XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical ...models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article.
A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses.
Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC.
Cabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing (ClinicalTrials.gov number NCT00215605).
Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between ...irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS).
Patients with AST received SBRT (30-50 Gy in 3-5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.v. every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65 mL. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11 matched) prior to pembrolizumab and were analyzed via RNA microarray.
Sixty-eight patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On multivariable analysis, TMC was independently associated with a reduced risk for death (HR, 0.36; 95% confidence interval, 0.17-0.75;
= 0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of
correlated with increased expression of cytolytic T-cell genes and irradiated tumor response.
In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings.
Purpose Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. ...Anti-PD-1-treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors. Patients and Methods Patients progressing on standard treatment received SBRT to two to four metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. SBRT dosing varied by site and ranged from 30 to 50 Gy in three to five fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Pembrolizumab was initiated within 7 days after completion of SBRT. Pre- and post-SBRT biopsy specimens were analyzed in a subset of patients to quantify interferon-γ-induced gene expression. Results A total of 79 patients were enrolled; three patients did not receive any treatment and three patients only received SBRT. Patients included in the analysis were treated with SBRT and at least one cycle of pembrolizumab. Most (94.5%) of patients received SBRT to two metastases. Median follow-up for toxicity was 5.5 months (interquartile range, 3.3 to 8.1 months). Six patients experienced dose-limiting toxicities with no radiation dose reductions. In the 68 patients with imaging follow-up, the overall objective response rate was 13.2%. Median overall survival was 9.6 months (95% CI, 6.5 months to undetermined) and median progression-free survival was 3.1 months (95% CI, 2.9 to 3.4 months). Expression of interferon-γ-associated genes from post-SBRT tumor biopsy specimens significantly correlated with nonirradiated tumor response. Conclusion Multisite SBRT followed by pembrolizumab was well tolerated with acceptable toxicity. Additional studies exploring the clinical benefit and predictive biomarkers of combined multisite SBRT and PD-1-directed immunotherapy are warranted.
We examine the long-run effects of forced migration for individuals who were displaced from Eastern Europe to Germany in the aftermath of World War II. Evidence suggests that displaced individuals ...were worse off economically, facing a considerably lower income and a higher unemployment risk than comparable nondisplaced Germans, even 20 years after being expelled. We extend this literature by investigating mortality outcomes. Using social security records that document the exact date of death and a proxy for pre-retirement lifetime earnings, we estimate a significantly and considerably higher mortality risk among forced migrants compared with nondisplaced West Germans. The adverse displacement effect persists throughout the earnings distribution except for the top quintile. Although forced migrants were generally worse off regarding mortality outcomes, those with successful labor market histories seem to have overcome the long-lasting negative consequences of flight and expulsion.
Background
Predictive markers can help tailor treatment to the individual in metastatic renal cell carcinoma (mRCC). De Ritis ratio (DRR) is associated with oncologic outcomes in various solid ...tumors.
Objective
To assess the value of DRR in prognosticating survival in mRCC patients treated with tyrosine-kinase inhibitors (TKI).
Methods
Overall, 220 mRCC patients treated with TKI first-line therapy were analyzed. An optimal cut-off point for DRR was determined with Youden’s J. We used multiple strata for DRR, performed descriptive, Kaplan–Meier and multivariable Cox-regression analyses to assess associations of DRR with progression-free (PFS) and overall survival (OS).
Results
Patients above the optimal cut-off point for DRR of ≥ 1.58 had fewer liver metastases (
p
= 0.01). There was no difference in PFS (
p
> 0.05) between DRR groups. DRR above the median of 1.08 (HR 1.42;
p
= 0.03), DRR ≥ 1.1(HR 1.44;
p
= 0.02), ≥ 1.8 (HR 1.56;
p
= 0.03), ≥ 1.9 (HR 1.59;
p
= 0.02) and ≥ 2.0 (HR 1.63;
p
= 0.047) were associated with worse OS. These associations did not remain after multivariable adjustment. In the intermediate MSKCC group, DRR was associated with inferior OS at cut-offs ≥ 1.0 (HR 1.78;
p
= 0.02), ≥ 1.1 (HR 1.81;
p
= 0.01) and above median (HR 1.88;
p
= 0.007) in multivariable analyses. In patients with clear-cell histology, DRR above median (HR 1.54;
p
= 0.029) and DRR ≥ 1.1 (HR 1.53;
p
= 0.029) were associated with OS in multivariable analyses.
Conclusion
There was no independent association between DRR and survival of mRCC patients treated with TKI in the entire cohort. However, OS of patients with intermediate risk and clear-cell histology were affected by DRR. DRR could be used for tailored decision-making in these subgroups.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This paper investigates the motion control system of an optical telescope system used for precision satellite tracking and ranging applications. The system uses direct-drive permanent magnet ...synchronous motors (PMSMs) for high precision positioning. To overcome the performance limitations due to system dynamics and position dependent plant variations, a disturbance observer based control system is utilized. This paper contributes the detailed analysis, design and implementation of such an advanced control concept for the performance improvement of precision satellite tracking systems. Satellite tracking experiments are conducted to verify the performance of the proposed system. Utilizing the proposed control concept, the RMS servo error is reduced by a factor of 3.8 to well below the arcsecond range, achieving seeing limited tracking.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The assessment of new antithrombotic agents with a favorable safety profile is clinically relevant.
