20 results on '"Castellano, D."'
Search Results
2. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer.
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Powles, T., Valderrama, B. P., Gupta, S., Bedke, J., Kikuchi, E., Hoffman-Censits, J., Iyer, G., Vulsteke, C., Park, S. H., Shin, S. J., Castellano, D., Fornarini, G., Li, J.-R., Gümüş, M., Mar, N., Loriot, Y., Fléchon, A., Duran, I., Drakaki, A., and Narayanan, S.
- Abstract
BACKGROUND No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma. METHODS We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival. RESULTS A total of 886 patients underwent randomization: 442 to the enfortumab vedotin- pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group. CONCLUSIONS Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.) [ABSTRACT FROM AUTHOR]
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- 2024
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3. A0731 - First results of the phase Ib-II BladderGATE clinical trial: intravenous atezolizumab + intravesical bacillus Calmette-Guérin (BCG) upfront combination in BCG-naïve high risk non-muscle invasive bladder cancer patients.
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Guerrero-Ramos, F., De Velasco, G., Duenas, M., Paramio, J., García, V.M., Gómez-Canizo, C., Rodríguez-Izquierdo, M., Hernández-Arroyo, M., Martín-Torres, M.P., Álvarez-Rodríguez, P., Suárez, C., Morales, L., Ponce, S., Rodríguez-Antolín, A., and Castellano, D.
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NON-muscle invasive bladder cancer , *BCG immunotherapy , *ATEZOLIZUMAB , *CANCER patients , *CLINICAL trials - Published
- 2024
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4. Induction avelumab followed by chemoimmunotherapy and maintenance versus chemotherapy alone as first-line therapy in cis-ineligible metastatic urothelial carcinoma (INDUCOMAIN): a randomized phase II study.
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Rodriguez-Vida A, Valderrama BP, Castellano D, Pinto A, Mellado B, Puente J, Climent MA, Domenech M, Vazquez F, Perez-Gracia JL, Bonfill T, Morales-Barrera R, Gonzalez-Billalabeitia E, Garcia-Del-Muro X, Maroto P, Navarro-Gorro N, Juanpere N, Juan O, and Bellmunt J
- Abstract
Background: Platinum-based chemotherapy (ChT) has been the standard first-line treatment for metastatic urothelial carcinoma (mUC). The purpose of this study was to evaluate the use of induction avelumab followed by avelumab in combination with carboplatin-gemcitabine (carbo/gem) followed by avelumab maintenance. We tested the hypothesis that induction immunotherapy (IO) could enhance the response to ChT and prevent its detrimental effect on immune cells., Materials and Methods: INDUCOMAIN is a multicenter, randomized, investigator-initiated, open-label phase II study evaluating the safety and efficacy of induction avelumab before carboplatin-gemcitabine-avelumab, followed by avelumab maintenance (arm A), compared to carbo/gem (arm B). Eligibility criteria included patients with mUC, no prior systemic therapy, and ineligibility for cisplatin by Galsky criteria. Patients were stratified by the presence/absence of visceral metastasis and Eastern Cooperative Oncology Group performance status 0-1 versus 2. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety., Results: Eighty-five patients were included and randomized to arm A (n = 42) and arm B (n = 43), respectively. ORR was similar between treatment arms: 59.5% in arm A and 53.5% in arm B (P = 0.57). Fourteen patients (33%) in arm A early progressed/died before or at first response assessment, compared to three patients (7%) in arm B. Median OS was 11.1 months in arm A and 13.2 months in arm B [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.57-1.46, P = 0.69]. Median PFS was 6.9 months in arm A versus 7.4 months in arm B (HR 0.99, 95% CI 0.61-1.60, P = 0.95). Treatment-related adverse events of grade 3-4 occurred in 70.7% of patients in arm A and in 72.1% in arm B. No predictive role of programmed death-ligand 1 expression was found., Conclusions: The hypothesis that induction avelumab could enhance the efficacy of subsequent ChT was not proven. Administering IO alone as induction before ChT is not an adequate strategy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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5. Satellite glial contact enhances differentiation and maturation of human iPSC-derived sensory neurons.
