAC trial, adjuvant sunitinib prolonged disease-free survival (DFS) versus placebo in patients with loco-regional renal cell carcinoma at high risk of recurrence after nephrectomy. An exploratory analysis evaluated associations between SNPs in several angiogenesis- or hypoxia-related genes and clinical outcomes in S-TRAC.Patients and Methods:Blood samples were genotyped for 10 SNPs and one insertion/deletion mutation using TaqMan assays. DFS was compared using log-rank tests for each genotype in sunitinib versus placebo groups and between genotypes within each of three (sunitinib, placebo, and combined sunitinib plus placebo) treatment groups. P values were unadjusted.Results:In all, 286 patients (sunitinib, n = 142; placebo, n = 144) were genotyped. Longer DFS [HR; 95% confidence interval (CI)] was observed with sunitinib versus placebo for VEGFR1 rs9554320 C/C (HR 0.44; 95% CI, 0.21–0.91; P = 0.023), VEGFR2 rs2071559 T/T (HR 0.46; 95% CI, 0.23–0.90; P = 0.020), and eNOS rs2070744 T/T (HR 0.53; 95% CI, 0.30–0.94; P = 0.028). Shorter DFS was observed for VEGFR1 rs9582036 C/A versus C/C with sunitinib, placebo, and combined therapies (P ≤ 0.05), and A/A versus C/C with sunitinib (P = 0.022). VEGFR1 rs9554320 A/C versus A/A was associated with shorter DFS in the placebo (P = 0.038) and combined (P = 0.006) groups.Conclusions:Correlations between VEGFR1 and VEGFR2 SNPs and longer DFS with sunitinib suggest germline SNPs are predictive of improved outcomes with adjuvant sunitinib in patients with renal cell carcinoma. Independent validation studies are needed to confirm these findings.

Supplementary Figure S5. Overexpression of VEGFC correlated with reduced overall survival of RCC patients. Analysis of in silico available data bases (TCGA Research Network) showed that overexpression of VEGFC is associated with a poor prognosis.

Supplementary Figure S3. Sorafenib stimulated VEGFC promoter activity, increased the VEGFC mRNA half-life and HuR and TTP bind the 3'UTR of VEGFC and VEGFA mRNA. Sorafenib-dependent induction of VEGFC expression is linked to increased transcription and mRNA stability. HuR and TTP directly bind to the VEGFC mRNA 3'UTR.

PDF file - 20KB

Patient baseline characteristics in the placebo versus sunitinib arm: all T3 patients in the gene signature cohort. aN0 or NX, any Fuhrman grade, ECOG PS 0 or Fuhrman grade 1 and ECOG PS ï,³1. bN0 or NX, Fuhrman grade {greater than or equal to}2, ECOG PS {greater than or equal to}1. cAny Fuhrman grade, any ECOG PS. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; SD, standard deviation; RS, Recurrence Score.

Summary of currently available data looking at biomarkers during antiantiogenic therapy

Kaplan-Meier analysis of progression-free survival (PFS; A-D) and overall survival (OS; E-F) according to baseline biomarker levels. HR, hazard ratio; CI, confidence interval.

PDF file - 22KB, Supplemental Table 1 contains the pharmacokinetic results from the study.

Supplementary Figure S6. Overexpression of VEGFC correlated with reduced overall survival of RCC patients. A, Kaplan-Meier survival curves of metastatic (M1) RCC patients with high or low VEGFC mRNA expression. These results are in whole or in part based upon data generated by the TCGA Research Network. B, Proportion of groups of patients with VEGFC low or high and its correlation with metastatic stage (M1). Statistical significance (Khi2 test) is indicated. C, Multivariate analysis for VEGFC, stage 3/4, metastatic stage (M1) and lymph node metastatic stage (N1). Statistical significance (p values) and the risk ratio are indicated.

Supplementary Figure S4. Sunitinib does not modified blood vessels. Blood vessels in experimental and patients' tumors are not normalized by sunitinib (equal coverage of CD31 labeled cells by alpha SMA labeled cells).

Kaplan-Meier estimates for RCSS by RS risk group in (A) placebo arm and (B) sunitinib arm. *Log-rank test for high vs low RS risk groups. †No events observed by 5 years. Abbreviations: CI, confidence interval; RCCS, renal cancer-specific survival; RS, recurrence score.

PDF file - 25KB, Supplemental Table 2 contains a summary of the newly occurring qualitative ECG abnormalities.

ORR in patients with sRCC and I/P-risk disease, per IRRC, by central or local pathology review.

Genotype frequency

Post hoc identification of patients with sRCC in CheckMate214.

Kaplan-Meier analysis of median (m) overall survival (A) and progression-free survival (A) according to response. HR, hazard ratio; CI, confidence interval.

Kaplan-Meier analysis of progression-free survival (PFS) and overall survival (OS) according to relative changes in biomarkers during cycle 1 (A-B) and cycle 2 (C). HR, hazard ratio; CI, confidence interval.

Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, VEGFC. In this study, we found that sunitinib can stimulate vegfc gene transcription and increase VEGFC mRNA half-life. In addition, sunitinib activated p38 MAPK, which resulted in the upregulation/activity of HuR and inactivation of tristetraprolin, two AU-rich element–binding proteins. Sunitinib stimulated a VEGFC-dependent development of lymphatic vessels in experimental tumors. This may explain our findings of increased lymph node invasion and new metastatic sites in 30% of sunitinib-treated patients and increased lymphatic vessels found in 70% of neoadjuvant treated patients. In summary, a therapy dedicated to destroying tumor blood vessels induced the development of lymphatic vessels, which may have contributed to the treatment failure. Cancer Res; 77(5); 1212–26. ©2017 AACR.

Treatment-free interval, duration of therapy, duration of response, and subsequent systemic therapy in all patients with sRCC and I/P-risk disease and confirmed response (A, complete responders; B, partial responders).