To test the efficacy and safety of revacept, a novel, lesion-directed antithrombotic drug, acting ...as a competitive antagonist to platelet glycoprotein VI.
A phase 2 randomized clinical trial; patients were enrolled from 9 centers in Germany from November 20, 2017, to February 27, 2020; follow-up ended on March 27, 2020. The study included patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous coronary intervention (PCI).
Single intravenous infusion of revacept, 160 mg, revacept, 80 mg, or placebo prior to the start of PCI on top of standard antithrombotic therapy.
The primary end point was the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin to at least 5 times the upper limit of normal within 48 hours from randomization. The safety end point was bleeding type 2 to 5 according to the Bleeding Academic Research Consortium criteria at 30 days.
Of 334 participants (median age, 67.4 years; interquartile range, 60-75.1 years; 253 men 75.7%; and 330 White participants 98.8%), 120 were allocated to receive the 160-mg dose of revacept, 121 were allocated to receive the 80-mg dose, and 93 received placebo. The primary end point showed no significant differences between the revacept and placebo groups: 24.4%, 25.0%, and 23.3% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .98). The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, with a median 26.5 AU × min (interquartile range, 0.5-62.2 AU × min) in the revacept, 160 mg, group; 43.5 AU × min (interquartile range, 22.8-99.5 AU × min) in the revacept, 80 mg, group; and 41.0 AU × min (interquartile range, 31.2-101.0 AU × min) in the placebo group (P = .02), while adenosine 5'-diphosphate-induced aggregation was not affected. Revacept did not increase Bleeding Academic Research Consortium type 2 or higher bleeding at 30 days compared with placebo: 5.0%, 5.9%, and 8.6% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .36).
Revacept did not reduce myocardial injury in patients with stable ischemic heart disease undergoing percutaneous coronary intervention. There were few bleeding events and no significant differences between treatment arms.
ClinicalTrials.gov Identifier: NCT03312855.
Background:
Sarcomatoid differentiation/histology of renal cell carcinoma (sRCC) in patients with metastatic renal cell carcinoma (mRCC) is still underresearched in current therapy regimes. We aimed ...to evaluate the impact of sRCC on outcomes in patients with mRCC treated with tyrosine kinase inhibitors (TKIs).
Methods:
We collected complete data of 262 consecutive mRCC patients from our institutional database for this retrospective study. All patients were treated with TKIs within a single or multimodal treatment approach. All analyses were adjusted for the presence of sRCC. Descriptive statistics as well as uni- and multivariable outcome metrics, including progression-free (PFS) and overall survival (OS) as endpoints were performed.
Results:
Overall, 18 patients had sRCC (6.9%). Patients with sRCC had more often clear-cell histology (
p
= 0.047), a higher T-stage (
p
= 0.048), and underwent cytoreductive nephrectomy more frequently (
p
< 0.001). The most common first-line TKIs were Sunitinib (65.6%), Sorafenib (19.5%), and Pazopanib (10.3%), respectively. At a median follow-up of 32 months, patients with sRCC had significantly reduced PFS (
p
= 0.02) and OS (
p
= 0.01) compared to patients without sRCC. In multivariable analyses that adjusted for the effects of standard mRCC predictors, the sarcomatoid feature retained its independent association with inferior PFS (HR: 2.39;
p
= 0.007) and OS (HR: 2.37;
p
= 0.001). This association remained statistically significant in subgroup analyses of patients with Sunitinib as first-line therapy (PFS
p
< 0.001; OS:
p
< 0.001).
Conclusion:
Despite its rare occurrence, our findings confirm sRCC as a powerful predictor for inferior outcomes in mRCC treated with targeted therapies. This suggests a need for more tailored treatment strategies in patients harboring mRCC with sarcomatoid histology to improve oncological outcomes.
Glowa-Danube (www.glowa-danube.de) is an interdisciplinary project that aims to develop integrated strategies and tools for water and land use management in the upper Danube catchment (Germany, ...Austria ∼77,000 km²). The project is one of five within the Glowa research program (www.glowa.org) dealing with Global Change effects on the water cycle in six meso-scale catchments (up to 100,000 km²) in Central Europe, West Africa and the Middle East. In the Glowa-Danube project, 16 natural science and socio-economic simulation models are integrated in the coupled simulation system Danubia. This article describes the underlying concept and implementation of WaterSupply, a multiactor-based model of the water supply sector with a focus on water resource utilization and distribution of individual water supply companies. Within Danubia, WaterSupply represents the link between water supply and demand, where the former is simulated by a groundwater and a surface water model and the latter by water consumption models of four different sectors (domestic, industrial, agricultural and tourism). WaterSupply interprets the quantitative state of water resources for defined spatial and temporal units according to sustainability requirements and assesses the state of resources in relation to present water supply schemes and the dynamics of user demand. WaterSupply then seeks both to optimize the resource use of supply companies and to identify critical regions for which further adaptation of the water supply scheme will become necessary under changing climatic conditions. In this article, a brief description of the Glowa-Danube project and the integrated simulation system Danubia is followed by a short presentation of the DeepActor framework, which provides a common conceptual and technical basis for the socio-economic simulation models of Glowa-Danube. The main body of the article is devoted to the concept, the implementation and simulation results of WaterSupply. Results from different scenario calculations demonstrate the capabilities and the potential fields of application of the model.
Full text
Available for:
CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
PDF
