Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), has a high diagnostic potential in neurodegenerative disorders and cancer. However, TSPO is considered a ...challenge for molecular imaging due to the poor availability of suitable radiotracers with adequate pharmacokinetic properties. Here, we describe the development of a radiofluorinated pyridinyl isoquinoline analogue of the established TSPO PET tracer (R)-11CPK11195 with improved binding properties in all known human TSPO phenotypes. We conducted a complete preclinical evaluation using in vitro, in vivo and ex vivo methods to assess the performance of this novel radiotracer and observed high specific binding of the radiotracer to TSPO, as well as high metabolic stability. Therefore, we propose this radiolabeled compound for further evaluation in animal models as well as in clinical trials.
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•Involvement of TSPO in several diseases has been amply described.•TSPO PET imaging is challenging due to the lack of appropriate radiotracers.•(R)-18FNEBIFQUINIDE exhibits favorable properties for TSPO PET imaging.•(R)-18FNEBIFQUINIDE is proposed for further evaluation in animal models and humans.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•In this real-world investigation we assess the impact of cytoreductive nephrectomy (CN) prior to tyrosine kinase inhibitor (TKI) therapy in metastatic renal cell carcinoma patients.•Overall, we ...found no difference for all endpoints between CN + TKI vs. TKI only treatment.•However, patients in some subgroups benefitted from CN.•Clear cell histology predicted improved progression-free survival and cancer-specific survival after CN.
Tyrosine kinase inhibitor therapy (TKI) has changed the treatment paradigm of metastatic renal cell carcinoma (mRCC). The recent CARMENA and SURTIME trials challenged the role of the cytoreductive nephrectomy (CN).
To assess the impact of CN prior to TKI therapy in patients with mRCC in a real-world setting.
Overall, 262 consecutive patients with mRCC were treated with CN plus TKI or TKI only at our institution between 2000 and 2016. Patients with prior immunotherapy or metastasectomy were excluded. Multiple imputation and inverse probability of treatment weighting (IPTW) were performed to account for missing values and imbalances between the treatment groups, respectively. Unadjusted and adjusted Kaplan-Meier estimates were used to determine differences in progression-free (PFS), overall (OS), and cancer-specific survival (CSS).
Overall, 104 (40%) patients received CN before TKI treatment. Most frequent first line therapy was Sunitinib (66%), followed by Sorafenib (20%) and Pazopanib (10%). After adjustment with IPTW, there was no difference in PFS, CSS, and OS (all P > 0.05) between the treatment groups. In subgroup analyses, CSS was improved when CN was performed in patients with sarcomatoid features and clear cell histology (P = 0.04 and P = 0.03) and PFS was improved in patients with clear cell histology when CN was performed 0.04). CN did not improve OS in any subgroup analysis.
The role of CN remains controversial. We found no difference in survival outcomes between patients treated with and without CN before TKI therapy. However, CN was associated with improved survival in specific patient subgroups. Tailored, individualized treatment is key to further improve oncological outcomes for mRCC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction:
Covert brain infarcts (CBI) are frequent incidental findings on MRI and associated with future stroke risk in patients without a history of clinically evident cerebrovascular events. ...However, the prognostic value of CBI in first-ever ischemic stroke patients is unclear and previous studies did not report on different etiological stroke subtypes. We aimed to test CBI phenotypes and their association with stroke recurrence in first-ever ischemic stroke patients according to stroke etiology.
Patients and methods:
This study is a pooled data analysis of two prospectively collected cohorts of consecutive first-ever ischemic stroke patients admitted to the comprehensive stroke centers of Bern (Switzerland) and Graz (Austria). CBI phenotypes were identified on brain MRI within 72 h after admission. All patients underwent a routine follow-up (median: 12 months) to identify stroke recurrence.
Results:
Of 1577 consecutive ischemic stroke patients (median age: 71 years), 691 patients showed CBI on brain MRI (44%) and 88 patients had a recurrent ischemic stroke (6%). Baseline CBI were associated with stroke recurrence in multivariable analysis (HR 1.9, 95% CI 1.1–3.3). CBI phenotypes with the highest risk for stroke recurrence were cavitatory CBI in small vessel disease (SVD)-related stroke (HR 7.1, 95% CI 1.6–12.6) and cortical CBI in patients with atrial fibrillation (HR 3.0, 95% CI 1.1–8.1).
Discussion and conclusion:
This study reports a ≈ 2-fold increased risk for stroke recurrence in first-ever ischemic stroke patients with CBI. The risk of recurrent stroke was highest in patients with cavitatory CBI in SVD-related stroke and cortical CBI in patients with atrial fibrillation.
Subject terms: Covert brain infarcts, stroke
Graphical abstract
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Background
Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to ...test this hypothesis.
Methods
Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample
t
test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin).
Results
24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (− 0.12 vs. − 0.16;
P
= 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities.
Conclusions
Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers.