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LeBlang CJ, Pazyra-Murphy MF, Silagi ES, Dasgupta S, Tsolias M, Miller T, Petrova V, Zhen S, Jovanovic V, Castellano D, Gerrish K, Ormanoglu P, Tristan C, Singeç I, Woolf CJ, Tasdemir-Yilmaz O, and Segal RA
- Abstract
Sensory neurons generated from induced pluripotent stem cells (iSNs) are used to model human peripheral neuropathies, however current differentiation protocols produce sensory neurons with an embryonic phenotype. Peripheral glial cells contact sensory neurons early in development and contribute to formation of the canonical pseudounipolar morphology, but these signals are not encompassed in current iSN differentiation protocols. Here, we show that terminal differentiation of iSNs in co-culture with rodent Dorsal Root Ganglion satellite glia (rSG) advances their differentiation and maturation. Co-cultured iSNs develop a pseudounipolar morphology through contact with rSGs. This transition depends on semaphorin-plexin guidance cues and on glial gap junction signaling. In addition to morphological changes, iSNs terminally differentiated in co-culture exhibit enhanced spontaneous action potential firing, more mature gene expression, and increased susceptibility to paclitaxel induced axonal degeneration. Thus, iSNs differentiated in coculture with rSGs provide a better model for investigating human peripheral neuropathies.
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- 2024
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6. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial.
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Tannir NM, Albigès L, McDermott DF, Burotto M, Choueiri TK, Hammers HJ, Barthélémy P, Plimack ER, Porta C, George S, Donskov F, Atkins MB, Gurney H, Kollmannsberger CK, Grimm MO, Barrios C, Tomita Y, Castellano D, Grünwald V, Rini BI, Jiang R, Desilva H, Federov V, Lee CW, and Motzer RJ
- Abstract
Background: Nivolumab+ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years median follow-up from CheckMate 214., Patients and Methods: Patients with aRCC (N=1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. Endpoints included OS, and independent radiology review committee-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients., Results: With 8 years (99.1 months) median follow-up, the HR (95% CI) for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all IMDC risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). Median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1-not estimable (NE) versus 19.8-33.2; ITT], 82.8 versus 19.8 months [54.1-NE versus 16.4-26.4; I/P], and 61.5 versus 33.2 months [27.8-NE versus 24.8-51.4; FAV]). Incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time., Conclusions: Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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7. Reversing anxiety by targeting a stress-responsive signaling pathway.
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Pandey S, Han W, Li J, Shepard R, Wu K, Castellano D, Tian Q, Dong L, Li Y, and Lu W
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- Animals, Mice, src-Family Kinases metabolism, Phosphorylation, Myosins metabolism, Male, Mice, Inbred C57BL, Depression drug therapy, Depression metabolism, Humans, Signal Transduction drug effects, Anxiety drug therapy, Anxiety metabolism, Stress, Psychological metabolism, Calmodulin metabolism
- Abstract
Current treatments of anxiety and depressive disorders are plagued by considerable side effects and limited efficacies, underscoring the need for additional molecular targets that can be leveraged to improve medications. Here, we have identified a molecular cascade triggered by chronic stress that exacerbates anxiety- and depressive-like behaviors. Specifically, chronic stress enhances Src kinase activity and tyrosine phosphorylation of calmodulin, which diminishes MyosinVa (MyoVa) interaction with Neuroligin2 (NL2), resulting in decreased inhibitory transmission and heightened anxiety-like behaviors. Importantly, pharmacological inhibition of Src reinstates inhibitory synaptic deficits and effectively reverses heightened anxiety-like behaviors in chronically stressed mice, a process requiring the MyoVa-NL2 interaction. These data demonstrate the reversibility of anxiety- and depressive-like phenotypes at both molecular and behavioral levels and uncover a therapeutic target for anxiety and depressive disorders., Competing Interests: Competing interests statement:The authors declare no competing interest.
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- 2024
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8. Incidence and outcome of perforations during medium vessel occlusion compared with large vessel occlusion thrombectomy.
