Publications by authors named "Cristina Suárez"

100 Publications

Metastatic nonclear renal cell carcinoma current review in evolving treatment strategies.

Curr Opin Urol 2021 May;31(3):242-248

Genitourinary, CNS and Sarcoma Tumor Unit, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

Purpose Of Review: Renal cell carcinoma (RCC) is the 6th most often diagnosed cancer in men and the 10th in women. Nearly 75% of the renal cancer cases are clear cell histologic subtype, whereas nonclear cell histologies represent the remaining 25%. Treatment options for clear renal type are well established. However, as nonclear RCC represents a heterogenous and less frequent group. Current treatment options for these tumors are limited and mostly based on evidence derived from small phase II clinical trials. The present review aims to provide an update of the available treatment options for nonclear RCC.

Recent Findings: In the past decade, the vascular endothelial growth factor tyrosine kinase inhibitor, sunitinib, and mammalian target of rapamycin inhibitors, everolimus, and temsirolimus, have demonstrated limited efficacy in nonclear RCC. Recent studies with MET inhibitors and immunotherapy-based combinations have proven promising activity, especially in certain subgroups of patients, such as patients with MET-driven disease or patients with sarcomatoid features RCC.

Summary: Here, we report currently available data about biology and treatment of nonclear cell RCC.
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http://dx.doi.org/10.1097/MOU.0000000000000869DOI Listing
May 2021

Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial.

Eur Urol 2021 May 5;79(5):665-673. Epub 2021 Mar 5.

Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively.

Objective: To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC.

Design, Setting, And Participants: IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab.

Intervention: Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy.

Outcome Measurements And Statistical Analysis: The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods.

Results And Limitations: Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19-37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6-13.7) mo. The median event follow-up duration was 19.4 (12.9-21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors.

Conclusions: The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC.

Patient Summary: Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.
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http://dx.doi.org/10.1016/j.eururo.2021.01.003DOI Listing
May 2021

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

N Engl J Med 2021 03;384(9):829-841

From the Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston (T.K.C.); the Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London (T.P.); the Bradford Hill Clinical Research Center, Santiago, Chile (M.B.); the Department of Medical Oncology, Gustave Roussy, Villejuif, France (B.E.); the Department of Hemato-Oncology, Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (M.T.B.), the Department of Medical Oncology, Centro Universitario contra el Cáncer, Hospital Universitario "Dr. José Eleuterio González," Universidad Autónoma de Nuevo León, Nuevo León (V.M.O.J.), and the Department of Medical Oncology, Hospital H+ Querétaro, Querétaro (J.P.F.) - all in Mexico; the Department of Outpatient Chemotherapy, Professor Franciszek Lukaszczyk Oncology Center, Bydgoszcz (B.Z.), and the Department of Clinical Oncology and Hematology, Regional Specialist Hospital, Biała Podlaska (J. Żołnierek) - both in Poland; the Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis (J.J.H.); Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IRCCS, Padua (U.B.), the Department of Medical Oncology, Ospedale San Donato, Istituto Toscano i, Arezzo (A.H.), the Department of Internal Medicine, University of Pavia, Pavia (C.P.), and the University of Bari "A. Moro," Bari (C.P.) - all in Italy; the Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston (A.Y.S.); the Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona (C.S.); the Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, QLD (J.C.G.), and Cabrini Monash University Department of Medical Oncology, Cabrini Health, Malvern, VIC (D.P.) - both in Australia; the Oncology Research Center, Hospital São Lucas, Porto Alegre, Brazil (C.B.); Fundacion Richardet Longo, Instituto Oncologico de Cordoba, Cordoba (M.R.), and Instituto Multidisciplinario de Oncología, Clínica Viedma, Viedma (R.K.) - both in Argentina; the Division of Medical Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora (E.R.K.); the Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata (Y.T.), and the Department of Urology, Keio University School of Medicine, Tokyo (R.M.) - both in Japan; the Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany (J.B.); the Departments of Clinical Research (J. Zhang.), Clinical Oncology (M.A.M.), Biostatistics (B.S.), and Health Economics and Outcomes Research (F.E.), Bristol Myers Squibb, Princeton, NJ; the Department of Clinical Oncology, Exelixis, Alameda, CA (G.M.S.); the Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.B.A.); and the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.J.M.).

Background: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.

Methods: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.

Results: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.

Conclusions: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).
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http://dx.doi.org/10.1056/NEJMoa2026982DOI Listing
March 2021

Toxicity and Surgical Complication Rates of Neoadjuvant Atezolizumab in Patients with Muscle-invasive Bladder Cancer Undergoing Radical Cystectomy: Updated Safety Results from the ABACUS Trial.

Eur Urol Oncol 2021 Feb 18. Epub 2021 Feb 18.

Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London, UK. Electronic address:

Background: There are limited data on toxicity and surgical safety associated with neoadjuvant programmed death ligand 1 (PD-L1) inhibitors prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC).

Objective: To present a comprehensive safety analysis of the largest neoadjuvant series, with focus on timing and severity of toxicity and surgical complications occurring after neoadjuvant atezolizumab in patients with MIBC enrolled in the ABACUS trial.

Design, Setting, And Participants: ABACUS (NCT02662309) is an open-label, multicenter, phase II trial for patients with histologically confirmed (T2-T4aN0M0) MIBC, awaiting RC. Patients either were ineligible or refused cisplatin-based neoadjuvant chemotherapy.

Intervention: Two cycles of neoadjuvant atezolizumab (1200 mg, every 3 wk) followed by RC.

Outcome Measurements And Statistical Analysis: Description of atezolizumab toxicity profile in the neoadjuvant setting, impact on surgery, and delayed immune-mediated adverse events (AEs) were assessed.