Impact
Combining metformin with sirolimus did not improve mTOR inhibition.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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Background: Preclinical models support a combinatorial role of high-dose irradiation with immunotherapy. Multi-site stereotactic body radiotherapy (SBRT) with pembrolizumab (P) has ...been demonstrated as safe in advanced solid tumors. Here, we report extended follow-up of treated metastasis control (TMC), progression-free survival (PFS), overall survival (OS) and describe transcriptional changes associated with TMC, PFS and OS. Methods: Patients (pts) with AST received 3-5 SBRT doses (30-50 Gy total dose) to 2-4 metastases based on anatomic location. Pembrolizumab (200 mg IV Q3W) began one week following the final SBRT. Mets >65cc received partial-tumor SBRT. Response was measured by RECIST principles. TMC, PFS, and OS were estimated by Kaplan-Meier method. Pre- and post-SBRT biopsies from 24 pts were assayed via RNA microarray. Results: 68 pts (140 mets) were enrolled. 18 pts (21 mets) received partial tumor SBRT. Median volume of partially irradiated tumors was 121cc vs 7cc of fully irradiated (p=0.001). Median follow-up was 8.4 months (mo; range 1.1-24.2). 1-year TMC was 89.6%. At 12 mo TMC of partial versus full tumor irradiation was not significantly different (p=0.09). On multiple Cox regression, metastasis size, histology, volume of irradiated tumor and PD-L1 status were not predictive of TMC, PFS or OS. However, irradiated metastasis response predicted OS (HR = 0.37; 95% CI, 0.19-0.71; p = 0.003). Pts with irradiated met PR or CR had 17.8 mo median OS vs 9.1 and 3.4 in pts with mixed response or PD, respectively (p=0.005). Unsupervised transcriptional analysis of tumor biopsies demonstrated that the magnitude of DNA repair and innate/adaptive immune pathways induced in irradiated mets following SBRT was significantly associated with irradiated met response (p=0.009) and OS (p=0.007) to SBRT+P. Conclusions: Partial tumor SBRT+P approximates full tumor SBRT+P despite major differences in tumor volume. Transcriptional changes and clinical response of irradiated mets to SBRT+P are highly predictive of OS. Further research is needed to optimize immuno-radiotherapy. Clinical trial information: NCT02608385.
Human language involves combining items into meaningful, syntactically structured wholes. The evolutionary origin of syntactic abilities has been investigated by testing pattern perception capacities ...in nonhuman animals. New World primates can respond spontaneously to structural changes in acoustic sequences and songbirds can learn to discriminate between various patterns in operant tasks. However, there is no conclusive evidence that songbirds respond spontaneously to structural changes in patterns without reinforcement or training. In this study, we tested pattern perception capacities of common ravens, Corvus corax, in a habituation–discrimination playback experiment. To enhance stimulus salience, call recordings of male and female ravens were used as acoustic elements, combined to create artificial territorial displays as target patterns. We habituated captive territorial raven pairs to displays following a particular pattern and subsequently exposed them to several test and control playbacks. Subjects spent more time visually orienting towards the loudspeaker in the discrimination phase when they heard structurally novel call combinations, violating the pattern presented during habituation. This demonstrates that songbirds, much like primates, can be sensitive to structural changes in auditory patterns and respond to them spontaneously, without training.
•Pattern perception capacities were tested by simulating a territorial intrusion.•Ravens are spontaneously sensitive to structural changes in an acoustic pattern.•Male ravens displayed a stronger interest in pattern changes than females.•Songbirds, much like primates, can perceive pattern structure without training.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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TPS11628
Background: Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR). Metformin has shown anti-cancer activity through its cellular (e.g., AMPK activation) and ...systemic effects (e.g., inhibition of IGF-1). We conducted a pilot study to test the hypothesis that metformin may potentiate mTOR inhibition by sirolimus. Methods: An open-label, randomized study was conducted in which eligible patients with advanced solid tumors were started on sirolimus (3mg daily) alone for the first 7 days. On day 8, patients were randomized to either receive metformin XL (500 mg daily) plus sirolimus (Arm A) or sirolimus alone (Arm B) for until day 21. From day 22 onwards, all patients recieved metformin XL plus sirolimus. The pharmacodynamic (PD) biomarkers were collected at baseline, day 8 and day 22 of cycle 1. The primary endpoint was to compare the change in PD biomarker phospho-p70S6K, using a two-sample t test (log ratio D22/D8 in arm A vs. arm B). The phospho-p70S6K was measured in peripheral blood T cells using Western blot. The secondary endpoints were to assess objective response rate (RECIST 1.1), toxicity (CTCAE V4.0) and changes in the serum levels of PD biomarkers: fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, leptin and adiponectin using two-sample t tests. Results: 24 patients were enrolled, at which time an interim futility analysis was conducted. 18 patients were evaluable for the primary endpoint (8 in arm A; 10 in arm B). The mean log ratios D22/D8 in phospho-p70S6K in arms A and B were -0.12 (SD = 0.13) and -0.16 (SD = 0.29), respectively (P = 0.64). Of the 17 pts evaluable for response, the best response was stable disease in 9 patients and progressive disease in 8 patients. There were no dose-limiting or unexpected toxicities. Of the 21 patients evaluable for serum PD biomarkers, there were no significant differences between arms A and B in fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-BP1, IGF-BP3, leptin and adiponectin (P > 0.05 for all). Conclusions: The addition of metformin to sirolimus, although well-tolerated, was not associated with significant changes in phospho-p70S6k and other PD biomarkers. Based on the results of the interim analysis, the trial was terminated. Clinical trial information: NCT02145559.
We obtain Berry-Esseen-type bounds for the sum of random variables with a dependency graph and uniformly bounded moments of order \(\delta \in (2,\infty\) using a Fourier transform approach. Our ...bounds improve the state-of-the-art in the regime where the degree of the dependency graph is large. As a Corollary of our results, we obtain a Central Limit Theorem for random variables with a sparse dependency graph that are uniformly bounded in \(L^{\delta}\) for some \(\delta\in(2,\infty\).
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