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Schulze-Zachau V, Brehm A, Ntoulias N, Krug N, Tsogkas I, Blackham KA, Möhlenbruch MA, Jesser J, Cervo A, Kreiser K, Althaus K, Maslias E, Michel P, Saliou G, Riegler C, Nolte CH, Maier I, Jamous A, Rautio R, Ylikotila P, Fargen KM, Wolfe SQ, Castellano D, Boghi A, Kaiser DPO, Cuberi A, Kirschke JS, Schwarting J, Limbucci N, Renieri L, Al Kasab S, Spiotta AM, Fragata I, Rodriquez-Ares T, Maurer CJ, Berlis A, Moreu M, López-Frías A, Pérez-García C, Commodaro C, Pileggi M, Mascitelli J, Giordano F, Casagrande W, Purves CP, Bester M, Flottmann F, Kan PT, Edhayan G, Hofmeister J, Machi P, Kaschner M, Weiss D, Katan M, Fischer U, and Psychogios MN
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- Humans, Female, Male, Aged, Retrospective Studies, Incidence, Middle Aged, Aged, 80 and over, Treatment Outcome, Intraoperative Complications epidemiology, Intraoperative Complications etiology, Cohort Studies, Thrombectomy methods, Thrombectomy adverse effects
- Abstract
Background: Vessel perforation during thrombectomy is a severe complication and is hypothesized to be more frequent during medium vessel occlusion (MeVO) thrombectomy. The aim of this study was to compare the incidence and outcome of patients with perforation during MeVO and large vessel occlusion (LVO) thrombectomy and to report on the procedural steps that led to perforation., Methods: In this multicenter retrospective cohort study, data of consecutive patients with vessel perforation during thrombectomy between January 1, 2015 and September 30, 2022 were collected. The primary outcomes were independent functional outcome (ie, modified Rankin Scale 0-2) and all-cause mortality at 90 days. Binomial test, chi-squared test and t -test for unpaired samples were used for statistical analysis., Results: During 25 769 thrombectomies (5124 MeVO, 20 645 LVO) in 25 stroke centers, perforation occurred in 335 patients (1.3%; mean age 72 years, 62% female). Perforation occurred more often in MeVO thrombectomy (2.4%) than in LVO thrombectomy (1.0%, p <0.001). More MeVO than LVO patients with perforation achieved functional independence at 3 months (25.7% vs 10.9%, p =0.001). All-cause mortality did not differ between groups (overall 51.6%). Navigation beyond the occlusion and retraction of stent retriever/aspiration catheter were the two most common procedural steps that led to perforation., Conclusions: In our cohort, perforation was approximately twice as frequent in MeVO than in LVO thrombectomy. Efforts to optimize the procedure may focus on navigation beyond the occlusion site and retraction of stent retriever/aspiration catheter. Further research is necessary in order to identify thrombectomy candidates at high risk of intraprocedural perforation and to provide data on the effectiveness of endovascular countermeasures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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9. Prognostic Implications of Blood Immune-Cell Composition in Metastatic Castration-Resistant Prostate Cancer.
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Perez-Navarro E, Conteduca V, Funes JM, Dominguez JI, Martin-Serrano M, Cremaschi P, Fernandez-Perez MP, Gordoa TA, Font A, Vázquez-Estévez S, González-Del-Alba A, Wetterskog D, Mellado B, Fernandez-Calvo O, Méndez-Vidal MJ, Climent MA, Duran I, Gallardo E, Rodriguez Sanchez A, Santander C, Sáez MI, Puente J, Tudela J, Marinas C, López-Andreo MJ, Castellano D, Attard G, Grande E, Rosino A, Botia JA, Palma-Mendez J, De Giorgi U, and Gonzalez-Billalabeitia E
- Abstract
The prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) varies, being influenced by blood-related factors such as transcriptional profiling and immune cell ratios. We aimed to address the contribution of distinct whole blood immune cell components to the prognosis of these patients. This study analyzed pre-treatment blood samples from 152 chemotherapy-naive mCRPC patients participating in a phase 2 clinical trial (NCT02288936) and a validation cohort. We used CIBERSORT-X to quantify 22 immune cell types and assessed their prognostic significance using Kaplan-Meier and Cox regression analyses. Reduced CD8 T-cell proportions and elevated monocyte levels were substantially connected with a worse survival. High monocyte counts correlated with a median survival of 32.2 months versus 40.3 months for lower counts (HR: 1.96, 95% CI 1.11-3.45). Low CD8 T-cell levels were associated with a median survival of 31.8 months compared to 40.3 months for higher levels (HR: 1.97, 95% CI 1.11-3.5). These findings were consistent in both the trial and validation cohorts. Multivariate analysis further confirmed the independent prognostic value of CD8 T-cell counts. This study highlights the prognostic implications of specific blood immune cells, suggesting they could serve as biomarkers in mCRPC patient management and should be further explored in clinical trials.
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- 2024
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10. Scalable Hypothalamic Arcuate Neuron Differentiation from Human Pluripotent Stem Cells Suitable for Modeling Metabolic and Reproductive Disorders.