Results And Limitations: Ninety-five patients received treatment. Of them, 44% (42/95) had atezolizumab-related AEs during the neoadjuvant period (fatigue [20%], decreased appetite [6%], and transaminases increased [6%]). Treatment-related grade 3-5 AEs occurred in 11% (10/95) of patients during the study. Of the patients, 21% (20/95) received only one cycle of atezolizumab due to AEs; 92% (87/95) underwent RC. No surgery was delayed due to atezolizumab-related toxicities. Surgical complications occurred in 62% (54/87) of patients. Of these patients, 43% (37/87) and 20% (17/87) had minor (grade 1-2) and major (grade 3-5) complications, respectively. Thirteen of 87 (15%) patients had post-RC atezolizumab-related AEs, including adrenal insufficiency and transaminases increased. Three deaths occurred during the period of study-related interventions (one non-treatment-related aspiration pneumonia, one immune-related myocardial infarction, and one cardiogenic shock after RC). Not all surgical safety parameters were available.

Conclusions: Two cycles of neoadjuvant atezolizumab are well tolerated and do not seem to impact surgical complication rates. Owing to the long half-life, AEs may occur in the postoperative period, including endocrine abnormalities requiring attention and intervention.

Patient Summary: Here, we report a comprehensive dataset of patients receiving neoadjuvant immune checkpoint inhibitors before radical cystectomy. Treatment with neoadjuvant atezolizumab is safe and does not seem to complicate surgery significantly.
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http://dx.doi.org/10.1016/j.euo.2020.11.010DOI Listing
February 2021

Open-Label, Single-Arm, Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma.

J Clin Oncol 2021 Mar 2;39(9):1029-1039. Epub 2021 Feb 2.

Georgetown Lombardi Comprehensive Cancer Center, Washington, DC.

Purpose: Programmed death 1 (PD-1) pathway inhibitors have not been prospectively evaluated in patients with non-clear cell renal cell carcinoma (nccRCC). The phase II KEYNOTE-427 study (cohort B) was conducted to assess the efficacy and safety of single-agent pembrolizumab, a PD-1 inhibitor, in advanced nccRCC.

Methods: Patients with histologically confirmed, measurable (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) nccRCC and no prior systemic therapy received pembrolizumab 200 mg intravenously once every 3 weeks for ≤ 24 months. The primary end point was objective response rate (ORR) per RECIST v1.1.

Results: Among enrolled patients (N = 165), 71.5% had confirmed papillary, 12.7% had chromophobe, and 15.8% had unclassified RCC histology. Most patients (67.9%) had intermediate or poor International Metastatic RCC Database Consortium risk status and tumors with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (61.8%). The median time from enrollment to database cutoff was 31.5 months (range, 22.7-38.8). In all patients, the ORR was 26.7%. The median duration of response was 29.0 months; 59.7% of responses lasted ≥ 12 months. The ORR by CPS ≥ 1 and CPS < 1 status was 35.3% and 12.1%, respectively. The ORR by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified. Overall, the median progression-free survival was 4.2 months (95% CI, 2.9 to 5.6); the 24-month rate was 18.6%. The median overall survival was 28.9 months (95% CI, 24.3 months to not reached); the 24-month rate was 58.4%. Overall, 69.7% of patients reported treatment-related adverse events, most commonly pruritus (20.0%) and hypothyroidism (14.5%). Two deaths were treatment related (pneumonitis and cardiac arrest).

Conclusion: First-line pembrolizumab monotherapy showed promising antitumor activity in nccRCC. The safety profile was similar to that observed in other tumor types.
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http://dx.doi.org/10.1200/JCO.20.02365DOI Listing
March 2021

A CT-based Radiomics Signature Is Associated with Response to Immune Checkpoint Inhibitors in Advanced Solid Tumors.

Radiology 2021 Apr 26;299(1):109-119. Epub 2021 Jan 26.

From the Radiomics Group, Vall d'Hebron Institute of Oncology (VHIO), Cellex Center, Natzaret 115-117, Barcelona 08035, Spain (M.L., A.G.R., R.P.L.); Oncology Data Science (ODysSey) Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain (C.V., G.V., R.D.); Institute of Radiology, Foundation IRCCS Polyclinic San Matteo, Pavia, Italy (M.V.R.); Department of Radiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Spain (J.L.); Department of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain (I.M., J.M.L., M.O.d.O., C.H., J.M., M.G., R.M.B., C.S., J.R., E.E., I.B., E.M.C., A.O., E.F., J.T., J.C., E.G.); Department of Molecular Oncology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain (R.F., P.N.); Computer Vision Center, Department of Computer Science, Autonomous University of Barcelona, Cerdanyola del Vallès, Spain (D.G.); Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital (HUVH), Autonomous University of Barcelona, Institució Catalana de Recerca i Estudis Avançats (ICREA) and CIBERONC, Barcelona, Spain (C.R.P., J.S.); Department of Radiology, Vall d'Hebron University Hospital, Barcelona, Spain (M.E., R.P.L.); and Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain (J.T.).

