PubMed · 6560255
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J Faehnrich. Extravasation.. https://pubmed.ncbi.nlm.nih.gov/6560255/
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Drug response differs substantially in cancer patients due to inter- and intra-tumor heterogeneity. Particularly, transcriptome context, especially tumor microenvironment, has been shown playing a significant role in shaping the actual treatment outcome. In this study, we develop a deep variational autoencoder (VAE) model to compress thousands of genes into latent vectors in a low-dimensional space. We then demonstrate that these encoded vectors could accurately impute drug response, outperform standard signature-gene based approaches, and appropriately control the overfitting problem. We apply rigorous quality assessment and validation, including assessing the impact of cell line lineage, cross-validation, cross-panel evaluation, and application in independent clinical data sets, to warrant the accuracy of the imputed drug response in both cell lines and cancer samples. Specifically, the expression-regulated component (EReX) of the observed drug response achieves high correlation across panels. Using the well-trained models, we impute drug response of The Cancer Genome Atlas data and investigate the features and signatures associated with the imputed drug response, including cell line origins, somatic mutations and tumor mutation burdens, tumor microenvironment, and confounding factors. In summary, our deep learning method and the results are useful for the study of signatures and markers of drug response.
PURPOSE: In 215 consecutive patients with advanced metastatic renal cell carcinoma seen at a single institution the efficacy and tolerance of different subcutaneous recombinant interleukin-2 based home therapies were assessed. MATERIALS AND METHODS: Treatment consisted of subcutaneous recombinant interleukin-2 alone and subcutaneous recombinant interleukin-2 in combination with recombinant interferon-alpha 2 with or without intravenous 5-fluorouracil. RESULTS: Overall objective response rate in 215 patients was 33% (95% confidence interval 26 to 39%). Among 16 patients receiving recombinant interleukin-2 alone there was 1 partial remission (overall response 6%). In 79 patients receiving recombinant interleukin-2 and interferon-alpha 2 in combination 6 complete and 16 partial remissions occurred (overall response 28%). Of 120 patients receiving a combination of recombinant interleukin-2, recombinant interferon-alpha 2 and 5-fluorouracil 13 achieved a complete and 34 a partial remission (overall response 39%). Of all patients 5% achieved long-lasting remissions and remain disease-free. Multivariate analyses identified pretreatment erythrocyte sedimentation rate greater than 70 mm. per hour and lactic dehydrogenase greater than 280 units per l. as independent prognostic factors of major significance (p < or = 0.0001) in metastatic renal cell carcinoma. Additionally, neutrophil count greater than 6,000/microliters., hemoglobin less than 100 gm./l., extrapulmonary metastases and bone lesions were identified as minor (p < or = 0.006) prognostic variables. Patients were assigned to 1 of 3 risk categories according to cumulative risk score defined as the function of the sum of all 6 independent variables. In 116 intermediate risk patients 2-year survival was 65% (median survival not reached after 32 months) with recombinant interleukin-2, recombinant interferon-alpha 2 and 5-fluorouracil, as opposed to 27% 2-year survival (median survival 15 months) with recombinant interleukin-2 and interferon-alpha 2 (p < 0.0001), and 0% (median survival 4.8 months) with single agent recombinant interleukin-2. In the majority of patients systemic toxicity of subcutaneous recombinant interleukin-2 based protocols was limited to grade 1 or 2 constitutional symptoms, that is fever, chills, malaise and anorexia, which allowed for outpatient therapy. CONCLUSIONS: The present outpatient recombinant interleukin-2 triple drug combination protocol was as effective as the most aggressive intravenous recombinant interleukin-2 regimen available. Combination home therapy eliminated the need for inpatient and/or intensive care as required for intravenous cytokine administration and, thereby, it substantially improved the therapeutic index and cost-effectiveness of recombinant interleukin-2 therapy in metastatic renal cell carcinoma stratified for risk.
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