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Jovanovic VM, Narisu N, Bonnycastle LL, Tharakan R, Mesch KT, Glover HJ, Yan T, Sinha N, Sen C, Castellano D, Yang S, Blivis D, Ryu S, Bennett DF, Rosales-Soto G, Inman J, Ormanoglu P, LeClair CA, Xia M, Schneider M, Hernandez-Ochoa EO, Erdos MR, Simeonov A, Chen S, Singeç I, Collins FS, Doege CA, and Tristan CA
- Abstract
The hypothalamus, composed of several nuclei, is essential for maintaining our body's homeostasis. The arcuate nucleus (ARC), located in the mediobasal hypothalamus, contains neuronal populations with eminent roles in energy and glucose homeostasis as well as reproduction. These neuronal populations are of great interest for translational research. To fulfill this promise, we used a robotic cell culture platform to provide a scalable and chemically defined approach for differentiating human pluripotent stem cells (hPSCs) into pro-opiomelanocortin (POMC), somatostatin (SST), tyrosine hydroxylase (TH) and gonadotropin-releasing hormone (GnRH) neuronal subpopulations with an ARC-like signature. This robust approach is reproducible across several distinct hPSC lines and exhibits a stepwise induction of key ventral diencephalon and ARC markers in transcriptomic profiling experiments. This is further corroborated by direct comparison to human fetal hypothalamus, and the enriched expression of genes implicated in obesity and type 2 diabetes (T2D). Genome-wide chromatin accessibility profiling by ATAC-seq identified accessible regulatory regions that can be utilized to predict candidate enhancers related to metabolic disorders and hypothalamic development. In depth molecular, cellular, and functional experiments unveiled the responsiveness of the hPSC-derived hypothalamic neurons to hormonal stimuli, such as insulin, neuropeptides including kisspeptin, and incretin mimetic drugs such as Exendin-4, highlighting their potential utility as physiologically relevant cellular models for disease studies. In addition, differential glucose and insulin treatments uncovered adaptability within the generated ARC neurons in the dynamic regulation of POMC and insulin receptors. In summary, the establishment of this model represents a novel, chemically defined, and scalable platform for manufacturing large numbers of hypothalamic arcuate neurons and serves as a valuable resource for modeling metabolic and reproductive disorders.
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- 2024
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11. Final Results from SAUL, a Single-arm International Study of Atezolizumab in Unselected Patients with Pretreated Locally Advanced/Metastatic Urinary Tract Carcinoma.
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Sternberg CN, Loriot Y, Choy E, Castellano D, Lopez-Rios F, Banna GL, Zengerling F, De Giorgi U, Gedye C, Masini C, Bamias A, Garcia Del Muro X, Duran I, Powles T, Retz M, Gamulin M, Geczi L, Huddart RA, Calabrò F, Kandula G, Skamnioti P, and Merseburger AS
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Background and Objective: We assessed the safety of atezolizumab in unselected patients (including understudied populations typically excluded from clinical trials) with pretreated urinary tract carcinoma (UTC). The prespecified final analysis updates previously reported safety and efficacy data., Methods: The single-arm prospective SAUL study (NCT02928406) enrolled 1004 patients with locally advanced/metastatic urothelial/non-urothelial UTC that had progressed during/after one to three prior treatment lines for advanced UTC (or <12 mo after [neo]adjuvant therapy). Broad eligibility criteria allowed enrollment of patients with complex comorbidities approximating the real-world setting. Patients received atezolizumab 1200 mg every 3 wk until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included duration of response and overall survival (OS)., Key Findings and Limitations: The treated cohort included 10% of patients with poor performance status, 5% with creatinine clearance <30 ml/min, and 4% with autoimmune disease. At median follow-up of 55 mo, median atezolizumab duration was 2.8 mo (range 0-62); 68 patients (7%) continued atezolizumab for >4 yr. Treatment-related grade ≥3 adverse events occurred in 16% of patients (death in 1%); 8% discontinued atezolizumab for adverse events. Median OS was 8.6 mo (95% confidence interval 7.8-9.7) and 136 patients (14%) had OS longer than 4 yr. Limitations include the small sample size for some subgroups of special interest., Conclusions and Clinical Implications: Long-term safety and efficacy data continue to show a benefit of atezolizumab in unselected patients with UTC. Remarkably, 14% of patients lived for >4 yr after starting atezolizumab. These results can inform multidisciplinary team discussions and treatment decision-making for patients with UTC with complex comorbidities., Patient Summary: The SAUL study looked at how well tolerated a drug called atezolizumab was in patients with urinary tract cancer who had already received up to three previous treatments for their cancer, including people who are usually not included in clinical trials because of other medical conditions. The length of survival after starting treatment was also assessed. Overall, the results show that atezolizumab was well tolerated. People for whom other therapies had failed lived for about 8.6 months on average after starting treatment, and 14% of the patients were still alive after 4 years., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
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- 2024
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12. A Signal-Finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration-Resistant Prostate Cancer: Results from CYCLONE 1.