Background Reliable predictive imaging markers of response to immune checkpoint inhibitors are needed. Purpose To develop and validate a pretreatment CT-based radiomics signature to predict response to immune checkpoint inhibitors in advanced solid tumors. Materials and Methods In this retrospective study, a radiomics signature was developed in patients with advanced solid tumors (including breast, cervix, gastrointestinal) treated with anti-programmed cell death-1 or programmed cell death ligand-1 monotherapy from August 2012 to May 2018 (cohort 1). This was tested in patients with bladder and lung cancer (cohorts 2 and 3). Radiomics variables were extracted from all metastases delineated at pretreatment CT and selected by using an elastic-net model. A regression model combined radiomics and clinical variables with response as the end point. Biologic validation of the radiomics score with RNA profiling of cytotoxic cells (cohort 4) was assessed with Mann-Whitney analysis. Results The radiomics signature was developed in 85 patients (cohort 1: mean age, 58 years ± 13 [standard deviation]; 43 men) and tested on 46 patients (cohort 2: mean age, 70 years ± 12; 37 men) and 47 patients (cohort 3: mean age, 64 years ± 11; 40 men). Biologic validation was performed in a further cohort of 20 patients (cohort 4: mean age, 60 years ± 13; 14 men). The radiomics signature was associated with clinical response to immune checkpoint inhibitors (area under the curve [AUC], 0.70; 95% CI: 0.64, 0.77; < .001). In cohorts 2 and 3, the AUC was 0.67 (95% CI: 0.58, 0.76) and 0.67 (95% CI: 0.56, 0.77; < .001), respectively. A radiomics-clinical signature (including baseline albumin level and lymphocyte count) improved on radiomics-only performance (AUC, 0.74 [95% CI: 0.63, 0.84; < .001]; Akaike information criterion, 107.00 and 109.90, respectively). Conclusion A pretreatment CT-based radiomics signature is associated with response to immune checkpoint inhibitors, likely reflecting the tumor immunophenotype. © RSNA, 2021 See also the editorial by Summers in this issue.
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http://dx.doi.org/10.1148/radiol.2021200928DOI Listing
April 2021

Cell Plasticity-Related Phenotypes and Taxanes Resistance in Castration-Resistant Prostate Cancer.

Front Oncol 2020 2;10:594023. Epub 2020 Nov 2.

Translational Genomics and Targeted Therapeutics in Solid Tumors Lab, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

The prostatic tumor cells plasticity is involved in resistance to hormone-therapy, allowing these cells to survive despite androgen receptor inhibition. However, its role in taxanes resistance has not been fully established. Gene expression of plasticity-related phenotypes such as epithelial-mesenchymal transition (EMT), stem cell-like and neuroendocrine (NE) phenotypes was studied , , in circulating tumor cells (CTCs) (=22) and in tumor samples (=117) from taxanes-treated metastatic castration-resistant prostate cancer (mCRPC) patients. Docetaxel (D)-resistant cells presented a more pronounced EMT phenotype than cabazitaxel (CZ)-resistant cells. analysis revealed down-regulation in taxane-exposed mCRPC samples. Cell plasticity-related changes occurred in CTCs after taxanes treatment. Tumor EMT phenotype was associated with lower PSA progression-free survival (PFS) to D (<0.001), and better to CZ (=0.002). High expression was independently associated with longer PSA-PFS (<0.001) and radiologic-PFS (=0.001) in D and shorter PSA-PFS in the CZ cohort (=0.041). High expression was independently associated with lower PSA-PFS in D (=0.003) and overall survival (OS) in CZ (=0.002), and high expression was associated with adverse OS in D-treated patients (=0.013). In conclusion, EMT profile in primary tumor is differentially associated with D or CZ benefit and NE dedifferentiation correlates with adverse taxanes clinical outcome.
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http://dx.doi.org/10.3389/fonc.2020.594023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667288PMC
November 2020

Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors.

Eur Urol 2021 Feb 8;79(2):200-211. Epub 2020 Nov 8.

The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK. Electronic address:

Background: Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some ATM loss PCs respond.

Objective: To characterise ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset.

Design, Setting, And Participants: We studied advanced PC biopsies using validated immunohistochemical (IHC) and next-generation sequencing (NGS) assays. In vitro cell line models modified using CRISPR-Cas9 to impair ATM function were generated and used in drug-sensitivity and functional assays, with validation in a patient-derived model.

Outcome Measurements And Statistical Analysis: ATM expression by IHC was correlated with clinical outcome using Kaplan-Meier curves and log-rank test; sensitivity to different drug combinations was assessed in the preclinical models.

Results And Limitations: Overall, we detected ATM IHC loss in 68/631 (11%) PC patients in at least one biopsy, with synchronous and metachronous intrapatient heterogeneity; 46/71 (65%) biopsies with ATM loss had ATM mutations or deletions by NGS. ATM IHC loss was not associated with worse outcome from advanced disease, but ATM loss was associated with increased genomic instability (NtAI:number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transitions, p = 0.05). In vitro, ATM loss PC models were sensitive to ATR inhibition, but had variable sensitivity to PARP inhibition; superior antitumour activity was seen with combined PARP and ATR inhibition in these models.

Conclusions: ATM loss in PC is not always detected by targeted NGS, associates with genomic instability, and is most sensitive to combined ATR and PARP inhibition.

Patient Summary: Of aggressive prostate cancers, 10% lose the DNA repair gene ATM; this loss may identify a distinct prostate cancer subtype that is most sensitive to the combination of oral drugs targeting PARP and ATR.
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http://dx.doi.org/10.1016/j.eururo.2020.10.029DOI Listing
February 2021

Kidney cancer PDOXs reveal patient-specific pro-malignant effects of antiangiogenics and its molecular traits.

EMBO Mol Med 2020 12 5;12(12):e11889. Epub 2020 Nov 5.

Tumor Angiogenesis Group, ProCURE Program, Catalan Institute of Oncology, OncoBell Program, IDIBELL, Barcelona, Spain.

