18F–FDG-PET/CT and diffusion-weighted MRI for monitoring a BRAF and CDK 4/6 inhibitor combination therapy in a murine model of human melanoma

Background: The purpose of the study was to investigate a novel BRAF and CDK 4/6 inhibitor combination therapy in a murine model of BRAF-V600-mutant human melanoma monitored by F-18-FDG-PET/CT and diffusionweighted MRI (DW-MRI). Methods: Human BRAF-V600-mutant melanoma (A375) xenograft-bearing balb/c nude mice (n = 21) were imaged by 18F-FDG-PET/CT and DW-MRI before (day 0) and after (day 7) a 1-week BRAF and CDK 4/6 inhibitor combination therapy (n = 12;dabrafenib, 20 mg/kg/d;ribociclib, 100 mg/kg/d) or placebo (n = 9). Animals were scanned on a small animal PET after intravenous administration of 20 MBq F-18-FDG. Tumor glucose uptake was calculated as the tumor-to-liver-ratio (TTL). Unenhanced CT data sets were subsequently acquired for anatomic coregistration. Tumor diffusivity was assessed by DW-MRI using the apparent diffusion coefficient (ADC). Anti-tumor therapy effects were assessed by ex vivo immunohistochemistry for validation purposes (microvascular density -CD31;tumor cell proliferation -Ki-67). Results: Tumor glucose uptake was significantly suppressed under therapy (Delta TTLTherapy -1.00 +/- 0.53 vs.Delta TTLControl 0.85 +/- 1.21;p < 0.001). In addition, tumor diffusivity was significantly elevated following the BRAF and CDK 4/6 inhibitor combination therapy (Delta ADC(Therapy) 0.12 +/- 0.14 x 10(-3) mm(2)/s;Delta ADCControl -0.12 +/- 0.06 x 10(-3) mm(2)/s;p < 0.001). Immunohistochemistry revealed a significant suppression of microvascular density (CD31, 147 +/- 48 vs. 287 +/- 92;p = 0.001) and proliferation (Ki-67, 3718 +/- 998 vs. 5389 +/- 1332;p = 0.007) in the therapy compared to the control group. Conclusion: A novel BRAF and CDK 4/6 inhibitor combination therapy exhibited significant anti-angiogenic and anti-proliferative effects in experimental human melanomas, monitored by F-18-FDG-PET/CT and DW-MRI

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

Background: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. Methods: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Findings: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction&gt;0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. Interpretation: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Funding: Novo Nordisk

Semi-Automatic MRI Feature Assessment in Small- and Medium-Volume Benign Prostatic Hyperplasia after Prostatic Artery Embolization

(1) Background: To assess the treatment response of benign prostatic syndrome (BPS) following prostatic artery embolization (PAE) using a semi-automatic software analysis of magnetic resonance imaging (MRI) features and clinical indexes. (2) Methods: Prospective, monocenter study of MRI and clinical data of n = 27 patients with symptomatic BPS before and (1, 6, 12 months) after PAE. MRI analysis was performed using a dedicated semi-automatic software for segmentation of the central and the total gland (CG, TG), respectively; signal intensities (SIs) of T1-weighted (T1w), T2-weighted (T2w), and diffusion-weighted images (DWI), as well as intravesical prostatic protrusion (IPP) and prostatic volumes (CGV, TGV), were evaluated at each time point. The semi-automatic assessed TGV was compared to conventional TGV by an ellipse formula. International prostate symptom score (IPSS) and international consultation on incontinence questionnaire&ndash;urinary incontinence short form (ICIQ-UI SF) questionnaires were used as clinical indexes. Statistical testing in the form of ANOVA, pairwise comparisons using Bonferroni correction, and multiple linear correlations, were conducted using SPSS. (3) Results: TGV was significantly reduced one, six, and 12 months after PAE as assessed by the semi-automatic approach and conventional ellipse formula (p = 0.005; p = 0.025). CGV significantly decreased after one month (p = 0.038), but showed no significant differences six and 12 months after PAE (p = 0.191; p = 0.283). IPP at baseline was demonstrated by 25/27 patients (92.6%) with a significant decrease one, six, and 12 months after treatment (p = 0.028; p = 0.010; p = 0.008). Significant improvement in IPSS and ICIQ-UI SF (p = 0.002; p = 0.016) after one month correlated moderately with TGV reduction (p = 0.031; p = 0.05, correlation coefficients 0.52; 0.69). Apparent diffusion coefficient (ADC) values of CG significantly decreased one month after embolization (p &lt; 0.001), while there were no significant differences in T1w and T2w SIs before and after treatment at each time point. (4) Conclusions: The semi-automatic approach is appropriate for the assessment of volumetric and morphological changes in prostate MRI following PAE, able to identify significantly different ADC values post-treatment without the need for manual identification of infarct areas. Semi-automatic measured TGV reduction is significant and comparable to the TGV calculated by the conventional ellipse formula, confirming the clinical response after PAE

Ventral Pallidum Neurons Encode Incentive Value and Promote Cue-Elicited Instrumental Actions

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Integrin-targeted quantitative optoacoustic imaging with MRI correlation for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma.