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Agarwal N, Castellano D, Alonso-Gordoa T, Arranz Arija JA, Colomba E, Gravis G, Mourey L, Oudard S, Fléchon A, González M, Rey PM, Schweizer MT, Gallardo E, Johnston E, Balar A, Haddad N, Appiah AK, Nacerddine K, and Piulats JM
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- Aged, Aged, 80 and over, Humans, Male, Middle Aged, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Neoplasm Metastasis, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors administration & dosage, Treatment Outcome, Aminopyridines administration & dosage, Aminopyridines therapeutic use, Aminopyridines adverse effects, Benzimidazoles administration & dosage, Benzimidazoles adverse effects, Benzimidazoles therapeutic use, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant pathology
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Purpose: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg twice daily was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%., Results: At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months [95% confidence interval (CI), 3.2-NA]; median radiographic PFS; 2.7 months (95% CI, 1.9-3.7); and median OS, 8.4 months (95% CI, 5.6-12.7). Most frequent grade ≥3 treatment-emergent adverse events (AE) were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib., Conclusions: Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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13. Exploratory analyses of treatment subgroup interaction by PD-L1 status and according to PD-L1 expression in the JAVELIN Bladder 100 trial.
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Climent MÁ, Álvarez C, Morales R, Maroto P, Rodríguez-Vida A, Méndez-Vidal MJ, Del Muro XG, Puente J, Láinez N, Vázquez S, Castellano D, Lang CG, Wang J, di Pietro A, Davis C, Sanz-Castillo B, Bolós MV, and Valderrama BP
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- Humans, Progression-Free Survival, Female, Male, Antineoplastic Agents, Immunological therapeutic use, Aged, Middle Aged, Maintenance Chemotherapy, Survival Rate, B7-H1 Antigen metabolism, Antibodies, Monoclonal, Humanized therapeutic use, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms metabolism, Urinary Bladder Neoplasms pathology, Urinary Bladder Neoplasms mortality, Carcinoma, Transitional Cell drug therapy, Carcinoma, Transitional Cell metabolism, Carcinoma, Transitional Cell pathology
- Abstract
Purpose: Post hoc analysis of the JAVELIN Bladder 100 trial of avelumab maintenance in locally advanced/metastatic urothelial carcinoma (la/mUC) to determine the interaction by programmed death ligand 1 (PD-L1) status for overall survival (OS), and additional analyses of survival per a different PD-L1 expression cutoff of ≥ 1% in tumor cells or immune cells (TC/IC)., Methods: JAVELIN Bladder 100 data were used for the analysis of the interaction by PD-L1 status (per cutoff used in the trial) for OS and, additionally, OS and progression-free survival (PFS) analyses per a different ≥ 1% TC/IC PD-L1 expression cutoff (Ventana SP263 assay)., Results: No significant interaction between treatment and PD-L1 status was observed for OS. Clinically meaningful and robust survival data were observed in favor of avelumab using the different ≥ 1% TC/IC PD-L1 expression cutoff., Conclusions: These results demonstrate the benefit of avelumab maintenance in la/mUC regardless of PD-L1 expression, consistent with approved labels., (© 2023. The Author(s).)
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- 2024
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14. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy.