An open debate in antiangiogenic therapies is about their consequence on tumor invasiveness and metastasis, which is undoubtedly relevant for patients currently treated with antiangiogenics, such as renal cell carcinoma patients. To address, this we developed an extensive series of 27 patient biopsy-derived orthotopic xenograft models (Ren-PDOX) that represent inter-patient heterogeneity. In specific tumors, antiangiogenics produced increased invasiveness and metastatic dissemination, while in others aggressiveness remained unchanged. Mechanistically, species-discriminative RNA sequencing identified a tumor cell-specific differential expression profile associated with tumor progression and aggressivity in TCGA RCC patients. Gene filtering using an invasion-annotated patient series pinpointed two candidate genes, of which ALDH1A3 differentiated the pro-invasive subtype of Ren-PDOXs. Validation in an independent series of 15 antiangiogenic-treated patients confirmed that pre-treatment ALDH1A3 can significantly discriminate patients with pro-aggressive response upon treatment. Overall, results confirm that effects of antiangiogenic drugs on tumor invasion and metastasis are heterogeneous and may profoundly affect the natural progression of tumors and promote malignancy. Furthermore, we identify a specific molecular biomarker that could be used to select patients that better benefit from treatment.
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http://dx.doi.org/10.15252/emmm.201911889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721359PMC
December 2020

Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial.

Lancet Oncol 2020 12 21;21(12):1574-1588. Epub 2020 Sep 21.

Beth Israel Deaconess Medical Center and PSMAR-IMIM Research Lab, Harvard Medical School, Boston, MA, USA.

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.

Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice-web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.

Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9-43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4-17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4-15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71-1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1-18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9-14·0) in the chemotherapy group (0·85, 95% CI 0·72-1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury).

Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(20)30541-6DOI Listing
December 2020

Minimizing acquisition-related radiomics variability by image resampling and batch effect correction to allow for large-scale data analysis.

Eur Radiol 2021 Mar 9;31(3):1460-1470. Epub 2020 Sep 9.

Radiomics Group, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus (Spain), Barcelona, Spain.

Objective: To identify CT-acquisition parameters accounting for radiomics variability and to develop a post-acquisition CT-image correction method to reduce variability and improve radiomics classification in both phantom and clinical applications.

Methods: CT-acquisition protocols were prospectively tested in a phantom. The multi-centric retrospective clinical study included CT scans of patients with colorectal/renal cancer liver metastases. Ninety-three radiomics features of first order and texture were extracted. Intraclass correlation coefficients (ICCs) between CT-acquisition protocols were evaluated to define sources of variability. Voxel size, ComBat, and singular value decomposition (SVD) compensation methods were explored for reducing the radiomics variability. The number of robust features was compared before and after correction using two-proportion z test. The radiomics classification accuracy (K-means purity) was assessed before and after ComBat- and SVD-based correction.

Results: Fifty-three acquisition protocols in 13 tissue densities were analyzed. Ninety-seven liver metastases from 43 patients with CT from two vendors were included. Pixel size, reconstruction slice spacing, convolution kernel, and acquisition slice thickness are relevant sources of radiomics variability with a percentage of robust features lower than 80%. Resampling to isometric voxels increased the number of robust features when images were acquired with different pixel sizes (p < 0.05). SVD-based for thickness correction and ComBat correction for thickness and combined thickness-kernel increased the number of reproducible features (p < 0.05). ComBat showed the highest improvement of radiomics-based classification in both the phantom and clinical applications (K-means purity 65.98 vs 73.20).

Conclusion: CT-image post-acquisition processing and radiomics normalization by means of batch effect correction allow for standardization of large-scale data analysis and improve the classification accuracy.

Key Points: • The voxel size (accounting for the pixel size and slice spacing), slice thickness, and convolution kernel are relevant sources of CT-radiomics variability. • Voxel size resampling increased the mean percentage of robust CT-radiomics features from 59.50 to 89.25% when comparing CT scans acquired with different pixel sizes and from 71.62 to 82.58% when the scans were acquired with different slice spacings. • ComBat batch effect correction reduced the CT-radiomics variability secondary to the slice thickness and convolution kernel, improving the capacity of CT-radiomics to differentiate tissues (in the phantom application) and the primary tumor type from liver metastases (in the clinical application).
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http://dx.doi.org/10.1007/s00330-020-07174-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880962PMC
March 2021

A Framework for User Adaptation and Profiling for Social Robotics in Rehabilitation.

Sensors (Basel) 2020 Aug 25;20(17). Epub 2020 Aug 25.

Virgen del Rocío University Hospital, 41013 Seville, Spain.

Physical rehabilitation therapies for children present a challenge, and its success-the improvement of the patient's condition-depends on many factors, such as the patient's attitude and motivation, the correct execution of the exercises prescribed by the specialist or his progressive recovery during the therapy. With the aim to increase the benefits of these therapies, social humanoid robots with a friendly aspect represent a promising tool not only to boost the interaction with the pediatric patient, but also to assist physicians in their work. To achieve both goals, it is essential to monitor in detail the patient's condition, trying to generate user profile models which enhance the feedback with both the system and the specialist. This paper describes how the project NAOTherapist-a robotic architecture for rehabilitation with social robots-has been upgraded in order to include a monitoring system able to generate user profile models through the interaction with the patient, performing user-adapted therapies. Furthermore, the system has been improved by integrating a machine learning algorithm which recognizes the pose adopted by the patient and by adding a clinical reports generation system based on the QUEST metric.
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http://dx.doi.org/10.3390/s20174792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506951PMC
August 2020

Early treatment with anti-tumor necrosis factor agents improves long-term effectiveness in symptomatic stricturing Crohn's disease.

United European Gastroenterol J 2020 11 28;8(9):1056-1066. Epub 2020 Jul 28.

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.

Background: There is limited evidence on the effectiveness of biological therapy in stricturing complications in patients with Crohn's disease.

