ABSTRACT
BACKGROUND: The genomic landscape of primary clear cell renal cell carcinoma (ccRCC) has been well described. However, little is known about cohort genomic alterations (GA) landscape in ccRCC metastases, or how it compares to primary tumours in aggregate. The genomic landscape of metastases may have biological, clinical, and therapeutic implications. METHODS: We collected targeted next-generation sequencing mutation calls from two independent cohorts and described the metastases GA landscape and descriptively compared it to the GA landscape in primary tumours. RESULTS: The cohort 1 (n = 578) consisted of 349 primary tumours and 229 metastases. Overall, the most common mutations in the metastases were VHL (66.8%), PBRM1 (41.87%), and SETD2 (24.7%). TP53 was more frequently mutated in metastases compared to primary tumours (14.85% versus 8.9%; p = 0.031). No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumours. Mutation burden was not significantly different between the metastases and primary tumours or between metastatic sites. The second cohort (n = 257) consisted of 177 primary tumours and 80 metastases. No differences in frequency of mutations or mutational burden were observed between primaries and metastases. CONCLUSIONS: These data support the theory that ccRCC primary tumours and metastases encompass a uniform distribution of common genomic alterations tested by next-generation sequencing targeted panels. This study does not address variability between matched primary tumours and metastases or the change in genomic alterations over time and after sequential systemic therapies.
Subject(s)
Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Cohort Studies , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genomics/methods , High-Throughput Nucleotide Sequencing/methods , Humans , Male , Middle Aged , Neoplasm Metastasis/genetics , Young AdultABSTRACT
BACKGROUND: An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB. METHODS: We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6 weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR. RESULTS: Median follow up was 16.6 months (range: 0.7-67.8). Median duration on therapy was 5.1 months (<1-61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3-42.4) at baseline and 4.1 (1.1-96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ≥25% from baseline to 6 weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS (p < 0.001) and OS (p = 0.004), whereas a decrease in NLR by ≥25% was associated with improved outcomes. CONCLUSIONS: Early decline and NLR at 6 weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Lymphocytes/drug effects , Neutrophils/drug effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/immunology , Female , Humans , Kidney Neoplasms/immunology , Lymphocytes/immunology , Male , Middle Aged , Neutrophils/immunology , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
Mobile robots (i.e., robots capable of translational movements) can be designed to become interesting tools for child development studies and pediatric rehabilitation. In this article, the authors present two of their projects that involve mobile robots interacting with children: One is a spherical robot deployed in a variety of contexts, and the other is mobile robots used as pedagogical tools for children with pervasive developmental disorders. Locomotion capability appears to be key in creating meaningful and sustained interactions with children: Intentional and purposeful motion is an implicit appealing factor in obtaining children's attention and engaging them in interaction and learning. Both of these projects started with robotic objectives but are revealed to be rich sources of interdisciplinary collaborations in the field of assistive technology. This article presents perspectives on how mobile robots can be designed to address the requirements of child-robot interactions and studies. The authors also argue that mobile robot technology can be a useful tool in rehabilitation engineering, reaching its full potential through strong collaborations between roboticists and pediatric specialists.