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Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, and Petrylak DP
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- Humans, Male, Female, Aged, Middle Aged, Urologic Neoplasms drug therapy, Urologic Neoplasms pathology, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms pathology, Antineoplastic Agents therapeutic use, Antineoplastic Agents adverse effects, Quality of Life, Carcinoma, Transitional Cell drug therapy, Carcinoma, Transitional Cell pathology, Antibodies, Monoclonal therapeutic use, Patient Reported Outcome Measures
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Background and Objective: In comparison to chemotherapy, enfortumab vedotin (EV) prolonged overall survival in patients with previously treated advanced urothelial carcinoma in EV-301. The objective of the present study was to assess patient experiences of EV versus chemotherapy using patient-reported outcome (PRO) analysis of health-related quality of life (HRQoL)., Methods: For patients in the phase 3 EV-301 trial randomized to EV or chemotherapy we assessed responses to the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, weekly for the first 12 wk, and then every 12 wk until discontinuation. We analyzed the QLQ-C30 change from baseline to week 12, the confirmed improvement rate, and the time to improvement or deterioration., Key Findings and Limitations: Baseline PRO compliance rates were 91% for the EV arm (n = 301) and 89% for the chemotherapy arm (n = 307); the corresponding average rates from baseline to week 12 were 70% and 67%. Patients receiving EV versus chemotherapy had reduced pain (difference in change from baseline to week 12: -5.7, 95% confidence interval [CI] -10.8 to -0.7; p = 0.027) and worsening appetite loss (7.3, 95% CI 0.90-13.69; p = 0.026). Larger proportions of patients in the EV arm reported HRQoL improvement from baseline than in the chemotherapy arm; the odds of a confirmed improvement across ten QLQ-C30 function/symptom scales were 1.67 to 2.76 times higher for EV than for chemotherapy. Patients in the EV arm had a shorter time to first confirmed improvement in global health status (GHS)/QoL, fatigue, pain, and physical, role, emotional, and social functioning (all p < 0.05). EV delayed the time to first confirmed deterioration in GHS/QoL (p = 0.027), but worsening appetite loss occurred earlier (p = 0.009) in comparison to chemotherapy., Conclusions and Clinical Implications: HRQoL with EV was maintained, and deterioration in HRQoL was delayed with EV in comparison to chemotherapy. Better results with EV were reported for some scales, with the greatest difference observed for pain. These findings reinforce the EV safety and efficacy outcomes and benefits observed in EV-301., Patient Summary: Patients with previously treated advanced cancer of the urinary tract receiving the drug enfortumab vedotin maintained their HRQoL in comparison to patients treated with chemotherapy. The EV-301 trial is registered on ClinicalTrials.gov as NCT03474107 and on EudraCT as 2017-003344-21., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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15. Retifanlimab in Advanced Penile Squamous Cell Carcinoma: The Phase 2 ORPHEUS Study.
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García Del Muro X, Páez López-Bravo D, Cuéllar-Rivas MA, Maroto P, Giannatempo P, Castellano D, Climent MA, P Valderrama B, Gómez de Liaño A, López-Montero L, Mina L, Alcalá-López D, Sampayo-Cordero M, and Necchi A
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Background and Objective: Patients with advanced penile squamous cell carcinoma (PSCC) have poor outcomes and very limited therapeutic options are available. Most PSCC cases have high PD-L1 expression, which is associated with worse prognosis. Immunotherapy targeting PD-L1 could benefit patients with PSCC. Our aim was to evaluate the efficacy and safety of the anti-PD-1 antibody retifanlimab in patients with advanced/metastatic PSCC., Methods: ORPHEUS was a single-arm, multicenter, phase 2 trial in 18 patients with advanced/metastatic PSCC, previously untreated with anti-PD-1/anti-PD-L1 agents. Patients received retifanlimab 500 mg intravenously every 4 wk for up to 2 yr. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included the clinical benefit rate (CBR), disease control rate, duration of response (DoR), time to response, progression-free survival (PFS), overall survival (OS), maximum tumor shrinkage, and safety. The Wilson method was used for the primary endpoint, and the Clopper-Pearson and Kaplan-Meier methods for secondary endpoints., Key Findings and Limitations: Median follow-up was 7.2 mo. The ORR was 16.7% (95% confidence interval [CI] 5.8-39.2); three patients had a partial response. Median DoR was 3.3 mo (range 1.8-8.5). The CBR was 22.2% (95% CI 6.4-47.6%). Median PFS was 2.0 mo (95% CI 1.6-3.3) and median OS was 7.2 mo (95% CI 3.0-9.8). One patient (5.6%) experienced grade 3 treatment-related adverse events (AEs). There were no grade >= 4 treatment-related AEs. The small sample size is the main limitation., Conclusions and Clinical Implications: Single-agent retifanlimab exhibited signals of clinical activity in advanced/metastatic PSCC, with no new safety signals. Further investigation of retifanlimab in this setting is warranted., Patient Summary: Advanced penile cancer of the squamous cell type is a rare tumor with poor prognosis. The aggressiveness of this cancer is usually associated with high levels of a protein called PD-L1. We investigated whether retifanlimab, an immunotherapy drug against PD-1, has activity against this type of penile cancer. Tumor regression or stabilization occurred in one-third of the patients and the side effects were manageable., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
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- 2024
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16. Non-hypermutator cancers access driver mutations through reversals in germline mutational bias.