Aim: The study aims to determine the effectiveness of anti-tumor necrosis factor (TNF) agents in Crohn's disease complicated with symptomatic strictures.

Methods: In this multicentric and retrospective study, we included adult patients with symptomatic stricturing Crohn's disease receiving their first anti-TNF therapy, with no previous history of biological, endoscopic or surgical therapy. The effectiveness of the anti-TNF agent was defined as a composite outcome combining steroid-free drug persistence with no use of new biologics or immunomodulators, hospital admission, surgery or endoscopic therapy during follow-up.

Results: Overall, 262 patients with Crohn's disease were included (53% male; median disease duration, 35 months, 15% active smokers), who received either infliximab ( = 141, 54%) or adalimumab ( = 121, 46%). The treatment was effective in 87% and 73% of patients after 6 and 12 months, respectively, and continued to be effective in 26% after a median follow-up of 40 months (IQR, 19-85). Nonetheless, 15% and 21% of individuals required surgery after 1 and 2 years, respectively, with an overall surgery rate of 32%. Postoperative complications were identified in 15% of patients, with surgical site infection as the most common. Starting anti-TNF therapy in the first 18 months after the diagnosis of Crohn's disease or the identification of stricturing complications was associated with a higher effectiveness (HR 1.62, 95% CI 1.18-2.22; and HR 1.55, 95% CI 1.1-2.23; respectively). Younger age, lower albumin levels, strictures located in the descending colon, concomitant aminosalicylates use or presence of lymphadenopathy were associated with lower effectiveness.

Conclusions: Anti-TNF agents are effective in approximately a quarter of patients with Crohn's disease and symptomatic intestinal strictures, and 68% of patients are free of surgery after a median of 40 months of follow-up. Early treatment and some potential predictors of response were associated with treatment success in this setting.
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http://dx.doi.org/10.1177/2050640620947579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724538PMC
November 2020

Providing Access to Urban Green Spaces: A Participatory Benefit-Cost Analysis in Spain.

Int J Environ Res Public Health 2020 04 19;17(8). Epub 2020 Apr 19.

European Centre for Environment and Human Health, University of Exeter Medical School, Truro Campus, RCH Treliske, Truro TR1 3HD, UK.

The opening up of green spaces could provide significant benefits to society. This study develops a framework to assess the economic benefits and costs of public interventions providing citizen access to urban green spaces. The Thinking Fadura project in Getxo (Spain) was used as a case study. A method for participatory benefit-cost analysis is developed, where a stakeholder-participatory evaluation is combined with a standard cost-benefit analysis. The participatory evaluation followed a bottom-up approach in a sequential evaluation including three main focal points: key stakeholders and experts, visitors and the general public. The assessment demonstrates that the Thinking Fadura project's benefits outweigh the costs. The results suggest that projects designed with the purpose of improving green space accessibility to the general public can be beneficial from a societal perspective. The highest economic benefits were an increase in the amenity and recreational value and an increase in people's physical activity. The participatory evaluation indicates that giving access to people of lower socio-economic status and vulnerable groups and improving recreational use were perceived as the most beneficial. An increase in noise, dirt, and risk of criminal activities as well as potential conflicts between green space users were perceived as the most negative impacts of opening a previously restricted area to the general public. The economic assessment of Thinking Fadura project could serve as a model in the decision-making process in locations where the use of greenspaces is restricted.
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http://dx.doi.org/10.3390/ijerph17082818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216070PMC
April 2020

Patient-reported outcomes in a phase 2 study comparing atezolizumab alone or with bevacizumab vs sunitinib in previously untreated metastatic renal cell carcinoma.

BJU Int 2020 07 24;126(1):73-82. Epub 2020 Apr 24.

Barts Cancer Institute, Royal Free Hospital, Queen Mary University of London, London, UK.

Objective: To evaluate patient-reported outcome (PRO) data from the IMmotion150 study. The phase 2 IMmotion150 study showed improved progression-free survival with atezolizumab plus bevacizumab vs sunitinib in patients with programmed death-ligand 1 (PD-L1)+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC).

Patients And Methods: Patients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (i.v.) every 3 weeks (n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg i.v. every 3 weeks (n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). The MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6-week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. The TTD was the first ≥2-point score increase over baseline. Absolute effect size ≥0.2 suggested a clinically important difference with checkpoint inhibitor therapy vs sunitinib.

Results: Completion rates were >90% at baseline and ≥80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue-related interference was observed with atezolizumab (both alone and in combination) vs sunitinib. Improved TTD (hazard ratio [HR], 95% confidence interval [CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22-0.71); RCC symptoms, 0.22 (0.12-0.41); and symptom interference, 0.36 (0.22-0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy vs sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions.

Conclusion: PROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone vs sunitinib (IMmotion150; ClinicalTrials.gov Identifier: NCT01984242).
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http://dx.doi.org/10.1111/bju.15058DOI Listing
July 2020

The future of bladder cancer therapy: Optimizing the inhibition of the fibroblast growth factor receptor.

Cancer Treat Rev 2020 Jun 13;86:102000. Epub 2020 Mar 13.

