To determine the efficacy of treatment using high-dose bolus interleukin 2 (IL-2) in patients with metastatic melanoma or renal cell cancer.
Consecutive series of all patients treated with high-dose ...IL-2 in the Surgery Branch of the National Cancer Institute from September 1985 through December 1992.
Two hundred eighty-three patients with metastatic melanoma or metastatic renal cell cancer who had failed standard treatment for their cancers.
Patients received IL-2 at a dose of 720,000 IU/kg intravenously every 8 hours for a maximum of 15 doses per cycle. Two cycles constituted a treatment course, and patients with stable or responding disease received additional treatment courses. A total of 447 courses of treatment were administered.
Regression of measurable tumor, durability of response to treatment, and survival.
Nine patients (7%) with metastatic melanoma achieved complete regression of all disease and 14 patients (10%) had partial regression. Ten patients (7%) with metastatic renal cell cancer experienced complete regression and 20 patients (13%) had partial regression. Of the 19 patients with complete regression, 15 have remained in complete remission from 7 to 91 months after treatment. Three treatment-related deaths (1.1%) occurred early in this series, but as experience with the administration of this IL-2 regimen increased, no treatment-related deaths occurred in 214 patients treated during the last 5 years of the study.
Biologic therapy with IL-2 can cause significant antitumor effects in patients with advanced metastatic melanoma or renal cell cancer. Because IL-2 does not have a direct effect on cancer cells but rather mediates its antitumor activity by altering host immune reactions, these data represent the best available evidence that immunologic therapy for cancer can be effective in selected patients.
Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution ...during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.
Autoimmune diseases are complex and heterogeneous in nature and show varying responses to therapeutic treatment. A more accurate biological characterization of individual patients would assist in ...disease classification, prognosis, and treatment decisions. This characterization ideally would incorporate cellular, biochemical, and molecular information that contribute to the inflammatory state. The advent of single-cell network profiling (SCNP) using phospho-flow multiparametric flow cytometry allows insight into the complexity of signaling networks in various cell types. Here, we describe the potential of SCNP to inform on the biological characterization of autoimmune disease, the application in clinical medicine, and the utility in drug development.
To determine the efficacy and toxicity of a high-dose interleukin-2 (IL-2) regimen in patients with metastatic renal cell carcinoma.
Two hundred fifty-five assessable patients were entered onto seven ...phase II clinical trials. Proleukin (aldesleukin; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous (i.v.) infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical cycle of treatment was scheduled following 5 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients.
The overall objective response rate was 14% (90% confidence interval CI, 10% to 19%), with 12 (5%) complete responses (CRs) and 24 (9%) partial responses (PRs). Responses occurred in all sites of disease, including bone, intact primary tumors, and visceral metastases, and in patients with large tumor burdens or bulky individual lesions. The median response duration for patients who achieved a CR has not been reached, but was 19.0 months for those who achieved a PR. Baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was the only predictive prognostic factor for response to IL-2. While treatment was associated with severe acute toxicities, these generally reversed rapidly after therapy was completed. However, 4% of patients died of adverse events judged to be possibly or probably treatment-related.
High-dose IL-2 appears to benefit some patients with metastatic renal cell carcinoma by producing durable CRs or PRs. Despite severe acute treatment-associated toxicities, IL-2 should be considered for initial therapy of patients with appropriately selected metastatic renal cell carcinoma.
To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator ...of inflammation.
We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants).
For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0·22 SD (95% CI 0·18–0·25; 12·5%; p=9·3 × 10−33), concentrations of interleukin 6 decreased by 0·02 SD (−0·04 to −0·01; −1·7%; p=3·5 × 10−3), and concentrations of C-reactive protein decreased by 0·03 SD (−0·04 to −0·02; −3·4%; p=7·7 × 10−14). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1·15 (1·08–1·22; p=1·8 × 10−6) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1·03 (1·02–1·04; p=3·9 × 10−10). Per-allele odds ratios were 0·97 (0·95–0·99; p=9·9 × 10−4) for rheumatoid arthritis, 0·99 (0·97–1·01; p=0·47) for type 2 diabetes, 1·00 (0·98–1·02; p=0·92) for ischaemic stroke, and 1·08 (1·04–1·12; p=1·8 × 10−5) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk.
Human genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations.
UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7.
Identifying terrain within satellite image data is a key issue in geographical information sciences, with numerous environmental and safety implications. Many techniques exist to derive ...classifications from spectral data captured by satellites. However, the ability to reliably classify vegetation remains a challenge. In particular, no precise methods exist for classifying forest vs. non-forest vegetation in high-level satellite images. This paper provides an initial proposal for a static, algorithmic process to identify forest regions in satellite image data through texture features created from detected edges and the NDVI ratio captured by Sentinel-2 satellite images. With strong initial results, this paper also identifies the next steps to improve the accuracy of the classification and verification processes.
Identification and SAR of a series of piperazine derivatives as inhibitors of the gp120–CD4 interaction is described.
A series of piperazine derivatives were designed and synthesised as gp120–CD4 ...inhibitors. SAR studies led to the discovery of potent inhibitors in a cell based anti viral assay represented by compounds
9 and
28. The rat pharmacokinetic and antiviral profiles of selected compounds are also presented.
The synthesis and SAR of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound
36.
...The synthesis and structure–activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound
36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.
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