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Tuffaha MZ, Castellano D, Colome CS, Gutenkunst RN, and Wahl LM
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Cancer is an evolutionary disease driven by mutations in asexually-reproducing somatic cells. In asexual microbes, bias reversals in the mutation spectrum can speed adaptation by increasing access to previously undersampled beneficial mutations. By analyzing tumors from 20 tissues, along with normal tissue and the germline, we demonstrate this effect in cancer. Non-hypermutated tumors reverse the germline mutation bias and have consistent spectra across tissues. These spectra changes carry the signature of hypoxia, and they facilitate positive selection in cancer genes. Hypermutated and non-hypermutated tumors thus acquire driver mutations differently: hypermutated tumors by higher mutation rates and non-hypermutated tumors by changing the mutation spectrum to reverse the germline mutation bias., Competing Interests: Competing interests: none.
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- 2024
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17. Corrigendum to "Sex differences on multikinase inhibitors toxicity in patients with advanced gastroenteropancreatic neuroendocrine tumours" [Eur J Cancer 188 (2023) 39-48].
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Hernando J, Roca-Herrera M, García-Álvarez A, Raymond E, Ruszniewski P, Kulke MH, Grande E, Carbonero RG, Castellano D, Salazar R, Ibrahim T, Teule A, Alonso V, Fazio N, Valle JW, Tafuto S, Carmona A, Navarro V, and Capdevila J
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- 2024
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18. Updated Overall Survival by Circulating Tumor DNA Status from the Phase 3 IMvigor010 Trial: Adjuvant Atezolizumab Versus Observation in Muscle-invasive Urothelial Carcinoma.
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Powles T, Assaf ZJ, Degaonkar V, Grivas P, Hussain M, Oudard S, Gschwend JE, Albers P, Castellano D, Nishiyama H, Daneshmand S, Sharma S, Sethi H, Aleshin A, Shi Y, Davarpanah N, Carter C, Bellmunt J, and Mariathasan S
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- Humans, Prospective Studies, Treatment Outcome, Neoplasm Recurrence, Local, Adjuvants, Immunologic therapeutic use, Muscles pathology, Recurrence, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Transitional Cell drug therapy, Carcinoma, Transitional Cell genetics, Carcinoma, Transitional Cell pathology, Circulating Tumor DNA genetics, Urinary Bladder Neoplasms, Antibodies, Monoclonal, Humanized
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Background: Interim results from IMvigor010 showed an overall survival (OS) benefit for adjuvant atezolizumab (anti-PD-L1) versus observation in patients with circulating tumor DNA (ctDNA)-positive muscle-invasive urothelial carcinoma (MIUC)., Objective: To report updated OS and safety by ctDNA status., Design, Setting, and Participants: This ad hoc analysis from a global, open-label, randomized, phase 3 trial (NCT02450331) included intention-to-treat (ITT) population with evaluable cycle 1 day 1 (C1D1) ctDNA samples., Intervention: Atezolizumab (1200 mg every 3 wk) or observation for ≤1 yr., Outcome Measurements and Statistical Analysis: OS, relapse rates, and safety by ctDNA status were assessed., Results and Limitations: Among 581 of 809 ITT patients included, 214 (37%) were ctDNA positive. Atezolizumab did not improve OS versus observation in ITT patients (hazard ratio [HR] 0.91 [95% confidence interval {CI} 0.73-1.13]; median follow-up 46.8 mo [interquartile range, 36.1-53.6]). In the observation arm, ctDNA positivity versus negativity was associated with shorter OS (HR 6.3 [95% CI 4.3-9.3]). The ctDNA positivity identified patients with an OS benefit favoring atezolizumab versus observation (HR 0.59 [95% CI 0.42-0.83]). A greater reduction in ctDNA levels with atezolizumab (C3D1) was associated with longer OS (100% clearance, 60.0 mo [95% CI 35.5-not estimable]; 50-99% reduction, 34.3 mo [95% CI 15.2-not estimable]; <50% reduction, 19.9 mo [95% CI 16.4-32.2]). The ctDNA positivity at C1D1 + C3D1 was associated with relapse with greater sensitivity than C1D1 alone (68% vs 57%). Adverse events were more frequent with atezolizumab than with observation, regardless of ctDNA status. A study limitation was its exploratory design., Conclusions: Evidence suggests that ctDNA positivity in MIUC predicts a benefit with atezolizumab. An in-progress prospective study will further evaluate these findings., Patient Summary: Among patients with urothelial cancer after surgery, survival was poorer if tumor-derived DNA was detected in their bloodstream; these patients' survival was longer with atezolizumab versus observation. Bloodstream tumor-derived DNA may identify patients who benefit from atezolizumab., (Copyright © 2023. Published by Elsevier B.V.)