Vall d'Hebron Institute of Oncology, Vall d' Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

Therapeutic options for metastatic bladder cancer (BC) have seen minimal evolution over the past 30 years, with platinum-based chemotherapy remaining the mainstay of standard of care for metastatic BC. Recently, five immune checkpoint inhibitors (ICIs) have been approved by the FDA as second-line therapy, and two ICIs are approved as first-line treatment in selected patients. Molecular alterations of muscle-invasive bladder cancer (MIBC) have been reported by The Cancer Genome Atlas. About 15% of patients with MIBC have molecular alterations in the fibroblast growth factor (FGF) axis. Several ongoing trials are testing novel FGF receptor (FGFR) inhibitors in patients with FGFR genomic aberrations. Recently, erdafitinib, a pan-FGFR inhibitor, was approved by the FDA in patients with metastatic BC who have progressed on platinum-based chemotherapy. We reviewed the literature over the last decade and provide a summary of current knowledge of FGF signaling, and the prognosis associated with FGFR mutations in BC. We cover the role of FGFR inhibition with non-selective and selective tyrosine kinase inhibitors as well as novel agents in metastatic BC. Efficacy and safety data including insights from mechanism-based toxicity are reported for selected populations of metastatic BC with FGFR aberrations. Current strategies to managing resistance to anti-FGFR agents is addressed, and the importance of developing reliable biomarkers as the therapeutic landscape moves towards an individualized therapeutic approach.
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http://dx.doi.org/10.1016/j.ctrv.2020.102000DOI Listing
June 2020

Letter to the Editor on "Predictors of Perioperative Vancouver B Periprosthetic Femoral Fractures Associated With the Direct Anterior Approach to Total Hip Arthroplasty".

J Arthroplasty 2020 06 24;35(6):1752-1753. Epub 2020 Jan 24.

Department of Orthopedics and Traumatology, Hospital Universitario Fundación Santa Fe de Bogotá, School of Medicine, Universidad del Rosario, Bogotá, Colombia; Department of Orthopedics and Traumatology, Hospital Universitario Fundación Santa Fe de Bogotá, School of Medicine, Universidad de Los Andes, School of Medicine, Universidad del Rosario, Bogotá, Colombia.

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http://dx.doi.org/10.1016/j.arth.2020.01.046DOI Listing
June 2020

Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma.

Invest New Drugs 2020 10 5;38(5):1570-1579. Epub 2020 Mar 5.

Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain.

Purpose Galunisertib, a TGF-β inhibitor, has demonstrated antitumor effects in preclinical and radiographic responses in some patients with malignant glioma. This Phase 1b/2a trial investigated the clinical benefit of combining galunisertib with temozolomide-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma (NCT01220271). Methods This is an open-label, 2-arm Phase 1b/2a study (N = 56) of galunisertib (intermittent dosing: 14 days on/14 days off per cycle of 28 days) in combination with TMZ/RTX (n = 40), versus a control arm (TMZ/RTX, n = 16). The primary objective of Phase 1b was to determine the safe and tolerable Phase 2 dose of galunisertib. The primary objective of Phase 2a was to confirm the tolerability and pharmacodynamic profile of galunisertib with TMZ/RTX, and the secondary objectives included determining the efficacy and pharmacokinetic (PK) profile of galunisertib with TMZ/RTX in patients with glioblastoma. This study also characterized the changes in the major T-cell subsets during TMZ/RTX plus galunisertib treatment. Results In the Phase 2a study, efficacy results for patients treated with galunisertib plus TMZ/RTX or TMZ/RTX were: median overall survival (18.2 vs 17.9 months), median progression-free survival (7.6 vs 11.5 months), and disease control rate (80% [32/40] vs 56% [9/16] patients) respectively. PK profile of galunisertib plus TMZ/RTX regimen was consistent with previously published PK data of galunisertib. The overall safety profile across treatment arms was comparable. Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms.
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http://dx.doi.org/10.1007/s10637-020-00910-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497674PMC
October 2020

Patient-Reported Outcomes from the Phase III Randomized IMmotion151 Trial: Atezolizumab Bevacizumab versus Sunitinib in Treatment-Naïve Metastatic Renal Cell Carcinoma.

Clin Cancer Res 2020 06 3;26(11):2506-2514. Epub 2020 Mar 3.

Gustave Roussy, Villejuif, France.

Purpose: Patient-reported outcomes (PRO) were evaluated in the phase III IMmotion151 trial (NCT02420821) to inform overall treatment/disease burden of atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (mRCC).

Patients And Methods: Patients were randomized 1:1 to receive atezolizumab 1,200 mg intravenous (i.v.) infusions every 3 weeks (q3w) plus bevacizumab 15 mg/kg i.v. q3w or sunitinib 50 mg per day orally 4 weeks on/2 weeks off. Patients completed the MD Anderson Symptom Inventory (MDASI), National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and Brief Fatigue Inventory (BFI) at baseline, q3w during treatment, at end of treatment, and during survival follow-up. Longitudinal and time to deterioration (TTD) analyses for core and RCC symptoms and their interference with daily life, treatment side-effect bother, and health-related quality of life (HRQOL) were evaluated.

Results: The intent-to-treat population included 454 and 461 patients in the atezolizumab plus bevacizumab and sunitinib arms, respectively. Completion rates for each instrument were 83% to 86% at baseline and ≥ 70% through week 54. Milder symptoms, less symptom interference and treatment side-effect bother, and better HRQOL at most visits were reported with atezolizumab plus bevacizumab versus sunitinib. The TTD HR (95% CI) favored atezolizumab plus bevacizumab for core (HR, 0.50; 0.40-0.62) and RCC symptoms (HR, 0.45; 0.37-0.55), symptom interference (HR, 0.56; 0.46-0.68), and HRQOL (HR, 0.68; 0.58-0.81).

Conclusions: PROs in IMmotion151 suggest lower overall treatment burden with atezolizumab plus bevacizumab compared with sunitinib in patients with treatment-naïve mRCC and provide further evidence for clinical benefit of this regimen.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2838DOI Listing
June 2020

A Technological Scenario for a Healthier, More Equitable and Sustainable Europe in 2040: Citizen Perceptions and Policy Implications.

Int J Environ Res Public Health 2019 12 28;17(1). Epub 2019 Dec 28.