PURPOSE:To investigate αvβ3-integrin-targeted optoacoustic imaging and MRI for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma. MATERIALS AND METHODS:Human BRAF V600E-positive melanoma xenograft (A375)-bearing Balb/c nude mice (n = 10) were imaged before (day 0) and after (day 7) a BRAF/MEK inhibitor combination therapy (encorafenib, 1.3 mg/kg/d; binimetinib, 0.6 mg/kg/d, n = 5) or placebo (n = 5), respectively. Optoacoustic imaging was performed on a preclinical system unenhanced and 5 h after i. v. injection of an αvβ3-integrin-targeted fluorescent probe. The αvβ3-integrin-specific tumor signal was derived by spectral unmixing. For morphology-based tumor response assessments, T2w MRI data sets were acquired on a clinical 3 Tesla scanner. The imaging results were validated by multiparametric immunohistochemistry (ß3 -integrin expression, CD31 -microvascular density, Ki-67 -proliferation). RESULTS:The αvβ3-integrin-specific tumor signal was significantly reduced under therapy, showing a unidirectional decline in all animals (from 7.98±2.22 to 1.67±1.30; p = 0.043). No significant signal change was observed in the control group (from 6.60±6.51 to 3.67±1.93; p = 0.500). Immunohistochemistry revealed a significantly lower integrin expression (ß3: 0.20±0.02 vs. 0.39±0.05; p = 0.008) and microvascular density (CD31: 119±15 vs. 292±49; p = 0.008) in the therapy group. Tumor volumes increased with no significant intergroup difference (therapy: +107±42 mm3; control +112±44mm3, p = 0.841). In vivo blocking studies with αvβ3-integrin antagonist cilengitide confirmed the target specificity of the fluorescent probe. CONCLUSIONS:αvβ3-integrin-targeted optoacoustic imaging allowed for the early non-invasive monitoring of a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma, adding molecular information on tumor receptor status to morphology-based tumor response criteria

Validation of the SSTR-RADS 1.0 for the structured interpretation of SSTR-PET/CT and treatment planning in neuroendocrine tumor (NET) patients

Objectives: The recently proposed standardized reporting and data system for somatostatin receptor (SSTR)-targeted PET/CT SSTR-RADS 1.0 showed promising first results in the assessment of diagnosis and treatment planning with peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NET). This study aimed to determine the intra- and interreader agreement of SSTR-RADS 1.0. Methods: SSTR-PET/CT scans of 100 patients were independently evaluated by 4 readers with different levels of expertise according to the SSTR-RADS 1.0 criteria at 2 time points within 6&nbsp;weeks. For each scan, a maximum of five target lesions were freely chosen by each reader (not more than three lesions per organ) and stratified according to the SSTR-RADS 1.0 criteria. Overall scan score and binary decision on PRRT were assessed. Intra- and interreader agreement was determined using the intraclass correlation coefficient (ICC). Results: Interreader agreement using SSTR-RADS 1.0 for identical target lesions (ICC ≥ 0.91) and overall scan score (ICC ≥ 0.93) was excellent. The decision to state "functional imaging fulfills requirements for PRRT and qualifies patient as potential candidate for PRRT" also demonstrated excellent agreement among all readers (ICC ≥ 0.86). Intrareader agreement was excellent even among different experience levels when comparing target lesion-based scores (ICC ≥ 0.98), overall scan score (ICC ≥ 0.93), and decision for PRRT (ICC ≥ 0.88). Conclusion: SSTR-RADS 1.0 represents a highly reproducible and accurate system for stratifying SSTR-targeted PET/CT scans with high intra- and interreader agreement. The system is a promising approach to standardize the diagnosis and treatment planning in NET patients. Key points: • SSTR-RADS 1.0 offers high reproducibility and accuracy. • SSTR-RADS 1.0 is a promising method to standardize diagnosis and treatment planning for patients with NET