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- 2024
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19. Phase II trial of afatinib in patients with advanced urothelial carcinoma with genetic alterations in ERBB1-3 (LUX-Bladder 1).
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Font A, Mellado B, Climent MA, Virizuela JA, Oudard S, Puente J, Castellano D, González-Del-Alba A, Pinto A, Morales-Barrera R, Rodriguez-Vida A, Fernandez PL, Teixido C, Jares P, Aldecoa I, Gibson N, Solca F, Mondal S, Lorence RM, Serra J, and Real FX
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- Humans, Mutation, Urinary Bladder pathology, Afatinib adverse effects, Carcinoma, Transitional Cell drug therapy, Carcinoma, Transitional Cell genetics, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms genetics
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Background: Preclinical and early clinical data suggest that the irreversible ErbB family blocker afatinib may be effective in urothelial cancers harbouring ERBB mutations., Methods: This open-label, phase II, single-arm trial (LUX-Bladder 1, NCT02780687) assessed the efficacy and safety of second-line afatinib 40 mg/d in patients with metastatic urothelial carcinoma with ERBB1-3 alterations. The primary endpoint was 6-month progression-free survival rate (PFS6) (cohort A); other endpoints included ORR, PFS, OS, DCR and safety (cohorts A and B). Cohort A was planned to have two stages: stage 2 enrolment was based on observed antitumour activity., Results: Thirty-four patients were enroled into cohort A and eight into cohort B. In cohorts A/B, PFS6 was 11.8%/12.5%, ORR was 5.9%/12.5%, DCR was 50.0%/25.0%, median PFS was 9.8/7.8 weeks and median OS was 30.1/29.6 weeks. Three patients (two ERBB2-amplified [cohort A]; one EGFR-amplified [cohort B]) achieved partial responses. Stage 2 for cohort A did not proceed. All patients experienced adverse events (AEs), most commonly (any/grade 3) diarrhoea (76.2%/9.5%). Two patients (4.8%) discontinued due to AEs and one fatal AE was observed (acute coronary syndrome; not considered treatment-related)., Conclusions: An exploratory biomarker analysis suggested that basal-squamous tumours and ERBB2 amplification were associated with superior response to afatinib., Clinical Trial Registration: NCT02780687., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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20. Metabolomic profile of neuroendocrine tumors identifies methionine, porphyrin, and tryptophan metabolisms as key dysregulated pathways associated with patient survival.
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La Salvia A, Lens-Pardo A, López-López A, Carretero-Puche C, Capdevila J, Benavent M, Jiménez-Fonseca P, Castellano D, Alonso T, Teule A, Custodio A, Tafuto S, La Casta A, Spada F, Lopez-Gonzalvez A, Gil-Calderon B, Espinosa-Olarte P, Barbas C, Garcia-Carbonero R, and Soldevilla B
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- Humans, Metabolomics, Methionine therapeutic use, Tryptophan, Case-Control Studies, Neuroendocrine Tumors pathology, Porphyrins therapeutic use
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Objective: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways., Design and Methods: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA)., Results: Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs., Conclusions: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients., Competing Interests: Conflict of interest: J.C. has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA, Advanz Pharma, Amgen, Bayer, Esteve, Hutchmed, Ipsen, Merck, Novartis, Roche, Sanofi, Lilly, Eisai, Bayer, and ITM, and has received research support from Pfizer, Novartis, Astrazeneca, Eisai, AAA, Amgen, Bayer, Roche, Gilead, and ITM. M.B. reports Advisory from Novartis, Ipsen, and Pfizer. P.J.-F. has received speaker honoraria or consultant honoraria from Adacap, Astellas, BMS, Lilly, and MSD. D.C. has provided scientific advice and/or received honoraria or funding for continuous medical education from Janssen Oncology, Roche/Genetech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, BMS, MSD, Bayer, Lilly, Sanofi, Pierre Fabre, and Boerhinger. F.S. has received honoraria for medical education and research activity from Ipsen, Novartis, Pfizer, Advanced Accelerator Applications, MSD/Merck, and Hutchmed. A.T. has provided scientific advice and/or received honoraria from ADACAP, Ipsen, Novartis, and Pfizer. R.G.-C. has provided scientific advice and/or received honoraria or funding for continuous medical education from ADACAP, Advanz Pharma, Amgen, Bayer, BMS, Boerhinger, Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pierre Fabre, Roche, Servier, and Sanofi, and has received research support from Pfizer, BMS, and MSD. The remaining authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)
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- 2024
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