The Institute of Public Health of the Republic of Macedonia (IJZRM), 1000 Skopje, North Macedonia.

This article aims at exploring, understanding and comparing European citizens' insights and perceptions towards "My life between realities", a positive future scenario which depicts a narrative of reaching healthier, more equitable and sustainable societies by 2040 with the support of technology and technological solutions. It responds to the need for gathering and incorporating more citizen insights into future policy developments and strategic actions to tackle the global challenge of unsustainable development. Citizens of five European countries-the Czech Republic, Germany, North Macedonia, Spain and the United Kingdom-have been consulted through focus groups. The exercise has uncovered citizens' preferences and attitudes towards four main lifestyle areas; namely, green spaces, energy efficient housing, active mobility and (food) consumption. The technological attributes of the scenario led to citizens expressing diametrically opposed and critical perceptions and attitudes. Given the prospects of technology in driving sustainable development, based on these insights, policy recommendations for the better integration and acceptance of technological advances by the public are discussed herein.
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http://dx.doi.org/10.3390/ijerph17010231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982210PMC
December 2019

Evaluation of a new Rapid Antimicrobial Susceptibility system for Gram-negative and Gram-positive bloodstream infections: speed and accuracy of Alfred 60AST.

BMC Microbiol 2019 11 29;19(1):268. Epub 2019 Nov 29.

St. George's University of London. Institute for Infection and Immunity, London, SW17 0RE, UK.

Background: Blood stream infections (BSIs) are a major cause of morbidity and mortality. The time from taking blood cultures to obtain results of antibiotic sensitivity can be up to five days which impacts patient care. The Alfred 60 AST™ can reduce laboratory time from positive culture bottle to susceptibility results from 16 to 25 h to 5-6 h, transforming patient care. To evaluate the diagnostic accuracy of a rapid antimicrobial susceptibility system, the Alfred 60 AST™, in clinical isolates from patients with BSIs and confirm time to results. 301 Gram-negative and 86 Gram-positive isolates were analysed directly from positive blood culture bottles following Gram staining. Antimicrobial susceptibility results and time-to-results obtained by rapid Alfred 60 AST system and BD Phoenix were compared .

Results: A total of 2196 antimicrobial susceptibility test results (AST) were performed: 1863 Gram-negative and 333 Gram-positive. AST categorical agreement (CA) for Alfred 60 AST™ was 95% (1772/1863) for Gram-negative and 89% (295/333) for Gram-positive isolates. Gram-negative CA: ampicillin 96% (290/301); ciprofloxacin 95% (283/297); ceftriaxone 96% (75/78); meropenem 97% (288/297); piperacillin-tazobactam 95% (280/295); gentamicin 94% (279/297) and amikacin 93% (277/298). The median time to susceptibility results from blood culture flagging positive was 6.3 h vs 20 h (p < 0.01) for Alfred system vs BD Phoenix™.

Conclusion: Alfred 60 AST system greatly reduced time to antimicrobial susceptibility results in Gram-negative and Gram-positive BSIs with good performance and cost, particularly for Gram-negative bacteraemia.
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http://dx.doi.org/10.1186/s12866-019-1654-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884782PMC
November 2019

Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.

Nat Med 2019 11 4;25(11):1706-1714. Epub 2019 Nov 4.

Department of Medical Oncology, Hospital 12 de Octubre, Madrid, Spain.

Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers. Biomarkers may facilitate identification of these responding tumors. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
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http://dx.doi.org/10.1038/s41591-019-0628-7DOI Listing
November 2019

Letter to the Editor on "Continuous Antibiotic Therapy Can Reduce Recurrence of Prosthetic Joint Infection in Patients Undergoing 2-Stage Exchange".

J Arthroplasty 2019 10 17;34(10):2519-2520. Epub 2019 Jun 17.

Department of Orthopedics and Traumatology, Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá, Colombia; School of Medicine, Universidad del Rosario, Bogotá, Colombia; School of Medicine, Universidad de Los Andes, Bogotá, Colombia.

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http://dx.doi.org/10.1016/j.arth.2019.06.022DOI Listing
October 2019

Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial.

Lancet 2019 06 9;393(10189):2404-2415. Epub 2019 May 9.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma.

Methods: In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821.

Findings: Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57-0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76-1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation.

Interpretation: Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma.

Funding: F Hoffmann-La Roche Ltd and Genentech Inc.
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http://dx.doi.org/10.1016/S0140-6736(19)30723-8DOI Listing
June 2019

Nanoparticles as theranostic vehicles in prostate cancer.

Ann Transl Med 2019 Mar;7(Suppl 1):S29

Vall d'Hebron Institute of Oncology, Vall d' Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.21037/atm.2019.01.77DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462597PMC
March 2019

Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer.

Curr Oncol Rep 2019 03 27;21(5):42. Epub 2019 Mar 27.

Prostate Cancer Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Cellex Center, Natzaret 115-117, 08035, Barcelona, Spain.

Purpose Of Review: Genomic studies of localized and metastatic prostate cancer have identified a high prevalence of clinically actionable alterations including mutations in DNA repair genes. In this manuscript, we review the current knowledge on DNA repair defects in prostate cancer and provide an overview of how these alterations can be targeted towards a personalized prostate cancer management.

Recent Findings: Twenty to 25% of metastatic prostate cancers harbor defects in DNA repair genes, most commonly in the homologous recombination genes. These defects confer increased sensitivity to platinum chemotherapy or poly (ADP-ribose) polymerase (PARP) inhibitors. Recent trials also support a synergistic effect of combining these therapies with androgen receptor-targeting agents. Identification of mismatch-repair defects could result in defining a prostate cancer population who may benefit from immune checkpoint inhibitors. These data have implications for family testing and early diagnosis, as many of these mutations are linked to inherited risk of prostate cancer. The DNA damage repair pathways are clinically relevant in prostate cancer, being a target for precision medicine; combination with standard-of-care androgen receptor (AR)-targeting agents may be synergistic.
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http://dx.doi.org/10.1007/s11912-019-0790-6DOI Listing
March 2019

The influence of treatment sequence in the prognostic value of TMPRSS2-ERG as biomarker of taxane resistance in castration-resistant prostate cancer.

Int J Cancer 2019 10 23;145(7):1970-1981. Epub 2019 Mar 23.

Translational Genomics and Targeted Therapeutics in Solid Tumors Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

TMPRSS2-ERG expression in blood has been correlated with low docetaxel benefit in metastatic castration-resistant prostate cancer (mCRPC). This multicenter study aimed to prospectively asses its role as a taxane-resistance biomarker in blood and retrospectively in tumors, exploring also the impact of prior abiraterone/enzalutamide (A/E) in patients and in vitro. TMPRSS2-ERG was tested by quantitative reverse-transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2-ERG expression was correlated with prostate-specific antigen (PSA)-progression-free survival (PFS), radiological-PFS (RX-PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. In vitro ERG knockdown and combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Prior A/E (HR 1.8, 95% CI 1.2-2.8) and blood TMPRSS2-ERG detection (HR 2, 95% CI 1.1-3.7) were independently associated to lower PSA-PFS. In patients without prior A/E, blood and tumor TMPRSS2-ERG independently predicted lower PSA-PFS (HR 3.3, 95% CI 1.4-7.9 and HR 1.8, 95% CI 1.02-3.3, respectively) to taxanes. When prior A/E was administered, TMPRSS2-ERG was not associated with outcome. There was a significant interaction between blood TMPRSS2-ERG and prior A/E related to PSA-PFS (p = 0.032) and RX-PFS (p = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced the expression of neuroendocrine markers and reduced that of E-cadherin. We conclude that prior hormone-therapy may influence taxanes response and TMPRSS2-ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow-up evaluation.
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http://dx.doi.org/10.1002/ijc.32238DOI Listing
October 2019

Best treatment options for advanced renal cell carcinoma (RCC) patients: a Delphi consensus study.

Med Oncol 2019 Feb 19;36(3):29. Epub 2019 Feb 19.

Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

The introduction of targeted therapy for the treatment of advanced renal cell carcinoma (RCC) has improved the outcome of these patients in the last decade. However, many patients still relapse. The aim of this consensus study was to establish common recommendations about the best treatment options in patients with RCC. A two-round Delphi methodology was used. A total of 25 statements were submitted to a panel of 30 specialists. If consensus was not obtained in the first round a second and last round was performed. Agreement was achieved for 19 of the proposed 25 statements (76%). When making a decision about the treatment option, considering the efficiency and response rate to previous treatment, drug's toxicity and the patients' clinical features are very relevant.
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http://dx.doi.org/10.1007/s12032-019-1251-7DOI Listing
February 2019

Phase 2 Randomized Study of Radiation Therapy and 3-Year Androgen Deprivation With or Without Concurrent Weekly Docetaxel in High-Risk Localized Prostate Cancer Patients.

Int J Radiat Oncol Biol Phys 2019 02 12;103(2):344-352. Epub 2018 Oct 12.

Radiation Oncology Department, Hospital del Mar, IMIM, Barcelona, Spain.

Purpose: Docetaxel improves survival in patients with metastatic prostate cancer. This randomized phase 2 trial aimed to assess the activity of weekly docetaxel with radiation therapy (RT) plus androgen deprivation in patients with high-risk localized prostate cancer. The study examined the benefit of 9 weekly docetaxel administrations to RT plus 3 years of luteinizing hormone-releasing hormone analogues.

Methods And Materials: A total of 132 patients were recruited for the study. Patients' characteristics included T3-T4 stage (81.1%), Gleason score ≥8 (77.3%), prostate-specific antigen level >20 ng/mL (28.9%), and pN+ (18.2%). All patients included in the trial received either the standard-of-care control arm with luteinizing hormone-releasing hormone analogues plus RT (arm A) or the experimental arm (RT + 9 weekly cycles of docetaxel + 3 years of androgen deprivation therapy, arm B). The primary objective was to achieve a high percentage of patients who were free of biochemical recurrence within 5 years of randomization. Secondary endpoints included biochemical recurrence-free survival (BRFS), progression-free survival (PFS), overall survival (OS), clinical response rate, biochemical response rate, and toxicity.

Results: No difference between the arms of the study was found in biochemical recurrence (93.4% at 60 months for arm A vs 85.3% for arm B; P = .3297). PFS at 60 months was 93.4% and 83.7% in arms A and B, respectively (P = .2532). Five-year survival was 93.3% (95% confidence interval, 83.1-97.45) in arm A versus 93.6% (83.8-97.55) in arm B; median PFS and OS have not been reached. Prostate-specific antigen level ≤0.2 ng/mL at 3 months after the end of treatment was seen in 81.25% of patients in arm A compared with 90.48% of patients in arm B (P = .2028). BRFS was not significantly different between treatment arms. Diarrhea was the main nonhematologic toxicity. Long-term follow-up has not yet been enough to meet median PFS and OS.

Conclusions: Concurrent weekly docetaxel can be administered safely with standard doses of RT without a significant increase in the toxicity profile. No statistically significant differences for 5-year BRFS, PFS, and OS have been observed when docetaxel was added to conventional treatment.
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http://dx.doi.org/10.1016/j.ijrobp.2018.10.005DOI Listing
February 2019